Colectomy with Permanent End Ileostomy Is More Cost-Effective than Ileal Pouch-Anal Anastomosis for Crohn's Colitis.

BACKGROUND: Much of the economic burden of Crohn's disease (CD) is related to surgery. Twenty percent of patients with CD have isolated colonic disease. While permanent end ileostomy (EI) is generally the procedure of choice for patients with refractory CD colitis, single-center experiences suggest that restorative proctocolectomy (IPAA) is durable in select patients. AIMS: We assessed the cost-effectiveness of total colectomy with permanent EI versus IPAA in medically refractory colonic CD. METHODS: We used a lifetime Markov model with 6-month cycles to simulate quality-adjusted life years (QALYs) and cost. In each of the EI and IPAA strategies, patients could transition between multiple health states. One-way and multivariable sensitivity analysis and tornado analysis were performed to identify thresholds for factors influencing cost-effectiveness. RESULTS: IPAA was more effective than EI surgery with an incremental cost-effectiveness ratio of $70,715 per QALY gained. We identified the following variables of importance in our model: (1) the cost of the EI surgery, (2) the cost of infliximab, and (3) the cost of gastroenterology ambulatory visit and labs. Threshold analysis revealed that if the costs associated with EI surgery exceeded $20,167 or if the utility of IPAA with CD remission without medical therapy exceeded 0.37, IPAA became the more cost-effective strategy. CONCLUSIONS: In patients with medically refractory CD isolated to the colon, colectomy with permanent EI is more cost-effective than IPAA unless the costs associated with the EI surgery exceed $20,167 or if the utility associated with IPAA and CD remission exceeds 0.37.

Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis.

We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we identified strong and significantly replicated associations (combined P < 10(-10)) with an intergenic region on 10q21.1 and a coding variant in ATG16L1, the latter of which was also recently reported by another group. We also report strong associations with independent replication to variation in the genomic regions encoding PHOX2B, NCF4 and a predicted gene on 16q24.1 (FAM92B). Finally, we demonstrate that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.

The impact of preoperative serum anti-TNFα therapy levels on early postoperative outcomes in inflammatory bowel disease surgery.

OBJECTIVE: Assess the impact of preoperative serum antitumor necrosis factor-α (anti-TNFα) drug levels on 30-day postoperative morbidity in inflammatory bowel disease (IBD) patients. BACKGROUND: Studies on the association of anti-TNFα drugs and postoperative outcomes in IBD are conflicting due to variable pharmacokinetics of anti-TNFα drugs. It remains to be seen whether preoperative serum anti-TNFα drug levels correlate with postoperative morbidity. METHODS: Thirty-day postoperative outcomes of consecutive IBD surgical patients with serum drawn within 7 days preoperatively were studied. The total serum level of 3 anti-TNFα drugs (infliximab, adalimumab, and certolizumab) was measured, with ≥ 0.98 µg/mL considered as detected. Data were also reviewed according to a clinical cutoff value of 3 µg/mL. RESULTS: A total of 217 patients [123 with Crohn disease (CD) and 94 with ulcerative colitis (UC)] were analyzed; 75 of 150 (50%) treated with anti-TNFα therapy did not have detected levels at the time of surgery. In the UC cohort, adverse postoperative outcome rates between the undetectable and detectable groups were similar when stratified according to type of UC surgery. In the CD cohort, there was a higher but statistically insignificant rate of adverse outcomes in the detectable versus undetectable groups. Using a cut off level of 3 µg/mL, postoperative morbidity (odds ratio [OR] = 2.5, P = 0.03) and infectious complications (OR = 3.0, P = 0.03) were significantly higher in the ≥ 3 µg/mL group. There were higher rates of postoperative morbidity (P = 0.047) and hospital readmissions (P = 0.04) in the ≥ 8 µg/mL compared with <3 µg/mL group. CONCLUSIONS: Increasing preoperative serum anti-TNFα drug levels are associated with adverse postoperative outcomes in CD but not UC patients.

Antibiotics for Treatment of Clostridium difficile Infection in Hospitalized Patients with Inflammatory Bowel Disease.

