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Diagnosis of cytomegalovirus (CMV) colitis in the setting of severe ulcerative colitis (UC) remains a clinical challenge. This study aimed to determine the utility of serum CMV polymerase chain reaction (PCR) as a non-invasive test for the diagnosis of CMV superinfection in patients hospitalized with UC.This retrospective study included consecutive admitted patients with UC who had serum testing for CMV completed as part of standard hospital procedure and CMV colitis diagnosed by expert pathologists.Two hundred and six patients with UC were included; 13 patients (6%) had histologically confirmed CMV colitis. Eleven of 13 patients with CMV colitis (84%) and 3 of 193 (1.5%) patients without CMV colitis had a positive serum PCR test (p 0.0001). ROC analysis showed that a CMV PCR level of 259 IU/mL had a sensitivity and specificity of 77% and 99%, respectively, for diagnosis of CMV colitis with an AUC of 0.9 (p 0.0001). Serum CMV PCR level significantly correlated to the number of inclusion bodies on biopsy specimens with data available (n = 8) (r = 0.8, p = 0.02). CMV positivity did not predict the need for salvage therapy, admission or 1-year colectomy rates.Serum CMV PCR has an excellent negative predictive value and demonstrates a strong correlation with CMV positivity on histology. This work supports a rationale for serum CMV PCR testing on admission to assess the risk of CMV colitis in patients with severe UC.

The association of chronic inflammation with colorectal carcinoma (CRC) development is well known in ulcerative colitis (UC). However, the role of inflammatory changes in sporadic CRC pathogenesis is less widely appreciated. In this study, in the first step using RNA-seq, we identified gene-pathway-level changes in UC-associated CRC (UC CRC, n = 10) and used the changes as a proxy for inflammation in human colon to ask if there were associations of inflammatory pathway dysregulations in sporadic CRC pathogenesis (n = 8). We found down-regulations of several inflammation-related metabolic pathways (nitrogen metabolism, sulfur metabolism) and other pathways (bile secretion, fatty acid degradation) in sporadic CRC. Non-inflammation-related changes included up-regulation of the proteasome pathway. In the next step, from a larger number of paired samples from sporadic CRC patients (n = 71) from a geographically and ethnically different population and using a different platform (microarray), we asked if the inflammation-CRC association could be replicated. The associations were significant even after stratification by sex, tumor stage, grade, MSI status, and KRAS mutation status. Our findings have important implications to widen our understanding of inflammatory pathogenesis of sporadic CRC. Furthermore, targeting of several of these dysregulated pathways could provide the basis for improved therapies for CRC.

Supplementary Figure 5 from EGFR Signals Downregulate Tumor Suppressors miR-143 and miR-145 in Western Diet–Promoted Murine Colon Cancer: Role of G1 Regulators

Supplementary Figure 1 from EGFR Signals Downregulate Tumor Suppressors miR-143 and miR-145 in Western Diet–Promoted Murine Colon Cancer: Role of G1 Regulators

Figure legends for supplemental figures

Supplementary Figure 2 from EGFR Signals Downregulate Tumor Suppressors miR-143 and miR-145 in Western Diet–Promoted Murine Colon Cancer: Role of G1 Regulators

Colorectal cancer is a leading cause of cancer deaths. The renin-angiotensin system (RAS) is upregulated in colorectal cancer, and epidemiologic studies suggest RAS inhibitors reduce cancer risk. Because vitamin D (VD) receptor negatively regulates renin, we examined anticancer efficacy of VD and losartan (L), an angiotensin receptor blocker. Control Apc+/LoxP mice and tumor-forming Apc+/LoxP Cdx2P-Cre mice were randomized to unsupplemented Western diet (UN), or diets supplemented with VD, L, or VD+L, the latter to assess additive or synergistic effects. At 6 months, mice were killed. Plasma Ca2+, 25(OH)D3, 1α, 25(OH)2D3, renin, and angiotensin II (Ang II) were quantified. Colonic transcripts were assessed by qPCR and proteins by immunostaining and blotting. Cancer incidence and tumor burden were significantly lower in Cre+ VD and Cre+ L, but not in the Cre+ VD+L group. In Apc+/LoxP mice, VD increased plasma 1,25(OH)2D3 and colonic VDR. In Apc+/LoxP-Cdx2P-Cre mice, plasma renin and Ang II, and colonic tumor AT1, AT2, and Cyp27B1 were increased and VDR downregulated. L increased, whereas VD decreased plasma renin and Ang II in Cre+ mice. VD or L inhibited tumor development, while exerting differential effects on plasma VD metabolites and RAS components. We speculate that AT1 is critical for tumor development, whereas RAS suppression plays a key role in VD chemoprevention. When combined with L, VD no longer increases active VD and colonic VDR in Cre- mice nor suppresses renin and Ang II in Cre+ mice, likely contributing to lack of chemopreventive efficacy of the combination.

