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Background & Aims: Pouchitis often is diagnosed based on symptoms alone.In this study, we evaluate whether symptoms correlate with endoscopic and histologic findings in patients with ulcerative colitis and an ileal pouch-anal anastomosis. Methods: Symptoms, endoscopy, and histology were assessed in 46 patients using Pouchitis Disease Activity Index (PDAI).Patients were classified as either having pouchitis (PDAI score ≥7; N=22) or as not having pouchitis (PDAI score Results: Patients with pouchitis had significantly higher mean total PDAI scores, symptom scores, endoscopy scores, and histology scores.There was a similar magnitude of contribution of each component score to the total PDAI for the pouchitis group.Of note, 25% of patients with symptoms suggestive of pouchitis did not meet the PDAI diagnostic criteria for pouchitis.In both groups, the correlation coefficients between symptom, endoscopy, and histology scores were near zero (range, −0.26 to 0.20; P > 0.05). Conclusions: The symptom, endoscopy, and histology scores each contribute to the PDAI and appear to be independent of each other.Symptoms alone do not reliably diagnose pouchitis. GASTROENTEROLOGY 2001;121:261-267

Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract, which is thought to result from the effect of environmental factors in a genetically predisposed host. A gene location in the pericentromeric region of chromosome 16, IBD1, that contributes to susceptibility to Crohn's disease has been established through multiple linkage studies, but the specific gene(s) has not been identified. NOD2, a gene that encodes a protein with homology to plant disease resistance gene products is located in the peak region of linkage on chromosome 16 (ref. 7). Here we show, by using the transmission disequilibium test and case-control analysis, that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease. Wild-type NOD2 activates nuclear factor NF-kappaB, making it responsive to bacterial lipopolysaccharides; however, this induction was deficient in mutant NOD2. These results implicate NOD2 in susceptibility to Crohn's disease, and suggest a link between an innate immune response to bacterial components and development of disease.

Functional abdominal pain, including the irritable bowel syndrome, is more common in females. Our aim was to determine if differences in motility or biomechanical properties of the colon could account for this gender difference. In 18 healthy subjects (nine males), a catheter assembly incorporating a balloon and perfused side holes, connected to a barostat, was positioned in the left colon. The system was used to determine compliance, sensation in response to phasic balloon distension, and changes in motor activity and tone in response to a meal. There was no significant difference in any of these variables between males and females. We conclude that there is no gender difference in colonic motor function or sensation to balloon distension. The increased prevalence of irritable bowel syndrome in females may be related to psychosocial factors rather than differences in colonic motor function.

The results of recently completed genome-wide association studies have advanced knowledge of inflammatory bowel disease (IBD) genetics, including the identification of over 30 genes or loci associated with Crohn's disease (CD). The possibility of interactions between genes, referred to by the term epistasis, needs to be carefully considered as both genetic and functional studies in IBD move forward. We review a paper in this issue of the Journal that reports evidence of epistasis in CD, and we discuss important issues that arise when trying to determine whether there is indeed interaction between genes and what their potential implications for disease pathogenesis and clinical outcome might be.

The results of recently completed genome-wide association studies have rapidly advanced knowledge of inflammatory bowel disease (IBD) genetics. Several promising associations between IBD and gene variants have been identified with the two best replicated so far being variants in the IL23R and ATG16L1 genes. These findings highlight the importance of the immune system and interactions with intestinal microflora in the pathogenesis of IBD.

To access publisher's full text version of this article click on the hyperlink at the bottom of the page Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases. Norwegian PSC Research Center German Ministry of Education and Research through the National Genome Research Network 01GS0809-GP7 Deutsche Forschungsgemeinschaft FR 2821/2-1 Integrated Research and Treatment Center-Transplantation 01EO0802 PopGen Biobank Wellcome Trust 098051 info:eu-repo/grantAgreement/EC/FP7/262055

BACKGROUND Genome-wide association studies have identified at least 71 Crohn's disease (CD) genetic risk loci, but the role of gene-gene interactions is unclear. The value of genetic variants in clinical practice is not defined because of limited explained heritability. METHODS We examined model predictability of combining the 71 CD risk alleles and genetic interactions in an ongoing inflammatory bowel disease genome-wide association study. The Wellcome Trust Case Control Consortium inflammatory bowel disease genome-wide association study was used as a replicate cohort. We used logic regression, an adaptive regression methodology, to search for high-order binary predictors (e.g., single-nucleotide polymorphism [SNP] interactions). RESULTS The combined 71 CD SNPs had good CD risk predictability (area under the curve of 0.75 and 0.73 in the 2 cohorts). Higher cumulative allele score predicted higher CD risk, but a relatively small difference in cumulative allele scores was observed between CD and controls (49 versus 47, P < 0.001). Through LR, we identified high-order genetic interactions and significantly improved the model predictability (area under the curve, from 0.75 to 0.77, P < 0.0001). A genetic interaction model, including NOD2, ATG16L1, IL10/IL19, C13orf31, and chr21q loci, was discovered and successfully replicated in the independent Wellcome Trust Case Control Consortium cohort. The explained heritability of the 71 CD SNPs alone was 24% and increased to 27% after adding the genetic interactions. CONCLUSIONS A novel approach allowed the identification and replication of genetic interactions among NOD2, ATG16L1, IL10/IL19, C13orf31, and chr21q loci. CD risk can be predicted by a model of 71 CD loci and improved by adding genetic interactions.

