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Background: Intestinal ultrasonography (US) allows for the characterization of the intestinal lesions and provides information on transmural inflammation. The aim of the study was to assess the clinical relevance of echopattern and correlation with Crohn's disease (CD) behavior and activity., Methods: We performed a prospective study including CD patients assessed by intestinal US. The echopattern was classified as hypoechoic, hyperechoic and stratified. Color-doppler US was also performed in the thickest segment., Results: One hundred CD patients were enrolled. The hypoechoic echopattern was significantly correlated with penetrating behavior (r = 0.44, p<0.0001), active disease (r = 0.21, p = 0.034), C-reactive protein/Fecal Calprotectin (r = 0.31, p = 0.004; r = 0.34, p = 0.031, respectively) and steroids (r = 0.33, p = 0.0008). Hypoechoic echopattern was associated with younger age than stratified (p = 0.046) and hyperechoic (p = 0.018) echopatterns. Bowel wall thickness was greater in the hypoechoic group than in the hyperechoic/stratified groups (p = 0.011 and p<0.0001, respectively). Hypoechoic echopattern was associated with fistulas (r = 0.52, p<0.0001) and increased vascularization (r = 0.32, p = 0.001). The hyperechoic echopattern showed a significant correlation with stricturing disease and an inverse correlation with fistulas. During a follow up period of 6 months, patients with hypoechoic echopattern had an increased risk of biological therapy need or surgery., Conclusions: The characterization of bowel wall echopattern allows for the identification of different CD behaviors., Competing Interests: Conflict of Interest EDC: None to declare LM: None to declare EL: None to declare LB: None to declare GM: served as a consultant for First Wave BioPharma and filed a patent related to the treatment of inflammatory bowel diseases with Smad7 antisense oligonucleotides. EC: Served as a speaker for AbbVie, Takeda, MSD and Janssen FZ: Served as a speaker for Janssen, Takeda, (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Therapeutic targets in Crohn's disease (CD) have evolved greatly over the past several decades to include endoscopic improvement along with clinical remission. Yet CD is characterized by transmural damage, and there is increasing evidence of improved outcomes associated with transmural healing. Intestinal ultrasonography is a noninvasive, highly accurate imaging modality that provides real-time results and can assess for transmural healing in CD. In this review, we present the definition of transmural healing by ultrasonography, its comparison with other imaging modalities and with endoscopy, the efficacy of diverse therapies on achieving transmural healing, and data on patient outcomes in those achieving transmural healing. This review can guide clinicians who care for patients with inflammatory bowel disease on the added value of achieving transmural healing and its eventual incorporation as a target of therapy., (Copyright © 2023 by The American College of Gastroenterology.)

Background: Endoscopic-post-operative-recurrence [ePOR] in Crohn's disease [CD] after ileocecal resection [ICR] is a major concern. We aimed to evaluate the effectiveness of early prophylaxis with biologics and to compare anti-tumour necrosis factor [anti-TNF] therapy to vedolizumab [VDZ] and ustekinumab [UST] in a real-world setting., Methods: A retrospective multicentre study of CD-adults after curative ICR on early prophylaxis was undertaken. ePOR was defined as a Rutgeerts score [RS] ≥ i2 or colonic-segmental-SES-CD ≥ 6. Multivariable logistic regression was used to evaluate risk factors, and inverse probability treatment weighting [IPTW] was applied to compare the effectiveness between agents., Results: The study included 297 patients (53.9% males, age at diagnosis 24 years [19-32], age at ICR 34 years [26-43], 18.5% smokers, 27.6% biologic-naïve, 65.7% anti-TNF experienced, 28.6% two or more biologics and 17.2% previous surgery). Overall, 224, 39 and 34 patients received anti-TNF, VDZ or UST, respectively. Patients treated with VDZ and UST were more biologic experienced with higher rates of previous surgery. ePOR rates within 1 year were 41.8%. ePOR rates by treatment groups were: anti-TNF 40.2%, VDZ 33% and UST 61.8%. Risk factors for ePOR at 1 year were: past-infliximab (adjusted odds ratio [adj.OR] = 1.73 [95% confidence interval, CI: 1.01-2.97]), past-adalimumab [adj.OR = 2.32 [95% CI: 1.35-4.01] and surgical aspects. After IPTW, the risk of ePOR within 1 year of VDZ vs anti-TNF or UST vs anti-TNF was comparable (OR = 0.55 [95% CI: 0.25-1.19], OR = 1.86 [95% CI: 0.79-4.38]), respectively., Conclusion: Prevention of ePOR within 1 year after surgery was successful in ~60% of patients. Patients treated with VDZ or UST consisted of a more refractory group. After controlling for confounders, no differences in ePOR risk were seen between anti-TNF prophylaxis and other groups., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background & Aims: Bowel ultrasonography (BUS) is a noninvasive tool for evaluating bowel activity in Crohn's disease (CD) patients. Aim of our multicenter study was to assess whether BUS helps to monitor intestinal activity improvement/resolution following different biological therapies., Methods: Adult CD patients were prospectively enrolled at 16 sites in Italy. Changes in BUS parameters [i.e. bowel wall thickening (BWT), lesion length, echo pattern, blood flow changes and transmural healing (TH: normalization of all BUS parameters)] were analyzed at baseline and after 3, 6 and 12 months of different biological therapies., Results: One hundred eighty-eight out of 201 CD patients were enrolled and analyzed (116 males [62%]; median age 36 years). Fifty-five percent of patients were treated with adalimumab, 16% with infliximab, 13% with vedolizumab and 16% with ustekinumab. TH rates at 12 months were 27.5% with an NNT of 3.6. TH at 12 months after adalimumab was 26.8%, 37% after infliximab, 27.2% after vedolizumab and 20% after ustekinumab. Mean BWT improvement from baseline was statistically significant at 3 and 12 months (P < .0001). Median Harvey-Bradshaw index, C-reactive protein and fecal calprotectin decreased after 12 months from baseline (P < .0001). Logistic regression analysis showed colonic lesion was associated with a higher risk of TH at 3 months and a greater BWT at baseline was associated with a lower risk of TH at 3 months [P = .03 (OR 0.70, 95% CI 0.50-0.97)] and 12 months [P = .01 (OR 0.58, 95% CI 0.38-0.89)]. At 3 months therapy optimization during the study was the only independent factor associated with a higher risk of no ultrasonographic response [P = .02 (OR 3.34, 95% CI 1.18-9.47)] and at 12 months disease duration [P = .02 (OR 3.03, 95% CI 1.15-7.94)]., Conclusions: Data indicate that BUS is useful to monitor biologics-induced bowel activity improvement/resolution in CD., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Finger clubbing has been associated with inflammatory bowel disease (IBD)., Aims: In a prospective single-center study, we aimed to assess the frequency of finger clubbing in a cohort of IBD patients. Whether finger clubbing is associated with clinical characteristics of IBD was also investigated., Methods: IBD patients with a detailed clinical history were enrolled. Finger clubbing was assessed by visual inspection. Data were expressed as median (range), chi-square, t-test. Multivariate logistic regression analysis was used to assess risk factors for finger clubbing, when considering demographic and clinical characteristics, smoking habits and chronic pulmonary diseases (CPD)., Results: Finger clubbing was searched in 470 IBD patients: 267 Crohn's disease and 203 ulcerative colitis. Finger clubbing was more frequent in Crohn's disease than in ulcerative colitis: 45/267 (16.8%) vs. 15/203 (7.3%) [odds ratio (OR), 2.54 (1.37-4.70); P = 0.003]. Crohn's disease involved the ileum (59.9%), colon (4.5%), ileum-colon (25.8%) and upper gastrointestinal (GI) (9.8%). Ulcerative colitis extent included proctitis (E1) (13.4%), left-sided (E2) (43.3%) and pancolitis (E3) (43.3%). Upper GI lesions, but not other Crohn's disease localizations, were more frequent in patients with finger clubbing [9/45 (20%) vs. 17/222 (7.7%); P = 0.032]. Crohn's disease-related surgery was more frequent in patients with finger clubbing [36/45 (80%) vs. 107/222 (48.1%); P < 0.001]. In Crohn's disease, the only risk factors for finger clubbing were upper GI lesions and Crohn's disease-related surgery [OR, 2.58 (1.03-6.46), P = 0.04; OR, 4.07 (1.86-8.91), P = 0.006]. Ulcerative colitis extent was not associated with finger clubbing [E1: OR, 0.27 (0.02-3.44), P = 0.33; E2: OR, 0.93 (0.24-3.60), P = 0.92; E3:OR, 0.64 (0.22-1.86), P = 0.59]. In ulcerative colitis, but not in Crohn's disease, finger clubbing was more frequent in smokers [13/15 (86.6%) vs. 99/188 (52.6%); P = 0.01] and in patients with CPD [5/15 (33.3%) vs. 16/188 (8.5%); P = 0.002]. Smoking and CPD were the only risk factors for finger clubbing in ulcerative colitis [OR, 7.18 (1.44-35.78), P = 0.01; OR, 10.93 (2.51-47.45), P = 0.001]., Conclusion: In the tested IBD population, finger clubbing was more frequent in Crohn's disease than in ulcerative colitis. In Crohn's disease, upper GI lesions and history of Crohn's disease-related surgery were risk factors for finger clubbing, suggesting the possible role of finger clubbing as a subclinical marker of Crohn's disease severity., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: A recent phase III trial did not confirm the previous clinical and endoscopic improvements seen in patients with Crohn's disease (CD) receiving Mongersen, an oral Smad7 antisense oligonucleotide. Factors accounting for such a discrepancy are unknown., Objective: Our objective was to further assess whether Mongersen was effective as induction therapy in active CD and evaluate the in vitro inhibitory effect of various batches of Mongersen used in the previous and present trials on Smad7 expression., Methods: In a phase II, open-label study, 18 patients with active CD (Crohn's Disease Activity Index [CDAI] score > 220 and evidence of endoscopic lesions) received Mongersen 160 mg/day for 12 weeks. The rates of clinical remission, defined as CDAI < 150, and clinical response, defined as a CDAI score decrease ≥ 100, were evaluated at week 4, 8, and 12. The fraction of circulating CCR9-expressing leukocytes was assessed by flow cytometry. Smad7 expression was evaluated in the human colorectal cancer cell line HCT-116 transfected with different batches of Mongersen using real-time polymerase chain reaction (PCR) and Western blotting, RESULTS: The proportions of patients experiencing clinical remission were 38.9%, 55.6%, and 50.0% at week 4, 8, and 12, respectively. At the same time points, the rates of clinical response were 72.2%, 77.8%, and 77.8%, respectively. Mongersen reduced the percentages of CCR9-expressing CD45+ cells. The batch of Mongersen used in this study, but not two batches used in the phase III study, inhibited Smad7 expression in HCT-116 cells., Conclusions: The present findings support the clinical benefit of Mongersen in active CD and show that various batches manufactured during the GED0301 program differ in their ability to inhibit in vitro Smad7., Trial Registration Number: NCT02685683; EudraCT 2015-001693-18.