Epidermal growth factor receptors (EGFR) contribute to colonic tumorigenesis in experimental models of colon cancer. We previously showed that EGFR was also required for colonic tumor promotion by Western diet. The goal of this study was to identify EGFR-regulated microRNAs that contribute to diet-promoted colonic tumorigenesis. Murine colonic tumors from Egfrwt and hypomorphic Egfrwa2 mice were screened using micro RNA (miRNA) arrays and miR-143 and miR-145 changes confirmed by Northern, real-time PCR, and in situ analysis. Rodent and human sporadic and ulcerative colitis (UC)-associated colon cancers were examined for miR-143 and miR-145. Effects of EGFR on miR-143 and miR-145 expression were assessed in murine and human colonic cells and their putative targets examined in vitro and in vivo. miR-143 and miR-145 were readily detected in normal colonocytes and comparable in Egfrwt and Egfrwa2 mice. These miRNAs were downregulated in azoxymethane and inflammation-associated colonic tumors from Egfrwt mice but upregulated in Egfrwa2 tumors. They were also reduced in human sporadic and UC colon cancers. EGFR signals suppressed miR-143 and miR-145 in human and murine colonic cells. Transfected miR-143 and miR-145 inhibited HCT116 cell growth in vitro and in vivo and downregulated G1 regulators, K-Ras, MYC, CCND2, cdk6, and E2F3, putative or established targets of these miRNAs. miRNA targets Ras and MYC were increased in colonic tumors from Egfrwt but not Egfrwa2 mice fed a Western diet. EGFR suppresses miR-143 and miR-145 in murine models of colon cancer. Furthermore, Western diet unmasks the tumor suppressor roles of these EGFR-regulated miRNAs. Mol Cancer Res; 9(7); 960–75. ©2011 AACR.

Supplementary Figure 4 from EGFR Signals Downregulate Tumor Suppressors miR-143 and miR-145 in Western Diet–Promoted Murine Colon Cancer: Role of G1 Regulators

Supplementary Figure 3 from EGFR Signals Downregulate Tumor Suppressors miR-143 and miR-145 in Western Diet–Promoted Murine Colon Cancer: Role of G1 Regulators

Plasma calciums

Transcripts of Notch signaling components

Supplementary Methods

Supplementary Figure 1. IL17RD potentiates EGF-induced EGFR signaling. A) Cellular proliferation of HT29 and HCT116 cells 96 hours after transfection with a plasmid encoding IL-17RD compared to an EV plasmid. B) Cellular proliferation of HT29 and HCT116 cells treated with EGF for 96 hrs following transfection with a plasmid encoding IL-17RD or EV plasmid. C) pEGFR, EGFR, pAKT, and pERK expression in HT29 cells 15 minutes after treatment with EGF ( ) or media without EGF (-) and transfected with Flag-tagged IL17RD, EV plasmid, or no transfection (vehicle) (representative images of two blots containing 3 samples per group). D) pAKT expression in HT29 cells 30 minutes after treatment with media with or without EGF and transfected with a Flag-tagged IL17RD plasmid or EV plasmid. E) EGFR expression in untreated cells 96 hours after transfection with IL17RD.

Patient demographics and disease specific characteristics.

Note loss of ADAM17 staining in tumor epithelial cells in ADAM17Î"Î" tumors.