Background Genome-wide association studies identified a PTGER4 expression-modulating region on chromosome 5p13.1 as Crohn's disease (CD) susceptibility region. The study aim was to test this association in a large cohort of patients with inflammatory bowel disease (IBD) and to elucidate genotypic and phenotypic interactions with other IBD genes. Methodology/Principal Findings A total of 7073 patients and controls were genotyped: 844 CD and 471 patients with ulcerative colitis and 1488 controls were analyzed for the single nucleotide polymorphisms (SNPs) rs4495224 and rs7720838 on chromosome 5p13.1. The study included two replication cohorts of North American (CD: n = 684; controls: n = 1440) and of German origin (CD: n = 1098; controls: n = 1048). Genotype-phenotype, epistasis and transcription factor binding analyses were performed. In the discovery cohort, an association of rs4495224 (p = 4.10×10−5; 0.76 [0.67–0.87]) and of rs7720838 (p = 6.91×10−4; 0.81 [0.71–0.91]) with susceptibility to CD was demonstrated. These associations were confirmed in both replication cohorts. In silico analysis predicted rs4495224 and rs7720838 as essential parts of binding sites for the transcription factors NF-κB and XBP1 with higher binding scores for carriers of the CD risk alleles, providing an explanation of how these SNPs might contribute to increased PTGER4 expression. There was no association of the PTGER4 SNPs with IBD phenotypes. Epistasis detected between 5p13.1 and ATG16L1 for CD susceptibility in the discovery cohort (p = 5.99×10−7 for rs7720838 and rs2241880) could not be replicated in both replication cohorts arguing against a major role of this gene-gene interaction in the susceptibility to CD. Conclusions/Significance We confirmed 5p13.1 as a major CD susceptibility locus and demonstrate by in silico analysis rs4495224 and rs7720838 as part of binding sites for NF-κB and XBP1. Further functional studies are necessary to confirm the results of our in silico analysis and to analyze if changes in PTGER4 expression modulate CD susceptibility.

Efficacy of 5-aminosalicylic acids (5-ASAs) in ulcerative colitis (UC) has been studied previously in meta-analyses. However, no recent meta-analysis has studied the relative efficacies of differing routes of administration.MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through May 2011). Eligible trials recruited adults with mildly to moderately active UC, or quiescent UC, and compared oral 5-ASAs with either topical 5-ASAs or a combination of oral and topical 5-ASAs. Dichotomous data were pooled to obtain relative risk (RR) of failure to achieve remission in active UC, and RR of relapse of disease activity in quiescent UC, with a 95% confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference.The search identified 3,061 citations, and 12 randomized controlled trials (RCTs) were eligible. Four compared topical with oral 5-ASAs in active UC remission, with an RR of no remission with topical 5-ASAs of 0.82 (95% CI=0.52-1.28). Four trials compared combined with oral 5-ASAs in active UC (RR of no remission=0.65; 95% CI=0.47-0.91; NNT=5). Three RCTs compared intermittent topical with oral 5-ASAs in preventing relapse of quiescent UC (RR=0.64; 95% CI=0.43-0.95; NNT=4), and two compared combined with oral 5-ASAs (RR of relapse=0.48; 95% CI=0.17-1.38).Combined 5-ASA therapy appeared superior to oral 5-ASAs for induction of remission of mildly to moderately active UC. Intermittent topical 5-ASAs appeared superior to oral 5-ASAs for preventing relapse of quiescent UC.

The efficacy of 5-aminosalicylic acids (5-ASAs) in ulcerative colitis (UC) has been studied previously in meta-analyses. However, several randomized controlled trials (RCTs) have been published recently, and no previous meta-analysis has studied the effect of 5-ASA dosage used.MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through December 2010). Eligible trials recruited adults with active or quiescent UC, comparing different doses of 5-ASAs with themselves or placebo. Dichotomous data were pooled to obtain relative risk (RR) of failure to achieve remission in active UC, and RR of relapse of disease activity in quiescent UC, with a 95% confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference.The search identified 3,061 citations, and 37 RCTs were eligible. Of these, 11 compared 5-ASA with placebo in active UC remission, with the RR of no remission with 5-ASAs of 0.79 (95% CI 0.73-0.85; NNT=6). Doses of ≥ 2.0 g/day were more effective than2.0 g/day for remission (RR=0.91; 95% CI 0.85-0.98). There were 11 RCTs comparing 5-ASAs with placebo in preventing relapse of quiescent UC, with the RR of relapse of 0.65 (95% CI 0.55-0.76; NNT=4). Doses of ≥ 2.0 g/day appeared more effective than2.0 g/day for preventing relapse (RR=0.79; 95% CI 0.64-0.97).5-ASAs are highly effective for inducing remission and preventing relapse in UC. Evidence suggests that doses of ≥ 2.0 g/day have greater efficacy, although doses2.5 g/day do not appear to lead to higher remission rates.