Patients with inflammatory bowel disease (IBD), namely ulcerative colitis (UC) and Crohn's disease (CD), have worse outcomes with Clostridium difficile infection (CDI), including increased readmissions, colectomy, and death. Oral vancomycin is recommended for the treatment of severe CDI, while metronidazole is the standard of care for nonsevere infection. We aimed to assess treatment outcomes of CDI in IBD. We conducted a retrospective observational study of inpatients with CDI and IBD from January 2006 through December 2010. CDI severity was assessed using published criteria. Outcomes included readmission for CDI within 30 days and 12 weeks, length of stay, colectomy, and death. A total of 114 patients met inclusion criteria (UC, 62; CD, 52). Thirty-day readmissions were more common among UC than CD patients (24.2% versus 9.6%; P=0.04). Same-admission colectomy occurred in 27.4% of UC patients and 0% of CD patients (P<0.01). Severe CDI was more common among UC than CD patients (32.2% versus 19.4%; P=0.12) but not statistically significant. Two patients died from CDI-associated complications (UC, 1; CD, 1). Patients with UC and nonsevere CDI had fewer readmissions and shorter lengths of stay when treated with a vancomycin-containing regimen compared to those treated with metronidazole (30-day readmissions, 31.0% versus 0% [P=0.04]; length of stay, 13.62 days versus 6.38 days [P=0.02]). Patients with UC and nonsevere CDI have fewer readmissions and shorter lengths of stay when treated with a vancomycin-containing regimen relative to those treated with metronidazole alone. Patients with ulcerative colitis and CDI should be treated with vancomycin.

Assessing health status in inflammatory bowel disease using a novel single-item numeric rating scale.

BACKGROUND: Current instruments used to measure disease activity and health-related quality of life in patients with Crohn's disease (CD) and ulcerative colitis (UC) are often cumbersome, time-consuming, and expensive; although used in clinical trials, they are not convenient for clinical practice. A numeric rating scale (NRS) is a quick, inexpensive, and convenient patient-reported outcome that can capture the patient's overall perception of health. AIMS: The aim of this study was to assess the validity, reliability, and responsiveness of an NRS and evaluate its use in clinical practice in patients with CD and UC. METHODS: We prospectively evaluated patient-reported NRS scores and measured correlations between NRS and a range of severity measures, including physician-reported NRS, Crohn's disease activity index (CDAI), Harvey-Bradshaw index (HBI), inflammatory bowel disease questionnaire (IBDQ), and C-reactive protein (CRP) in patients with CD. Subsequently, we evaluated the correlation between the NRS and standard measures of health status (HBI or simple colitis clinical activity index [SCCAI]) and laboratory tests (sedimentation rate [ESR], CRP, and fecal calprotectin) in patients with CD and UC. RESULTS: The patient-reported NRS showed excellent correlation with CDAI (R (2) = 0.59, p < 0.0001), IBDQ (R (2) = 0.66, p < 0.0001), and HBI (R (2) = 0.32, p < 0.0001) in patients with CD. The NRS showed poor, but statistically significant correlation with SCCAI (R (2) = 0.25, p < 0.0001) in patients with UC. The NRS did not correlate with CRP, ESR, or calprotectin. The NRS was reliable and responsive to change. CONCLUSIONS: The NRS is a valid, reliable, and responsive measure that may be useful to evaluate patients with CD and possibly UC.

Does preoperative immunosuppression influence unplanned hospital readmission after surgery in patients with Crohn's disease?

BACKGROUND: Steroids, immunomodulators, and biologics, often in combination with one another, are frequently used in the treatment of Crohn's disease. Retrospective studies have yielded conflicting results regarding the influence of preoperative immunosuppressive therapy on postoperative complications after surgery in Crohn's disease. Unplanned hospital readmission is considered to be an index of quality surgical care. OBJECTIVE: The aim of this study was to examine the association, if any, between the number of preoperative immunosuppressive therapies and unplanned hospital readmission after surgery in patients with Crohn's disease. DESIGN: Consecutive patients with Crohn's disease requiring abdominal surgery were identified from a prospectively maintained database. Preoperative immunosuppressive therapy within 3 months before surgery was categorized into 3 classes: steroids, immunomodulators, and biologics. MAIN OUTCOME MEASURES: Unplanned readmission occurring within 30 days of hospital discharge was assessed. Trend analysis was performed with the use of the Cochrane-Armitage test. RESULTS: The study group included 338 patients. Preoperative medical therapy included steroids (n = 199; 59%), immunomodulators (n = 162; 48%), and biologics (n = 59; 18%). Sixty-three patients (19%) were not treated with any immunosuppressive medications preoperatively, whereas 148 patients (44%), 108 patients (32%), and 19 patients (6%) were treated with 1, 2, or 3 classes of immunosuppressive medications. Twenty-eight patients (8.3%) had an unplanned readmission. The incidence of unplanned readmission was similar among patients treated with steroids (11%), immunomodulators (9%), and biologics (12%). The incidence of unplanned readmission was 3%, 7%, 11%, and 16% in patients treated with 0, 1, 2, or 3 preoperative medication classes (trend analysis p = 0.02). No significant differences were observed between patient groups treated with 0, 1, 2, or 3 preoperative immunosuppressive therapies with respect to patient, disease, or surgical factors. CONCLUSIONS: Unplanned hospital readmission occurs frequently (8.3%) after surgery for Crohn's disease. Combination immunosuppressive therapy before surgery in patients with Crohn's disease appears to be associated with an increased incidence of postoperative unplanned hospital readmission.

