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.

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.

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.

Perianal Crohn's Disease is Associated with Distal Colonic Disease, Stricturing Disease Behavior, IBD-Associated Serologies and Genetic Variation in the JAK-STAT Pathway.

BACKGROUND: Perianal Crohn's Disease (pCD) is a particularly severe phenotype associated with poor quality of life with a reported prevalence of 12%-40%. Previous studies investigating the etiology of pCD have been limited in the numbers of subjects and the intensity of genotyping. The aim of this study was to identify clinical, serological, and genetic factors associated with pCD. METHODS: We performed a case-control study comparing patients with (pCD+) and without perianal (pCD) involvement in CD; defined as the presence of perianal abscesses or fistulae. Data on demographics and clinical features were obtained by chart review. Inflammatory bowel disease-related serology was determined by enzyme-linked immunosorbent assay. Genetic data were generated using Illumina genotyping platforms. RESULTS: We included 1721 patients with CD of which 524 (30.4%) were pCD+ and 1197 were pPCD. pCD was associated with distal colonic disease (Odds ratio 5.54 [3.23-9.52], P < 0.001), stricturing disease behavior (1.44 [1.14-1.81], P = 0.002) and family history of inflammatory bowel disease (4.98 [3.30-7.46], P < 0.001). pCD was associated with higher anti-sacharomyces cerevisae antibodies IgA (P < 0.001) and OmpC (P = 0.008) antibody levels. pCD was associated with known inflammatory bowel disease loci, including KIF3B, CRTC3, TRAF3IP2, JAZF1, NRIP1, MST1, FUT2, and PTGER (all P < 0.05). We also identified genetic association with genes involved in autophagy (DAPK1, P = 5.11 × 10), TNF alpha pathways (NUCB2, P = 8.68 × 10; DAPK1), IFNg pathways (DAPK1; NDFIP2, P = 8.74 × 10), and extracellular matrix and scaffolding proteins (USH1C, P = 8.68 × 10; NDFIP2; TMC07, P = 8.87 × 10). Pathway analyses implicated the JAK-Stat pathway (pc = 3.72 × 10). CONCLUSION: We have identified associations between pCD, more distal colonic inflammation, Crohn's disease-associated serologies, and genetic variation in the JAK-Stat pathway.

Microgeographic Proteomic Networks of the Human Colonic Mucosa and Their Association With Inflammatory Bowel Disease.

BACKGROUND & AIMS: Interactions between mucosal cell types, environmental stressors, and intestinal microbiota contribute to pathogenesis in inflammatory bowel disease (IBD). Here, we applied metaproteomics of the mucosal-luminal interface to study the disease-related biology of the human colonic mucosa. METHODS: We recruited a discovery cohort of 51 IBD and non-IBD subjects endoscopically sampled by mucosal lavage at 6 colonic regions, and a validation cohort of 38 no-IBD subjects. Metaproteome data sets were produced for each sample and analyzed for association with colonic site and disease state using a suite of bioinformatic approaches. Localization of select proteins was determined by immunoblot analysis and immunohistochemistry of human endoscopic biopsy samples. RESULTS: Co-occurrence analysis of the discovery cohort metaproteome showed that proteins at the mucosal surface clustered into modules with evidence of differential functional specialization (eg, iron regulation, microbial defense) and cellular origin (eg, epithelial or hemopoietic). These modules, validated in an independent cohort, were differentially associated spatially along the gastrointestinal tract, and 7 modules were associated selectively with non-IBD, ulcerative colitis, and/or Crohn's disease states. In addition, the detailed composition of certain modules was altered in disease vs healthy states. We confirmed the predicted spatial and disease-associated localization of 28 proteins representing 4 different disease-related modules by immunoblot and immunohistochemistry visualization, with evidence for their distribution as millimeter-scale microgeographic mosaic. CONCLUSIONS: These findings suggest that the mucosal surface is a microgeographic mosaic of functional networks reflecting the local mucosal ecology, whose compositional differences in disease and healthy samples may provide a unique readout of physiologic and pathologic mucosal states.

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.

Nonbloody Diarrhea but Not Significant Weight Loss at Diagnosis Is Associated with the Development of Denovo Crohn's Disease After Ileal Pouch-anal Anastomosis for Ulcerative Colitis.