Chronic inflammatory diseases, depending upon the duration and severity, are frequently associated with an increased risk of developing cancer. A classic paradigm is the enhanced risk of colorectal cancer (CRC) in patients with inflammatory bowel disease (IBD). Carcinogenesis is a multifactorial process that involves accumulation of genetic defects, protein modification, and cell-matrix interaction. In this review, we discuss aspects of chronic inflammation in IBD that influence the development of CRC and highlight the key molecular mediators involved in this process. Also, we identify potential targets that could facilitate earlier detection of dysplasia. The targeted manipulation of specific molecules or pathways could provide opportunities for the development of therapeutic and chemopreventive interventions, which may prove effective in arresting the progression of colitis-associated cancer (CAC), with clinical implications.

The majority of patients with Crohn's disease (CD) require surgery during the course of their disease, but such surgery is typically not curative. Although some studies suggest that the disease state is theoretically reset to its earliest phase following surgery, disease phenotype and natural history of CD do not change significantly after surgery, leading to high rates of recurrence. Factors predisposing to this recurrence are not well defined, so there is a need for and a unique opportunity to develop a better understanding of the pathogenesis of recurrent inflammation and associated risk factors after an ileocolic resection. This paper reviews the postoperative disease outcome and evolution based on defining the combination of the patient's microbial flora, environmental exposure history, immune response and genetic make-up.

Applications of probiotics in the treatment of gastrointestinal disorders are gaining acceptance among patients, despite evidence that probiotics can present substantial health risks, particularly for patients who are immunocompromised or seriously ill. Patients will likely formulate their attitudes and beliefs about probiotic therapies with reference to interpretive frameworks that compare probiotics with more familiar therapeutic modalities, including complementary and alternative medicines, pharmacological therapies, and gene-transfer technologies. Each of these frameworks highlights a different set of benefit-to-risk considerations regarding probiotic usage and reinforces extreme characterizations of both the therapeutic promise and peril of probiotics. Considerable effort may be required to help patients make informed choices about probiotic therapies.

The purpose of our study was to measure relative and absolute wall attenuations and wall thickness in normal small bowel on contrast-enhanced CT enterography and to study the efficacy of relative attenuation, absolute attenuation, and wall thickness in distinguishing normal from active inflammatory Crohn's disease of the terminal ileum.Using a case-control study design, we reviewed 630 CT enterography examinations, of which 191 were normal and 36 had active inflammatory Crohn's disease in the terminal ileum. In healthy individuals, wall thickness and attenuation in distended and collapsed loops were measured in the duodenum and four abdominal quadrants. Wall thickness and attenuation were also measured in the terminal ileum. All measurements of intraarterial attenuation were taken at the same slice level. In the examinations of patients with Crohn's disease, only terminal ileum wall thickness and attenuation as well as arterial attenuation at the same slice level were measured. Normal segments were compared with a linear model. Terminal ileum data were fit to a multivariate logistic regression model.Relative attenuation and absolute attenuation in the normal distended and collapsed duodenum and left upper quadrant were significantly greater than in all other segments (p0.001 and0.048 for relative attenuation and p0.001 and0.032 for absolute attenuation, respectively). Relative attenuation and wall thickness models and absolute attenuation and wall thickness models discriminated normal from active terminal ileum Crohn's disease significantly better than the same measurements without wall thickness (p = 0.017 and 0.001, respectively). When the bowel wall is3 mm, a relative attenuation cutoff of 0.5 is 89% sensitive and 81% specific.In normal small bowel, when wall measurement is taken into account, the duodenum and jejunum have a greater relative attenuation and absolute attenuation than other segments. Relative attenuation and absolute attenuation with wall thickness models discriminate normal from active terminal ileum Crohn's disease better than the same measurements without wall thickness.

Objective: To assess long-term outcomes after ileal pouch-anal anastomosis (IPAA) in Crohn's disease (CD). Summary Background Data: Although considered the procedure of choice in ulcerative colitis, performance of ileal pouch-anal anastomosis (IPAA) is controversial in CD. Methods: CD patients were identified from a prospectively maintained IPAA database. Time-to-diagnosis and pouch retention rates were analyzed using Kaplan-Meier curves. Demographic, clinical, and pathologic factors associated with pouch retention were evaluated with log-rank test and Cox proportional hazards model. Results: Two hundred and four CD patients (108 female, median age 33 years, and median follow-up 7.4 years) with primary IPAA were included. CD diagnosis was before IPAA (intentional) in 20(10%), from postoperative histopathology (incidental) in 97(47%) or made in a delayed fashion at median 36 months after IPAA in 87(43%). Overall 10-year pouch retention was 71%. On multivariate analysis, pouch loss was associated with delayed diagnosis (P = 0.03, hazard ratio [HR] 2.6 (95% confidence interval [CI] 1.1–6.5)), pouch-vaginal fistula (P = 0.01, HR 2.8 (95% CI 1.3–6.4)), and pelvic sepsis (P = 0.0001, HR 9.7(95% CI 3.4–27.3)). Patients with retained IPAA at follow-up had near-perfect/perfect continence (72%), rare/no urgency (68%) with median daily bowel movements 7 (range 2–20). Median overall quality of life, quality of health, level of energy, and happiness with surgery were 9, 9, 8, and 10 of 10, respectively. Conclusions: For CD patients with IPAA, when the diagnosis is established preoperatively or immediately following surgery, pouch loss rates are low and functional results are favorable. Outcomes in patients with delayed diagnosis are worse but half retain their pouch at 10 years with good functional outcomes.