Supplemental Figure S3. Marimastat suppresses colonic EGFR signals. Mice received vehicle or marimastat and were fed WD. After 2 wks, colonic proteins measured by WB. A. Alzet pump. B. Protocol. C. EGFR signals. D. Quantitative levels (*p

Supplemental Methods and Figure Legends

Purpose: Epidermal growth factor receptors (EGFR) are required for tumor promotion by Western diet. The metalloprotease, ADAM17 activates EGFR by releasing pro-EGFR ligands. ADAM17 is regulated by G-protein–coupled receptors, including CXCR4. Here we investigated CXCR4–ADAM17 crosstalk and examined the role of ADAM17 in tumorigenesis.Experimental Design: We used CXCR4 inhibitor, AMD3100 and ADAM17 inhibitor, BMS566394 to assess CXCR4–ADAM17 crosstalk in colon cancer cells. We compared the expression of CXCR4 ligand, CXCL2, and ADAM17 in mice fed Western diet versus standard diet. Separately, mice were treated with marimastat, a broad-spectrum ADAM17 inhibitor, or AMD3100 to assess EGFR activation by ADAM17 and CXCR4. Using Apc-mutant Min mice, we investigated the effects of ADAM17/10 inhibitor INCB3619 on tumorigenesis. To assess the effects of colonocyte ADAM17, mice with ADAM17 conditional deletion were treated with azoxymethane (AOM). ADAM17 expression was also compared in colonocytes from primary human colon cancers and adjacent mucosa.Results: CXCL12 treatment activated colon cancer cell EGFR signals, and CXCR4 or ADAM17 blockade reduced this activation. In vivo, Western diet increased CXCL12 in stromal cells and TGFα in colonocytes. Marimastat or AMD3100 caused >50% reduction in EGFR signals (P < 0.05). In Min mice, INCB3619 reduced EGFR signals in adenomas and inhibited intestinal tumor multiplicity (P < 0.05). In the AOM model, colonocyte ADAM17 deletion reduced EGFR signals and colonic tumor development (P < 0.05). Finally, ADAM17 was upregulated >2.5-fold in human malignant colonocytes.Conclusions: ADAM17 is a Western diet–inducible enzyme activated by CXCL12–CXCR4 signaling, suggesting the pathway: Western diet→CXCL12→CXCR4→ADAM17→TGFα→EGFR. ADAM17 might serve as a druggable target in chemoprevention strategies. Clin Cancer Res; 23(2); 549–61. ©2016 AACR.

Supplemental Materials and Methods: real time PCR, immunostaining, Western blotting, ADAM17 activity; Supplemental references for supplemental Methods Supplemental Figure Legends; Supplemental Table 1: real time PCR primer sequences

Supplemental Figure S2. EGF induces Snail in HT29 colon cancer cells. Cells were plated on collagen-coated 6 well plates in 10% serum. Twenty-four hrs later cells were deprived of serum and treated with vehicle (phosphate-buffered saline), 10 ng/ml EGF or 40 ng/ml TGFβ. After 72 hrs cells were lysed and extracts probed for indicated proteins. Shown are blots representative of three independent platings.

Fig S1. BMS566394 inhibits EGFR signaling in CXCL12 treated HCT116 cells; Fig S2. Schema for CXCL12-CXCR4 transactivation of colon cancer cell EGFR. Shown in the figure are inhibitors or antibodies used in this study: AMD3100 blocks CXCR4; BMS566394 blocks ADAM17 and INCB3619 blocks ADAM17 and ADAM10; C225 antibodies block ligand binding to EGFR.

Supplementary Material, Methods, and Figure Legend

Purpose: Patients with ulcerative colitis are at increased risk for colorectal cancer, although mechanisms underlying neoplastic transformation are poorly understood. We sought to evaluate the role of microRNAs in neoplasia development in this high-risk population.Experimental Design: Tissue from 12 controls, 9 ulcerative colitis patients without neoplasia, and 11 ulcerative colitis patients with neoplasia was analyzed. miRNA array analysis was performed and select miRNAs assayed by real-time PCR on the discovery cohort and a validation cohort. DNA methylation of miR-193a was assessed. Following transfection of miR-193a-3p, proliferation, IL17RD expression, and luciferase activity of the 3′UTR of IL17RD were measured. Tumor growth in xenografts as well as EGFR signaling were assessed in HCT116 cells expressing IL17RD with either a mutant 3′ untranslated region (UTR) or wild-type (WT) 3′UTR.Results: miR-31, miR-34a, miR-106b, and miR-193a-3p were significantly dysregulated in ulcerative colitis-neoplasia and adjacent tissue. Significant down-regulation of miR-193a-3p was also seen in an independent cohort of ulcerative colitis cancers. Changes in methylation of miR-193a or expression of pri-miR-193a were not observed in ulcerative colitis cancer. Transfection of miR-193a-3p resulted in decreased proliferation, and identified IL17RD as a direct target of miR-193a-3p. IL17RD expression was increased in ulcerative colitis cancers, and miR-193a-3p treatment decreased growth and EGFR signaling of HCT116 cells in xenografts expressing both IL17RD with WT 3′UTR compared with cells expressing IL17RD with mutant 3′UTR.Conclusions: miR-193a-3p is downregulated in ulcerative colitis neoplasia, and its loss promotes carcinogenesis through upregulation of IL17RD. These findings provide novel insight into inflammation-driven colorectal cancer and could suggest new therapeutic targets in this high-risk population. Clin Cancer Res; 23(17); 5281–91. ©2017 AACR.