Background: In Crohn's disease (CD), one of the major inflammatory bowel disease (IBD) in human beings, there is over-expression of Smad7, an intracellular inhibitor of the suppressive cytokine TGF-β1. The aim of this study was to assess whether Smad7 over-expression occurs in the early and/or late phases of CD., Methods: Mucosal samples were taken from the neo-terminal ileum of CD patients undergoing ileocolonic resection, with or without (early CD) post-operative endoscopic recurrence, and terminal ileum of CD patients with long-standing disease undergoing intestinal resection (late CD). Smad7 was examined by immunohistochemistry and cytokine expression was analysed by flow-cytometry., Results: Before the appearance of endoscopic lesions, the mucosa of the neo-terminal ileum contained high number of Smad7-expressing cells in both the epithelial and lamina propria compartments. Transition from this stage to endoscopic recurrence was marked by persistence of high number of Smad7-positive cells, which reduced significantly in the late stages of the disease, where Smad7 expression remained, however, greater than that seen in normal controls. In samples with early lesions, Smad7 expression positively correlated with the number of interferon-γ-secreting cells., Conclusions: Smad7 induction is an early event in the inflammatory sequence occurring in CD, thus suggesting that knockdown of Smad7 can help prevent post-operative recurrence.

Objective: Crohn's Disease (CD) has been associated with non-Hodgkin lymphoma. Follicular Lymphoma (FL) limited to the liver is extremely rare, accounting for 1% to 4.4% of all Primary Hepatic Lymphoma (PHL)., Case Presentation: In 2018, an 85-years old male patient with post-operative recurrence of ileal CD referred rare episodes of fever and mild diffuse abdominal pain. Since cholecystectomy in 2001, clinical history was characterized by recurrent episodes of cholangitis and common bile duct stones. In 2018, ultrasonography and MRI showed a solid focal hepatic lesion (FHL)(4.5 cm x 2.5 cm) in the IV hepatic segment. The radiographic aspect of the lesion was unusual. Initially, focal nodular hyperplasia was suspected. Clinical history of cholangitis and radiological findings subsequently suggested a diagnosis of Hepatic Abscess (HA). A progressive enlargement of the FHL (7.3 cm x 5.8 cm) despite antibiotic treatments, led to perform a liver biopsy. Histological and immunophenotypical analysis of the FHL (7.5 cm x 5.4 cm) enabled a final diagnosis of FL. The "in situ" hybridization for Epstein-Barr virus (EBER) was negative. No additional lesions related to FL were initially detected, thus suggesting a very rare case of PHL in an old patient with CD never treated with thiopurines., Conclusions: This case report highlights the need to consider a rare diagnosis of FL of the liver in patients showing a challenging focal hepatic lesion of unknown origin.

Background & Aims: Mucosal healing, determined by ileocolonoscopy, is a goal for treatment of Crohn's disease (CD), but this is an invasive assessment procedure. We investigated whether response to tumor necrosis factor (TNF) antagonists, determined by small-intestine contrast ultrasonography, associates with long-term outcomes., Methods: We performed observational study of 80 patients with CD treated with anti-TNF agents for at least 1 year who underwent serial small intestine contrast ultrasonography (SICUS) at the University of Rome, in Italy. SICUS was used to evaluate disease site (based on bowel wall thickness), extent of lesions, and presence of complications. Inclusion criteria required pre-therapy SICUS with follow-up SICUS after 18 months. At second SICUS, patients were assigned to categories of complete or partial responder or non-responder. CD-related outcomes (corticosteroid need, hospitalization, and surgery) were assessed at 1 year from the second SICUS, using multivariate models, and were analyzed after long term follow up (5 years) using Kaplan-Meier survival analysis., Results: Based on SICUS, after a median of 18 months, 36 patients (51%) were complete responders, 30 were partial responders (34%), and 13 were non-responders (15%). At 1 year from the second SICUS, no patients with a complete response, based on ultrasonography, underwent surgery, in comparison to partial responders (P = .0003) or non-responders (P = .001). Complete responders used smaller amounts of corticosteroids than partial responders (P = .0001) or non-responders (P < .0001). Complete responders required fewer hospitalizations than non-responders (P = .001). Kaplan-Meier survival analysis of long-term follow up data demonstrated a lower cumulative probability of need for surgery, hospitalization, and need for steroids among SICUS-categorized complete responders (P < .0001, P = .003 and P = .0001 respectively) than SICUS-categorized non-responders., Conclusions: In patients with CD, response to anti-TNF agents, determined by SICUS, is associated with better long-term outcomes than partial or no response. Ultrasonographic assessment therefore provides a relatively non-invasive method for monitoring response to treatment in patients with CD., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The unavailability of standardized parameters in bowel ultrasonography (US) commonly used in Crohn's disease (CD) and the shortage of skilled ultrasonographers are 2 limiting factors in the use of this imaging modality around the world. The aim of this study is to evaluate interobserver agreement among experienced sonographers in the evaluation of bowel US parameters in order to improve standardization in imaging reporting and interpretation., Methods: Fifteen patients with an established diagnosis of CD underwent blinded bowel US performed by 6 experienced sonographers. Prior to the evaluation, the sonographers and clinical and radiological IBD experts met to formally define the US parameters. Interobserver agreement was tested with the Quatto method (s)., Results: All operators agreed on the presence/absence of CD lesions and distinguished absence of/mild activity or moderate/severe lesions in all patients. S values were moderate for bowel wall thickness (s = 0.48, P = n.s.), bowel wall pattern (s = 0.41, P = n.s.), vascularization (s = 0.52, P = n.s.), and presence of lymphnodes (s = 0.61, P = n.s.). Agreement was substantial for lesion location (s = 0.68, P = n.s.), fistula (s = 0.74, P = n.s.), phlegmon (s = 0.78, P = 0.04), and was almost perfect for abscess (s = 0.95, P = 0.02). Poor agreement was observed for mesenteric adipose tissue alteration, lesion extent, stenosis, and prestenotic dilation., Conclusions: In this study, the majority of the US parameters used in CD showed moderate/substantial agreement. The development of shared US imaging interpretation patterns among sonographers will lead to improved comparability of US results among centers and facilitate the development of multicenter studies and the spread of bowel US training, thereby allowing a wider adoption of this useful technique., (© 2018 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are multifactorial disorders that result from a dysregulated inflammatory response to environmental factors in genetically predisposed individuals. Recently, microRNAs (miRNAs) have been shown to be involved in the development of IBDs., Aims: We investigated common variants in five miRNA genes in a cohort of Italian IBD patients, to evaluate their possible role in the disease's susceptibility and phenotype manifestations., Methods: The analysis included 267 CD patients, 207 UC patients, and 298 matched healthy controls. Polymorphisms in the MIR122, MIR499, MIR146A, MIR196A2, and MIR124A genes were evaluated by allelic discrimination assay., Results: We did not find associations between mir polymorphisms and IBD susceptibility. In both diseases, rs17669 and rs11614913 (MIR122 and MIR196A2) seem to contribute to clinical phenotypes: ileal location in CD (odds ratio [OR] = 1.82, p = 0.03; OR = 0.51, p = 0.01), and left-sided extent in UC (OR = 0.43, p = 0.05; OR = 0.28, p = 0.002). In CD, the MIR124A polymorphism (rs531564) contributed to colon location (p = 0.03, OR = 2.74). Finally, the variant allele of rs11614913 was associated with early age at onset in both diseases (p = 0.05 and p = 0.02)., Conclusions: We showed for the first time that polymorphisms in MIR122, MIR196A2, and MIR124A could play a role in clinical phenotype modulation in IBD.