Electronic health records (EHRs) have been shown to reduce medication errors, improve patient outcomes, and create administrative efficiencies. Numerous public and private efforts are currently underway to achieve universal EHR adoption in the United States by the year 2014. EHRs hold a great potential to integrate clinical care and research by allowing input of clinical data in a structured format, facilitating electronic data capture for clinical trials and providing linkage with genomic information. The goal of this article is to inform the academic gastrointestinal community about the research opportunities created by the widespread adoption of EHRs and present a systematic approach in utilizing EHR-derived data for observational, experimental, or translational studies.

Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 x 10(-13), combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 x 10(-12), combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 x 10(-16), combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 x 10(-8), combined OR = 0.56; rs10889677, combined P = 1.3 x 10(-8), combined OR = 1.29).

Aminosalicylates are the first-line therapy for patients with mild to moderate active ulcerative colitis. Treatment should start at dosages of 4.8 g per day of the active 5-aminosalicylate moiety, rather than starting at a lower dosage and increasing if treatment fails. Infliximab has been shown to be effective and is now approved by the US Food and Drug Administration for the treatment of moderately to severely active ulcerative colitis in patients who have had an inadequate response to conventional therapy.

Background: The NIDDK IBD Genetics Consortium (IBDGC) collects DNA and phenotypic data from inflammatory bowel disease (IBD) subjects to provide a resource for genetic studies. No previous studies have been performed on the reliability and validity of phenotypic determinations in either Crohn's disease (CD) or ulcerative colitis (UC) using primary records. Our aim was to determine the reliability and validity of these phenotypic assessments. Methods: The de-identified records of 30 IBD patients were reviewed by 2 phenotypers per center using a standard protocol for phenotypic assessment. Each phenotyper evaluated 10 charts on 2 occasions 5 months apart. Reliability was expressed as the kappa (κ) statistic. Performance characteristics were determined by comparison to a consensus-derived “gold standard” and by generation of receiver operating characteristic (ROC) curves. Results: Agreement for diagnosis was excellent (κ = 0.82; 95% confidence interval [CI]: 0.71–0.92). Agreement for CD location was good for jejunal, ileal, colorectal, and perianal disease with κ between 0.60 and 0.74 but was fair for esophagogastroduodenal (κ = 0.36). Agreement for UC extent (κ = 0.67; 95% CI: 0.48–0.85), and CD behavior (κ = 0.67; 95% CI: 0.49–0.83) were very good. Area under the ROC curves was greater than 0.84 for diagnosis, CD behavior, UC extent, and ileal and colonic CD location. Conclusions: IBD phenotype classification using a standard protocol exhibited very good to excellent inter- and intrarater agreement and validity. This study highlights the importance of standard protocols in generating reliable and valid phenotypic assessments. The data will facilitate estimates of phenotyping misclassification rates that should be considered when making inferences from IBD genotype–phenotype studies. (Inflamm Bowel Dis 2007)

SUMMARY Background: Management of antibiotic-dependent pouchitis is often challenging. Oral bacteriotherapy with probiotics (such as VSL #3) as maintenance treatment has been shown to be effective in relapsing pouchitis in European trials. However, this agent has not been studied in the US, and its applicability in routine clinical practice has not been evaluated. Aim: To determine compliance and efficacy of probiotic treatmentinpatientswithantibiotic-dependentpouchitis. Methods: Thirty-one patients with antibiotic-dependent pouchitis were studied. VSL #3 is a patented probiotic preparation of live freeze-dried bacteria. All patients received 2 weeks of ciprofloxacin 500 mg b.d. followed by VSL #3 6 g/day for 8 months. Baseline Pouchitis Disease Activity Index scores were calculated. Patients’ symptoms were reassessed at week 3 when VSL #3 therapy was initiated and at the end of the 8-month trial. Some patients underwent repeat pouch endoscopy at the end of the trial. Results: All 31 patients responded to the 2-week ciprofloxacin trial with resolution of symptoms and they were subsequently treated with VSL #3. The mean duration of follow-up was 14.5 ± 5.3 months (range: 8‐26 months). At the 8-month follow-up, six patients were still on VSL #3 therapy, and the remaining 25 patients had discontinued the therapy due to either recurrence of symptoms while on treatment or development of adverse effects. All six patients who completed the 8-month course with a mean treatment period of 14.3 ± 7.2 months (range: 8‐26 months) had repeat clinical and endoscopic evaluation as out-patients. At the end of 8 months, these six patients had a mean Pouchitis Disease Activity Index symptom score of 0.33 ± 0.52 and a mean Pouchitis Disease Activity Index endoscopy score of 1.83 ± 1.72, which was not statistically different from the baseline Pouchitis Disease Activity Index endoscopy score of 2.83 ± 1.17 (P ¼ 0.27). Conclusion: This study was conducted to evaluate bacteriotherapy in routine care. The use of probiotics has been adopted as part of our routine clinical practice with only anecdotal evidence of efficacy. Our review of patient outcome from the treatment placebo showed that only a minority of patients with antibiotic-dependent pouchitis remained on the probiotic therapy and in symptomatic remission after 8 months.

