Comprehensive Association Analyses of Extraintestinal Manifestations in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) frequently develop extraintestinal manifestations (EIMs) that contribute substantially to morbidity. We assembled the largest multicohort data set to date to investigate the clinical, serologic, and genetic factors associated with EIM complications in IBD. METHODS: Data were available in 12,083 unrelated European ancestry IBD cases with presence or absence of EIMs (eg, ankylosing spondylitis [ankylosing spondylitis and sacroiliitis], primary sclerosing cholangitis [PSC], peripheral arthritis, and skin and ocular manifestations) across 4 cohorts (Cedars-Sinai Medical Center, National Institute for Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium, Sinai Helmsley Alliance for Research Excellence Consortium, and Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease cohort). Clinical and serologic parameters were analyzed by means of univariable and multivariable regression analyses using a mixed-effects model. Within-case logistic regression was performed to assess genetic associations. RESULTS: Most EIMs occurred more commonly in female subjects (overall EIM: P = 9.0E-05, odds ratio [OR], 1.2; 95% CI, 1.1-1.4), with CD (especially colonic disease location; P = 9.8E-09, OR, 1.7; 95% CI, 1.4-2.0), and in subjects who required surgery (both CD and UC; P = 3.6E-19, OR, 1.7; 95% CI, 1.5-1.9). Smoking increased risk of EIMs except for PSC, where there was a "protective" effect. Multiple serologic associations were observed, including with PSC (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-flagellin) and any EIM (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-Pseudomonas fluorescens-associated sequence). We identified genome-wide significant associations within major histocompatibility complex (ankylosing spondylitis and sacroiliitis, P = 1.4E-15; OR, 2.5; 95% CI, 2.0-3.1; PSC, P = 2.7E-10; OR, 2.8; 95% CI, 2.0-3.8; ocular, P = 2E-08, OR, 3.6; 95% CI, 2.3-5.6; and overall EIM, P = 8.4E-09; OR, 2.2; 95% CI, 1.7-2.9) and CPEB4 (skin, P = 2.7E-08; OR, 1.5; 95% CI, 1.3-1.8). Genetic associations implicated tumor necrosis factor, JAK-STAT, and IL6 as potential targets for EIMs. Contrary to previous reports, only 2% of our subjects had multiple EIMs and most co-occurrences were negatively correlated. CONCLUSIONS: We have identified demographic, clinical, and genetic associations with EIMs that revealed underlying mechanisms and implicated novel and existing drug targets-important steps toward a more personalized approach to IBD management.

Comparative Persistence of Non-tumor Necrosis Factor (TNF) vs. TNF Antagonists for Post-operative Prophylaxis in Crohn's Disease (CD).

BACKGROUND: The comparative safety and effectiveness of available biologics for post-operative prophylaxis in Crohn's disease (CD) is uncertain. Drug persistence may serve as a real-world proxy for tolerability and effectiveness. We evaluated the comparative persistence of non-TNF and TNF antagonists for post-operative prophylaxis and their comparative effectiveness for preventing early endoscopic post-operative recurrence (POR). METHODS: We conducted a single-center, retrospective study of surgically naïve CD subjects undergoing ileocecal or small bowel resection between 1/1/2000 and 12/31/2021 and prescribed a biologic for post-operative prophylaxis. We compared the risk of prophylaxis failure (requiring recurrent surgery or discontinuation of therapy due to persistent POR despite optimized drug level or dose escalation, immunogenicity, and/or adverse event) and early endoscopic POR (Rutgeert's score ≥ i2 within 15 months postoperatively) between non-TNF and TNF antagonist prophylaxis using Cox proportional hazard and logistic regression, respectively, adjusting for demographic and disease characteristics. RESULTS: The study included 291 subjects (81% TNF antagonists). After multivariable adjustment, non-TNF antagonist prophylaxis was associated with a significantly lower risk of prophylaxis failure than TNF antagonists (hazard ratio 0.26; 95% confidence interval (CI) [0.13-0.53]). Prophylaxis with non-TNF and TNF antagonists had similar risk of early endoscopic POR (odds ratio 0.66; 95% CI [0.32-1.36]). Stratifying the non-TNF antagonists by anti-integrin and anti-IL12/23 yielded similar results. CONCLUSION: In a cohort of surgically naïve CD subjects prescribed a biologic for post-operative prophylaxis, non-TNF antagonists had greater persistence than TNF antagonists with similar risk for early endoscopic POR. If confirmed by large, prospective studies, these findings can inform post-operative management strategies in CD.