Purpose: We previously showed that EGF receptor (EGFR) promotes tumorigenesis in the azoxymethane/dextran sulfate sodium (AOM/DSS) model, whereas vitamin D suppresses tumorigenesis. EGFR–vitamin D receptor (VDR) interactions, however, are incompletely understood. Vitamin D inhibits the renin–angiotensin system (RAS), whereas RAS can activate EGFR. We aimed to elucidate EGFR–VDR cross-talk in colorectal carcinogenesis.Experimental Design: To examine VDR–RAS interactions, we treated Vdr+/+ and Vdr−/− mice with AOM/DSS. Effects of VDR on RAS and EGFR were examined by Western blotting, immunostaining, and real-time PCR. We also examined the effect of vitamin D3 on colonic RAS in Vdr+/+ mice. EGFR regulation of VDR was examined in hypomorphic EgfrWaved2 (Wa2) and Egfrwild-type mice. Angiotensin II (Ang II)–induced EGFR activation was studied in cell culture.Results:Vdr deletion significantly increased tumorigenesis, activated EGFR and β-catenin signaling, and increased colonic RAS components, including renin and angiotensin II. Dietary VD3 supplementation suppressed colonic renin. Renin was increased in human colon cancers. In studies in vitro, Ang II activated EGFR and stimulated colon cancer cell proliferation by an EGFR-mediated mechanism. Ang II also activated macrophages and colonic fibroblasts. Compared with tumors from EgfrWaved2 mice, tumors from Egfrwild-type mice showed upregulated Snail1, a suppressor of VDR, and downregulated VDR.Conclusions: VDR suppresses the colonic RAS cascade, limits EGFR signals, and inhibits colitis-associated tumorigenesis, whereas EGFR increases Snail1 and downregulates VDR in colonic tumors. Taken together, these results uncover a RAS-dependent mechanism mediating EGFR and VDR cross-talk in colon cancer. Clin Cancer Res; 20(22); 5848–59. ©2014 AACR.

Background Clinical and molecular subcategories of inflammatory bowel disease (IBD) are needed to discover mechanisms of disease and predictors of response and disease relapse. We aimed to develop a study of a prospective adult research cohort with IBD (SPARC IBD) including longitudinal clinical and patient-reported data and biosamples. Methods We established a cohort of adults with IBD from a geographically diverse sample of patients across the United States with standardized data and biosample collection methods and sample processing techniques. At enrollment and at time of lower endoscopy, patient-reported outcomes (PRO), clinical data, and endoscopy scoring indices are captured. Patient-reported outcomes are collected quarterly. The quality of clinical data entry after the first year of the study was assessed. Results Through January 2020, 3029 patients were enrolled in SPARC, of whom 66.1% have Crohn’s disease (CD), 32.2% have ulcerative colitis (UC), and 1.7% have IBD-unclassified. Among patients enrolled, 990 underwent colonoscopy. Remission rates were 63.9% in the CD group and 80.6% in the UC group. In the quality study of the cohort, there was 96% agreement on year of diagnosis and 97% agreement on IBD subtype. There was 91% overall agreement describing UC extent as left-sided vs extensive or pancolitis. The overall agreement for CD behavior was 83%. Conclusion The SPARC IBD is an ongoing large prospective cohort with longitudinal standardized collection of clinical data, biosamples, and PROs representing a unique resource aimed to drive discovery of clinical and molecular markers that will meet the needs of precision medicine in IBD.

