Accuracy of optical diagnosis with narrow band imaging in the surveillance of ulcerative colitis: a prospective study comparing Kudo, Kudo-IBD and NICE classifications.

PURPOSE: The diagnostic accuracy of Narrow Band Imaging (NBI) in the endoscopic surveillance of ulcerative colitis (UC) has been disappointing in most trials which used the Kudo classification. We aim to compare the performance of NBI in the lesion characterization of UC, when applied according to three different classifications (NICE, Kudo, Kudo-IBD). METHODS: In a prospective, real-life study, all visible lesions found during consecutive surveillance colonoscopies with NBI (Exera-II CV-180) for UC were classified as suspected or non-suspected for neoplasia according to the NICE, Kudo and Kudo-IBD criteria. The sensitivity (SE), specificity (SP), positive (+LR) and negative (-LR) likelihood ratios of the three classifications were calculated, using histology as the reference standard. RESULTS: 394 lesions (mean size 6 mm, range 2-40 mm) from 84 patients were analysed. Twenty-one neoplastic (5%), 49 hyperplastic (12%), and 324 inflammatory (82%) lesions were found. The diagnostic accuracy of the NICE, Kudo and Kudo-IBD classifications were, respectively: SE 76%-71%-86%; SP 55-69%-79% (p < 0.05 Kudo-IBD vs. both Kudo and NICE); +LR 1.69-2.34-4.15 (p < 0.05 Kudo-IBD vs. both Kudo and NICE); -LR 0.43-0.41-0.18. CONCLUSION: The diagnostic accuracy of NBI in the differentiation of neoplastic and non-neoplastic lesions in UC is low if used with conventional classifications of the general population, but it is significantly better with the modified Kudo classification specific for UC.

Noninvasive Monitoring After Azathioprine Withdrawal in Patients With Inflammatory Bowel Disease in Deep Remission.

BACKGROUND & AIMS: There is uncertainty regarding the optimal duration of treatment with azathioprine (AZA) in ulcerative colitis (UC) and Crohn's disease (CD). We analyzed the clinical course and predictors of relapse after AZA withdrawal in patients in sustained deep remission. METHODS: A prospective study was performed on patients who stopped their treatment with AZA while being in steroid-free, extended deep remission (normal clinical, endoscopic, and histologic indexes, C-reactive protein, and fecal calprotectin [FC]). Standard biochemical tests and FC were measured at 3 and 6 months, then every 6 months. Bowel ultrasounds and ileocolonoscopy were performed every 6 and 12 months, respectively. Multivariate analysis for predictors of relapse was performed using a Cox proportional hazards model and hazard ratios were calculated. Spearman nonparametric correlation test was also used. The accuracy of significant predictors was calculated. RESULTS: Fifty-seven patients with inflammatory bowel disease stopped AZA after median 7 years (range, 5-19) and were followed up for median 50 months (range, 25-85). Twenty-six patients (18/31 UC, 8/26 CD; P = .003) relapsed, within a median 15 months (range, 2-37). FC was the only variable significantly correlated with later relapse of both diseases (UC: hazard ratio, 3.3; 95% confidence interval, 1.2-10; CD: hazard ratio, 4.5; 95% confidence interval, 1.4-12.5). The sensitivity, specificity, and positive and negative predictive values of FC were 50%, 100%, 100%, and 59% in UC and 50%, 94%, 80%, and 81% in CD. CONCLUSIONS: More than half patients with UC and one-third of patients with CD relapse after AZA withdrawal despite previous deep remission. FC positivity is associated with high risk of relapse, allowing early correction of the therapeutic strategy.

CELL THERAPY IN INFLAMMATORY BOWEL DISEASE.