Crohn's disease (CD) is a chronic inflammatory disorder that primarily affects small intestine and colon and causes tissue damage. The aetiology of CD is unknown, but a large body of evidence suggests that the pathological process is driven by excessive immune response, which is direct against components of the luminal flora and sustained by defects in counter-regulatory mechanisms. CD is a transmural progressive and destructive disease leading to irreversible bowel damage characterized by stenosis of the intestinal lumen and penetrating lesions such as fistulas and abscesses. The goals of medical therapy in CD are to: 1) induce symptomatic remission; 2) maintain steroid-free remission; 3) enhance quality of life; 4) prevent/treat complications of disease; 5) avoid short and long term toxicity of therapy. Achieving these goals requires a sophisticated approach that tailors therapy to each patient, involving attempts to risk stratify the patient, optimizing each therapy, and monitoring for objective evidence of resolution of inflammation. Although the number of medications available to treat CD has increased in the last 15 years, with the important addition of biologic therapies, including anti-TNF antibodies such as infliximab, adalimumab, and certolizumab pegol, and more recently, vedolizumab, an anti-α4β7 integrin antibody, the number of agents remains relatively small.

Background: We aimed to prospectively assess whether endoscopic recurrence severity at 1 year in Crohn's disease is predictive of clinical recurrence within 5 years., Methods: Clinical recurrence (Crohn's Disease Activity Index>150) was assessed yearly for 5 years in Crohn's disease patients undergoing ileo-colonic resection. At 1 year, recurrence was assessed by colonoscopy (Rutgeerts' score ≥i1 or ≥2i) and small intestine contrast ultrasonography., Results: 40 patients were included (23 males, median age 39 [16-69] years). Clinical recurrence occurred within 5 years in 16 (40%) patients (years 1, 2, 3, 4, 5: 2 [5%]; 10 [25%]; 4 [10%]; 2 [5%]; 4 [10%], respectively). At 1 year, endoscopic recurrence (score≥i1) occurred in 39 (97.5%) patients (score≥i2: 33 [82.5%]). Ultrasound detected lesions compatible with recurrence in 39/40 (97.5%) patients. Endoscopic score at 1 year was correlated with clinical score at 2 years (p=0.007; r=0.41). Endoscopic score at 1 year was higher in patients with (n=10) vs without (n=30) clinical recurrence at 2 years (3 [2-4] vs 2 [0-4]; p=0.003). Higher endoscopic score (>i2) at 1 year was a risk factor for clinical recurrence within 5 years (OR=0.18; 95% CI 0.04-0.71; p=0.008)., Conclusions: In Crohn's disease, severity of endoscopic recurrence at 1 year remains a predictive marker of clinical recurrence within 5 years. Small intestine contrast ultrasonography is useful for assessing 1-year recurrence., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Bowel ultrasonography (US) is considered a useful technique for assessing mural inflammation and complications in Crohn's disease (CD). The aim of this review is to appraise the evidence on the accuracy of bowel US for CD. In addition, we aim to provide recommendations for its optimal use., Methods: Publications were identified by literature search from 1992 to 2014 and selected based on predefined criteria: 15 or more patients; bowel US for diagnosing CD, complications, postoperative recurrence, activity; adequate reference standards; prospective study design; data reported to allow calculation of sensitivity, specificity, agreement, or correlation values; articles published in English., Results: The search yielded 655 articles, of which 63 were found to be eligible and retrieved as full-text articles for analysis. Bowel US showed 79.7% sensitivity and 96.7% specificity for the diagnosis of suspected CD, and 89% sensitivity and 94.3% specificity for initial assessment in established patients with CD. Bowel US identified ileal CD with 92.7% sensitivity, 88.2% specificity, and colon CD with 81.8% sensitivity, 95.3% specificity, with lower accuracy for detecting proximal lesions. The oral contrast agent improves the sensitivity and specificity in determining CD lesions and in assessing sites and extent., Conclusions: Bowel US is a tool for evaluation of CD lesions in terms of complications, postoperative recurrence, and monitoring response to medical therapy; it reliably detects postoperative recurrence and complications, as well as offers the possibility of monitoring disease progression.

In Crohn's disease, one of the two major forms of inflammatory bowel diseases in human beings, persistent and chronic inflammation promotes fibrotic processes thereby facilitating formation of strictures, the most common indication for surgical intervention in this disorder. The pathogenesis of Crohn's disease-associated fibrosis is not fully understood, but variants of genes involved in the recognition of microbial components/products [e.g. CARD15 (caspase-activating recruitment domain 15) and ATG16L1 (autophagy-related 16-like 1)] are associated with this phenotype, and experimental evidence suggests that intestinal fibrosis results from an altered balance between deposition of ECM (extracellular matrix) and degradation of ECM by proteases. Studies have also contributed to identify the main phenotypic and functional alterations of cells involved in the fibrogenic process, as well as molecules that stimulate such cells to produce elevated amounts of collagen and other ECM-related proteins. In the present review, we assess the current knowledge about cellular and molecular mediators of intestinal fibrosis and describe results of recent studies aimed at testing the preventive/therapeutic effect of compounds in experimental models of intestinal fibrosis., (© 2015 Authors; published by Portland Press Limited.)

Background & Aims: Therapeutic antibodies against tumor necrosis factor α (anti-TNF) are effective in patients with Crohn's disease (CD). Mucosal healing is a surrogate marker of efficacy, but little is known about the effects of anti-TNF agents on structural damage in the intestine. Small-intestine contrast ultrasonography (SICUS) is a valuable tool for assessing CD lesions. A new sonographic quantitative index (the sonographic lesion index for CD [SLIC]) was developed to quantify changes in CD lesions detected by SICUS. We explored whether the SLIC can be used to monitor transmural bowel damage in CD patients during anti-TNF therapy., Methods: We performed a prospective study of 29 patients with ileal or ileocolonic CD treated with anti-TNF agents; patients underwent SICUS before and after scheduled induction and maintenance therapy. To determine whether changes that can be detected by SICUS occur independently of anti-TNF therapy, 7 patients with ileal CD treated with mesalamine were enrolled as controls. A clinical response was defined as steroid-free remission, with CD activity index scores less than 150., Results: We observed significant improvements in SLIC scores and subscores after induction and maintenance therapy with anti-TNFs, compared with before therapy. SLIC scores and subscores and index classes were improved significantly in patients with vs without clinical responses. Controls had no improvements in terms of CD activity index or SLIC scores, or index classes., Conclusions: Sonographic assessment using the quantitative index SLIC can be used to monitor changes in transmural bowel damage during anti-TNF therapy for CD., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Colonic metaplasia has been described in pouchitis. In a prospective study, we investigated whether colonic phenotype may develop in Crohn's disease (CD) ileum. The expression of sulfomucins (colonic mucin), sialomucins, and CD10 (small intestine mucin and phenotype) was evaluated before and after ileocolonic resection for CD., Methods: From February 2007 to March 2010, 22 patients with CD undergoing surgery were enrolled. Clinical (Crohn's Disease Activity Index >150) and endoscopic recurrence (Rutgeerts score ≥1) rates were assessed at 6 and 12 months. Ileal samples were taken at surgery (T0), at 6 (T1), and 12 months (T2) for histology, histochemistry (High Iron Diamine-Alcian Blue), and immunohistochemistry (anti-CD10)., Results: In 22 patients, recurrence was assessed at 6 and 12 months (clinical recurrence 9% and 18%; endoscopic recurrence 73% and 77%). In all 22 patients, ileal samples were taken at 6 and 12 months (involved area in patients with recurrence). In 19 of 22 (86.3%) patients, the involved ileum was also studied at surgery. At T0, T1, and T2, the expression of sialomucins and CD10 (small intestine mucin and phenotype) was comparable and higher (P < 0.0001) than the expression of sulfomucins (colonic mucin) (mean [range], T0:82 [35-100] versus 75 [0-100] versus 16 [0-50]; T1:96 [60-100] versus 94.7 [50-100] versus 3.89 [0-40]; T2:93.3 [60-100] versus 88.1 [25-100] versus 6.6 [0-40]). The expression of small-intestine mucin and phenotype was higher at T1 (P = 0.025) versus T0 (P = 0.026). Differently, the expression of colonic mucin was lower at T1 versus T0 (P = 0.027)., Conclusions: In CD, the ileum involved by severe/established lesions develops a "metaplastic" colonic mucosa phenotype. Differently, CD ileum with no lesions or with early recurrence maintains the "native" small intestine type mucin secretion and phenotype.