BACKGROUND: Denovo Crohn's disease (CD) develops in 5% to 10% of patients after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) leading to increased morbidity and rates of pouch failure. Initial nonbloody diarrhea and weight loss at diagnosis are independent risk factors for a change in diagnosis from UC to CD in nonsurgical patients. We investigated whether these features were risk factors for denovo CD in a longitudinal cohort of patients with UC undergoing IPAA. METHODS: Prospective profiles of patients with UC undergoing IPAA followed over a 22-year period by 1 surgeon were analyzed. Denovo CD was diagnosed when mucosal inflammation (5 or more ulcers) involved the small bowel mucosa proximal to the ileal pouch any time after surgery and/or when a pouch fistula or other perianal complication developed more than 3 months after ileostomy closure. Patients with inflammatory bowel disease unclassified, acute pouchitis, chronic pouchitis, and those lost to follow-up were excluded from analysis. Cox regression analysis was performed for statistical significance. RESULTS: Of the 199 study patients included in the analysis, denovo CD developed in 42 patients (21%). Patients who developed denovo CD had an increased incidence of nonbloody diarrhea (n = 12; 29%) compared with patients who had no evidence of pouch inflammation (n = 25; 16%) (P = 0.03). In contrast, the incidence of weight loss was not significantly increased in patients with denovo CD (n = 7; 17%) compared with patients who never had pouch inflammation (n = 16; 10%) (P = 0.12). CONCLUSIONS: Initial nonbloody diarrhea is associated with denovo CD after IPAA. This association warrants close consideration before surgery.

Ocular Manifestations in Inflammatory Bowel Disease Are Associated with Other Extra-intestinal Manifestations, Gender, and Genes Implicated in Other Immune-related Traits.

BACKGROUND: There has been considerable progress in identifying inflammatory bowel disease [IBD] susceptibility genes but little progress in examining the role of genetic variation in the development of the extra-intestinal manifestations [EIMs] of IBD. This study identified clinical, serological, and genetic factors associated with ocular EIMs [O-EIMs] in IBD. METHODS: We performed a retrospective case-control study of IBD patients, comparing those with and without O-EIMs using the Cedars-Sinai IBD Research Repository and the NIDDK IBD Genetics Consortium Repository. Genotyping was performed using Illumina whole genome platforms. RESULTS: In all, 124 cases and 3328 controls with available clinical data were identified; 103 cases and 2808 controls had genetic data available. Erythema nodosum and peripheral arthritis particularly were common in patients with O-EIMs [p = 2.77 x 10(-13) and p = 2.58 x 10(-13), respectively] with increasing odds ratios for O-EIMs with each additional non-ocular-EIM [for ≥ 2 EIMs, odds ratio 14.72]. Nominal association with O-EIMs was observed at several known IBD susceptibility single nuclear polymorphisms. One locus, containing RBM19, achieved genome-wide level of significance for association with O-EIMs. CONCLUSIONS: In IBD, O-EIMs co-occur with musculoskeletal and skin manifestations and, in this study, are nominally associated with known IBD loci. Additional cohorts are needed to verify these results and identify additional genes.

Combined Immunosuppression Impairs Immunogenicity to Tetanus and Pertussis Vaccination Among Patients with Inflammatory Bowel Disease.

BACKGROUND: Pertussis epidemics have recently emerged across the United States, prompting broad public health recommendations for adult Tdap vaccination (tetanus, diphtheria, acellular pertussis). The impact of immunosuppressive regimens for inflammatory bowel disease (IBD) on vaccine responses to the Tdap vaccine is not known. METHODS: We performed a prospective controlled trial between April 2011 and March 2012. Adults with IBD were consecutively stratified based on therapeutic regimen into one of 5 groups: A: no IBD therapy or 5-aminosalicylates alone; B: maintenance biologic monotherapy; C: maintenance immunomodulator monotherapy; D: combined biologic and immunomodulator therapy; and E: healthy age-matched controls. Subjects received Tdap, and serum antibody levels against tetanus toxoid, pertussis toxoid, and filamentous hemagglutinin (FHA) were drawn just before and approximately 4 weeks after vaccination. The primary outcome was the booster response rate to each antigen. Secondary outcomes included the differences in pregeometric and postgeometric mean titers. RESULTS: A total of 98 subjects enrolled, and 84 completed the study. Tetanus response rates were 55%, 56%, 40%, 27%, and 63% across groups A to E, respectively. Group D rates were lower than those of group B (P = 0.02). Postvaccination pertussis toxoid responses were 59%, 72%, 47%, 45%, and 75%, while FHA responses were 86%, 72%, 80%, 64%, and 75% across groups A to E, respectively. Prevaccination and postvaccination geometric mean titer differences for FHA were lower in group D than those in group A (P = 0.05). CONCLUSIONS: Antibody responses to tetanus and pertussis vaccination may be affected by therapeutic drug regimen. Patients with IBD should optimally receive Tdap before starting immunomodulators, particularly when used in combination with anti-tumor necrosis factor alpha agents.