Primary sclerosing cholangitis (PSC) is an autoimmune-like disease of the bile ducts that co-occurs with inflammatory bowel disease (IBD) in almost 90% of cases. Colorectal cancer is a major complication of patients with both PSC and IBD, and these patients are at a much greater risk compared to patients with IBD without concomitant PSC. Combining flow cytometry, bulk and single cell transcriptomics, and T- and B-cell receptor repertoire analysis of right colon tissue from PSC, IBD, and healthy controls we identified a unique adaptive inflammatory transcriptional signature associated with greater risk and shorter time to dysplasia specifically in patients with PSC. This inflammatory signature is characterized by antigen-driven IL-17A+ Foxp3+ CD4 T-cell and IgG-secreting B-cell responses. These data suggest that the mechanisms of PSC and IBD dysplasia are distinct and provide molecular insights to guide prevention of colorectal cancer in PSC.

The diversity of regulatory T (Treg) cells in health and in disease remains unclear. Individuals with colorectal cancer harbor a subpopulation of RORγt+ Treg cells with elevated expression of β-catenin and pro-inflammatory properties. Here we show progressive expansion of RORγt+ Treg cells in individuals with inflammatory bowel disease during inflammation and early dysplasia. Activating Wnt-β-catenin signaling in human and murine Treg cells was sufficient to recapitulate the disease-associated increase in the frequency of RORγt+ Treg cells coexpressing multiple pro-inflammatory cytokines. Binding of the β-catenin interacting partner, TCF-1, to DNA overlapped with Foxp3 binding at enhancer sites of pro-inflammatory pathway genes. Sustained Wnt-β-catenin activation induced newly accessible chromatin sites in these genes and upregulated their expression. These findings indicate that TCF-1 and Foxp3 together limit the expression of pro-inflammatory genes in Treg cells. Activation of β-catenin signaling interferes with this function and promotes the disease-associated RORγt+ Treg phenotype.

Background and Aims: Vitamin D deficiency has been associated with disease activity in Crohn’s disease (CD). We assessed whether there is a correlation between vitamin D levels and the risk of postoperative recurrence in CD. Methods: CD patients who underwent surgery were identified from a prospectively maintained database at the University of Chicago. The primary endpoint was the correlation of serum 25-hydroxy vitamin D levels measured at 6–12 months after surgery and the proportion of patients in endoscopic remission, defined as a simple endoscopic score for CD of 0. Clinical, biological (C-reactive protein), and histologic recurrences were also studied. Results: Among a total of 89 patients, 17, 46, and 26 patients had vitamin D levels of 30 ng/mL, respectively. Patients with higher vitamin D levels were significantly more likely to be in endoscopic remission compared to those with lower levels (23, 42, and 67% in ascending tertile order; p = 0.028). On multivariate analysis, vitamin D >30 ng/mL (odds ratio [OR] 0.22, 95% confidence interval [CI] 0.07–0.66, p = 0.006) and anti-tumor necrosis factor agent treatment (OR 0.25, 95% CI 0.08–0.83, p = 0.01) were associated with reduced risk of endoscopic recurrence. Rates of clinical, biological, and histologic remission trended to be higher in patients with higher vitamin D levels (p = 0.17, 0.55, 0.062, respectively). Conclusion: In the present study, higher vitamin D level was associated with lower risk of postoperative endoscopic CD recurrence. Further, studies are warranted to assess the role of vitamin D in postoperative CD recurrence.

A subset of patients with Crohn's disease (CD) do not respond to ustekinumab at the standard dose of 90 mg every 8 weeks. Little is known about the efficacy of shortening the interval between doses.We performed a retrospective study to determine the effectiveness of ustekinumab dose interval shortening, collecting data from 506 patients with CD who received subcutaneous ustekinumab 90 mg every 8 weeks at a single center. We obtained data from 110 patients who initially received subcutaneous ustekinumab 90 mg every 8 weeks and then had their interval shortened to every 4 weeks. Harvey Bradshaw Index (HBI) scores before and after the dose interval shortening was available for 78 patients in the cohort (71%), levels of C-reactive protein (CRP) for 60 patients (55%), and levels of fecal calprotectin for 8 patients (7%).Following dose interval shortening, the patients' median HBI decreased from 4.5 to 3 (P = .002), the median level of CRP decreased from 8 mg/L to 3 mg/L (P = .031), and median level of fecal calprotectin decreased from 378 μg/g to 157 μg/g (P = .57). Among patients who had an HBI4, a level of CRP ≥5mg/dL, a level of fecal calprotectin250ug/g, or endoscopic evidence for disease activity before dose interval shortening, after the dose interval was shortened, 28% achieved clinical remission (an HBI score ≤4), 22% had a normal level of CRP (5 mg/dL), 50% had reduced levels of fecal calprotectin, and 36% achieved endoscopic remission.Shortening the ustekinumab 90 mg dose interval to 4 weeks for patients with CD who did not respond to doses every 8 weeks improved clinical and biological indices of disease activity. Patients who lose response to the standard dose of ustekinumab might benefit from dose interval shortening, which was effective and safe.