Background: Discrepancies between severity of lesions and symptoms may be observed in Crohn's disease. We prospectively assessed whether Crohn's disease may be diagnosed among asymptomatic relatives of patients, using Small Bowel Contrast Ultrasonography., Methods: Diagnosis of asymptomatic Crohn's disease relatives was defined ultrasonographically as: bowel wall thickness >3mm, bowel dilation/stricture, lumen diameter >2.5 cm. Diagnosis was confirmed by ileocolonoscopy. Subjects were also screened for the Leu3020insC mutation., Results: Consent was given by 35 asymptomatic first-degree relatives of 18 Crohn's disease patients. Ultrasonography indicated increased bowel wall thickness (5mm) compatible with ileal Crohn's disease in 1 relative (2.8%), a 42 year-old male. Ileocolonoscopy, histology, and radiology confirmed the diagnosis of stricturing ileal Crohn's disease. Gallbladder stones were detected in 7/35 (20%) relatives and Leu3020insC mutation in 3/35 (8.5%)., Conclusions: Small Bowel Contrast Ultrasonography may be a useful tool to diagnose asymptomatic small bowel Crohn's disease among first-degree relatives of patients., (Copyright © 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: Small-intestine contrast ultrasonography (SICUS) is a radiation-free technique that can detect intestinal damage in patients with Crohn's disease (CD). We evaluated the diagnostic accuracy of SICUS in determining the site, extent, and complications of CD, compared with computed tomography (CT) enteroclysis as the standard., Methods: We performed a retrospective analysis of data from 59 patients with CD evaluated by SICUS and CT enteroclysis 3 months apart, between January 2007 and April 2012. We evaluated disease site (based on bowel wall thickness), extent of lesions, and presence of complications (stenosis, prestenotic dilation, abscess, or fistulas) using CT enteroclysis as the standard. Sensitivity, specificity, and diagnostic accuracy were calculated. We determined the correlations in maximum wall thickness and disease extent in the small bowel between results from SICUS and CT enteroclysis., Results: SICUS identified the site of small bowel CD with 98% sensitivity, 67% specificity, and 95% diagnostic accuracy; it identified the site of colon CD with 83% sensitivity, 97.5% specificity, and 93% diagnostic accuracy. Results from SICUS and CT enteroclysis correlated in determination of bowel wall thickness (rho, 0.79) and disease extent (rho, 0.89; P < .0001 for both). SICUS detected ileal stenosis with 95.5% sensitivity, 80% specificity, and 91.5% diagnostic accuracy, and prestenotic dilation with 87% sensitivity, 67% specificity, and 75% diagnostic accuracy. SICUS detected abscesses with 78% sensitivity, 100% specificity, and 97% diagnostic accuracy, and fistulas with 78.5% sensitivity, 95.5% specificity, and 91.5% diagnostic accuracy., Conclusions: SICUS identified lesions and complications in patients with CD with high levels of sensitivity, specificity, and accuracy compared with CT enteroclysis. SICUS might be used as an imaging tool as part of a focused diagnostic examination of patients with CD., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The principle to avoid surgery for haemorrhoids and/or anal fissure in Crohn's disease (CD) patients is still currently valid despite advances in medical and surgical treatments. In this study we report our prospectively recorded data on medical and surgical treatment of haemorrhoids and anal fissures in CD patients over a period of 8 years., Methods: Clinical data of patients affected by perianal disease were routinely and prospectively inserted in a database between October 2003 and October 2011 at the Department of Surgery, Tor Vergata University Hospital, Rome. We reviewed and divided in two groups records on CD patients treated either medically or surgically according to the diagnosis of haemorrhoids or anal fissures. Moreover, we compared in each group the outcome in patients with prior diagnosis of CD and in patients diagnosed with CD only after perianal main treatment., Results: Eighty-six CD patients were included in the study; 45 were treated for haemorrhoids and 41 presented with anal fissure. Conservative approach was initially adopted for all patients; in case of medical treatment failure, the presence of stable intestinal disease made them eligible for surgery. Fifteen patients underwent haemorrhoidectomy (open 11; closed 3; stapled 1), and two rubber band ligation. Fourteen patients required surgery for anal fissure (Botox ± fissurectomy 8; LIS 6). In both groups we observed high complication rate, 41.2% for haemorrhoids and 57.1% for anal fissure. Patients who underwent haemorrhoidectomy without certain diagnosis of CD had significantly higher risk of complications., Conclusions: Conservative treatment of proctologic diseases in CD patients has been advocated given the high risk of complications and the evidence that spontaneous healing may also occur. From these preliminary results a role of surgery is conceivable in high selected patients, but definitve conclusions can't be made. Further randomized trials are needed to establish the efficacy of the surgical approach, giving therapeutic recommendations and guidelines.

Background: The development of symptomatic strictures in Crohn's Disease after anti-Tumour Necrosis Factor-α antibodies is undefined., Aim: To assess, in a prospective longitudinal study, the frequency of sub/obstructions in Crohn's Disease patients after treatment with Infliximab or Adalimumab. Changes of small bowel lesions after these biological therapies were searched by ultrasonography., Materials and Methods: From January 2007 to October 2008, 36 Crohn's Disease patients with no previous sub/obstructions were treated with either Infliximab (n=13) or Adalimumab (n=23) for ≥12months (mean follow-up duration after the first treatment 23.2±6.8months). Small Intestine Contrast Ultrasonography was performed before and after treatment in 19/36 patients. Sonographic parameters included: bowel wall thickness, lumen diameter, bowel dilation and lesion extent., Results: Sub/obstructions developed in 3/36 patients treated with Infliximab (n=1) or Adalimumab (n=2), all with fibrostricturing Crohn's Disease. Sonographic parameters did not significantly change after treatment., Conclusions: Sub/obstructive symptoms may develop in one tenth of Crohn's Disease patients treated with anti-Tumour Necrosis Factor-α antibodies, with no significant sonographic changes of the small bowel lesions., (Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objective: Crohn's Disease (CD)-associated inflammation is supposed to be driven by T helper (Th)1/Th17 cell-derived cytokines, even though there is evidence that the mucosal profile of cytokine may vary with the evolution of the disease. We aimed at comparing the pattern of effector cytokines in early and established lesions of CD., Design: Mucosal samples were taken from the neo-terminal ileum of CD patients undergoing ileocolonic resection, with (early lesions) or without post-operative recurrence, and terminal ileum of CD patients with long-standing disease undergoing intestinal resection (established lesions). Inflammatory cell infiltrate was examined by immunofluorescence and cytokine expression was analysed by real-time PCR, flow-cytometry and ELISA., Results: Before the appearance of endoscopic lesions, the mucosa of the neo-terminal ileum contained high number of T cells and macrophages, elevated levels of Th1-related cytokines and TNF-α and slightly increased IL-17A expression. Transition from this stage to endoscopic recurrence was marked by abundance of Th1 cytokines, marked increase in IL-17A, and induction of IL-6 and IL-23, two cytokines involved in the control of Th17 cell responses. In samples with established lesions, there was a mixed Th1/Th17 response with no TNF-α induction. Expression of IL-4 and IL-5 was up-regulated in both early and established lesions even though the fraction of IL-4-producing cells was lower than that of cells producing either interferon-γ or IL-17A., Conclusions: Distinct mucosal profiles of cytokines are produced during the different phases of CD. A better understanding of the cytokines temporally regulated in CD tissue could help optimize therapeutic interventions in CD.

In the last few years the management of Crohn's disease (CD) has changed due to the introduction of new therapeutic agents that provide more alternative options in patients with severe diseases, introducing new concepts regarding treatment timing. At the moment, the absence of good predictors of disease outcome and a subclinical marker available to predict relapse during clinical remission are major problems in the management of CD. In recent decades, the evaluation of several variables has been proposed to address this issue, including disease behavior, clinical-endoscopic activity and intestinal damage. In particular, definition of mucosal restitution or healing after therapy has been proposed as a surrogate of efficacy and new goal of the therapy. Regarding this concept, several criticisms have been raised, such as the need to better define the role of mucosal healing in a transmural disease. In order to address this issue, new alternative techniques providing both extraluminal and luminal intestinal damage have been proposed, including ultrasonography, computed tomography and magnetic resonance imaging.