In recent years, cell-based therapies have been explored in various immune-mediated inflammatory diseases, including inflammatory bowel disease (IBD). Cell therapy is the process of introducing new cells into an organism or tissue in order to treat a disease. The most studied cellular treatment in IBD was "stem cells-based therapy", which was explored according to different protocols in terms of type of donors, stem cells sources, study design and clinical endpoints. More recently, preliminary studies have also described the clinical use of "regulatory cells", which include T-reg and Tr1 cells, and "tolerogenic" dendritic cells. Finally, induced pluripotent stem cells are the subject of an intensive preclinical research program on animal models, including those related to colitis.

Lower incidence of COVID-19 in patients with inflammatory bowel disease treated with non-gut selective biologic therapy.

BACKGROUND AND AIM: Since the outbreak of COVID-19, concerns have been raised as to whether inflammatory bowel disease (IBD) patients under biologic therapy may be more susceptible to the disease. This study aimed to determine the incidence and outcomes of COVID-19 in a large cohort of IBD patients on biologic therapy. METHODS: This observational retrospective multicenter study collected data about COVID-19 in IBD patients on biologic therapy in Italy, between February and May 2020. The main end-points were (i) to assess both the cumulative incidence and clinical outcome of COVID-19, according to different biologic agents and (ii) to compare them with the general population and a cohort IBD patients undergoing non-biologic therapies. RESULTS: Among 1816 IBD patients, the cumulative incidence of COVID-19 was 3.9 per 1000 (7/1816) with a 57% hospitalization rate and a 29% case-fatality rate. The class of biologic agents was the only risk factor of developing COVID-19 (P = 0.01). Non-gut selective agents were associated with a lower incidence of COVID-19 cases, related symptoms, and hospitalization (P < 0.05). Compared with the general population of Lombardy, an overall lower incidence of COVID-19 was observed (3.9 vs 8.5 per 1000, P = 0.03). Compared with 565 IBD patients on non-biologic therapies, a lower rate of COVID-19 symptoms was observed in our cohort (7.5% vs 18%, P < 0.001). CONCLUSIONS: Compared with the general population, IBD patients on biologic therapy are not exposed to a higher risk of COVID-19. Non-gut selective agents are associated with a lower incidence of symptomatic disease, supporting the decision of maintaining the ongoing treatment.

Plasma miRNA-based signatures in CRC screening programs.

Colorectal cancer (CRC) screening programs help diagnose cancer precursors and early cancers and help reduce CRC mortality. However, currently recommended tests, the fecal immunochemical test (FIT) and colonoscopy, have low uptake. There is therefore a pressing need for screening strategies that are minimally invasive and consequently more acceptable to patients, most likely blood based, to increase early CRC identification. MicroRNAs (miRNAs) released from cancer cells are detectable in plasma in a remarkably stable form, making them ideal cancer biomarkers. Using plasma samples from FIT-positive (FIT+) subjects in an Italian CRC screening program, we aimed to identify plasma circulating miRNAs that detect early CRC. miRNAs were initially investigated by quantitative real-time PCR in plasma from 60 FIT+ subjects undergoing colonoscopy at Fondazione IRCCS Istituto Nazionale dei Tumori, then tested on an internal validation cohort (IVC, 201 cases) and finally in a large multicenter prospective series (external validation cohort [EVC], 1121 cases). For each endoscopic lesion (low-grade adenoma [LgA], high-grade adenoma [HgA], cancer lesion [CL]), specific signatures were identified in the IVC and confirmed on the EVC. A two-miRNA-based signature for CL and six-miRNA signatures for LgA and HgA were selected. In a multivariate analysis including sex and age at blood collection, the areas under the receiver operating characteristic curve (95% confidence interval) of the signatures were 0.644 (0.607-0.682), 0.670 (0.626-0.714) and 0.682 (0.580-0.785) for LgA, HgA and CL, respectively. A miRNA-based test could be introduced into the FIT+ workflow of CRC screening programs so as to schedule colonoscopies only for subjects likely to benefit most.

Virtual Chromoendoscopy With FICE for the Classification of Polypoid and Nonpolypoid Raised Lesions in Ulcerative Colitis.