Pyoderma Gangrenosum among Patients with Inflammatory Bowel Disease: A Descriptive Cohort Study.

BACKGROUND: Pyoderma gangrenosum (PG) is a severe extraintestinal manifestation of inflammatory bowel disease (IBD). OBJECTIVE: To better characterize PG features and management among an IBD cohort. METHODS: Subjects with PG were identified using a large database at a tertiary center. Patient demographics and clinical characteristics were summarized using descriptive statistics. RESULTS: Eighty patients with an episode(s) of PG were identified, yielding an overall prevalence of 1.9%. Overall, 93% of patients with PG had some degree of colonic inflammation. Thirty-one (39%) patients required hospitalization for PG. Underlying bowel disease was active at the time of PG episode(s) in 52 (65%) patients. The PG location was variable, with the lower extremity being the most common. Most patients (71.3%) required multiple therapies to achieve PG healing. CONCLUSIONS: We describe one of the largest case series of PG among patients with IBD. The variety of treatment strategies used highlights the lack of clear guidelines in managing this complex group of patients.

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.

Pyoderma Gangrenosum among Patients with Inflammatory Bowel Disease: A Descriptive Cohort Study.

BACKGROUND: Pyoderma gangrenosum (PG) is a severe extraintestinal manifestation of inflammatory bowel disease (IBD). OBJECTIVE: To better characterize PG features and management among an IBD cohort. METHODS: Subjects with PG were identified using a large database at a tertiary center. Patient demographics and clinical characteristics were summarized using descriptive statistics. RESULTS: Eighty patients with an episode(s) of PG were identified, yielding an overall prevalence of 1.9%. Overall, 93% of patients with PG had some degree of colonic inflammation. Thirty-one (39%) patients required hospitalization for PG. Underlying bowel disease was active at the time of PG episode(s) in 52 (65%) patients. The PG location was variable, with the lower extremity being the most common. Most patients (71.3%) required multiple therapies to achieve PG healing. CONCLUSIONS: We describe one of the largest case series of PG among patients with IBD. The variety of treatment strategies used highlights the lack of clear guidelines in managing this complex group of 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.

Clinical, serologic, and genetic factors associated with pyoderma gangrenosum and erythema nodosum in inflammatory bowel disease patients.

BACKGROUND: Pyoderma gangrenosum (PG) and erythema nodosum (EN) are the most common cutaneous manifestations of inflammatory bowel disease (IBD) but little is known regarding their etiopathogenesis. METHODS: We performed a case-control study comparing characteristics between IBD patients with a documented episode of PG (PG+) and/or EN (EN+) with those without PG (PG-) and EN (EN-). Data on clinical features were obtained by chart review. IBD-related serology was determined using enzyme-linked immunosorbent assay and genome-wide data generated using Illumina technology. Standard statistical tests for association were used. RESULTS: We identified a total of 92 cases of PG and 103 cases of EN with genetic and clinical characteristics, of which 64 PG and 55 EN cases were available for serological analyses. Fewer male subjects were identified in the PG(+) (odds ratio 0.6, P = 0.009) and EN(+) groups (odds ratio 0.31, P = 0 < 0.0001). Colonic disease, previous IBD-related surgery, and noncutaneous extra-intestinal manifestations were more common among both PG(+) and EN(+) patients compared with controls. PG(+) was associated with anti-nuclear cytoplasmic antibody seropositivity (P = 0.03) and higher anti-nuclear cytoplasmic antibody level (P = 0.02) in Crohn's disease. Genetic associations with PG included known IBD loci (IL8RA [P = 0.00003] and PRDM1 [0.03]) as well as with USP15 (4.8 × 10) and TIMP3 (5.6 ×10). Genetic associations with EN included known IBD susceptibility genes (PTGER4 [P = 8.8 × 10], ITGAL [0.03]) as well as SOCS5 (9.64 × 10), CD207 (3.14 × 10), ITGB3 (7.56 × 10), and rs6828740 (4q26) (P < 5.0 × 10). Multivariable models using clinical, serologic, and genetic parameters predicted PG (area under the curve = 0.8) and EN (area under the curve = 0.97). CONCLUSION: Cutaneous manifestations in IBD are associated with distinctive genetic characteristics and with the similar clinical characteristics, including the development of other extra-intestinal manifestations suggesting shared and distinct etiologies.

A modular organization of the human intestinal mucosal microbiota and its association with inflammatory bowel disease.