Variants in ZNF365 isoform D are associated with Crohn's disease.

OBJECTIVE: Genome-wide association studies have identified multiple Crohn's disease (CD) susceptibility loci, including association with non-coding intergenic single-nucleotide polymorphisms (SNPs) at 10q21. DESIGN: To fine-map the 10q21 locus, the authors genotyped 86 SNPs in 1632 CD cases and 961 controls and performed single-marker and conditional analyses using logistic regression. RESULTS: Association with CD risk spanning 11 SNPs (p<0.001) was observed. The most significant association observed was at the non-synonymous SNP, rs7076156 (Ala62Thr), in ZNF365. The alanine allele was over-represented in CD (p=5.23×10⁻7; OR=1.39 (95% CI 1.22 to 1.58)); allele frequency of 76% in CD and 69.7% in controls). Conditional analysis on rs7076156 nullified all other significant associations, suggesting that this is the causative variant at this locus. Four isoforms of ZNF365 have previously been identified, and rs7076156 is located in an exon unique to ZNF365 isoform D. The authors demonstrated, using reverse transcription-PCR, expression of ZNF365D in intestinal resections from both CD subjects and controls. Markedly reduced mean expression levels of ZNF365D were identified in Epstein-Barr virus-transformed lymphoblastoid cell lines from CD subjects homozygous for the risk allele (Ala). A whole-genome microarray expression study further suggested that the Ala62Thr change in ZNF365 isoform D is related to differential expression of the genes ARL4A, MKKS, RRAGD, SUMF2, TDR1 and ZNF148 in CD. CONCLUSIONS: Collectively, these data support the hypothesis that the non-synonymous Ala62Thr SNP, rs7076156, underlies the association between 10q21 and CD risk and suggest that this SNP acts by altering expression of genes under the control of ZNF365 isoform D.

Crohn's disease in endoscopic remission, obesity, and cases of high genetic risk demonstrates overlapping shifts in the colonic mucosal-luminal interface microbiome.

BACKGROUND: Crohn's disease (CD) patients demonstrate distinct intestinal microbial compositions and metabolic characteristics compared to unaffected controls. However, the impact of inflammation and underlying genetic risk on these microbial profiles and their relationship to disease phenotype are unclear. We used lavage sampling to characterize the colonic mucosal-luminal interface (MLI) microbiome of CD patients in endoscopic remission and unaffected controls relative to obesity, disease genetics, and phenotype. METHODS: Cecum and sigmoid colon were sampled from 110 non-CD controls undergoing screening colonoscopy who were stratified by body mass index and 88 CD patients in endoscopic remission (396 total samples). CD polygenic risk score (GRS) was calculated using 186 known CD variants. MLI pellets were analyzed by 16S ribosomal RNA gene sequencing, and supernatants by untargeted liquid chromatography-mass spectrometry. RESULTS: CD and obesity were each associated with decreased cecal and sigmoid MLI bacterial diversity and distinct bacterial composition compared to controls, including expansion of Escherichia/Shigella. Cecal and sigmoid dysbiosis indices for CD were significantly greater in obese controls than non-overweight controls. CD, but not obesity, was characterized by altered biogeographic relationship between the sigmoid and cecum. GRS was associated with select taxonomic shifts that overlapped with changes seen in CD compared to controls including Fusobacterium enrichment. Stricturing or penetrating Crohn's disease behavior was characterized by lower MLI bacterial diversity and altered composition, including reduced Faecalibacterium, compared to uncomplicated CD. Taxonomic profiles including reduced Parasutterella were associated with clinical disease progression over a mean follow-up of 3.7 years. Random forest classifiers using MLI bacterial abundances could distinguish disease state (area under the curve (AUC) 0.93), stricturing or penetrating Crohn's disease behavior (AUC 0.82), and future clinical disease progression (AUC 0.74). CD patients showed alterations in the MLI metabolome including increased cholate:deoxycholate ratio compared to controls. CONCLUSIONS: Obesity, CD in endoscopic remission, and high CD genetic risk have overlapping colonic mucosal-luminal interface (MLI) microbiome features, suggesting a shared microbiome contribution to CD and obesity which may be influenced by genetic factors. Microbial profiling during endoscopic remission predicted Crohn's disease behavior and progression, supporting that MLI sampling could offer unique insight into CD pathogenesis and provide novel prognostic biomarkers.