Because ADAM17 promotes colonic tumorigenesis, we investigated potential miRNAs regulating ADAM17; and examined effects of diet and tumorigenesis on these miRNAs. We also examined pre-miRNA processing and tumour suppressor roles of several of these miRNAs in experimental colon cancer. Using TargetScan, miR-145, miR-148a, and miR-152 were predicted to regulate ADAM17. miR-143 was also investigated as miR-143 and miR-145 are co-transcribed and associated with decreased tumour growth. HCT116 colon cancer cells (CCC) were co-transfected with predicted ADAM17-regulating miRNAs and luciferase reporters controlled by ADAM17-3’UTR. Separately, pre-miR-143 processing by colonic cells was measured. miRNAs were quantified by RT-PCR. Tumours were induced with AOM/DSS in WT and transgenic mice (Tg) expressing pre-miR-143/miR-145 under villin promoter. HCT116 transfection with miR-145, −148a or −152, but not scrambled miRNA inhibited ADAM17 expression and luciferase activity. The latter was suppressed by mutations in ADAM17-3’UTR. Lysates from colonocytes, but not CCC, processed pre-miR-143 and mixing experiments suggested CCC lacked a competency factor. Colonic miR-143, miR-145, miR-148a, and miR-152 were downregulated in tumours and more moderately by feeding mice a Western diet. Tg mice were resistant to DSS colitis and had significantly lower cancer incidence and tumour multiplicity. Tg expression blocked up-regulation of putative targets of miR-143 and miR-145, including ADAM17, K-Ras, XPO5, and SET. miR-145, miR-148a, and miR-152 directly suppress colonocyte ADAM17 and are down-regulated in colon cancer. This is the first direct demonstration of tumour suppressor roles for miR-143 and miR-145 in an in vivo model of colonic tumorigenesis.

DNA 5-hydroxymethylcytosine (5hmC) modification is known to be associated with gene transcription and frequently used as a mark to investigate dynamic DNA methylation conversion during mammalian development and in human diseases. However, the lack of genome-wide 5hmC profiles in different human tissue types impedes drawing generalized conclusions about how 5hmC is implicated in transcription activity and tissue specificity. To meet this need, we describe the development of a 5hmC tissue map by characterizing the genomic distributions of 5hmC in 19 human tissues derived from ten organ systems. Subsequent sequencing results enabled the identification of genome-wide 5hmC distributions that uniquely separates samples by tissue type. Further comparison of the 5hmC profiles with transcriptomes and histone modifications revealed that 5hmC is preferentially enriched on tissue-specific gene bodies and enhancers. Taken together, the results provide an extensive 5hmC map across diverse human tissue types that suggests a potential role of 5hmC in tissue-specific development; as well as a resource to facilitate future studies of DNA demethylation in pathogenesis and the development of 5hmC as biomarkers., DNA 5-hydroxymethylcytosine (5hmC) modification is associated with gene transcription and used as a mark of mammalian development. Here the authors report a comprehensive 5hmC tissue map and analysis of 5hmC genomic distributions in 19 human tissues derived from 10 organ systems, thus providing insights into the role of 5hmC in tissue-specific development.

BACKGROUND Insufficient data exist for peristomal pyoderma gangrenosum (PPG), which primarily affects patients with inflammatory bowel disease (IBD). AIMS To evaluate the risk factors and treatment response of PPG in IBD patients in a real-life cohort. METHODS Cases of PPG were identified retrospectively using ICD-9/10 codes in patients with IBD who had an ostomy at a tertiary care centre. Disease-specific characteristics were compared between groups with and without PPG, and response to therapy was evaluated in patients with PPG. RESULTS The cohort included 41 IBD patients with PPG and 123 IBD controls with an ostomy who never developed PPG. Patients with PPG were more likely to be female (76% vs 51%, P = 0.006), had higher BMIs (29.78 ± 0.89 vs 23.53 ± 0.51, P