Abnormalities of the intestinal microbiota are implicated in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC), two spectra of inflammatory bowel disease (IBD). However, the high complexity and low inter-individual overlap of intestinal microbial composition are formidable barriers to identifying microbial taxa representing this dysbiosis. These difficulties might be overcome by an ecologic analytic strategy to identify modules of interacting bacteria (rather than individual bacteria) as quantitative reproducible features of microbial composition in normal and IBD mucosa. We sequenced 16S ribosomal RNA genes from 179 endoscopic lavage samples from different intestinal regions in 64 subjects (32 controls, 16 CD and 16 UC patients in clinical remission). CD and UC patients showed a reduction in phylogenetic diversity and shifts in microbial composition, comparable to previous studies using conventional mucosal biopsies. Analysis of weighted co-occurrence network revealed 5 microbial modules. These modules were unprecedented, as they were detectable in all individuals, and their composition and abundance was recapitulated in an independent, biopsy-based mucosal dataset 2 modules were associated with healthy, CD, or UC disease states. Imputed metagenome analysis indicated that these modules displayed distinct metabolic functionality, specifically the enrichment of oxidative response and glycan metabolism pathways relevant to host-pathogen interaction in the disease-associated modules. The highly preserved microbial modules accurately classified IBD status of individual patients during disease quiescence, suggesting that microbial dysbiosis in IBD may be an underlying disorder independent of disease activity. Microbial modules thus provide an integrative view of microbial ecology relevant to IBD.

Multidimensional prognostic risk assessment identifies association between IL12B variation and surgery in Crohn's disease.

BACKGROUND: The ability to identify patients with Crohn's disease (CD) at highest risk of surgery would be invaluable in guiding therapy. Genome-wide association studies have identified multiple IBD loci with unknown phenotypic consequences. The aims of this study were to: (1) identify associations between known and novel CD loci with early resective CD surgery and (2) develop the best predictive model for time to surgery using a combination of phenotypic, serologic, and genetic variables. METHODS: Genotyping was performed on 1,115 subjects using Illumina-based genome-wide technology. Univariate and multivariate analyses tested genetic associations with need for surgery within 5 years. Analyses were performed by testing known CD loci (n = 71) and by performing a genome-wide association study. Time to surgery was analyzed using Cox regression modeling. Clinical and serologic variables were included along with genotype to build predictive models for time to surgery. RESULTS: Surgery occurred within 5 years in 239 subjects at a median time of 12 months. Three CD susceptibility loci were independently associated with surgery within 5 years (IL12B, IL23R, and C11orf30). Genome-wide association identified novel putative loci associated with early surgery: 7q21 (CACNA2D1) and 9q34 (RXRA, COL5A1). The most predictive models of time to surgery included genetic and clinical risk factors. More than a 20% difference in frequency of progression to surgery was seen between the lowest and highest risk groups. CONCLUSIONS: Progression to surgery is faster in patients with CD with both genetic and clinical risk factors. IL12B is independently associated with need and time to early surgery in CD patients and justifies the investigation of novel and existing therapies that affect this pathway.

Surgical outcome of ileal pouch-anal anastomosis when used intentionally for well-defined Crohn's disease.

BACKGROUND: Crohn's disease (CD) is considered a contraindication to ileal pouch--anal anastomosis (IPAA). In this study, we compare outcomes of CD and ulcerative colitis (UC) patients undergoing IPAA. METHODS: Patients were considered to have CD before surgery based on a history of small bowel disease, perianal disease, noncrypt-associated granuloma, or pretreatment skip colonic lesions. Patients were prospectively assessed for pouchitis or CD. Postoperative CD (pouch inflammation into the afferent limb or pouch fistula) or pouch failure (need for permanent diversion) were assessed. Preoperative serum was assayed for IBD-associated antibodies using enzyme-linked immunosorbent assay (ELISA). RESULTS: Seventeen patients with preoperative CD were identified. Seven (41%) patients developed postoperative recurrent CD in the afferent limb (n = 3) or pouch fistulizing disease (n = 4). One patient (6%) required pouch excision. The incidence of postoperative CD was higher (P = 0.002) in preoperative CD patients (41%) than UC patients (11%). There was no significant difference in pouchitis or pouch failure. There was also no significant difference in any preoperative clinical feature between patients with or without postoperative CD. Afferent limb inflammation developed in three (50%) of the six patients with pANCA+/OmpC- expression compared to none of the 11 patients without this serologic profile (P = 0.03). CONCLUSIONS: Although the intentional use of IPAA in CD has a higher incidence of postoperative disease vs. UC patients, there was no significant difference in pouch failure. Demographics, clinical features, and serologic factors do not predict outcome of CD patients undergoing IPAA. IBD serology may identify the phenotype manifestation of postoperative recurrent CD.

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.