Double-Balloon Endoscopy in Crohn Disease: A Tertiary Referral Center Experience.

BACKGROUND: Crohn disease (CD) affects the small bowel in 80% of patients. Double balloon endoscopy (DBE) provides the potential for direct and extensive mucosal visualization with the potential for diagnostic monitoring and therapeutic intervention. This study aimed to investigate the safety and effectiveness of DBE in small-bowel CD. METHODS: From our DBE database, patients with CD at the time of index DBE (January 2004-January 2013) were identified. Data collection included demographics, CD phenotype (age at diagnosis, disease location, disease activity), procedural information, adverse events (perforation, pancreatitis, death), therapeutic intervention (stricture dilation), and outcome (escalation or maintenance of existing therapy, referral to surgery). RESULTS: A total of 184 DBEs were performed in patients with inflammatory bowel disease over 162 endoscopic sessions. In this cohort, 115 patients had previously diagnosed CD. A diagnosis of CD was made in 22 patients. Of those with known CD, 140 DBEs were performed in 82 patients; DBE findings led to escalation of medical therapy in 26% of patients, maintenance of therapy in 26% of patients, and surgery in 18% of patients. We considered DBE to have failed in 11% (n = 18) of patients. During 46 endoscopic sessions, in 29 patients, 103 strictures were dilated via balloon dilation. Of patients undergoing dilation with clinical follow-up, 19 of 24 (79%) patients were surgery-free during the study period. Overall, there were 2 perforations. CONCLUSIONS: We found that DBE is a safe and effective procedure in patients with suspected or established CD. Furthermore, patients undergoing dilation of strictures via DBE had an 80% surgery-free rate within the follow-up period.

Immunosuppression impairs response to pneumococcal polysaccharide vaccination in patients with inflammatory bowel disease.

OBJECTIVES: The treatment of inflammatory bowel disease (IBD) often includes immunosuppressive medications, which may increase the risk of vaccine-preventable illnesses. We aimed to assess the impact of immunosuppression on immune responses to pneumococcal vaccination in patients with IBD. METHODS: The study design consists of a prospective controlled clinical trial. This study was carried out at a tertiary-care IBD clinic. The subjects for the study belonged to one of the following three groups: adult patients with IBD on combination TNF-blockers and immunomodulators (Group A), those without immunosuppressive therapy (Group B), and age-matched healthy controls (Group C). The treatment consisted of immunization with 23-valent pneumococcal polysaccharide vaccines (PSVs). The main outcome was immune response for five serotypes defined as a twofold or greater increase from pre-vaccination titers and > or =1 microg post-vaccination titer. RESULTS: Sixty-four subjects participated in the study: 20 in Group A, 25 in Group B, and 19 in Group C. Pre-vaccination titers were similar among the three groups. Vaccine responses were lower in Group A than in Group B (P< or =0.01 for four out of five antigens) and Group C (P<0.01 for all five antigens). Overall vaccine response was seen in 45, 80, and 85% of Groups A, B, and C (P=0.01), respectively. CONCLUSIONS: Immune response to PSV-23 is impaired in Crohn's disease (CD) patients on combination immunosuppressive therapy but is normal among non-immunosuppressed patients. Given the unpredictable likelihood for immunosuppressive therapy, newly diagnosed patients with IBD should undergo vaccination before the initiation of immunosuppressive therapy.

Capsule endoscopy in patients with Crohn's disease: diagnostic yield and safety.