Ileal pouch-anal anastomosis (IPAA) improves quality of life (QOL) for ulcerative colitis patients who require surgery. Crohn's disease (CD) of the pouch, pouchitis, cuffitis, and irritable pouch syndrome (IPS) have an adverse impact on physical and psychological well-being, which can compromise the gain in QOL after the surgery. Their clinical, endoscopic, and histologic features have not been fully characterized. The aim of this study was to compare demographic, clinical, endoscopic, and histologic features between CD of the pouch, pouchitis, cuffitis, IPS, and normal pouches. METHODS We enrolled 124 patients: normal pouches (N = 26), CD of the pouch (N = 23), pouchitis (N = 22), cuffitis (N = 21), and IPS (N = 32). Symptomatology, endoscopy, histology, and the Cleveland Global QOL and the Irritable Bowel Syndrome-QOL scores were compared among the groups.Univariate analysis of demographic and clinical data showed a possible association between NSAID use and pouchitis, extraintestinal manifestation and cuffitis, and antidepressant use and IPS. There were no differences in the Pouchitis Disease Activity Index symptom scores between the disease groups, with an exception of bleeding, which occurred almost exclusively in cuffitis. Endoscopy was useful in discriminating between CD of the pouch, pouchitis, cuffitis, and normal pouches or IPS. Patients with diseased IPAA had worse QOL scores.Symptoms largely overlapped among the disease groups of IPAA. Endoscopy is valuable for diagnosis. Inflammatory or noninflammatory sequelae of IPAA adversely affected patients' QOL.

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the treatment of choice in the majority of patients with ulcerative colitis (UC) who require surgery. To ease the construction of the IPAA and improve functional outcome by minimizing sphincter related stretch injury, a stapling technique is being commonly used in the pouch-anal anastomosis. Despite its advantages, the procedure normally leaves a 1-2 cm of anal transitional zone or rectal cuff, which is susceptible to recurrence of residual UC or cuffitis. Cuffitis can cause symptoms mimicking pouchitis.To conduct an open-labeled trial of topical mesalamine in patients with cuffitis.We treated 14 consecutive patients with cuffitis by giving mesalamine suppositories 500 mg b.i.d. (mean 3.2 months, range 1-9 months). The Cuffitis Activity Index (adapted from the Pouchitis Disease Activity Index) scores and improvement in symptoms of bloody bowel movements and arthralgias were measured as primary and secondary outcomes.All patients had surgery for medically refractory UC. There were significant reductions in the total Cuffitis Activity Index scores after the therapy (11.93 +/- 3.17 vs 6.21 +/- 3.19, p0.001). Symptom (3.24 +/- 1.28 vs 1.79 +/- 1.31), endoscopy (3.14 +/- 1.29 vs 1.00 +/- 1.52), and histology (4.93 +/- 1.77 vs 3.57 +/- 1.39) scores each were significantly reduced (p0.05). Ninety-two percent of patients with bloody bowel movements and 70% of patients with arthralgias improved after the therapy. No systemic or topical adverse effects were reported.Topical mesalamine appears well tolerated and effective in treating patients with cuffitis, with improvement in symptom as well as endoscopic and histologic inflammation.

Background & Aims: Some patients who undergo ileal pouch-anal anastomosis (IPAA) surgery for ulcerative colitis (UC) or indeterminate colitis are subsequently diagnosed with Crohn's disease (CD). Making the diagnosis of CD in patients with IPAA can be difficult, but it is important for prognostic and therapeutic purposes. The aim of this study was to identify diagnostic features of CD in patients with IPAA. Methods: We evaluated 87 patients who had undergone IPAA for inflammatory bowel disease. Patients were classified as having UC (n = 28), CD (n = 27), or indeterminate colitis (n = 32) based on review of the original colectomy pathology and the postoperative clinical course. Each patient underwent a pouch endoscopy with biopsies of the pouch and afferent limb. Both the endoscopist and pathologist were blinded to the patient's diagnosis. Results: Afferent limb ulcers (ALUs) were seen on endoscopy in 12 of 27 patients with CD (45%) and 4 of 28 patients with UC (14%) ( P = 0.019). After excluding patients who had taken nonsteroidal anti-inflammatory drugs (NSAIDs) within the past month, ALUs were found in 7 of 18 patients with CD (39%) and 0 of 17 patients with UC ( P = 0.010). Controlling for NSAID use and smoking, the odds ratio for ALUs indicating CD was 4.67 ( P = 0.03). In the UC population, ALUs were seen in 4 of 11 patients (36%) who had taken NSAIDs in the past month and 0 of 17 patients who had not taken NSAIDs ( P = 0.016). Conclusions: ALUs seen on endoscopy are suggestive of CD in patients with inflammatory bowel disease who are not taking NSAIDs.

