Melissa H. Rosen

Escalation of Immunosuppressive Therapy for Inflammatory Bowel Disease Is Not Associated With Adverse Outcomes After Infection With Clostridium difficile

BACKGROUND Clostridium difficile infection (CDI) is common in patients with inflammatory bowel disease (IBD), often leading to diagnostic confusion and delays in IBD therapy escalation. This study sought to assess outcomes after CDI in IBD patients exposed to new or escalated immunosuppressive therapy. METHODS This multicenter retrospective cohort study included IBD patients with documented CDI at 4 academic medical centers. Data were abstracted from clinical databases at each institution. Outcomes at 30 and 90 days were compared between patients undergoing new or intensified immunosuppressive therapy and those without therapy escalation. Continuous variables were compared using t tests, and proportions using chi-square tests. Multivariable logistic regression was used to determine the association of individual variables with severe outcomes (including death, sepsis, and/or colectomy) within 90 days. Secondary outcomes included CDI recurrence, rehospitalization, worsening of IBD, and severe outcomes within 30 days. RESULTS A total of 207 adult patients with IBD and CDI were included, of whom 62 underwent escalation to biologic or corticosteroid therapy (median time to escalation, 13 days). Severe outcomes within 90 days occurred in 21 (15.6%) nonescalated and 1 (1.8%) therapy-escalated patients. Serum albumin <2.5 mg/dL, lactate >2.2 mg/dL, intensive care unit admission, hypotension, and comorbid disease were associated with severe outcomes. Likelihood of severe outcomes was decreased in patients undergoing escalation of IBD therapy after CDI (adjusted odds ratio [aOR], 0.12) and increased among patients aged >65 years (aOR, 4.55). CONCLUSIONS Therapy escalation for IBD within 90 days of CDI was not associated with worse clinical outcomes. Initiation of immunosuppression for active IBD may therefore be appropriate in carefully selected patients after treatment of CDI.

Perioperative Care of the Orthopedic Patient with Gastrointestinal and Liver Issues

Several gastrointestinal problems occur with relative frequency in the perioperative orthopedic setting. Abnormal preoperative liver function studies are often benign although various conditions, specifically cirrhosis, are important to define before surgery is performed; other gastrointestinal complications arise postoperatively. These include nausea, vomiting, and more severe conditions such as abdominal ileus and C. difficile colitis. Physicians involved in postoperative care need to be familiar with these conditions, the presentation of which may be subtle but may evolve producing severe morbidity. This chapter reviews the most common of the postoperative gastrointestinal problems, and the best strategy for avoiding and dealing with these perioperative complications is anticipation, prevention, and early therapy.

Su1249 The Association Between Increased Body Mass Index and Failure of Infliximab Treatment for Inflammatory Bowel Disease

Introduction: The pathogenesis of inflammatory bowel disease (IBD) is related to an unchecked inflammatory response in the gut mediated by tumor necrosis factor alpha (TNFa). Infliximab, an anti-TNFa chimeric IgGmonoclonal antibody, is a staple therapy for moderateto-severe IBD. Recent literature describes obesity as a low-grade inflammatory state as adipose tissue releases cytokines including TNFa. The purpose of this study was to determine if there is greater failure rate of infliximab therapy in obese IBD patients given theoretical increased TNFa activity. Methods: A retrospective study was performed. 103 patients who received infliximab from 2006-2012 were identified. Patient were grouped based on BMI (group 1 BMI , 18.5, group 2 BMI 18.5-25, group 3 BMI 25-30, group 4 BMI . 40). Logistic regression was performed on outcomes of the impact of weight and body mass index on surgery and loss of clinical response within one year of initiation of infliximab. Linear regression was performed on the impact of weight and body mass index on length of time of durable response of infliximab. Results: 52 women and 51 men were evaluated. The average age of the patient population when diagnosed with IBD was 26.38 years old (STD +/12.9). The average age of initiation of infliximab therapy was 33.7 years old (STD +/-13.1) with mean disease duration of 11 years (STD +/-10.79). Average BMI was 23.76lbs/ in2 (STD +/-4.44) with average weight of 155.6lbs (STD +/-38.6lbs). Average duration of infliximab therapy was 17 months (STD +/-13.67). There were no patients in group 4 (BMI . 30) that required surgery or hospitalization for complications of IBD within 1 year of initiating infliximab. Among all groups, there was no statistical significance in surgical requirements for IBD complications at 1 year. There was no significant relationship between BMI and duration of infliximab treatment, though there was a trend towards shorter duration in patients with normal BMI. Finally, there was no significant difference in ESR and CRP at 1 month into infliximab treatment across all BMI groups. Conclusions: IBD and obesity are two separate inflammatory states with shared elevated TNFa activity. This study demonstrated no statistical difference in failure rates within anti-TNFa treatment with infliximab in patients with different BMIs as measured by hospitalization and surgery secondary to complications of IBD at 1 year of therapy initiation. This study would benefit from an increase the sample size to determine if there is significance in these outcomes.