Genetic coding variant in complement factor B (CFB) is associated with increased risk for perianal Crohn's disease and leads to impaired CFB cleavage and phagocytosis.

OBJECTIVE: Perianal Crohn's disease (pCD) occurs in up to 40% of patients with CD and is associated with poor quality of life, limited treatment responses and poorly understood aetiology. We performed a genetic association study comparing CD subjects with and without perianal disease and subsequently performed functional follow-up studies for a pCD associated SNP in Complement Factor B (CFB). DESIGN: Immunochip-based meta-analysis on 4056 pCD and 11 088 patients with CD from three independent cohorts was performed. Serological and clinical variables were analysed by regression analyses. Risk allele of rs4151651 was introduced into human CFB plasmid by site-directed mutagenesis. Binding of recombinant G252 or S252 CFB to C3b and its cleavage was determined in cell-free assays. Macrophage phagocytosis in presence of recombinant CFB or serum from CFB risk, or protective CD or healthy subjects was assessed by flow cytometry. RESULTS: Perianal complications were associated with colonic involvement, OmpC and ASCA serology, and serology quartile sum score. We identified a genetic association for pCD (rs4151651), a non-synonymous SNP (G252S) in CFB, in all three cohorts. Recombinant S252 CFB had reduced binding to C3b, its cleavage was impaired, and complement-driven phagocytosis and cytokine secretion were reduced compared with G252 CFB. Serine 252 generates a de novo glycosylation site in CFB. Serum from homozygous risk patients displayed significantly decreased macrophage phagocytosis compared with non-risk serum. CONCLUSION: pCD-associated rs4151651 in CFB is a loss-of-function mutation that impairs its cleavage, activation of alternative complement pathway, and pathogen phagocytosis thus implicating the alternative complement pathway and CFB in pCD aetiology.

Hypoalbuminemia and Bandemia Predict Failure of Infliximab Rescue Therapy in Acute Severe Ulcerative Colitis.

BACKGROUND AND AIMS: Infliximab rescue therapy is effective in patients with corticosteroid refractory acute severe ulcerative colitis, but predictors of response remain poorly understood. We aimed to identify predictors of colectomy in this high-risk patient population. METHODS: Patients hospitalized with acute severe ulcerative colitis who received infliximab after failing intravenous corticosteroid therapy between July 2012 and June 2017 were retrospectively identified. Stepwise regression with backward elimination was used to identify predictors of colectomy at 90 days and 1 year. Ninety-day and 1-year colectomy rates were compared between the patients who received 5 mg/kg and 10 mg/kg IFX rescue dose. RESULTS: Sixty-three patients met the eligibility criteria. Twenty-nine patients received 5 mg/kg, and 34 received 10 mg/kg infliximab dose. Serum albumin on admission (OR 0.10; p = 0.04) and band neutrophil percentage at the time of infliximab administration (OR 1.21; p = 0.02) were independent predictors of 90-day colectomy. A combination of serum albumin ≤ 2.5 g/dl and band neutrophil count ≥ 13% had a 100% positive predictive value for 90-day colectomy. Unadjusted 90-day and 1-year colectomy rates were similar in the 5 mg/kg and 10 mg/kg infliximab groups. After adjusting for confounding factors, 10 mg/kg infliximab dose was potentially protective for 90-day (OR 0.07; p = 0.06) but not for 1-year colectomy (OR 0.19; p = 0.16). CONCLUSIONS: Bandemia and low serum albumin are independent predictors of failure of infliximab rescue therapy in acute severe ulcerative colitis. Serum albumin ≤ 2.5 g/dl and band neutrophil count ≥ 13% had a 100% positive predictive value for 90-day colectomy.

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.

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.

Pre-operative visceral adipose tissue radiodensity is a potentially novel prognostic biomarker for early endoscopic post-operative recurrence in Crohn's disease.