Infliximab has been shown to be efficacious for treating perianal fistulae in patients with Crohn's disease. There is limited information regarding response to infliximab in patients with other types of fistulae.Sixty consecutive patients with fistulous Crohn's disease and at least three months of follow-up after three infliximab infusions were evaluated. Patients with enteroenteric fistulae were excluded. Complete response was defined as complete closure of the fistulae or complete cessation of fistula drainage.Thirty-five patients had external fistulae, 16 had internal fistulae, and 9 had mixed (both external and internal) fistulae. Complete response rates were significantly higher in patients with external fistulae (69%) compared to those with internal fistulae (13%); p= 0.001, or those with mixed fistulae (11%); p= 0.01. In the external fistula group, patients with perianal fistulae had a higher rate of complete response (78%) compared to those with abdominal wall fistulae (38%); p= 0.04. The rate of complete response to infliximab was significantly lower among 14 patients with rectovaginal fistulae (14%) compared to those with perianal fistulae (78%); p= 0.0007. In the mixed fistula group only 11% of the patients achieved complete response. This is significantly lower than the rate observed for patients with perianal fistulae (78%); p= 0.004. The Cox proportional hazards model showed that the hazard of relapse for smokers who achieved complete response was nearly twice that of nonsmokers; however, this difference did not reach statistical significance.There is an association between type of fistulae and complete response to infliximab in patients with fistulous Crohn's disease. External fistulae in general and perianal fistulae in particular have a higher rate of closure in response to infliximab compared to other types of fistulae.

Nuclear Factor-kappaB (NF-kappaB) is a major transcription regulator of immune response, apoptosis and cell-growth control genes, and is upregulated in inflammatory bowel disease (IBD), both ulcerative colitis (UC) and Crohn's disease. The NFKB1 gene encodes the NF-kappaB p105/p50 isoforms. Genome-wide screens in IBD families show evidence for linkage on chromosome 4q where NFKB1 maps. We sequenced the NFKB1 promoter, exon 1 and all coding exons in 10 IBD probands and two controls, and identified six nucleotide variants, including a common insertion/deletion promoter polymorphism (-94ins/delATTG). Using pedigree-based transmission disequilibrium tests, we observed modest evidence for linkage disequilibrium (LD), independent of linkage, between the -94delATTG allele and UC in 131 out of 235 IBD pedigrees with UC offspring (P=0.047-0.052). This allele was also more frequent in the 156 non-Jewish UC probands from the 235 IBD pedigrees than in 149 non-Jewish controls (P=0.015). The -94delATTG association with UC was replicated in a second set of 258 unrelated, non-Jewish UC cases and 653 new, non-Jewish controls (P=0.021). Nuclear proteins from normal human colon tissue and colonic cell lines, but not ileal tissue, showed significant binding to -94insATTG but not to -94delATTG containing oligonucleotides. NFKB1 promoter/exon 1 luciferase reporter plasmid constructs containing the -94delATTG allele and transfected into either HeLa or HT-29 cell lines showed less promoter activity than comparable constructs containing the -94insATTG allele. Therefore, we have identified the first potentially functional polymorphism of NFKB1 and demonstrated its genetic association with a common human disease, ulcerative colitis.

OBJECTIVES: Autoantibodies that bind to the perinuclear region of neutrophils have been suggested to represent subclinical markers of genetic susceptibility and indicators of genetic heterogeneity in ulcerative colitis (UC). However, results from more recent studies have contradicted this statement. To address this discrepancy, we assayed perinuclear neutrophil antibodies in the UC-affected members of 53 families with at least one relative pair affected with UC. METHODS: Perinuclear neutrophil antibodies were detected using an indirect immunofluorescence assay. RESULTS: Perinuclear neutrophil antibodies were present in 53% of the study subjects with ulcerative colitis (UC). In 15 families (28%), all members with UC were positive for perinuclear neutrophil antibodies, whereas in 12 families (23%), none of the UC-affected members were positive. In the remaining 26 families (49%), the results for the UC-affected relatives were discordant. Similar results were found when only sibling pairs were evaluated. Statistical analysis revealed that for all affected relative pairings, observed concordance did not significantly exceed expected concordance. Logistic regression analyses demonstrated that the degree of relationship was not enough to predict concordance for perinuclear neutrophil antibodies, and that these antibodies are not markers of genetic heterogeneity. CONCLUSIONS: Perinuclear neutrophil antibodies are not markers for genetic susceptibility or indicators of genetic heterogeneity in UC.