GOALS: The aim of this study was to analyze the performance of Fuji Intelligent Color Enhancement (FICE) using the classification of Kudo in the differentiation of neoplastic and non-neoplastic raised lesions in ulcerative colitis (UC). BACKGROUND: The Kudo classification of mucosal pit patterns is an aid for the differential diagnosis of colorectal polyps in the general population, but no systematic studies are available for all forms of raised lesions in UC. STUDY: All raised, polypoid and nonpolypoid, lesions found during consecutive surveillance colonoscopies with FICE for long-standing UC were included. In the primary prospective analysis, the Kudo classification was used to predict the histology by FICE. In a post hoc analysis, further endoscopic markers were also explored. RESULTS: Two hundred and five lesions (mean size, 8 mm; range, 2 to 30 mm) from 59 patients (mean age, 56 y; range, 21 to 79 y) were analyzed. Twenty-three neoplastic (11%), 18 hyperplastic (9%), and 164 inflammatory (80%) lesions were found. Thirty-one lesions (15%), none of which were neoplastic, were unclassifiable according to Kudo. After logistic regression, a strong negative association resulted between endoscopic activity and neoplasia, whereas the presence of a fibrin cap was significantly associated with endoscopic activity. Using FICE, the sensitivity, specificity, and positive and negative likelihood ratios of the Kudo classification were 91%, 76%, 3.8, and 0.12, respectively. The corresponding values by adding the fibrin cap as a marker of inflammation were 91%, 93%, 13, and 0.10, respectively. CONCLUSIONS: FICE can help to predict the histology of raised lesions in UC. A new classification of pit patterns, based on inflammatory markers, should be developed in the setting of UC to improve the diagnostic performance.

Crohn's disease loci are common targets of protozoa-driven selection.

Previous studies indicated that a few risk variants for autoimmune diseases are subject to pathogen-driven selection. Nonetheless, the proportion of risk loci that has been targeted by pathogens and the type of infectious agent(s) that exerted the strongest pressure remain to be evaluated. We assessed whether different pathogens exerted a pressure on known Crohn's disease (CD) risk variants and demonstrate that these single-nucleotide polymorphisms (SNPs) are preferential targets of protozoa-driven selection (P = 0.008). In particular, 19% of SNPs associated with CD have been subject to protozoa-driven selective pressure. Analysis of P values from genome-wide association studies (GWASs) and meta-analyses indicated that protozoan-selected SNPs display significantly stronger association with CD compared with nonselected variants. This same behavior was not observed for GWASs of other autoimmune diseases. Thus, we integrated selection signatures and meta-analysis results to prioritize five genic SNPs for replication in an Italian cohort. Three SNPs were significantly associated with CD risk, and combination with meta-analysis results yielded P values < 4 × 10(-6). The bona fide risk alleles are located in ARHGEF2, an interactor of NOD2, NSF, a gene involved in autophagy, and HEBP1, encoding a possible mediator of inflammation. Pathway analysis indicated that ARHGEF2 and NSF participate in a molecular network, which also contains VAMP3 (previously associated to CD) and is centered around miR-31 (known to be disregulated in CD). Thus, we show that protozoa-driven selective pressure had a major role in shaping predisposition to CD. We next used this information for the identification of three bona fide novel susceptibility loci.

Endoscopic characterization of neoplastic and non-neoplastic lesions in inflammatory bowel disease: systematic review in the era of advanced endoscopic imaging.