BACKGROUND: Capsule endoscopy (CE) is increasingly used in patients with suspected or known Crohn's disease (CD). OBJECTIVE: To determine the diagnostic yield of CE and the distribution of small-bowel (SB) lesions in symptomatic patients with known CD. DESIGN AND SETTING: Retrospective review of CE procedures performed in patients with CD between 2001 and 2005 in a tertiary care center. PATIENTS: One hundred thirty-four patients with an established diagnosis of CD and symptoms suggestive of active disease. INTERVENTIONS: Swallowing the capsule. MAIN OUTCOME MEASUREMENTS: Diagnostic yield of CE and distribution of SB lesions in patients with CD. RESULTS: One hundred forty-six CE procedures were performed on 134 CD patients. Fifty-two (39%) of 134 patients had CE findings diagnostic of active CD (> 3 ulcerations), and 17 (13%) had findings suggestive of active CD (< or = 3 ulcerations). Fifty-seven (42%) patients had normal findings, and 6% had normal but incomplete studies. The distribution of SB lesions was 32% in the duodenum, 53% in the jejunum, 67% in the proximal ileum, and 85% in the distal ileum. CE was comparable to ileoscopy in detecting ileal ulcerations (55% vs 48%), but superior to SB follow-through in detecting CD lesions in the SB (incremental yield of 32%; 95% CI, 9%-54%; P = .0017). LIMITATIONS: Retrospective study from a single center. CONCLUSIONS: CE identified SB lesions in approximately half of symptomatic CD patients. Large-scale prospective studies are needed to evaluate whether positive CE findings may affect disease outcomes.

New clinical method for distinguishing D-IBS from other gastrointestinal conditions causing diarrhea: the LA/IBS diagnostic strategy.

Modern methods of diagnosing diarrhea-predominant irritable bowel syndrome (D-IBS) require a "diagnosis of exclusion" approach. In this study we aim to test the diagnostic ability of using the fluctuation of frequency and consistency of bowel patterns in IBS to discriminate it from other causes of diarrhea. Eligible subjects were asked to complete a questionnaire on the changes in form and frequency of bowel habits by time. The primary endpoint was to evaluate the diagnostic effectiveness of having irregularly irregular bowel function and form as more characteristic of IBS versus non-IBS causes. Patients were prospectively recruited from a tertiary care GI clinic. Subjects had to have diarrhea as their primary complaint. In the case of IBS, D-IBS subjects were recruited. Subjects with celiac disease, Crohn's and ulcerative colitis were recruited for comparison and were categorically called "non-IBS." Non-IBS subjects could not have a recent history of blood in stool or a history of bowel surgery, fistulae or narcotic use. Sixty-two IBS and 37 non-IBS subjects were recruited. Among the 62 IBS subjects, 49 (79%) stated that their bowel habits varied in form and frequency on a daily basis compared to 35% in non-IBS subjects (OR = 8.9, CI = 3.5-22.5, P < 0.00001). When subjects were compared by the number of different stool forms they had witnessed in the prior week, IBS subjects noted 3.58 +/- 0.19 types and non-IBS reported 2.35 +/- 0.16 (P < 0.00001). Using > or = 3 stool forms per week as a method of discriminating IBS from non-IBS, 50 out of 62 subjects with IBS (81%) reported this greater number of forms compared to 15 out of 37 (41%) non-IBS subjects (sensitivity = 0.81; specificity = 0.60). The use of this simple tool that identifies an irregularly irregular bowel form and function is successful in separating D-IBS from non-IBS subjects.

A prospective evaluation of the long-term outcome of ileal pouch-anal anastomosis in patients with inflammatory bowel disease-unclassified and indeterminate colitis.

PURPOSE: The long-term outcome of ileal pouch-anal anastomosis in patients with indeterminate colitis is controversial. The aim of this study was to prospectively evaluate the long-term outcome of ileal pouch-anal anastomosis in a closely monitored cohort of patients with ulcerative colitis or indeterminate colitis. METHODS: Prospectively generated clinical profiles on consecutive patients with ulcerative colitis or indeterminate colitis undergoing ileal pouch-anal anastomosis with close postoperative follow-up by one surgeon were reviewed. All patients were classified before surgery as either ulcerative colitis or inflammatory bowel disease-unclassified, and after surgery as either ulcerative colitis or indeterminate colitis. Long-term outcomes included acute pouchitis (antibiotic responsive), chronic pouchitis (antibiotic dependent or refractory), or de novo Crohn's disease (small inflammation above the pouch inlet or pouch fistula). RESULTS: The study cohort of 334 patients were classified before surgery as ulcerative colitis in 237 (71 percent) and inflammatory bowel disease-unclassified in 97 (29 percent). After surgery, patients were classified as ulcerative colitis in 236 (71 percent) and indeterminate colitis in 98 (29 percent). After a median follow-up after stoma closure of 26 months, 53 patients (16 percent) developed acute pouchitis, 37 patients (11 percent) developed chronic pouchitis, and 40 patients (12 percent) developed de novo Crohn's disease. There was no significant difference in the incidence of acute pouchitis, chronic pouchitis, or de novo Crohn's disease between the ulcerative colitis, inflammatory bowel disease-unclassified, and indeterminate colitis patient groups. CONCLUSION: The incidence of acute pouchitis, chronic pouchitis, and de novo Crohn's disease after ileal pouch-anal anastomosis do not differ significantly between patients with ulcerative colitis, inflammatory bowel disease-unclassified, or indeterminate colitis. Patients with inflammatory bowel disease-unclassified and indeterminate colitis can undergo ileal pouch-anal anastomosis and expect a long-term outcome equivalent to patients with ulcerative colitis.