BACKGROUND: Evidence suggests inflammatory mesenteric fat is involved in post-operative recurrence (POR) of Crohn's disease (CD). However, its prognostic value is uncertain, in part, due to difficulties studying it non-invasively. AIM: To evaluate the prognostic value of pre-operative radiographic mesenteric parameters for early endoscopic POR (ePOR). METHODS: We conducted a retrospective cohort study of CD subjects ≥ 12 years who underwent ileocecal or small bowel resection between 1/1/2007 to 12/31/2021 with computerized tomography abdomen/pelvis ≤ 6 months pre-operatively and underwent ileocolonoscopy ≤ 15 months post-operatively. Visceral adipose tissue (VAT) volume (cm3), ratio of VAT:subcutaneous adipose tissue (SAT) volume, VAT radiodensity, and ratio of VAT:SAT radiodensity were generated semiautomatically. Mesenteric lymphadenopathy (LAD, largest lymph node > 10 mm) and severe vasa recta (VR) engorgement (diameter of the VR supplying diseased bowel ≥ 2 × VR supplying healthy bowel) were derived manually. The primary outcome was early ePOR (Rutgeert's score ≥ i2 on first endoscopy ≤ 15 months post-operatively) and the secondary outcome was ePOR severity (Rutgeert's score i0-4). Regression analyses were performed adjusting for demographic and disease-related characteristics to calculate adjusted odds ratio (aOR) and 95% confidence interval (CI). RESULTS: Of the 139 subjects included, 45% of subjects developed early ePOR (n = 63). VAT radiodensity (aOR 0.59, 95%CI: 0.38-0.90) and VAT:SAT radiodensity (aOR 8.54, 95%CI: 1.48-49.28) were associated with early ePOR, whereas, VAT volume (aOR 1.23, 95%CI: 0.78-1.95), VAT:SAT volume (aOR 0.80, 95%CI: 0.53-1.20), severe VR engorgement (aOR 1.53, 95%CI: 0.64-3.66), and mesenteric LAD (aOR 1.59, 95%CI: 0.67-3.79) were not. Similar results were observed for severity of ePOR. CONCLUSION: VAT radiodensity is potentially a novel non-invasive prognostic imaging marker to help risk stratify CD patients for POR.

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.

Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease.

Genetic variation in both innate and adaptive immune systems is associated with Crohn's disease (CD) susceptibility, but much of the heritability to CD remains unknown. We performed a genome-wide association study (GWAS) in 896 CD cases and 3204 healthy controls all of Caucasian origin as defined by multidimensional scaling. We found supportive evidence for 21 out of 40 CD loci identified in a recent CD GWAS meta-analysis, including two loci which had only nominally achieved replication (rs4807569, 19p13; rs991804, CCL2/CCL7). In addition, we identified associations with genes involved in tight junctions/epithelial integrity (ASHL, ARPC1A), innate immunity (EXOC2), dendritic cell biology [CADM1 (IGSF4)], macrophage development (MMD2), TGF-beta signaling (MAP3K7IP1) and FUT2 (a physiological trait that regulates gastrointestinal mucosal expression of blood group A and B antigens) (rs602662, P=3.4x10(-5)). Twenty percent of Caucasians are 'non-secretors' who do not express ABO antigens in saliva as a result of the FUT2 W134X allele. We demonstrated replication in an independent cohort of 1174 CD cases and 357 controls between the four primary FUT2 single nucleotide polymorphisms (SNPs) and CD (rs602662, combined P-value 4.90x10(-8)) and also association with FUT2 W143X (P=2.6x10(-5)). Further evidence of the relevance of this locus to CD pathogenesis was demonstrated by the association of the original four SNPs and CD in the recently published CD GWAS meta-analysis (rs602662, P=0.001). These findings strongly implicate this locus in CD susceptibility and highlight the role of the mucus layer in the development of CD.

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.

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.

Pre-pouch Ileitis is Associated with Development of Crohn's Disease-like Complications and Pouch Failure.

BACKGROUND AND AIMS: It is unclear whether pre-pouch ileitis heralds an aggressive inflammatory pouch disease in patients with ileal pouch-anal anastomosis [IPAA]. We compared outcomes of patients with pouchitis and concomitant pre-pouch ileitis with those with pouchitis alone. METHODS: Patients undergoing IPAA surgery for inflammatory bowel disease, who subsequently developed pouchitis with concomitant pre-pouch ileitis [pre-pouch ileitis group], were matched by year of IPAA surgery and preoperative diagnosis [ulcerative colitis or inflammatory bowel disease-unclassified] with patients who developed pouchitis alone [pouchitis group]. Primary outcomes were development of Crohn's disease [CD]-like complications [non-anastomotic strictures or perianal disease >6 months after ileostomy closure] and pouch failure. Secondary outcomes were need for surgical/endoscopic interventions and immunosuppressive therapy. Log-rank testing was used to compare outcome-free survival, and Cox regression was performed to identify predictors of outcomes. RESULTS: There were 66 patients in each group. CD-like complications and pouch failure developed in 36.4% and 7.6% patients in the pre-pouch ileitis group and 10.6% and 1.5% in pouchitis group, respectively. CD-like complications-free survival [log-rank p = 0.0002] and pouch failure-free survival [log-rank p = 0.046] were significantly lower in the pre-pouch ileitis group. The pre-pouch ileitis group had a higher risk of requiring surgical/endoscopic interventions [log-rank p = 0.0005] and immunosuppressive therapy [log-rank p <0.0001]. Pre-pouch ileitis was independently associated with an increased risk of CD-like complications (hazard ratio [HR] 3.8; p = 0.0007), need for surgical/endoscopic interventions [HR 4.1; p = 0.002], and immunosuppressive therapy [HR 5.0; p = 0.0002]. CONCLUSIONS: Pre-pouch ileitis is associated with a higher risk of complicated disease and pouch failure than pouchitis. It should be considered a feature of CD.