Crohn's disease and ulcerative colitis, the two major forms of idiopathic inflammatory bowel disease (IBD), are heritable, complex traits that appear to share some but not all susceptibility loci. We report that transmission/disequilibrium test analysis of a Crohn's disease genome scan dataset has detected an inflammatory bowel disease locus on chromosome 3p26 (nominal P=0.000052 and genome-wide corrected P=0.039 at D3S1297). An allele sharing method shows significant linkage (multipoint lod=3.69) in a larger, independent sample of inflammatory bowel disease-affected sibling pairs. A survey of 16 chromosome 3p26 short tandem repeat polymorphisms in a combined sample of 234 independent nuclear families with 324 IBD-affected sibling pairs shows significant linkage to chromosome 3p26 (multipoint lod=3.78) and significant transmission/disequilibrium test results at two adjacent markers (nominal P values in two different transmission/disequilibrium analysis methods=0.00011 and 0.0011 for the first marker, and 0.00071 and 0.00013 for the second marker). There is highly significant under-transmission of a common allele and modest over-transmission of other alleles at both markers. Families with no transmission to affected individuals of the under-transmitted alleles show significant linkage (multipoint lod=4.50) that is significantly greater in four simulation studies (P=0.0001, 0.0000625, 0.0000625 and 0.0000625, respectively) than the linkage evidence in families with transmission of the under-transmitted alleles (multipoint lod=0.12). Thus, the existence of an inflammatory bowel disease locus on chromosome 3p26 is supported by significant linkage, transmission/disequilibrium and partitioning of linkage evidence.

OBJECTIVE: Pouchitis often is diagnosed based on symptoms alone. However, increased stool frequency, urgency, and abdominal pain could be due to a condition resembling irritable bowel syndrome. This study was designed to assess the etiology of bowel symptoms using the Pouchitis Disease Activity Index (PDAI). METHODS: Symptoms, endoscopy, and histology were assessed in 61 consecutive symptomatic patients with ulcerative colitis after ileal pouch–anal anastomosis. Pouchitis was defined as a PDAI score of 7, cuffitis was defined as endoscopic and histological inflammation of the rectal cuff and no inflammation of the pouch, and irritable pouch syndrome (IPS) was defined as symptoms with a PDAI of 7 and the absence of cuffitis. RESULTS: Thirty-one patients (50.8%) had pouchitis, four (6.5%) had cuffitis, and 26 (42.6%) had IPS. Demographics were similar in the three groups. Increased stool frequency, urgency, and abdominal cramps were the most common symptoms in the three groups. Rectal bleeding was seen only in cuffitis ( p 0.001). No patient in the three groups had fever. Twenty-seven patients (87.1%) with pouchitis responded to a 2-wk course of ciprofloxacin or metronidazole with a reduction in PDAI scores of 3. All four patients with cuffitis responded to topical hydrocortisone or mesalamine with a reduction in the PDAI symptom component score of 1. Twelve patients with IPS (46.2%) responded to antidiarrheal, anticholinergic, and/or antidepressant therapies with a reduction in the PDAI symptom component score of 1, whereas the remaining patients had persistent symptoms despite therapy. CONCLUSIONS: A substantial number of symptomatic patients after ileal pouch–anal anastomosis do not meet the diagnostic criteria for either pouchitis or cuffitis and have been classified as having IPS. There is an overlap of symptoms among patients with pouchitis, cuffitis, and IPS, and endoscopic evaluation can differentiate among these groups. Distinction between these three groups has therapeutic implications. (Am J Gastroenterol 2002;97:972–977. © 2002 by Am. Coll. of Gastroenterology)

commercial insurance patients. Themean procedure time (+/SE) was borderline significantly longer for Medicare patients under 65y (1.9 +/1.0 minutes; p=0.064)) and for Medicaid/ CICP patients (2.0 +/1.0 minutes; p=0.048). Although a suboptimal bowel prep was associated with a decrease in the overall ADR (OR 0.75; 95% CI: 0.58-0.96), Medicare patients under 65y had a significantly higher ADR (OR 1.48; 95% CI: 1.03-2.11) and a higher AADR (OR 2.02; 95% CI: 1.20-3.40) compared to commercial insurance patients. Medicare patients over 65y, Tricare/VA patients, and Medicaid/CICP patients had similar ADRs and AADRs compared to commercial insurance patients. Conclusions: Medicare patients under 65y and Medicaid/CICP patients are unique groups of patients. The magnitude of the increased odds of having a suboptimal bowel prep was substantial for these two groups. Understanding the reasons for the high rate of a suboptimal bowel prep in these two groups is critical. This may be particularly pertinent for Medicare patients under 65y, who were much more likely to have adenomas and advanced adenomas.

Chronic inflammatory diseases, depending upon the duration and severity, are frequently associated with an increased risk of developing cancer. A classic paradigm is the enhanced risk of colorectal cancer (CRC) in patients with inflammatory bowel disease (IBD). Carcinogenesis is a multifactorial process that involves accumulation of genetic defects, protein modification, and cell-matrix interaction. In this review, we discuss aspects of chronic inflammation in IBD that influence the development of CRC and highlight the key molecular mediators involved in this process. Also, we identify potential targets that could facilitate earlier detection of dysplasia. The targeted manipulation of specific molecules or pathways could provide opportunities for the development of therapeutic and chemopreventive interventions, which may prove effective in arresting the progression of colitis-associated cancer (CAC), with clinical implications.