Aim: To compare computed tomography enteroclysis (CTE) vs small intestine contrast ultrasonography (SICUS) for assessing small bowel lesions in Crohn's disease (CD), when using surgical pathology as gold standard., Methods: From January 2007 to July 2008, 15 eligible patients undergoing elective resection of the distal ileum and coecum (or right colon) were prospectively enrolled. All patients were under follow-up. The study population included 6 males and 9 females, with a median age of 44 years (range: 18-80 years)., Inclusion Criteria: (1) certain diagnosis of small bowel requiring elective ileo-colonic resection; (2) age between 18-80 years; (3) elective surgery in our Surgical Unit; and (4) written informed consent. SICUS and CTE were performed ≤ 3 mo before surgery, followed by surgical pathology. The following small bowel lesions were blindly reported by one sonologist, radiologist, surgeon and histolopathologist: disease site, extent, strictures, abscesses, fistulae, small bowel dilation. Comparison between findings at SICUS, CTE, surgical specimens and histological examination was made by assessing the specificity, sensitivity and accuracy of each technique, when using surgical findings as gold standard., Results: Among the 15 patients enrolled, CTE was not feasible in 2 patients, due to urgent surgery in one patients and to low compliance in the second patient, refusing to perform CTE due to the discomfort related to the naso-jejunal tube. The analysis for comparing CTE vs SICUS findings was therefore performed in 13 out of the 15 CD patients enrolled. Differently from CTE, SICUS was feasible in all the 15 patients enrolled. No complications were observed when using SICUS or CTE. Surgical pathology findings in the tested population included: small bowel stricture in 13 patients, small bowel dilation above ileal stricture in 10 patients, abdominal abscesses in 2 patients, enteric fistulae in 5 patients, lymphnodes enlargement (> 1 cm) in 7 patients and mesenteric enlargement in 9 patients. In order to compare findings by using SICUS, CTE, histology and surgery, characteristics of the small bowel lesions observed in CD each patient were blindly reported in the same form by one gastroenterologist-sonologist, radiologist, surgeon and anatomopathologist. At surgery, lesions related to CD were detected in the distal ileum in all 13 patients, also visualized by both SICUS and CTE in all 13 patients. Ileal lesions > 10 cm length were detected at surgery in all the 13 CD patients, confirmed by SICUS and CTE in the same 12 out of the 13 patients. When using surgical findings as a gold standard, SICUS and CTE showed the exactly same sensitivity, specificity and accuracy for detecting the presence of small bowel fistulae (accuracy 77% for both) and abscesses (accuracy 85% for both). In the tested CD population, SICUS and CTE were also quite comparable in terms of accuracy for detecting the presence of small bowel strictures (92% vs 100%), small bowel fistulae (77% for both) and small bowel dilation (85% vs 82%)., Conclusion: In our study population, CTE and the non-invasive and radiation-free SICUS showed a comparable high accuracy for assessing small bowel lesions in CD.

Background: In Crohn's disease (CD), knockdown of Smad7, an inhibitor of Transforming Growth Factor (TGF)-β1 activity, with a specific antisense oligonucleotide (GED0301) seems to be safe and tolerable and associates with TGF-β1-mediated suppression of inflammatory pathways., Aim: Since TGF-β1 has pro-fibrogenic effects in many organs, we evaluated whether GED0301 treatment associates with the formation of small bowel strictures., Methods: Fifteen patients with active, inflammatory CD, receiving oral GED0301 once daily for 7 days, were monitored for the formation of small bowel strictures by Small Intestine Contrast Ultrasonography (SICUS). Serum basic fibroblast growth factor (bFGF) and human chitinase 3-like 1 (also known as YKL-40), two markers of CD-related intestinal strictures, and matrix metalloproteinases (MMP) and tissue inhibitor 1 of MMPs (TIMP1) were analysed at day 0 and day 180 by ELISA. Crohn's disease activity index (CDAI) changes were also monitored., Results: Fourteen patients completed the 6-month study; the remaining underwent intestinal resection for a severe relapse not responsive to medical treatment. No patient developed small bowel stricture and none experienced obstructive symptoms during the study period. GED0301 treatment induced no significant change in the circulating levels of bFGF, YKL-40, MMPs and TIMP1. Seven of 12 patients who reached clinical remission following GED0301 treatment maintained a CDAI < 150 at day 180., Conclusion: Short-term treatment of patients with Crohn's disease using GED0301 is not associated with the development of small bowel stricture, thus reinforcing the concept that this drug is safe at least at early time points.

Over the past few years, the technical evolution of ultrasound equipment, the use of oral and intravenous contrast agents, and an increase in the expertise of sonographers has enhanced the role of ultrasonography that plays in the assessment of the gastrointestinal tract. In chronic inflammatory conditions, primarily CD, this technology can be used not only for diagnostic purposes, but it has also been suggested that it could play a role in the management of the disease.

Small intestine contrast ultrasonography (SICUS) has emerged as a valuable tool in the detection of intestinal damage in Crohn's disease (CD). Our aim was to develop a numerical index quantitating small bowel damage as detected by SICUS in patients with an established diagnosis of CD. One hundred and ten patients with ileal or ileocolonic CD were prospectively enrolled and followed up for one year. Disease activity was assessed by CDAI and CRP levels. Study variables included bowel wall thickness, lumen diameter, lesion length and number of lesion site. Fistula, mesenteric adipose tissue alteration, abscess and lymphnodes were also considered. Bowel segments were considered as a hollow cylinder. Standardized variations of variables were combined into a statistical and mathematical model to create an algorithm scoring an index value ranging from 0 to 200. Index was subdivided into a severity scale with 5 classes from the lower (A) to the higher score (E). Median lesion index value was significantly higher (p<0.005) in patients with a CDAI>150 and in patients with CRP>5 mg/l (p=0.003). Patients classified in class E and D at SICUS underwent surgery within one year follow up more frequently than those in class C, B and A (p<0.0001). We propose a new index for assessment of small bowel lesions in CD (SLIC: sonographic lesion index for CD) developed by using SICUS. This index may turn ultrasonography in CD from a descriptive qualitative assessment to a quantitative numerical index suitable for comparison studies., (Copyright © 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Background & Aims: The combined role of immunomodulators (IMM) and clinical characteristics of Inflammatory Bowel Disease (IBD) in determining the cancer risk is undefined. The aim was to assess whether clinical characteristics of IBD are independent risk factors for cancer, when considering thiopurines and anti-TNFs use., Methods: In a single-center cohort study, clinical characteristics of IBD patients with IBD duration ≥1 year and ≥2 visits from 2000 to 2009 were considered. Tests for crude rates and survival analysis methods were used to assess differences of incidence of cancer between groups. The methods were adjusted for the time interval between diagnosis and immunomodulatory treatments., Results: IBD population included 1222 patients :615 Crohn's disease (CD), 607 ulcerative colitis (UC). Cancer was diagnosed in 51 patients (34 CD,17 UC), with an incidence rate of 4.3/1000 pt/year. The incidence rate of cancer was comparable between CD and UC (4.6/1000 pt/year vs 2.9/1000 pt/year ;p=n.s.). Cancer most frequently involved the breast, the GI tract, the skin. Lymphoma was diagnosed in CD (1HL, 1NHL,0 HSTCL). Risk factors for cancer included older age at diagnosis of IBD (CD: HR 1.25;95%CI 1.08-1.45; UC:HR 1.33;95%CI 1.15-1.55 for an increase by 5 years; p=0.0023; p=0.0002), fistulizing pattern in CD (HR 2.55; 95%CI 1.11-5.86,p=0.0275), pancolitis in UC (HR 2.79;95%CI 1.05-7.40 p=0.0396 vs distal). IMM and anti-TNFs did not increase the cancer risk in CD, neither IMM in UC (anti-TNFs risk in UC not feasible as no cases observed)., Conclusions: Fistulizing pattern in CD, pancolitis in UC and older age at diagnosis of IBD are independent risk factors for cancer., (Copyright © 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Background: Infliximab and adalimumab are highly effective in Crohn's Disease (CD). This is supported by clinical trials and open-label studies using either infliximab or adalimumab, thus not allowing a proper comparison between these anti-TNFs in CD., Aim: To evaluate the efficacy and safety of infliximab and adalimumab in active CD., Methods: In a longitudinal study, CD patients with indication for anti-TNFs were treated with infliximab or adalimumab., Results: Ninety-three patients were treated with infliximab (n = 44) or adalimumab (n = 49). In the infliximab group, the induction was completed by 77.3% of patients, due to no response (n = 2), delayed hypersensitivity reactions (DHR) or infusion reactions (n = 8). Maintenance with infliximab was completed by 60% of patients, due to clinical worsening or loss of efficacy (n = 5), DHR or infusion reactions (n = 5). In the adalimumab group, all patients completed the induction, while maintenance was completed by 67% of patients, due to clinical worsening or loss of efficacy (n = 8), DHR (n = 1), other causes (n = 7). In both groups, the CDAI significantly reduced at baseline vs. each visit (P < 0.04). The Kaplan-Meier survival analysis performed to evaluate the risk of steroid-free remission in patients treated with infliximab vs. adalimumab detected no differences (log-rank test P = 0.4). Cox proportional-hazards regression identified two predictors of steroid-free remission using anti-TNFs: no smokers [HR = 2.94 (1.52-5.70), P = 0.001] and non stricturing non penetrating behaviour [HR = 3.116 (1.06-9.13), P = 0.03826]., Conclusions: Infliximab and adalimumab showed a similar efficacy. No smoking and non-stricturing non-penetrating behaviour were predictors of steroid-free remission., (© 2012 Blackwell Publishing Ltd.)