BACKGROUND: There is conflicting data assessing the impact of isolated postoperative anastomotic inflammation on future disease progression. The aim of this study was to determine the relative risk of severe disease progression in postoperative Crohn’s disease patients with isolated anastomotic disease. METHODS: Retrospective cohort study of adult Crohn’s disease patients undergoing ileocolonic resection between 2009-2020. Patients with a postoperative ileocolonoscopy ≤18 months from surgery and ≥1 subsequent ileocolonoscopy were included. Disease activity was assessed using the modified Rutgeerts’ score. Primary outcome was severe endoscopic progression, defined as i3 or i4 disease, on immediate subsequent ileocolonoscopy and during entire postoperative follow up. Secondary outcome was surgical recurrence. RESULTS: 199 Crohn’s disease patients had an ileocolonoscopy ≤18 months from surgery, index Rutgeerts’ score of i0-i2b, and ≥1 subsequent ileocolonoscopy. At index ileocolonoscopy, 34.7% had i0 disease, 16.1% i1, 24.6% i2a, and 24.6% i2b. On multivariable logistic regression, i2b disease was associated with severe endoscopic progression compared to i0 or i1 (aOR 5.53; p

Background The modified Rutgeerts’ score [RS] differentiates i2a—lesions confined to the anastomosis—and i2b—more than five aphthous ulcers in the neoterminal ileum with normal intervening mucosa, with or without anastomotic lesions—categories. Its relevance for the therapeutic management of Crohn’s disease [CD] patients after ileocolic resection is still debated. Our objective was to compare the postoperative recurrence risk in patients with an i2a or i2b score, using an individual patient data meta-analysis. Methods We conducted a systematic literature search until July 2020, to identify all relevant studies reporting the i2a/i2b status in the year following ileocolic resection and clinical and/or surgical postoperative CD recurrence in their follow-up. Individual patient-level data were obtained from the corresponding authors. The association between the modified RS and time-to-event was evaluated using a mixed Cox model with the centre as the random effect. Results Seven studies published between 2008 and 2019 were included, corresponding to 400 patients: 189 [47%] i2a and 211 [53%] i2b. Median [interquartile range, IQR] time from ileocolic resection to ileocolonoscopy was 6.2 [5.5, 7.9] months and median [IQR] follow-up time after ileocolonoscopy was 4.5 [2.9, 7.3] years. The risk of clinical postoperative recurrence at 1 and 3 years was 11% [6–15%], and 25% [18–32%] in the i2a group versus 9% [5–13%] and 33% [26–41%] in the i2b group [p = 0.63 and p = 0.12, respectively]. No significant difference was observed in terms of time to clinical postoperative recurrence [p = 0.16] or surgical postoperative recurrence [p = 0.87]. Results did not change after excluding patients having initiated an immunosuppressant or a biologic in the 3 months after endoscopy [remaining cohort, n = 361]. Conclusions In this individual patient data meta-analysis, no difference was observed between i2a and i2b subcategories with regards to clinical or surgical postoperative recurrence. As we wait for prospective trials, the same treatment strategy could be applied to all patients classified as i2 on the Rutgeerts score.

Background Models to predict colectomy in ulcerative colitis (UC) are valuable for identification, clinical management, and follow-up of high-risk patients. Our aim was to develop a clinical predictive model based on admission data for one-year colectomy in adults hospitalized for severe UC. Methods We performed a retrospective analysis of patients hospitalized at a tertiary academic center for management of severe UC from 1/2013 to 4/2018. Multivariate regression was performed to identify individual predictors of one-year colectomy. Outcome probabilities of colectomy based on the prognostic score were estimated using a bootstrapping technique. Results Two hundred twenty-nine individuals were included in the final analytic cohort. Four independent variables were associated with one-year colectomy which were incorporated into a point scoring system: (+) 1 for single class biologic exposure prior to admission; (+) 2 for multiple classes of biologic exposure; (+) 1 for inpatient salvage therapy with cyclosporine or a TNF-alpha inhibitor; (+) 1 for age Conclusion Risk factors most associated with one-year colectomy for severe UC included: prior biologic exposure, need for inpatient salvage therapy, and younger age. We developed a simple scoring system using these variables to identify and stratify patients during their index hospitalization.