Metronidazole is effective for the treatment of acute pouchitis after ileal pouch-anal anastomosis, but it has not been directly compared with other antibiotics. This randomized clinical trial was designed to compare the effectiveness and side effects of ciprofloxacin and metronidazole for treating acute pouchitis. Acute pouchitis was defined as a score of 7 or higher on the 18-point Pouchitis Disease Activity Index (PDAI) and symptom duration of 4 weeks or less. Sixteen patients were randomized to a 2-week course of ciprofloxacin 1,000 mg/d (n = 7) or metronidazole 20 mg/kg/d (n = 9). Clinical symptoms, endoscopic findings, and histologic features were assessed before and after therapy. Both ciprofloxacin and metronidazole produced a significant reduction in the total PDAI score as well as in the symptom, endoscopy, and histology subscores. Ciprofloxacin lowered the PDAI score from 10.1+/-2.3 to 3.3+/-1.7 (p = 0.0001), whereas metronidazole reduced the PDAI score from 9.7+/-2.3 to 5.8+/-1.7 (p = 0.0002). There was a significantly greater reduction in the ciprofloxacin group than in the metronidazole group in terms of the total PDAI (6.9+/-1.2 versus 3.8+/-1.7; p = 0.002), symptom score (2.4+/-0.9 versus 1.3+/-0.9; p = 0.03), and endoscopic score (3.6+/-1.3 versus 1.9+/-1.5; p = 0.03). None of patients in the ciprofloxacin group experienced adverse effects, whereas three patients in the metronidazole group (33%) developed vomiting, dysgeusia, or transient peripheral neuropathy. Both ciprofloxacin and metronidazole are effective in treating acute pouchitis with significant reduction of the PDAI scores. Ciprofloxacin produces a greater reduction in the PDAI and a greater improvement in symptom and endoscopy scores, and is better tolerated than metronidazole. Ciprofloxacin should be considered as one of the first-line therapies for acute pouchitis.

Although our existing medical management improves the quality of life of the majority of patients with Crohn’s disease (CD), a substantial proportion of individuals still experience unpleasant symptoms from either the disease or therapy. Many patients ultimately require surgery. In the near future it is highly likely that new drugs will be available that are able to favorably modify the natural history of the disease.

Clinical recurrence of Crohn's disease after surgical resection is a significant problem, with reported rates as high as 55% at 5 yr and 76% at 15 yr. Specific factors that predispose to postoperative recurrence of Crohn's disease have not been well defined. In addition, the underlying pathophysiology of recurrent disease and the reason for its localization to the neoterminal ileum are not well understood. Various operative techniques have been evaluated but none, aside from formation of an ostomy, has been shown to reduce the risk of recurrence. In contrast, there is increasing evidence that postoperative medical therapy has the potential to decrease the risk of postoperative recurrence. Historically, sulfasalazine may have a modest effect on reducing postoperative recurrence of ileal or ileocolonic disease. However, 5-ASA preparations that can selectively deliver mesalamine to the small bowel or anastomotic margin should be more effective. Indeed, in several studies and as confirmed by a meta-analysis, mesalamine has been demonstrated to reduce significantly postoperative recurrence of Crohn's disease. Metronidazole and 6-mercaptopurine or azathioprine also seem to be of benefit in postoperative prophylaxis of disease recurrence, but additional controlled studies are required to define better the efficacy and dose-response of these agents. Corticosteroids are ineffective at reducing postoperative recurrence.

The aim of the study was to define the clinical characteristics and outcome of patients found to have an undetected hepatocellular carcinoma (HCC) at liver transplantation. Patients who underwent liver transplantation and were found to have a hepatoma with a prior workup showing normal alpha-fetoprotein levels and no corresponding lesion on radiological evaluation were defined as having an undetected HCC. Detailed information was collected, and the last abdominal computed tomographic (CT) scan before transplantation was performed was retrospectively reviewed. Thirty-nine patients had a tumor that met the criteria for an undetected hepatoma. The most common causes for pretransplantation liver disease were hepatitis C virus (HCV) (49%) and alcohol use (28%). Tumor size was 2 cm or less in 85% of the patients, vascular invasion was detected in 31% of the patients, and tumor, node, metastasis (TNM) classification was stage I or II in 77% of the patients. Review of the last CT scan before transplantation showed that the lesion was evident in retrospect in only 15% of the patients. Thirty-two patients (82%) remained alive at the time of the study with a mean follow-up of 30 months. Metastatic HCC was detected in 1 patient 7 months after transplantation. There were no other tumor recurrences. Survival analysis showed no significant differences when tumor size, stage, presence of vascular invasion, or causes of pretransplantation liver disease were compared. Undetected HCCs represent a significant percentage of total hepatomas in patients undergoing liver transplantation. Most patients have small, early-stage tumors, but tumors greater than 2 cm or of advanced stage are also frequently found in this population. Overall and tumor-free survival appear to be favorable.