Background: Current guidelines strongly recommend the use of validated classifications to support optical diagnosis of lesions with advanced endoscopic imaging in the lower gastrointestinal tract. However, the optimal strategy in inflammatory bowel disease (IBD) is still a matter of debate. Objectives: To analyze the accuracy of endoscopic classifications or single predictors for in vivo lesion characterization during endoscopic surveillance of IBD with advanced endoscopic imaging. Design: Systematic review. Data sources and methods: Medline and PubMed were used to extract all studies which focused on lesion characterization of neoplastic and non-neoplastic lesions in IBD. The diagnostic accuracy of endoscopic classifications and single endoscopic predictors for lesion characterization were analyzed according to type of patients, lesions, and technology used. When available, the rates of true and false positives or negatives for neoplasia were pooled and the sensitivity (SE), specificity (SP), positive predictive value, and negative predictive value (NPV) were calculated. Results: We included 35 studies (2789 patients; 5925 lesions - 1149 neoplastic). Advanced endoscopic imaging included dye-based chromoendoscopy, virtual chromoendoscopy (VCE), magnification and high-definition endoscopy, confocal laser endomicroscopy (CLE), endocytoscopy, and autofluorescence imaging. The Kudo classification of pit patterns was most frequently used, with pooled SE 83%, SP 83%, and NPV 95%. The endoscopic criteria with the highest accuracy, with minimum SE ⩾ 90%, SP ⩾ 80%, and NPV ⩾ 90% were: the Kudo-IBD classification used with VCE (Fuji Intelligent Color Enhancement and i-SCAN); combined irregular surface and vascular patterns used with narrow band imaging; the Mainz classification used with CLE. Multiple clinical and technical factors were found to influence the accuracy of optical diagnosis in IBD. Conclusion: No single endoscopic factor has yet shown sufficient accuracy for lesion characterization in IBD surveillance. Conventional classifications developed in the non-IBD setting have lower accuracy in IBD. The use of new classifications adapted for IBD (Kudo-IBD), and new technologies based on in vivo microscopic analysis show promise.

An evolutionary analysis of RAC2 identifies haplotypes associated with human autoimmune diseases.

The human RAC2 gene encodes a small GTP-binding protein with a pivotal role in immune activation and in the induction of peripheral immune tolerance through restimulation-induced cell death (RICD). Different human pathogens target the protein product of RAC2, suggesting that the gene may be subject to natural selection, and that variants in RAC2 may affect immunological phenotypes in humans. We scanned the genomic region encompassing the entire transcription unit for the presence of putative noncoding regulatory elements conserved across mammals. This information was used to select two RAC2 gene regions and analyze their intraspecific genetic diversity. Results suggest that a region covering the 3' untranslated region has been a target of multiallelic balancing selection (or diversifying selection), and three major RAC2 haplogroups occur in human populations. Haplotypes belonging to one of these clades are associated with increased susceptibility to multiple sclerosis (P = 0.022) and earlier onset of disease symptoms (P = 0.025). This same haplogroup is significantly more common in patients with Crohn's disease compared with healthy controls (P = 0.048). These data reinforce recent evidences that susceptibility alleles/haplotypes are shared among multiple autoimmune disorders and support a causal "role for RAC2" variants in the pathogenesis of autoimmune diseases. Other genes with a role in RICD have previously been associated with autoimmunity in humans, suggesting that this pathway and RAC2 may represent novel therapeutic targets in autoimmune disorders.

Immunosuppressive and biologic therapy for ulcerative colitis.

INTRODUCTION: Recent insight into the pathogenesis of ulcerative colitis have led to the development of new treatment options. A better understanding of IBD pathophysiology has progressively led to a more frequent use of immunosuppressants and biologics. AREAS COVERED: The use of the conventional immunomodulators, such as azathioprine, 6-mercaptopurine, methotrexate, cyclosporine and tacrolimus, and anti-TNF-α agents, such as infliximab and adalimumab, in the treatment of ulcerative colitis are reviewed. Moreover, the ongoing studies evaluating the efficacy of emerging immunosuppressants in treating patients with ulcerative colitis are discussed. An effort is made to explore some critical areas in which early and more diffuse use of these agents may be advocated. EXPERT OPINION: Ulcerative colitis is a chronic condition mainly affecting young people in their more productive age, and determining high indirect costs to the patient and to society. Thus, there is a need for optimizing and renewing our traditional therapeutic approach to UC, and new therapies beyond conventional treatment options possibly aiming to change the poor clinical course of many patients with ulcerative colitis. Keeping in mind this potentially new therapeutic scenario, there are some critical areas in which early and more diffuse use of conventional and emerging new immunomodulators is advocated.