Background Anti-TNF therapy remains the cornerstone of moderate to severe inflammatory bowel disease (IBD) treatment. There are few data regarding switching from subcutaneous (SubQ) to intravenous (IV) agents. We evaluated the clinical utility of cycling adalimumab (ADA) for infliximab (IFX) in IBD patients (pts) treated at a tertiary center. Methods This is a retrospective observational study where we evaluated pts with IBD who cycled from ADA to IFX from 2010 to 2018. Pts were followed for 1 year following IFX initiation. We reviewed baseline demographic and clinical data. Primary outcomes included changes in CRP and clinical disease activity indices which were statistically analyzed using Wilcoxon Signed Rank Test. Results 24 pts with Crohn’s disease (CD) and 11 with ulcerative colitis (UC) were included. Median age at time of IFX initiation in the overall cohort was 33 years with median disease duration of 10 years. Most pts in the UC cohort had pancolitis (63.6%), while the CD cohort mostly had ileocolonic disease (79.2%). Prior to IFX initiation, median baseline CRP was 8 (IQR 15), with median HBI of 3.5 (IQR 5), and SCCAI of 3.5 (IQR 4) in the CD and UC cohorts, respectively. Additional baseline demographics are in Table 1. Following median 12 months on ADA therapy in the overall cohort, 16 pts (45.7%) discontinued ADA due to primary or secondary loss of response, 8 pts (22.8%) due to anti-drug antibody formation, and 11 pts (31.4%) due to adverse events or unclear causes. At the time of starting IFX therapy, 17 pts (48.6%) were using steroids, while 24 pts (68.6%) were on immunomodulatory therapy. In the overall cohort, after cycling to IFX, median CRP was lower at 8 weeks (4; IQR 9), 26 weeks (3; IQR 11), and 52 weeks (5; IQR 10) as compared to baseline; only the 8 week CRP reached statistical significance (P=0.0447, 0.0662, and 0.0876, respectively). In the CD cohort, median CRP was significantly lower at 8 weeks (7; IQR 6; P=0.0314) and 52 weeks (5; IQR 7; P=.0410) as compared to baseline (12.5; IQR 14). Although signals of median HBI and SCCAI scores trended lower after 8 weeks, 26 weeks, and 52 weeks of IFX therapy, these did not reach statistical significance. A total of 15 pts (43.0%) stopped IFX prior to one year. Subgroup analysis of 5 pts who developed anti-ADA antibodies demonstrated statistically significant reduction of median CRP (10; IQR 22.5; P=.043) after 52 weeks of IFX therapy. Additional results are detailed in Table 2. Conclusion Cycling anti-TNF therapy from ADA to IFX offers clinical utility in preserving mechanistic benefit of TNF-α blockade in IBD pts leading to improvement of CRP, particularly in CD pts and those who developed immunogenicity to ADA.

The endoscopic appearance in patients with "pouchitis" after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) can be quite heterogenous. Patients with an endoscopic phenotype resembling Crohn's disease (CD) are at high risk of pouch loss.We aimed to assess how the histopathology of colectomy specimens predicts endoscopic pouch phenotypes in UC.We retrospectively assessed pouchoscopies from patients with UC who underwent IPAA and classified pouch findings into 7 main phenotypes: (1) normal, (2) afferent limb involvement, (3) inlet involvement, (4) diffuse, (5) focal inflammation of the pouch body, (6) cuffitis, and (7) pouch with fistulas noted ≥ 6 months from ileostomy takedown. We assessed the clinical and pathological data including deep, focal inflammation, granulomas, and terminal ileal involvement in the colectomy specimens. Logistic regression analysis was performed to identify contributing factors to each phenotype.This study included 1,203 pouchoscopies from 382 patients with UC. On multivariable analysis, deep inflammation was significantly associated with pouch fistulas (Odds ratio 3.27; 95% confidence interval 1.65-6.47; P = 0.0007). Of the 75 patients with deep inflammation, only two patients (2.7%) were diagnosed with CD based on pathology review. Terminal ileal involvement significantly increased the risk of afferent limb involvement (Odds ratio 2.96; 95% confidence interval 1.04-8.47; P = 0.04). There were no significant associations between other microscopic features and phenotypes.We identify histologic features of colectomy specimens in UC that predict subsequent pouch phenotypes. Particularly, deep inflammation in the resected colon was significantly associated with pouch fistulas, a pouch phenotype with poor prognosis.