Chung Sang Tse

Postoperative Outcomes in Vedolizumab-Treated Patients Undergoing Abdominal Operations for Inflammatory Bowel Disease

Introduction: Vedolizumab was recently approved by the Food and Drug Administration for the treatment of moderate to severe ulcerative colitis [UC] and Crohn’s disease [CD]. No study to date has examined the rate of postoperative infectious complications among patients who received vedolizumab in the perioperative period. We sought to determine the 30-day postoperative infectious complication rate among inflammatory bowel disease [IBD] patients who received vedolizumab within 12 weeks of an abdominal operation as compared to patients who received tumour necrosis factor &agr; [TNF&agr;] inhibitors or no biological therapy. Methods: A retrospective chart review between May 1, 2014 and December 31, 2015 of adult IBD patients who underwent an abdominal operation was performed. The study cohort comprised patients who received vedolizumab within 12 weeks of their abdominal operation and the control cohorts were patients who received TNF&agr; inhibitors or no biological therapy. Results: In total, 94 patients received vedolizumab within 12 weeks of an abdominal operation. Fifty experienced postoperative complications [53%], 35 of which were surgical site infections [SSIs] [36%]. The vedolizumab group experienced significantly higher rates of any postoperative infection [53% vs 33% anti-TNF and 28% non-biologics; p<0.001] and SSI [37% vs 10% and 13%; p<0.001]. On univariate and multivariate analysis, exposure to vedolizumab remained a significant predictor of postoperative SSI [p<0.001]. Conclusions: Thirty-seven per cent of IBD patients who received vedolizumab within 30 days of a major abdominal operation experienced a 30-day postoperative SSI, significantly higher than patients receiving TNF&agr; inhibitors or no biological therapy. Vedolizumab within 12 weeks of surgery remained the only predictor of 30-day postoperative SSI on multivariate analysis.

Postoperative outcomes in vedolizumab-treated Crohn's disease patients undergoing major abdominal operations

Up to 80% of patients with Crohns disease require an abdominal operation in their lifetime. As the use of vedolizumab is increasing for the treatment of Crohns disease, it is important to understand its potential association with post‐operative complications.

Nonrelaxing Pelvic Floor Dysfunction Is an Underestimated Complication of Ileal Pouch–Anal Anastomosis

Background & Aims Nonrelaxing pelvic floor dysfunction (N‐RPFD), or dyssynergic defecation, is the paradoxical contraction and/or impaired relaxation of pelvic floor and anal muscles during defecation. Few studies have evaluated this disorder in patients with an ileal pouch–anal anastomosis (IPAA). We investigated the frequency of N‐RPFD in patients with and without chronic pouchitis following IPAA and the effectiveness of biofeedback therapy within this population. Methods We conducted a retrospective study of all patients with an IPAA who underwent anorectal manometry between January 2000 and March 2015 (n = 111). N‐RPFD was diagnosed in patients with symptoms consistent with a pouch evacuation disorder and 1 or more of the following abnormal tests: anorectal manometry, balloon expulsion test, barium or magnetic resonance defecography, or external anal sphincter electromyography. Patients who completed biofeedback therapy were identified and assessed to determine symptomatic response. Results Of the 111 patients evaluated, 83 (74.8%) met criteria for N‐RPFD. A significantly higher proportion of patients with chronic pouchitis were diagnosed with N‐RPFD than patients without chronic pouchitis (83.3% vs 62.2%, respectively; P = .012). Most patients diagnosed with N‐RPFD had abnormal results from the balloon expulsion test (78.3%); 53.0% of patients diagnosed with N‐RPFD had abnormal findings from external anal sphincter electromyography, 25.3% had abnormal defecography findings, and 20.5% had abnormal findings from anorectal manometry. Twenty‐two patients completed biofeedback therapy: 15 patients (68.2%) had mild–moderate improvement and 5 patients (22.7%) had significant improvement of symptoms. Conclusions N‐RPFD occurs in almost 75% of patients with an IPAA, especially in patients with chronic pouchitis. Biofeedback seems to be an effective therapy for patients with an IPAA and N‐RPFD, but further studies are needed for validation.