Evidence-based efficacy of methotrexate in adult Crohn's disease in different intestinal and extraintestinal indications.

Introduction: Methotrexate (MTX) is included in the therapeutic armamentarium of Crohn's disease (CD), although its positioning is currently uncertain in an era in which many effective biological drugs are available. No systematic reviews or meta-analysis have stratified the clinical outcomes of MTX according to the specific clinical scenarios of its use. Methods: Medline, PubMed and Scopus were used to extract eligible studies, from database inception to May 2021. A total of 163 studies were included. A systematic review was performed by stratifying the outcomes of MTX according to formulation, clinical indication and criteria of efficacy. Results: The use of MTX is supported by randomized clinical trials only in steroid-dependent CD, with similar outcomes to thiopurines. The use of MTX in patients with steroid-refractoriness, failure of thiopurines or in combination with biologics is not supported by high levels of evidence. Combination therapy with biologics can optimize the immunogenic profile of the biological drug, but the impact on long-term clinical outcomes is described only in small series with anti-TNFα. Other off-label uses, such as fistulizing disease, mucosal healing, postoperative prevention and extraintestinal manifestations, are described in small uncontrolled series. The best performance in most indications was shown by parenteral MTX, favouring higher doses (25 mg/week) in the induction phase. Discussion: Evidence from high-quality studies in favour of MTX is scarce and limited to the steroid-dependent disease, in which other drugs are the leading players today. Many limitations on study design have been found, such as the prevalence of retrospective underpowered studies and the lack of stratification of outcomes according to specific types of patients and formulations of MTX. Conclusion: MTX is a valid option as steroid-sparing agent in steroid-dependent CD. Numerous other clinical scenarios require well-designed clinical studies in terms of patient profile, drug formulation and dosage, and criteria of efficacy.

Continuous clinical remission with biologics in ulcerative colitis: the 'AURORA' comparison study.

OBJECTIVES: Comparative trials among biological drugs for the treatment of ulcerative colitis (UC) provided conflicting results. After patent expire of infliximab originator, adalimumab, infliximab biosimilar, golimumab and vedolizumab have been approved in Italy.We compared the efficacy of these four biologics in UC according to the concept of continuous clinical remission (CCR). METHODS: In a retrospective, multicentre study, all UC patients treated with adalimumab, infliximab biosimilar, golimumab or vedolizumab between 2014 and 2019 were included. All drugs were compared to each other according to the 1-year CCR rate, defined as Mayo partial score ≤2, with bleeding subscore = 0, without any relapse or optimization with dose escalation, topical treatments or steroid use after first clinical remission. RESULTS: Four-hundred sixteen patients (adalimumab = 90, infliximab biosimilar = 105, golimumab = 79, vedolizumab = 142) were included. CCR was achieved in similar percentages among the groups (33%, 37%, 28%, 37%, respectively). All drugs were equivalent in biologic-naive patients, while vedolizumab was better than a second anti-TNFα in prior anti-TNFα agent failures. No differences were found according to type of adverse events or severe adverse events. CONCLUSIONS: Based on a strict definition of clinical remission, all biologics appear equally effective at 1 year. Changing to vedolizumab is more effective than switching to another anti-TNFα in TNFα failures.

Mucosal healing predicts late outcomes after the first course of corticosteroids for newly diagnosed ulcerative colitis.