In the gut of patients with Crohn's disease (CD), high Smad7 blocks the immune-suppressive activity of transforming growth factor (TGF)-β1, thereby contributing to amplify inflammatory signals. In vivo in mice, knockdown of Smad7 with a Smad7 antisense oligonucleotide (GED0301) attenuates experimental colitis. Here, we provide results of a phase 1 clinical, open-label, dose-escalation study of GED0301 in patients with active, steroid-dependent/resistant CD, aimed at assessing the safety and tolerability of the drug. Patients were allocated to three treatment groups receiving oral GED0301 once daily for 7 days at doses of 40, 80, or 160 mg. A total of 15 patients were enrolled. No serious adverse event was registered. GED0301 was well tolerated and no patient dropped out during the study. Twenty-five adverse events were documented in 11 patients, the majority of whom were judged to be of mild intensity and unrelated to treatment. GED0301 treatment reduced the percentage of inflammatory cytokine-expressing CCR9-positive T cells in the blood. The study shows for the first time that GED0301 is safe and well tolerated in patients with active CD.

Background & Aims: The diagnostic role of Small Bowel Capsule Endoscopy (SBCE) in Crohn's Disease (CD) is under investigation. In a prospective study we investigated the diagnostic role of SBCE in patients with symptoms highly compatible with CD and undefined diagnosis after conventional techniques., Methods: From September 2005 to May 2009, all patients with clinically suspected CD and not conclusive diagnosis after Ileocolonoscopy (IC), Small Bowel Follow Through (SBFT) and Small Intestine Contrast Ultrasonography (SICUS) were enrolled. Findings compatible with CD included: bowel wall thickness (BWT) >3mm (for SICUS), ulcers, stenosis/strictures, fistulae (for SICUS, SBFT); >5 aphtoid ulcers, deep ulcers and/or strictures (for SBCE)., Results: Conventional techniques did not lead to a conclusive diagnosis in 30 patients (19 F, median age 31 years, range 8-57), showing chronic diarrhoea (n=27), abdominal pain (n=23), weight loss (n=5), fever (n=5), Iron Deficiency Anaemia (IDA)(n=5) and/or perianal disease (n=4). Findings compatible but not diagnostic for small bowel CD were detected in 19 (63%) by IC in 12 (40%) by SICUS and in 15 (50%) by SBFT. SBCE showed ileal lesions in 15 (50%) patients, including findings compatible with CD in 12 (40%). SBCE retention requiring surgery was observed in 1 patient. A significant concordance was observed between SBCE and IC k=0.33 C(k)=[0.25;0.42], but not between SBCE and SICUS k=0.13 IC(k)=[0.045;0.22] and between SBCE and SBFT k=0 IC(k)=[-0.089;0.089]., Conclusions: SBCE may detect lesions compatible with small bowel CD in almost one third of patients with symptoms highly compatible with CD and not conclusive diagnosis by using conventional techniques., (Copyright © 2010 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Background: The long-term risk of neoplasia in Crohn's disease (CD) patients treated with infliximab is undefined. The aim was to assess, in a multicenter, matched-pair study, whether infliximab use in CD is associated with an increased frequency of neoplasia in the long term., Methods: A multicenter, long-term, matched-pair study was conducted in 12 referral inflammatory bowel disease (IBD) centers. An initial cohort of 808 CD patients, including 404 infliximab-treated (CD-IFX) and 404 matched CD controls never treated with infliximab (CD-C) studied from 1999 to 2004, was followed up for an additional 4 years (2004-2008). Cases and controls were matched for: sex, age (±5 years), CD site, follow-up (±5 years), immunosuppressant use, and CD duration (±5 years). From 1999 to 2008 the frequency and characteristics of neoplasia were compared between CD-IFX and CD-C., Results: In 2008, 591 patients (304 CD-IFX, 287 CD-C) were in follow-up. Matched couples included 442 patients: 221 CD-IFX and 221 CD-C (median follow-up, months: 72, range 48-114 versus 75, range 44-114). From 1999 to 2008 the frequency of neoplasia among the 591 patients did not differ between CD-IFX (12/304; 3.94%) and CD-C (12/287; 4.19%; P = 0.95). A comparable frequency of neoplasia was also observed between the 221 matched couples (CD-IFX: 8/221; 3.61% versus CD-C: 9/221; 4.07%; P = 1). No specific histotype of cancer appeared associated with infliximab use., Conclusions: The frequency of neoplasia was comparable in an adult population of CD patients treated or not with infliximab, matched for clinical variables and followed up for a median of 6 years., (Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.)

Thiopurines represent an effective and widely used immunosuppressant in the therapeutic armamentarium of inflammatory bowel disease. However up to 25% of patients may be unable to continue the drug due to side effects. The incidence of hepatotoxicity associated with thiopurine use is reported between 0% and 32%. Veno-occlusive disease, peliosis hepatis, perisinusoidal fibrosis and nodular regenerative hyperplasia have all been described with thiopurines. Recent trials of 6-tioguanine, although successful in patients with allergies to azathioprine or mercaptopurine, have been compromised by increased hepatotoxicity, either veno-occlusive disease or nodular regenerative hyperplasia. We describe a report of nodular regenerative hyperplasia in a Crohn's disease patient associated with 6-mercaptopurine therapy and have reviewed the management and the literature regarding this complication. Our report strengthens the importance of further safety studies to evaluate the etiology, prevalence, risk factors and screening modalities for hepatotoxicity, in particular of nodular regenerative hyperplasia, in patients treated with thiopurines for inflammatory bowel disease., (Copyright © 2010 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Ileocolonoscopy (IC) is the gold standard for assessing Crohn's Disease (CD) recurrence after ileo-colonic resection. In a prospective longitudinal study we compared findings related to CD recurrence when using techniques visualizing either the luminal or the extraluminal surface (IC and small bowel follow through, SBFT vs Small Intestine Contrast Ultrasonography, SICUS)., Methods: From 2003 to 2008, 25 CD patients undergoing ileo-colonic resection were enrolled. Clinical assessment (CDAI) was performed at 1, 2 and 3 years. IC was performed at 1 (n=25) and 3 years (n=15), SBFT at 2 years (n=21) and SICUS at 1 (n=25), 2 (n=21) and 3 years (n=15). Recurrence was assessed by SBFT and SICUS (bowel wall thickness, BWT) when using IC as gold standard., Results: At 1 year, all patients were inactive and recurrence was detected by IC in 24/25 (96%) and by SICUS in 25/25 patients. At 2 years, 6/21 patients (29%) were active and recurrence was detected by SBFT in 12/21 (57%) and by SICUS in 21/21 patients. At 3 years, 5/15 patients (33%) were active, IC showed recurrence in 14/15 (93%), and SICUS in 15/15 patients. The endoscopic score at 1 year was higher in patients developing relapse at 2 years (n=5) than in patients maintaining remission (n=10) (median: 4, range 3-4 vs 2, range 0-3; p=0.003). The same finding was not observed by using SICUS (median BWT at 1 year: 5, range 4-7 vs 3.7, range 3.5-6; p=0.19)., Conclusions: Although IC and SICUS provide a different view of the bowel wall, in experienced hands SICUS provides findings compatible with endoscopic recurrence after ileo-colonic resection for CD. Discrepant findings may be observed in a low proportion of patients with minor lesions related to CD recurrence., (Copyright © 2010 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Aim: To investigate the prevalence of proximal small bowel (SB) lesions detected by wireless capsule endoscopy (WCE) in Crohn's disease (CD)., Methods: WCE was performed in 64 patients: 32 with CD of the distal ileum, and 32 controls with iron-deficiency anemia (IDA) or diarrhea. WCE was performed using the Given SB-WCE, followed by small intestine contrast ultrasonography (SICUS). Findings compatible with CD by using WCE included erosions, aphthoid or deep ulcers, and strictures/stenosis., Results: WCE detected proximal SB lesions in 16/32 (50%) patients (14 aphthoid ulcers, 2 deep ulcers, one stricture), which appeared not to be related to clinical parameters [epigastric pain, age, smoking, non-steroidal anti-inflammatory drugs (NSAIDs), IDA]. Among patients with proximal SB lesions, 6 (37%) were smokers, 3 (19%) NSAID users, 3 (19%) had epigastric pain and 4 (25%) had IDA. SICUS detected proximal SB lesions in 3/32 patients (19%) also showing lesions with WCE. No correlations were observed between proximal SB lesions assessed by WCE or by SICUS (chi(2) = 1.5, P = 0.2)., Conclusion: The use of WCE allows the detection of previously unknown upper SB lesions in a high proportion of patients with a previous diagnosis of CD involving the distal ileum.