Postoperative Outcomes in Ustekinumab-Treated Patients Undergoing Abdominal Operations for Crohn’s Disease

Background Ustekinumab, a monoclonal antibody targeting interleukins-12 and -23 is used to treat adults with Crohns disease [CD]. We determined the 30-day postoperative infectious complication rate among CD patients who received ustekinumab within the 12 weeks prior to an abdominal operation as compared with patients who received anti-tumor necrosis factor [TNF] agents. Methods A retrospective chart review of adults with CD who underwent an abdominal operation between January 1, 2015 and May 1, 2017 was performed across six sites. Surgical site infection [SSI] was defined as superficial skin and soft tissue infection, intra-abdominal abscess, anastomotic leak, and mucocutaneous separation of the stoma. Results Forty-four patients received ustekinumab and 169 patients received anti-TNF therapy within the 12 weeks prior to surgery. The two groups were similar, except anti-TNF patients were more likely to have received combination therapy with an immunomodulator [P = 0.006]. There were no significant differences in postoperative SSI [13% in ustekinumab versus 20% in anti TNF-treated patients, p = 0.61] or hospital readmission rates [18% versus 10%, respectively, p = 0.14], but ustekinumab-treated patients had a higher rate of return to the operating room [16% versus 5%; P = 0.01]. There were no significant predictors identified on multivariable analysis. Conclusions Of the 44 patients with CD who received ustekinumab within the 12 weeks prior to a major abdominal operation, 13% experienced a 30-day postoperative SSI, not statistically different from the 20% found in the anti-TNF cohort. Ustekinumab treatment within 12 weeks of surgery does not appear to increase the risk of postoperative SSI above that of CD patients treated with anti-TNF medications.

Effects of vedolizumab, adalimumab and infliximab on biliary inflammation in individuals with primary sclerosing cholangitis and inflammatory bowel disease

Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic biliary disease associated with inflammatory bowel disease (IBD) with no known cure.

Postoperative Outcomes in Vedolizumab-Treated Patients Undergoing Major Abdominal Operations for Inflammatory Bowel Disease: Retrospective Multicenter Cohort Study

Background Vedolizumab is now widely available for the treatment of moderate to severe ulcerative colitis (UC) and Crohns disease (CD). We sought to quantify the rates of postoperative complications with preoperative vedolizumab compared with anti-tumor necrosis factor (anti-TNF) therapy. Methods A multicenter retrospective review of adult inflammatory bowel disease (IBD) patients who underwent an abdominal operation between May 20, 2014, and December 31, 2015, was performed. The study cohort was comprised of patients who had received vedolizumab within 12 weeks of their abdominal operation, and the control cohort was IBD patients who had received anti-TNF therapy. Results A total of 146 patients received vedolizumab within 12 weeks before an abdominal operation (64% female; n = 93; median age, 33 years; range, 15-74 years), and 289 patients received anti-TNF therapy (49% female; n = 142; median age, 36 years; range, 17-73 years). Vedolizumab-treated patients were younger (P = 0.015) and were more likely to have taken corticosteroids (P < 0.01) within the 12 weeks before surgery. Vedolizumab-treated patients had a significantly increased risk of any postoperative surgical site infection (SSI; P < 0.01), superficial SSI (P < 0.01), deep space SSI (P = 0.39), and mucocutaneous separation of the diverting stoma (P < 0.00) as compared with patients taking anti-TNF therapy. On multivariate analysis, after adjusting for body mass index, steroids at the time of operation, and institution, exposure to vedolizumab remained a significant predictor of postoperative SSI (P < 0.01). Conclusions We observed that vedolizumab-treated patients were at significantly increased risk of postoperative SSIs after a major abdominal operation, as compared with anti-TNF-treated patients.

Phenotype and Clinical Course of Inflammatory Bowel Disease With Co-existent Celiac Disease