BACKGROUND & AIMS: It is uncertain whether mucosal healing after the first course of corticosteroids therapy predicts outcome in patients with ulcerative colitis (UC). We evaluated whether early clinical and endoscopic responses to this therapy are associated with late outcomes in UC. METHODS: Patients with newly diagnosed UC who were prescribed corticosteroid therapy (n = 157) were followed up for 5 years. They were evaluated using clinical (Powel-Tuck [PT]) and endoscopic (Baron) indexes after 3 and 6 months, then every 6 months. Outcomes at month 3 (early response) were used to identify patients with complete (group A: PT, 0-1; Baron, 0), partial (group B: PT, 0-1; Baron, 1-3), or no response (group C: persistence of clinical and endoscopic activity). The association between early and late outcomes was assessed. RESULTS: After 5 years, there were significant differences between complete and partial responders in the rates of hospitalization (25% in group A vs 48.7% in group B; P = .0152; odds ratio [OR], 2.85; 95% confidence interval [CI], 1.21-6.72), immunosuppression therapy (5% in group A vs 25.6% in group B; P = .0030; OR, 6.55; 95% CI, 1.67-25.67), colectomy (3.3% in group A vs 18.0% in group B; P = .0265; OR, 6.34; 95% CI, 1.24-32.37), and their combination (26.7% in group A vs 48.7% in group B; P = .0249; OR, 2.61; 95% CI, 1.12-6.11). After multivariate analysis, lack of mucosal healing was the only factor associated with negative outcomes at 5 years (immunosuppressors: hazard risk [HR], 10.581; 95% CI, 2.193-51.039; P = .0033; hospitalization: HR, 3.634; 95% CI, 1.556-8.485; P = .0029; colectomy: HR, 8.397; 95% CI, 1.278-55.186; P = .0268). CONCLUSIONS: No mucosal healing after corticosteroid therapy is associated with a more aggressive disease course.

Anti-tumour necrosis factor α antibodies and circulating lymphocyte phenotypes in inflammatory bowel disease.

OBJECTIVE: Circulating lymphocyte subtypes are not fully explored parameters for monitoring chronic T cell activation during inflammatory bowel disease (IBD). Tumor necrosis factor α (TNFα), one of the main mediators of IBD related inflammation induces expression of CD70 on T cells. CD70 limits T cell expansion and controls CD27 receptor on activated B lymphocytes. Aim of this study was to assess the number and the frequency of CD70+ T cells and CD27+ B cells in IBD patients during inactive phase of the disease under or without anti-TNFα treatment. DESIGN: We studied 91 patients with inactive IBD, 31 untreated, 29 treated with infliximab (IFX), and 31 treated with adalimumab (ADA). Lymphocyte phenotypes were assessed by flow cytometry using anti-CD45, CD19, CD27, CD3, and CD70 monoclonal antibodies. IFX and ADA actual capacity of TNFα neutralization in serum was estimated by the recoveryELISA technique. RESULTS: Whereas CD3+ T cells were increased in treated compared to untreated patients, the percentage of the CD70+ T cells was significantly lower in treated patients indicating a 'cooling' effect of the biological therapy. This effect differs between samples according to the therapeutic range of the circulating drug. Although the CD19+ B-cell percentage tended to be lower in treated patients, CD19+27+ memory B cells did not show significant differences between groups. CONCLUSIONS: Frequency of peripheral blood CD70+ T cells was significantly reduced by treatment with anti-TNFα antibodies. Monitoring of this parameter of T cells can give better insight to the disease progression and therapy application in IBD patients.

Prevalence and pathogenesis of anemia in inflammatory bowel disease. Influence of anti-tumor necrosis factor-alpha treatment.