Both preoperative perinuclear antineutrophil cytoplasmic antibody and anti-CBir1 expression in ulcerative colitis patients influence pouchitis development after ileal pouch-anal anastomosis.

BACKGROUND & AIMS: Acute pouchitis (AP) and chronic pouchitis (CP) are common after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis. The aim of this study was to assess associations of preoperative perinuclear antineutrophil cytoplasmic antibody (pANCA) and anti-CBir1 flagellin on AP or CP development. METHODS: Patients were assessed prospectively for clinically and endoscopically proven AP (antibiotic responsive) or CP (antibiotic-dependent or refractory to antibiotic therapy). Sera from 238 patients were analyzed for ANCA and anti-CBir1 using an enzyme-linked immunosorbent assay. pANCA(+) patients were substratified into high-level (>100 EU/mL) and low-level (<100 EU/mL) groups. RESULTS: After a median follow-up period of 47 months, 72 patients (30%) developed pouchitis. Pouchitis developed in 36% of pANCA(+) patients versus 16% of pANCA(-) patients (P = .005), 46% of anti-CBir1(+) patients versus 26% of anti-CBir1(-) patients (P = .02), and 54% of 35 pANCA(+)/anti-CBir1(+) patients versus 31% of 136 pANCA(+)/anti-CBir1(-) patients (P = .02). AP developed in 37 pANCA(+) patients (22%) versus 6 pANCA(-) patients (9%) (P = .02), and 12 anti-CBir1(+) patients (26%) versus 31 anti-CBir1(-) patients (16%) (P = .1). Although AP was not influenced by pANCA level, AP was seen in 38% of low-level pANCA(+)/anti-CBir1(+) patients versus 18% low-level pANCA(+)/anti-CBir1(-) patients (P = .03). CP was seen in 29% of high-level pANCA(+) patients versus 11% of low-level pANCA(+) patients (P = .03). CONCLUSIONS: Both pANCA and anti-CBir1 expression are associated with pouchitis after IPAA. Anti-CBir1 increases the incidence of AP only in patients who have low-level pANCA expression, and increases the incidence of CP only in patients who have high-level pANCA expression. Diverse patterns of reactivity to microbial antigens may manifest as different forms of pouchitis after IPAA.

A prospective multivariate analysis of clinical factors associated with pouchitis after ileal pouch-anal anastomosis.

BACKGROUND & AIMS: Although acute pouchitis (AP) after ileal pouch-anal anastomosis (IPAA) for UC is common and easily treated, chronic pouchitis (CP) remains a difficult management issue. The aim of this study was to identify important clinical risk factors associated with AP or CP. METHODS: AP and CP were prospectively assessed, and demographic, disease, and treatment characteristics were tabulated. Univariate and multivariate analyses were performed to evaluate associations between AP or CP and potential risk factors. RESULTS: Two hundred IPAA patients were followed for a median of 24 months (range, 3-117 months). Thirty-six patients (18%) developed AP, and 23 patients (12%) developed CP. On univariate analysis, the use of steroids before colectomy and smoking were associated with the development of AP. CP was associated with male gender, smoking, length of follow-up, extraintestinal manifestations, backwash ileitis, and elevated (450x10(9)/L) platelet count. On multivariate analysis, the following risk factors were found to be independently associated with AP: use of steroids before colectomy (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.5-8.9; P = .004) and smoking (OR, 2.3; 95% CI, 1.1-5.3; P = .04). CP was directly associated with extraintestinal manifestations (OR, 3.5; 95% CI, 1.1-11.1; P = .03), elevated platelet count (OR, 3.1; 95% CI, 1.1-8.9; P = .03), and increased length of follow-up (OR, 1.3; 95% CI, 1.1-1.6; P = .002). Smoking reduced the incidence of CP (OR, 0.2; 95% CI, 0.05-0.74; P = .04). CONCLUSIONS: Clinical factors associated with AP included use of steroids before colectomy and smoking. Factors directly related to CP were extraintestinal manifestations, elevated platelet count, and length of follow-up after IPAA. Smoking appears to protect against the development of CP.