Background and Aims Inflammatory bowel diseases, principally Crohns disease and ulcerative colitis, and celiac disease are among the most common immune-mediated gastrointestinal diseases. We aim to elucidate the clinical course and outcomes of patients with concomitant inflammatory bowel disease and celiac disease, a unique population that remains scarcely studied to date. Methods A retrospective matched case-control study of adults with co-existent inflammatory bowel disease [IBD] and celiac disease was performed at a tertiary referral institution in North America. Logistic regression and Kaplan-Meier curves compared disease characteristics and clinical outcomes of the two groups. Results A total of 342 inflammatory bowel disease patients were included in this study, of whom 114 had co-existent celiac disease and 228 did not. Patients with co-existent inflammatory bowel disease and celiac disease had higher rates of primary sclerosing cholangitis [19.3% vs 5.7%; odds ratio, 4.4; 95% confidence interval, 2.1-9.4; p <0.001], extensive ulcerative colitis [78.1% vs 59.0%; odds ratio, 2.8; 95% confidence interval, 1.5-5.5; p =0.002], and family history of celiac disease [10.5% vs 3.5%; odds ratio 3.2; 95% confidence interval, 1.3-8.2; p =0.01], compared with patients without concomitant celiac disease. Conclusions Patients with inflammatory bowel disease with concomitant celiac disease have unique phenotypic features compared with non-celiac inflammatory bowel disease, with higher risks for colitis-related hospitalisations, extensive colitis, and primary sclerosing cholangitis. Increased recognition of co-existent IBD and celiac disease can prompt clinicians to investigate for concomitant disease sooner, particularly in patients with seemingly refractory disease.

Editorial: biologic therapies for primary sclerosing cholangitis-more disappointment than promise? Authors’ reply

Primary sclerosing cholangitis (PSC), an immune-mediated cholestatic liver disease characterised by chronic inflammation and fibrosis of the bile ducts, can progress to biliary cirrhosis and is a risk factor for cholangiocarcinoma. PSC is epidemiologically related to IBD such that up to 80% of PSC patients have concomitant IBD, primarily ulcerative colitis (UC). To date, ursodeoxycholic acid (UDCA), glucocorticoids and anti-tumour necrosis factor alpha agents have not been proven to halt the progression of PSC. While a cure has not yet been found, we remain hopeful in the exploration of novel therapies that may alter the natural history of PSC. One class of novel therapy being studied is bile acid derivatives, which includes 24-norursodeoxycholic acid (norUDCA) and obeticholic acid (OCA). norUDCA is a side chain-shortened derivative of UDCA that has recently been shown to significantly reduce serum alkaline phosphatase (ALP) dose-dependently in a phase II clinical trial; the efficacy and safety of norUDCA is now being evaluated in a phase III clinical trial (ClinicalTrials.gov number: NCT01755507). OCA, an analogue of chenodeoxycholic acid that functions as a farnesoid X receptor agonist, significantly reduced ALP and total bilirubin in a phase II clinical trial of patients with primary biliary cholangitis (PBC), another chronic cholestatic liver disease that results in cirrhosis and liver failure. OCA was approved by the US Food and Drug Administration (FDA) in May 2016 for the treatment of PBC and its efficacy in PBC is currently under study in a phase III clinical trial (ClinicalTrials.gov Identifier: NCT01473524). Oral biological therapies constitute another pharmacological class that could be studied as potential treatments for PSC. Molecular studies on the pathogenesis of PSC have suggested that gut-activated mucosal T lymphocytes migrate to the hepatobiliary tree and cause focal inflammation and fibrosis. Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) has been shown to be strongly expressed on inflamed portal veins and sinusoidal endothelium in autoimmune-mediated liver disease. Vedolizumab is an intravenously administered inhibitor of the a4b7 integrin, a molecule that binds to MAdCAM-1, and is involved in the trafficking of lymphocytes in the gut in IBD. Vedolizumab has been shown to be safe and efficacious in the treatment of UC and CD, and it was approved by the FDA in May 2014 for the treatment of moderateto-severe CD and UC. Tofacitinib, an oral inhibitor of janus kinase 1 (JAK1) and janus kinase 3 (JAK3), was demonstrated in phase III clinical trials to be efficacious in the treatment of moderately to severely active UC. While intravenous administration of biological therapies has not been shown to reduce biliary inflammation among patients with PSC, perhaps oral formulations of biological therapies with hepatic clearance would prove more efficacious than intravenous formulations with renal clearance. By utilising hepatic clearance, the bile ducts, in addition to the gut mucosa, would be directlty exposed to these agents. This is an important area for further exploration, as we continue to seek a cure for patients with chronically progressive PSC.