BACKGROUND: Anemia is a common complication of inflammatory bowel disease, but its epidemiology may be changing due to earlier diagnosis and improved treatments. We investigated the prevalence and pathogenesis of anemia in patients with inflammatory bowel disease. DESIGN AND METHODS: In a cross-sectional study 263 out-patients with inflammatory bowel disease (165 with Crohn's disease, 98 with ulcerative colitis) were investigated. The influence of time from diagnosis, disease activity, inflammation and the status of iron and hematinic vitamins on the level of hemoglobin and prevalence of anemia were evaluated. In a second group of 27 patients with Crohn's disease, undergoing anti-tumor necrosis factor-alpha treatment with infliximab because of refractory or fistulizing disease, we determined the effects of infliximab on disease activity, hemoglobin, serum erythropoietin levels, iron status and inflammation. RESULTS: In all, 104 of the 263 patients with inflammatory bowel disease were anemic. Age, gender and azathioprine treatment had no influence on anemia. The prevalence of anemia was highest at diagnosis (65%), decreased during the first 4 years after disease onset, and was stable thereafter. Active disease was associated with higher rates of anemia. At diagnosis most anemic patients had anemia of chronic disease; during follow-up iron deficiency and multifactorial forms of anemia became more prevalent. Eighteen of 27 patients undergoing treatment with infliximab were anemic; most of them had anemia of chronic disease. Infliximab reduced disease activity and improved anemia in 12 patients. This was mediated by an increased production of erythropoietin for the degree of anemia. In vitro infliximab increased the growth of erythroid progenitors from the peripheral blood of patients with active disease. Conclusions Anemia is a common problem in out-patients with inflammatory bowel disease; the prevalence and severity of anemia are related to the activity of the bowel disorder. The pathogenesis of anemia changes during the course of the disease, with anemia of chronic disease having a major role at diagnosis and iron deficiency and multifactorial forms of anemia during follow-up. In patients requiring anti-tumor necrosis factor-alpha treatment, response to therapy improves erythropoiesis.

Modified Kudo classification can improve accuracy of virtual chromoendoscopy with FICE in endoscopic surveillance of ulcerative colitis.

Background and study aims Virtual chromoendoscopy with Fuji Intelligent Color Enhancement (FICE) has never been studied in prospective trials of endoscopic surveillance for ulcerative colitis (UC). We compared FICE and white light endoscopy (WLE) in differentiation of visible lesions in UC. Patients and methods In a prospective parallel study, we compared consecutive outpatients with UC submitted to surveillance colonoscopy with FICE or WLE. At least one visible polypoid or non-polypoid lesion for each patient was required. Random biopsies from normal mucosa, targeted biopsies or removal of suspected neoplastic lesions and targeted biopsies of unsuspected lesions were performed. In the FICE arm, neoplasia was suspected according to a modified Kudo classification (FICE-KUDO/inflammatory bowel disease [IBD]). Sensitivity (SE), specificity (SP), positive and negative likelihood ratios (LR) and negative predictive value (NPV) were analyzed. Results One hundred patients were submitted to FICE (n = 46) or WLE (n = 54). Twenty-two patients (11 in WLE, 11 in FICE) had a least one neoplastic lesion. No neoplasia was found in random biopsies. Among 275 lesions, 17 of 136 by FICE and 27 of 139 by WLE were suspected neoplasia, but 28 (14 in each arm) were true neoplastic lesions. The accuracy of FICE-KUDO/IBD vs WLE (per lesion) was: SE 93 % vs 64 % ( P  = 0.065), SP 97 % vs 86 % ( P  = 0.002), positive-LR 28.3 vs 4.5 ( P  = 0.001), negative-LR 0.07 vs 0.42 ( P  = 0.092), NPV 99 % vs 96 % ( P  = 0.083). FICE-KUDO/IBD detected more non-polypoid lesions than WLE ( P  = 0.016). Conclusions Targeted biopsies of polypoid and non-polypoid lesions, using the modified Kudo classification with FICE are more accurate than WLE in UC surveillance.

HLA and autoimmune digestive disease: a clinically oriented review for gastroenterologists.