Predicting a change in diagnosis from ulcerative colitis to Crohn's disease: a nested, case-control study.

BACKGROUND & AIMS: Some patients diagnosed with UC undergo a change in diagnosis to CD. Identification of predictors of a diagnostic change could potentially impact the management of patients with colonic inflammation. Our aim was to characterize clinical and serologic predictors of a change in diagnosis from UC to CD. METHODS: A nested, case-controlled study was performed to compare individuals with a change in diagnosis from UC to CD (cases) with age-matched UC and CD controls; primary analysis compared cases with UC controls. Subjects underwent chart review for clinical "red flags" identified by gastroenterologists with expertise in IBD. Serum collected at the time of database enrollment was tested for antibodies to oligomannan (anti-Saccharomyces cerevisiae), Pseudomonas fluorescens-related protein, Escherichia coli outer membrane porin C, CBir1 flagellin, and perinuclear antineutrophil cytoplasmic antibodies. RESULTS: Twenty-one cases, 52 UC controls, and 56 CD controls were assessed. Three red flags, but no serologic markers, differed between cases and UC controls. At initial colonoscopy, cases were more likely to have extensive colonic involvement than UC controls (P = .008). Multivariate regression identified non-bloody diarrhea at initial presentation (P = .01) and weight loss >10% at presentation (P = .007) as independent predictors of diagnostic change. Serologic markers did not add to the contribution of these 2 clinical factors in predicting a change in diagnosis from UC to CD. Diagnostic change was evident in 6 of 6 (100%) patients with both predictors, compared with 8 of 50 (16%) with neither of these factors (P < .0001). CONCLUSIONS: Patients with a diagnosis of UC with initial non-bloody diarrhea or weight loss have an increased likelihood of subsequent change in diagnosis to CD and might thus warrant further diagnostic work-up.

Anti-flagellin (CBir1) phenotypic and genetic Crohn's disease associations.

BACKGROUND: Antibody reactivity to microbial antigens correlates with distinct Crohn's disease (CD) phenotypes such as fistulizing or fibrostenosing disease. We examined the association between anti-CBir1 and clinical phenotypes and NOD2 variants in a large cohort of adult CD patients. METHODS: Sera and genomic DNA were collected from 731 patients with CD and tested for immune responses to I2, CBir1, oligomannan, and outer membrane porin C (OmpC) and the 3 most common CD-associated NOD2 variants. RESULTS: Anti-CBir1 reactivity was significantly associated with fibrostenosis (FS), internal penetrating (IP) disease phenotypes, small bowel (SB) involvement, and SB surgery but negatively associated with ulcerative colitis (UC)-like CD. Multivariate logistic regression analysis showed that anti-CBir1 was independently associated with FS and UC-like CD irrespective of the antibody reactivity to I2, oligomannan, or OmpC, but not with SB involvement or SB surgery. The magnitude of anti-CBir1 reactivity, when added to the quantitative response toward the other 3 CD-associated antigens, enhances the discrimination of FS, IP, UC-like CD, and SB involvement, but not SB surgery. Finally, although the frequency of anti-CBir1 was similar in patients with none versus at least 1 NOD2 variant, the quantitative response to CBir1 flagellin was significantly higher in patients with CD carrying at least 1 NOD2 variant versus those carrying no variants (median anti-CBir1 titer 33.39 versus 28.36, respectively; P = 0.01). CONCLUSIONS: Anti-CBir1 serum reactivity in CD patients is independently associated with FS and complicated SB CD. Quantitative, but not qualitative, response to CBir1 is also significantly associated with the CD-associated NOD2 variants.

Outcomes with Anti-Tumour Necrosis Factor-Alpha Therapy and Serology in Patients with Denovo Crohn's Disease After Ileal Pouch Anal Anastomosis.