Postoperative outcomes in vedolizumab-treated pediatric patients undergoing abdominal operations for inflammatory bowel disease

INTRODUCTION Recent studies have found vedolizumab to be an independent predictor of increased rates of postoperative complications and surgical site infections (SSIs) in adults with inflammatory bowel disease (IBD), but studies in the pediatric surgical population are lacking. We sought to determine the 30-day postoperative infectious complication rate among pediatric IBD patients who received vedolizumab within 12weeks of a major abdominal operation. METHODS A retrospective chart review was performed on pediatric IBD patients who underwent an abdominal operation between 5/20/2014 and 6/1/2017. The study cohort was comprised of pediatric patients (≤18years) who received vedolizumab within 12weeks prior to their abdominal operation. The control cohort was all patients operated on for IBD during the same time on anti-TNF therapy within 12weeks of their abdominal operation. RESULTS Thirteen pediatric patients (5 female) received vedolizumab within 12weeks of an abdominal operation and 36 patients received anti TNF therapy (20 female). There were no differences in the vedolizumab and anti-TNF therapy with regard to sex, median age of diagnosis or operation, IBD type, body mass index (BMI), smoking status, diabetes mellitus (DM), preoperative serum laboratory values, steroid or immunomodulatory use. The number of biologics previously exposed to was significantly higher in the vedolizumab treated patients (p<0.0001). There were no significant differences in operative characteristics including laparoscopic versus open surgery, construction of an anastomosis, or diversion of an anastomosis. There were also no significant differences found in 30-day postoperative complications including nonsurgical site infections (SSIs), all SSIs, small bowel obstruction (SBO)/ileus, hospital readmission, or return to the operating room (ROR). There were four RORs in total: one in the vedolizumab group was for a missed enterotomy and stoma revision; three in the anti-TNF cohort were for ileostomy revisions. CONCLUSIONS None of the thirteen pediatric patients who received vedolizumab within 12weeks of an abdominal operation experienced a 30-day postoperative SSI or non SSI infectious complication, suggesting that vedolizumab is safe in the perioperative period for pediatric patients with IBD. Owing to the small sample size, future study, perhaps multi-institutional, will be important to confirm these findings. LEVEL OF EVIDENCE Retrospective comparative study, Level III.

Preoperative Clostridium difficile Infection Does Not Affect Pouch Outcomes in Patients with Ulcerative Colitis Who Undergo Ileal Pouch-anal Anastomosis

Background: The operation of choice for patients with chronic ulcerative colitis (CUC) is restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA). Pouchitis is the most common complication after IPAA. The incidence of Clostridium difficile infection (CDI) is higher in CUC patients than the general population and can lead to significant disease flares and higher rates of colectomy. We sought to determine the risk of pouchitis in patients with precolectomy CDI and 90-day postoperative IPAA complications. Methods: A retrospective case–control study was conducted on patients with CUC who underwent an IPAA between January 1, 2000 and January 10, 2015. The study cohort was comprised of patients diagnosed with CDI within 90 days before colectomy; patients with CUC without CDI comprised the control cohort. The primary outcome measure was the frequency of pouchitis after IPAA. Secondary outcomes included time to pouchitis, 90-day postoperative pouch morbidity: surgical site infection, hemorrhage, anastomotic leak, fistula formation, pouchitis treatment and response, and pouch failure requiring end-ileostomy or fecal diversion. Univariate and multivariable analysis was used to determine differences between CDI and non-CDI groups. Results: Forty-eight case patients and 154 control patients were included. Patients with preoperative CDI were younger (P = 0.010), had higher rates of medically refractory disease (P = 0.002), and had greater use of biologic therapy (P = 0.046). The rate of pouchitis was 50.0% (n = 24) and 46.8% (n = 72) (P = 0.694) among patients with and without preoperative CDI, respectively. Patients with preoperative CDI who developed pouchitis post-IPAA were more likely to require medical management with an anti-TNF&agr; (P = 0.042) and surgical management with end/diverting ileostomy (P = 0.042). Preoperative CDI was associated with higher rates of postoperative IPAA anastamotic or pouch strictures (P = 0.018). Multivariable analysis revealed primary sclerosing cholangitis (PSC) as the only variable associated with increased risk for pouchitis (OR 10.59; 95% CI, 3.07–51.08; P < 0.001). Conclusions: Preoperative CDI does not seem to be associated with an increased risk of pouchitis in patients with CUC.