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.

Preoperative wireless capsule endoscopy does not predict outcome after ileal pouch-anal anastomosis.

PURPOSE: The extent of preoperative small-bowel mucosal inflammation may be an important predictor of pouchitis after ileal pouch-anal anastomosis. This study examined the value of preoperative wireless capsule endoscopy in predicting outcome of ileal pouch-anal anastomosis in patients with ulcerative colitis or indeterminate colitis. METHODS: Patients undergoing complete wireless capsule endoscopy before ileal pouch-anal anastomosis were identified. Findings on wireless capsule endoscopy were classified as positive (erosions, ulcers or erythema) or negative. Outcome was assessed prospectively and included no pouchitis, acute pouchitis, chronic pouchitis, or de novo Crohn disease. Patients with acute pouchitis, chronic pouchitis, or de novo Crohn disease were considered to have pouch inflammation. RESULTS: The 68 study patients (48 ulcerative colitis; 20 indeterminate colitis) had a median age of 38 years and included 34 males. Median follow-up time after ileostomy closure was 12 months (range, 3-63 months). Wireless capsule endoscopy was positive in 15 patients (22%) and negative in 53 patients (78%). Pouch inflammation was observed in 23 patients (34%), and included 8 patients with acute pouchitis, 3 patients with chronic pouchitis, and 12 patients with de novo Crohn disease. The incidence of acute pouchitis, chronic pouchitis, de novo Crohn disease, and pouch inflammation in the wireless capsule endoscopy-positive patient group was 7%, 7%, 20%, and 33% compared with 13%, 4%, 17%, and 34% in the wireless capsule endoscopy-negative patient group (all P = NS). CONCLUSION: There was no statistical association between the results of preoperative wireless capsule endoscopy and outcome after ileal pouch-anal anastomosis in patients with ulcerative colitis or indeterminate colitis. There seems to be little value of wireless capsule endoscopy in the preoperative evaluation of these patients.

A prospective analysis of clinical variables, serologic factors, and outcome of ileal pouch-anal anastomosis in patients with backwash ileitis.

PURPOSE: The outcome of ileal pouch-anal anastomosis in patients with backwash ileitis is controversial. We prospectively compared the outcomes of ileal pouch-anal anastomosis in colitis patients with backwash ileitis and colitis patients without backwash ileitis. METHODS: Consecutive colitis patients undergoing ileal pouch-anal anastomosis were reviewed. All patients were classified after surgery as being either backwash ileitis-positive or backwash ileitis-negative. Serum drawn preoperatively was assayed, using enzyme-linked immunosorbent assay, for anti-Saccharomyces cerevisiae, anti-outer membrane of porin C, anti-CBir1, anti-I2, and perinuclear anti-neutrophil cytoplasmic antibody. 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: Out of 334 patients, 39 (12%) were backwash ileitis-positive. Compared with backwash ileitis-negative patients, backwash ileitis-positive patients had a higher incidence of pancolitis (100% vs 74%; P = .0001), primary sclerosing cholangitis (15% vs 2%; P = .001) and high-level (>100 enzyme-linked immunosorbent assay units/ml) perinuclear anti-neutrophil cytoplasmic antibody expression (29% vs 9%; P = .001). After a median follow-up of 26 months, 53 patients (16%) developed acute pouchitis, 37 (11%) developed chronic pouchitis, and 40 (12%) developed de novo Crohn's disease. There was no significant difference between the backwash ileitis-positive and backwash ileitis-negative patient groups in the incidence of acute pouchitis, chronic pouchitis, or de novo Crohn's disease. CONCLUSION: There was a significantly higher incidence of pancolitis, primary sclerosing cholangitis, and high-level perinuclear anti-neutrophil cytoplasmic antibody expression in backwash ileitis-positive patients than in backwash ileitis-negative patients. The incidence of acute pouchitis, chronic pouchitis, and de novo Crohn's disease after ileal pouch-anal anastomosis does not differ significantly between backwash ileitis-positive and backwash ileitis-negative patients.

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.