Background: Crohn's disease (CD) recurrence is currently assessed by ileocolonoscopy. Small intestine contrast ultrasonography (SICUS) visualizes the small bowel lesions in CD, although its role after curative resection is undefined. We aimed to investigate the accuracy of SICUS in assessing CD recurrence after ileocolonic resection when using ileocolonoscopy as a gold standard. The correlation between the bowel wall thickness (BWT) measured by SICUS and the endoscopic score of recurrence was also assessed., Methods: The analysis included 72 CD patients with ileocolonic resection requiring ileocolonoscopy, undergoing SICUS within 6 months. Recurrence was assessed by ileocolonoscopy using the Rutgeerts' score. SICUS was performed after PEG ingestion and findings compatible with recurrence included: increased BWT (>3 mm), bowel dilation (>25 mm) or stricture (<10 mm)., Results: Ileocolonoscopy detected recurrence in 67/72 (93%) patients. SICUS detected findings compatible with recurrence in 62/72 (86%) patients (5 false negative (FN), 4 false positive (FP), 1 true negative (TN), 62 true positive (TP)), showing a 92.5% sensitivity, 20% specificity, and 87.5% accuracy for detecting CD recurrence. The BWT detected by SICUS was correlated with the Rutgeerts' score (P = 0.0001; r = 0.67). The median BWT, the extent of the ileal lesions, and the prestenotic dilation were higher in patients with an endoscopic degree of recurrence >or=3 versus or=3 versus

Background: The frequency of recurrence in Crohn's disease (CD) patients after curative resection different from the ileo-colonic is undefined. We aimed to assess the frequency, pattern, outcome, and risk factors of postoperative recurrence in CD patients under regular follow-up after anastomosis different from ileo-colonic., Materials and Methods: In a retrospective study, clinical records of 537 CD patients under regular follow-up from January 2001 to August 2007 were reviewed. The outcome after surgery was assessed on the basis of clinical records prospectively recorded., Results: Previous resection was observed in 183 of 537 (34%) patients, including the ileo-colon in 145 (79%) and other gastrointestinal (GI) segments in 38 (21%). Recurrence was detected in 16 of 38 (42%) patients (all symptomatic) including five of 14 (35%) with ileostomy, five of five (100%) with ileo-rectal, three of 11 (27%) with ileo-ileal, one or four (25%) with colorectal, and two of three (33%) with duodenum-jejunal anastomosis. Ileo-colonic resection was reported in 145 of 183 (79%) patients, showing recurrence in 128 (88.3%) and symptomatic in 47 (36.7%) patients. The frequency of recurrence was higher in patients with ileo-colonic resection than in patients with other types of resection (128/145, 88% vs 16/38, 42%, p < 0.001). The frequency of symptomatic recurrence was lower in patients with ileo-colonic resection than in those with other resections (47/128, 37% vs 16/16, 100%; p < 0.001). Risk factors for recurrence were comparable in the two subgroups (smoke, odds ratio, OR 1.5 vs 1.4; appendectomy, OR 0.32 vs 0.33; familial inflammatory bowel disease, OR 0.43 vs 1.26)., Conclusions: Postoperative recurrence is observed in a high proportion of CD patients after resection different from ileo-colon (including ileostomy), although at a lower frequency than observed after ileo-colonic resection.

Postoperative recurrence after ileo-colonic resection is a feature of Crohn's Disease (CD), almost 73% of patients show endoscopic recurrence at 1 year and 90% at 3 years. After surgical resection for CD, symptoms may be related to the surgical resection itself. Moreover, the development of an early severe endoscopic recurrence within 1 year represents a risk factor for early clinical recurrence. On the basis of these observations, the early detection and assessment of asymptomatic endoscopic recurrence may allow a timely and appropriate treatment of CD patients after ileo-colonic resection. At this purpose, conventional colonoscopy with ileoscopy currently represents the gold standard for assessing CD recurrence, graded according to the Rutgeerts' score. Lesions compatible with CD recurrence can be also detected by conventional radiology, including small bowel follow through and enema, both associated with a high radiation exposure. Due to the ineluctable course of CD after resection, and to the need of a proper follow up for assessing CD recurrence, several alternative, non invasive techniques have been searched in order to assess the post-operative recurrence, including: faecal alpha 1-antitrypsin clearance, faecal calprotectin, 99Tc-HMPAO scintigraphy, virtual colonoscopy, ultrasonography and, more recently, wireless capsule endoscopy (WCE) and Small Intestine Contrast Ultrasonography (SICUS). Among these, current evidences suggest that in experienced hands, ultrasound examination by SICUS represents a non-invasive technique useful for assessing recurrence in CD patients under regular follow up after surgery. The same findings are suggested for WCE, although the impact risk related to the recurrence or to the surgical anastomosis itself limits the use of this non-invasive technique for assessing CD recurrence after surgery.

Possible relations between surgical approaches, frequency, and severity of Crohn's disease recurrence after ileo-colonic resection is unknown. We aimed to assess perioperative outcomes and postsurgical complications of laparoscopic versus standard open surgery and to detect differences between the two groups in endoscopical recurrence and patients' satisfaction. Twenty-eight consecutive patients undergoing elective ileo-colonic resection by either laparoscopic approach (n = 15) or conventional open surgery (n = 13) were prospectively enrolled. No mortality or major intraoperative complications were observed in both groups. Significant differences between groups were the median operating time found shorter in the open group than in the laparoscopic group (p = 0.003), the higher dosage of pain killers needed in the open group (p = 0.05), the passage of flatus and\or stool after surgery found faster in group A (p = 0.004) and the shorter recovery period in the laparoscopic group (p = 0.007). Colonoscopy was performed in 27 patients. The frequency and pattern of recurrence did not differ between the two groups (p = 0.63). Patients' satisfaction was significantly in favor of laparoscopy. Present findings support the feasibility and advantages in the short-term of laparoscopic ileo-colonic resection in patients with Crohn's disease. No differences were observed in terms of frequency, time of onset, and severity of recurrence in a 1-year follow-up.

Background: The best available tool to assess recurrence of Crohn's disease (CD) is ileocolonoscopy (CC). Small intestine contrast ultrasonography (SICUS) and wireless capsule endoscopy (WCE) are noninvasive techniques able to detect small bowel lesions. In a prospective longitudinal study, we aimed to investigate the usefulness of SICUS and WCE for assessing postoperative recurrence of CD 1 year after surgery, using CC as the gold standard., Methods: Twenty-two patients (11 men, median age 33 years, range 22-67 years) undergoing ileocolonic resection for CD were prospectively followed from July 2003 to May 2006, with the Crohn's Disease Activity Index (CDAI) used for clinical assessment every 3 months for 1 year. At 1 year, recurrence was assessed by SICUS and CC, followed by WCE. CD recurrence was assessed by CC (Rutgeerts score). SICUS was performed after ingestion of polyethylene glycol, and WCE was performed with Given M2A equipment., Results: At 1 year, all 22 patients had inactive CD (CDAI < 150). In 5 patients, WCE was not performed because of luminal narrowing or stenosis. Seventeen of the 22 patients had all 3 techniques performed. CC detected recurrence in 21 of 22 patients. Lesions compatible with recurrence were detected by SICUS in all 22 patients (1 false positive). When considering only the 17 patients studied by all 3 techniques, recurrence was detected by CC in 16 of 17 patients, whereas lesions compatible with recurrence were detected by SICUS in all 17 patients (16 true positives [TPs], 1 FP) and by WCE in 16 of 17 patients (16 TPs, 1 true negative)., Conclusions: The present findings suggest that SICUS and WCE may be used as noninvasive techniques for the assessment of recurrence of CD in patients being regularly followed up after ileocolonic resection.