558 Outcomes After Retreatment with Cyclosporine a (CsA) in Hospitalized Ulcerative Colitis (UC) Patients: A 7-Year Review from a Single Institution

Background and Aims: Although expression of the di/tripeptide transporter PepT1 has been observed in colon under inflammatory conditions, the inducing factors and underlying mechanisms have not yet been investigated. Here, we addressed the role of pathogenic bacteria in the regulation of colonic PepT1 expression/function and the potential role of PepT1 in bacterial-epithelial interaction. Methods: Colonic HT29-Cl.19A cells were infected with enteropathogenic E. coli (EPEC). PepT1 promoter activity and PepT1 expression/activity were analyzed using the luciferase assay, RT-PCR, nuclear run-on assay, immunoblotting, immunofluorescence staining and uptake experiments. Cdx2-PepT1 promoter binding was assessed by gel-shift and chromatin immunoprecipitation assay. In Vitro experiments were validated by ex vivo and In Vivo infection of wild type and PepT1 over-expressing mice with Citrobacter rodentium. Interleukin (IL)-8 and keratinocyte-derived chemokine (KC) expression levels were quantified by real-time RT-PCR and ELISA. Results: EPEC transcriptionally induced PepT1 expression/activity in HT29-Cl.19A cells. Cdx2 over-expression in HT29-Cl.19A cells induced PepT1 expression and Cdx2 silencing markedly reduced EPECinduced PepT1 expression, indicating the importance of Cdx2 in PepT1 expression. Furthermore, PepT1 expression required intimate adherence of EPEC to host cells through lipid rafts (LRs). Importantly, PepT1 expressed upon EPEC infection is functionally localized in LRs, and PepT1 associated with LRs delayed EPEC-LR binding as monitored in real time by an electric cell-substrate impedance-sensing technique. Remarkably, PepT1 over-expression in HT29-Cl.19A cells reduced EPEC-triggered NF-κB and MAP kinase activation and IL-8 production. In agreement with In Vitro data, ex vivo and In Vivo experiments showed that C. rodentium increased PepT1 mRNA and protein expression levels in mouse colon. Furthermore, PepT1 over-expression in mouse colon reduced C. rodentium adherence and C. rodentium-induced KC production. Conclusions: We demonstrate that i) EPEC transcriptionally induces functional PepT1 expression in LRs of colonocytes by intimately attaching to host cell membranes through LRs, ii) the transcription factor Cdx2 is crucial for EPECinduced PepT1 expression, and iii) PepT1 associated with LRs is involved in bacterialepithelial interaction and intestinal inflammation. Our findings not only reveal a novel mechanism underlying the regulation of colonic epithelial PepT1 expression/function under pathological conditions, but also highlight the potential contribution of this transporter to host defense mechanisms in response to pathogenic attack.

557 colectomy rate in hospitalized ulcerative colitis patients undergoing therapy with cyclosporine (csa)

Background and Aims: Although expression of the di/tripeptide transporter PepT1 has been observed in colon under inflammatory conditions, the inducing factors and underlying mechanisms have not yet been investigated. Here, we addressed the role of pathogenic bacteria in the regulation of colonic PepT1 expression/function and the potential role of PepT1 in bacterial-epithelial interaction. Methods: Colonic HT29-Cl.19A cells were infected with enteropathogenic E. coli (EPEC). PepT1 promoter activity and PepT1 expression/activity were analyzed using the luciferase assay, RT-PCR, nuclear run-on assay, immunoblotting, immunofluorescence staining and uptake experiments. Cdx2-PepT1 promoter binding was assessed by gel-shift and chromatin immunoprecipitation assay. In Vitro experiments were validated by ex vivo and In Vivo infection of wild type and PepT1 over-expressing mice with Citrobacter rodentium. Interleukin (IL)-8 and keratinocyte-derived chemokine (KC) expression levels were quantified by real-time RT-PCR and ELISA. Results: EPEC transcriptionally induced PepT1 expression/activity in HT29-Cl.19A cells. Cdx2 over-expression in HT29-Cl.19A cells induced PepT1 expression and Cdx2 silencing markedly reduced EPECinduced PepT1 expression, indicating the importance of Cdx2 in PepT1 expression. Furthermore, PepT1 expression required intimate adherence of EPEC to host cells through lipid rafts (LRs). Importantly, PepT1 expressed upon EPEC infection is functionally localized in LRs, and PepT1 associated with LRs delayed EPEC-LR binding as monitored in real time by an electric cell-substrate impedance-sensing technique. Remarkably, PepT1 over-expression in HT29-Cl.19A cells reduced EPEC-triggered NF-κB and MAP kinase activation and IL-8 production. In agreement with In Vitro data, ex vivo and In Vivo experiments showed that C. rodentium increased PepT1 mRNA and protein expression levels in mouse colon. Furthermore, PepT1 over-expression in mouse colon reduced C. rodentium adherence and C. rodentium-induced KC production. Conclusions: We demonstrate that i) EPEC transcriptionally induces functional PepT1 expression in LRs of colonocytes by intimately attaching to host cell membranes through LRs, ii) the transcription factor Cdx2 is crucial for EPECinduced PepT1 expression, and iii) PepT1 associated with LRs is involved in bacterialepithelial interaction and intestinal inflammation. Our findings not only reveal a novel mechanism underlying the regulation of colonic epithelial PepT1 expression/function under pathological conditions, but also highlight the potential contribution of this transporter to host defense mechanisms in response to pathogenic attack.