BACKGROUND AND AIMS: A subset of patients who undergo ileal pouch-anal anastomosis [IPAA] for ulcerative colitis [UC] will later be diagnosed with denovo Crohn's disease [CD]. These patients have a higher risk of pouch failure. In this study we evaluated inflammatory bowel disease [IBD] serology in patients with denovo CD and examined the success of anti-tumour necrosis factor-alpha [anti-TNFα] therapy in preventing ileostomy in denovo CD patients who failed anti-TNFα therapy before IPAA. METHODS: A prospectively maintained database of patients undergoing IPAA was reviewed to identify patients who developed denovo CD [defined as small bowel inflammation above the pouch inlet or pouch fistula/perianal disease appearing more than 3 months after stoma closure]. Clinical characteristics and IBD serology were analysed. Treatment failure was defined as pouch failure requiring ileostomy or pouchectomy. RESULTS: Of 350 patients included in the study, 92 [26%] patients developed denovo CD. Significantly more denovo CD patients had anti-I2 positivity postoperatively versus preoperatively [p = 0.007]. Anti-TNFα therapy successfully treated denovo CD in 28 out of 38 [74%] patients. Out of 17 patients with denovo CD who had failed to respond to anti-TNFα agents before surgery and were treated with anti-TNFα therapy after surgery, 12 [71%] patients responded to treatment. CONCLUSIONS: I2 serology may possibly help identify patients who have developed or are at risk for developing denovo CD. Anti-TNFα therapy for denovo CD after IPAA can help prevent permanent ileostomy in almost 75% of cases, even in patients who previously failed anti-TNFα treatment before surgery.

Colonic Phenotypes Are Associated with Poorer Response to Anti-TNF Therapies in Patients with IBD.

BACKGROUND: Although anti-tumor necrosis factor (TNF) agents are effective in patients with inflammatory bowel disease (IBD), many patients either do not respond to anti-TNF treatment or lose response over time. The aim of this study was to determine factors associated with response to anti-TNF therapy in IBD. METHODS: Patients with Crohn's disease (CD) or ulcerative colitis who had consented to participate in a genetics registry and been treated with anti-TNF agents were evaluated retrospectively and categorized as primary nonresponders or secondary nonresponders. We evaluated clinical, serological, and genetic characteristics associated with primary nonresponse or time to loss of response to anti-TNF agents. RESULTS: We included 314 CD (51 [16.2%] primary nonresponders and 179 [57.0%] secondary nonresponders) and 145 subjects with ulcerative colitis (43 [29.7%] primary nonresponders and 74 [51.0%] secondary nonresponders). Colonic involvement (P = 0.017; odds ratio = 8.0) and anti-TNF monotherapy (P = 0.017; odds ratio = 4.9) were associated in a multivariate analysis with primary nonresponse to anti-TNF agents in CD. In addition, higher anti-nuclear cytoplasmic antibody levels (P = 0.019; hazard ratio = 1.01) in CD, anti-nuclear cytoplasmic antibody positivity (P = 0.038; hazard ratio = 1.6) in ulcerative colitis, and a positive family history of IBD (P = 0.044; hazard ratio = 1.3) in all patients with IBD were associated with time to loss of response to anti-TNF agents. Furthermore, various known IBD susceptibility single-nucleotide polymorphisms and additional variants in immune-mediated genes were shown to be associated with primary nonresponse or time to loss of response. CONCLUSIONS: Our results may help to optimize the use of anti-TNF agents in clinical practice and position these therapies appropriately as clinicians strive for a more personalized approach to managing IBD.

Antibodies to I2 predict clinical response to fecal diversion in Crohn's disease.

OBJECTIVES: Fecal diversion is occasionally indicated in patients with advanced perianal or colorectal Crohn's disease (CD). Because CD may result from an aberrant immunologic response to bacteria within the gut lumen, fecal diversion should be effective in managing these complications. However, not all patients achieve a clinical response after fecal diversion. CD patients can be characterized by their antibody responses against Pseudomonas fluorescens (I2), E.coli outer membrane porin C (OmpC), oligomannan (anti-Saccharomyces cerevisiae antibodies [ASCA]), and antinuclear antigens (perinuclear antineutrophil cytoplasmic antibodies [pANCA]). This study examines the association between clinical features and seroreactivity to these microbial and auto-antigens in predicting a clinical response to fecal diversion. METHODS: Twenty-seven consecutive CD patients undergoing fecal diversion were included. Sera were drawn and tested for anti-I2, anti-OmpC, ASCA, and pANCA in a blinded fashion. Response was assessed using clinical parameters. RESULTS: Seventeen (63%) patients underwent fecal diversion for medically resistant proctocolitis and 10 (37%) for severe perianal disease. Median follow-up was 41 months. Seventeen (63%) patients achieved a clinical response. No preoperative clinical or surgical factor predicted response to diversion. Clinical response after fecal diversion was seen in 15 of 16 (94%) patients who were I2 positive compared with only 2 of 11 (18%) patients who were I2 negative (P = 0.0001). Seroreactivity to OmpC, ASCA, or pANCA was not associated with a clinical response to diversion. CONCLUSION: Expression of I2 antibodies against a bacterial antigen of Pseudomonas fluorescens was highly associated with clinical response to fecal diversion in CD patients.