Background: Local injection of infliximab in Crohn's disease (CD) lesions may reduce the risk of rare side effects, reduce the dose, and increase the efficacy of the drug. The objective was to prospectively assess the feasibility and the safety of local injection of infliximab for the postoperative recurrence of patients with CD who were followed for at least 1 year., Methods: In a pilot, open-label study, 8 patients with CD (3 men; median age 48 years, range 35-82 years) undergoing ileocolonoscopy were prospectively enrolled. Inclusion criteria included the following: (1) localized (<5 cm) recurrence, (2) inflammatory pattern, and (3) clinically inactive CD. At the first endoscopy, lesions were injected with infliximab (median, 30 mg; range, 8-60 mg); a control endoscopy was performed at 2 weeks in 4 patients (3 received a second injection followed by a control endoscopy at 6 weeks) and at 4 weeks in 4 patients (2 received a second injection followed by a control endoscopy at 8 weeks)., Observations: No patients showed side effects or clinical relapse in the short term and the long term (median follow-up, 20 months; range, 14-21 months). Endoscopic score improved in 3/8 patients. The histologic scores were reduced in 4 patients, worsened in 3, and were unchanged in one patient with CD., Conclusions: Local injection of infliximab into patients with CD recurrence is feasible and safe, requiring a low dose. Present findings suggest the need of placebo-controlled trials to assess the efficacy of this new and safe procedure in subgroups of patients with CD.

Background & Aims: There is evidence that, in Crohn's disease (CD), lamina propria T lymphocytes (LPLs) are resistant to FAS-mediated apoptosis and that this defect contributes to the mucosal T-cell accumulation. In this study we examined the functional role of Flip, a Flice inhibitor protein, in the resistance of CD LPL to FAS-mediated apoptosis., Methods: Biopsy specimens and LPLs were taken from CD and ulcerative colitis (UC) patients and normal controls and analyzed for Flip by Western blotting. We also examined whether inhibition of Flip by antisense oligonucleotide restored the susceptibility of CD LPLs to FAS-induced apoptosis. LPL apoptosis was assessed by flow cytometry., Results: After FAS stimulation, the rate of apoptosis of CD3+ LPLs was higher in normal controls and patients with UC than in patients with CD. Enhanced expression of both long and short Flip isoforms was seen in biopsy specimens and purified CD3+ and CD45RO+ LPLs of CD patients in comparison with UC patients and normal controls. No increase in Flip was documented in untreated celiac disease mucosa, thus suggesting the possibility that induction of Flip in the gut does not simply rely on the ongoing inflammation. Finally, we showed that inhibition of Flip by antisense oligonucleotide reverted the resistance of CD LPLs to FAS-induced apoptosis., Conclusions: Data suggest a role for Flip in the resistance of CD LPLs to FAS-mediated apoptosis.

Background and Aims: The widespread use of anti-tumour necrosis factor alpha antibody (Infliximab) in Crohn's disease (CD) raises concerns about a possible cancer risk in the long term. In a matched pair study, we assessed whether Infliximab is associated with an increased risk of neoplasia., Methods: In a multicentre matched pair study, 404 CD patients treated with Infliximab (CD-IFX) were matched with 404 CD patients who had never received Infliximab (CD-C). Cases and controls were matched for sex, age (+/-5 years), site of CD, age at diagnosis (+/-5 years), immunosuppressant use, and follow up. New diagnoses of neoplasia from April 1999 to October 2004 were recorded., Results: Among the 404 CD-IFX, neoplasia was diagnosed in nine patients (2.22%) while among the 404 CD-C, seven patients developed neoplasia (1.73%) (odds ratio 1.33 (95% confidence interval 0.46-3.84); p=0.40). The survival curve adjusted for patient year of follow up showed no differences between CD-IFX and CD-C (p=0.90; log rank test). In the CD-IFX group, there was one cholangiocarcinoma, three breast cancers, one skin cancer, one leukaemia, one laryngeal cancer, and two anal carcinomas. Among the 7/404 (1.73%) CD-C, there were three intestinal adenocarcinomas (two caecum, one rectum), one basalioma, one spinalioma, one non-Hodgkin's lymphoma, and one breast cancer. Age at diagnosis of neoplasia did not differ between groups (CD-IFX v CD-C: median 50 (range 40-70 years) v 45 (27-72); p=0.50)., Conclusion: In our multicentre matched pair study, the frequency of a new diagnosis of neoplasia in CD patients treated with Infliximab was comparable with CD patients who had never received Infliximab.

Background: Small intestine contrast ultrasonography (SICUS), when performed after distention of the small bowel lumen with an iso-osmolar polyethylene glycol electrolyte-balanced solution, shows high sensitivity (100%) and specificity (97%) in detecting small bowel abnormalities in patients who have not received a diagnosis but in whom there is a suspicion of intestinal diseases. The diagnostic yield of SICUS remains to be established in detecting small bowel lesions in patients with proven Crohn's disease (CD) in comparison with transabdominal ultrasonography (TUS), and in relationship to the experience of the operator, using small bowel enema (SBE) as the "gold standard.", Aim: The aim of this study was to evaluate the diagnostic value of SICUS, when performed by a sonologist with 1 year of experience, and TUS, when performed by a sonologist with 10 years of experience, compared to SBE in the assessment of the site, extension, and stenosis of small intestinal lesions in CD patients., Patients and Methods: A total of 28 consecutive patients (men, 16; women, 12; age range, 21 to 60 yr) with a diagnosis of CD underwent TUS and SICUS, which were performed by 2 sonologists who were unaware of the radiologic findings, on the same day. SICUS was performed after the ingestion of 375 mL of a polyethylene glycol contrast solution. A standard SBE was performed on a different day by an expert radiologist who was unaware of the sonographic findings., Results: Sensitivities in the detection of small bowel lesions were 96% for TUS and 100% for SICUS. Compared with SBE, SICUS detected the presence of 4 lesions in the jejunum that had been missed by TUS. The mean (+/-SD) extent of the ileal disease was 22 +/- 12.5 cm when measured during SBE, 14.5 +/- 8.6 cm when measured during TUS, and 19.5 +/- 12.5 cm when measured during SICUS [P = 0.05 (SICUS versus SBE)]. The correlation of the extension of the lesions between SICUS and SBE (r = 0.88) was better than that between TUS and SBE (r = 0.64). The sensitivities of TUS and SICUS in the detection of at least 1 stricture were 76% and 94%, respectively. Sensitivity and specificity in assessing prestenotic dilatation were 50% and 100%, respectively, at TUS, and 100% and 90%, respectively, at SICUS., Conclusion: In inexperienced hands, SICUS is a more accurate technique for assessing CD lesions, and the accuracy is better than that of TUS performed by an expert sonologist. The use of SICUS, instead of SBE, could be indicated for the follow-up of patients with CD.

Background: Radiology and transabdominal ultrasonography (TUS) are used in the evaluation of the small bowel; however, the former technique is limited by radiation exposure, and the latter by its inability to visualize the entire small bowel., Aim: To evaluate the diagnostic accuracy of small intestine contrast ultrasonography (SICUS) to assess the presence, number, site, and extension of small bowel lesions., Subjects and Methods: TUS, SICUS, and small bowel follow-through (SBFT) were performed in 148 consecutive patients (78 women; age range, 12 to 89 yr), 91 with undiagnosed conditions, and 57 with previously diagnosed Crohn's disease (CD)., Results: In the undiagnosed patients, the sensitivity and specificity of TUS and SICUS were 57% and 100%, and 94.3% and 98%, respectively. In the CD patients, the sensitivity of TUS and SICUS was 87.3% and 98%, respectively. In comparison with SBFT, the extension of lesions was correctly assessed with SICUS and greatly underestimated with TUS. The concordance index between SBFT and SICUS for the number and site of lesions was 1 and 1 (P < 0.001), respectively, in undiagnosed patients, and 0.81 and 0.83 (P < 0.001), respectively, in CD patients. Between SBFT and TUS, the concordance index was 0.28 and 0.27 (not significant), respectively, in undiagnosed patients, and 0.28 and 0.31 (not significant), respectively, in CD patients., Conclusions: The diagnostic accuracy of SICUS is comparable to that of a radiologic examination, and is superior to that of TUS in detecting the presence, number, extension, and sites of small bowel lesions. These findings support the use of noninvasive SICUS for an initial investigation when small bowel disease is suspected and in the follow-up of CD patients.

After first resection in Crohn's disease at 1 year 60-80% of patients have endoscopic recurrence, 10-20% have clinical relapse, and 5% have surgical recurrence.1, 2 This review focuses on the actual evidence on the prevention of recurrence and relapse dealing with risk factors and with drugs. Smoking is the only risk factor for Crohn's disease, that has been shown to be related to both endoscopic and surgical recurrence and relapse. Among the different drugs evaluated, some (Mesalamine and Metronidazole) have been shown to be effective, whereas others (immunosuppressive) need to be evaluated in further, new trials.