OBJECTIVES: The human leukocyte antigen (HLA) system includes genes involved in graft-vs-host rejection and in immune response. The discovery that HLAs are associated with several diseases led to appealing developments both in basic biomedical research and in clinical medicine, and offered the opportunity to improve the understanding of pathogenesis and classification of diseases, as well as to provide diagnostic and prognostic indicators. The aim of this article is to review the association between HLA alleles and autoimmune digestive disease and its current relationship with modern HLA nomenclature and clinical practice. METHODS: Articles dealing with the association between HLAs and autoimmune digestive disease (including celiac disease, inflammatory bowel disease, autoimmune hepatitis, sclerosing cholangitis and primary biliary cirrhosis) were searched for using Pubmed and SCOPUS databases from earliest records to January 2008. RESULTS: The review has provided two sections. In the first, we explain the basic principles of HLA structure, function, and nomenclature, as an introduction to the second section, which describes current associations between HLA alleles and digestive diseases. The clinical implications of each HLA association are critically discussed. Actually, a clinical role for HLA typing is suggested for only a few conditions, e.g., celiac disease. CONCLUSIONS: The knowledge of current HLA nomenclature and of its association with some digestive diseases such as celiac disease can be useful in clinical practice for diagnostic and prognostic purposes. This can avoid improper HLA typing as well as stressing the need for further studies on other possible clinical applications.

CARD15 gene variants and risk of reoperation in Crohn's disease patients.

OBJECTIVES: Several studies have investigated, with conflicting results, the risk factors for reoperation in Crohn's disease (CD) patients. CARD15 gene variants have been identified as a major genetic risk factor for CD patients and associated with ileal disease, stenosis, and risk of surgery. However, data regarding the association between these variants and the need for reoperation are very few and conflicting. This study evaluated the risk factors of reoperation, including CARD15 gene variants. METHODS: A total of 253 consecutive CD patients, recruited in four Italian tertiary-care inflammatory bowel disease (IBD) referral centers, who had submitted to surgery for CD, were included in the study. Clinical characteristics of CD patients, time and main indications for surgery, type of operation, postoperative therapy, and time to second surgery were recorded. CARD15 gene variants were determined by DNA sequencing analysis in each center. Factors related to surgical recurrence, including CARD15 variants, were estimated by Cox proportional hazard regression. RESULTS: In all, 89 patients (35.1%) showed at least one surgical recurrence. Reoperation was significantly correlated with stenosis as indications at initial surgery only. CARD15 variants were found in 36.0% of patients, but did not correlate significantly with the demographic and clinical characteristics of the patients, rate of first surgical recurrence, and time to second operation. CARD15 variants did not significantly affect the reoperation rate, irrespective of indications for surgery. CONCLUSIONS: Reoperation for CD is correlated with stenosis at initial surgery, but not with CARD15 gene variants. This finding does not justify more aggressive prophylactic therapy on the basis of CARD15 genotype.

Maintenance treatment with azathioprine in ulcerative colitis: outcome and predictive factors after drug withdrawal.

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

Use of double-balloon enteroscopy in the management of patients with Crohn's disease: feasibility and diagnostic yield in a high-volume centre for inflammatory bowel disease.

BACKGROUND: Double-balloon enteroscopy (DBE) is theoretically useful in Crohn's disease (CD) since it is potentially able to investigate the whole small intestine, but sparse data are available. AIM: To assess the feasibility, safety, and diagnostic yield of DBE in CD. METHODS: The study was conducted in a tertiary care centre for inflammatory bowel disease. Thirty-seven patients with CD (18/19 male/female, mean age 42 years, range 13-77 years) were considered. Thirty-two DBEs from the oral approach and 18 from the anal (in 6 patients from both ways with a complete exploration in 4, 10.8%) were performed. Indications were: first diagnosis/staging in 16 cases, diagnosis of stenosis in 7, obscure bleeding in 10, suspected neoplasia in 2, and postsurgical evaluation in 2. One hundred and thirty-three other procedures (3.7 per patient) were performed with the same indication. RESULTS: Insertion depth from the oral route was 266.5 ± 100 cm and from the anal route 72.5 ± 60 cm. Ileocecal valve was passed in 8/13 patients, but in 4 DBE explored less than 50 cm of ileum. Diagnostic yield was 59.4% but changed according to indication (40% in obscure bleeding, 100% in case of strictures) and was higher when DBE was conducted on the basis of previous investigations (77.8% versus 40%, p = 0.037). CONCLUSION: DBE is a feasible, useful, but technically demanding method in CD. Definition of the proper introduction route by means of previous investigations is associated with a higher efficacy of DBE.