Surgery for Crohn's Disease Is Associated with a Dysbiotic Microbiome and Metabolome: Results from Two Prospective Cohorts.

BACKGROUND AND AIMS: Crohn's disease is associated with alterations in the gut microbiome and metabolome described as dysbiosis. We characterized the microbial and metabolic consequences of ileal resection, the most common Crohn's disease surgery. METHODS: Patients with and without intestinal resection were identified from the Diet to Induce Remission in Crohn's Disease and Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease studies. Stool samples were analyzed with shotgun metagenomics sequencing. Fecal butyrate was measured with 1H nuclear magnetic resonance spectroscopy. Fecal bile acids and plasma 7α-hydroxy-4-cholesten-3-one (C4) was measured with mass spectrometry. RESULTS: Intestinal resection was associated with reduced alpha diversity and altered beta diversity with increased Proteobacteria and reduced Bacteroidetes and Firmicutes. Surgery was associated with higher representation of genes in the KEGG pathway for ABC transporters and reduction in genes related to bacterial metabolism. Surgery was associated with reduced concentration of the But gene but this did not translate to reduced fecal butyrate concentration. Surgery was associated with decreased abundance of bai operon genes, with increased plasma C4 concentration, increased primary bile acids and reduced secondary bile acids, including isoLCA. Additionally, E lenta, A equalofaciens and G pamelaeae were lower in abundance among patients with prior surgery in both cohorts. CONCLUSIONS: In two different populations, prior surgery in Crohn's disease is associated with altered fecal microbiome. Patients who had undergone ileal resection had reduction in the potentially beneficial bacteria E lenta and related actinobacteria as well as secondary bile acids, including isoLCA, suggesting that these could be biomarkers of patients at higher risk for disease progression.

Preoperative Exclusive Enteral Nutrition Is Associated With Reduced Skin and Soft Tissue and Intra-abdominal Infections in Patients With Crohn's Disease Undergoing Intestinal Surgery: Results from a Meta-Analysis.

BACKGROUND: Malnutrition is an independent risk factor for adverse postoperative outcomes and is common among patients with Crohn's disease (CD). The objective of this meta-analysis was to precisely quantify the association of preoperative exclusive enteral nutrition (EEN) and total parenteral nutrition (TPN) with surgical outcomes in patients undergoing intestinal surgery for CD. METHODS: PubMed, Embase, and Scopus were queried for comparative studies evaluating the impact of preoperative nutritional support on postoperative outcomes in patients undergoing surgery for CD. Random effects modeling was used to compute pooled estimates of risk difference. Heterogeneity was assessed using I2. RESULTS: Fourteen studies, all nonrandomized cohort studies, met inclusion criteria for studying EEN. After pooling data from 14 studies (874 EEN treated and 1044 control patients), the relative risk of intra-abdominal septic complications was decreased 2.1-fold in patients receiving preoperative EEN (relative risk 0.47, 95% confidence interval [CI], 0.35-0.63, I2 = 0.0%). After pooling data from 9 studies (638 EEN treated and 819 control patients), the risk of skin and soft tissue infection was decreased 1.6-fold (relative risk 0.63; 95% CI, 0.42-0.94, I2 = 42.7%). No significant differences were identified in duration of surgery, length of bowel resected, or operative blood loss. Among the 9 studies investigating TPN, no significant differences were identified in infectious outcomes. CONCLUSIONS: Preoperative nutritional optimization with EEN was associated with reduced risk of infectious complications in CD patients undergoing intestinal surgery. Preoperative nutritional support with EEN should be considered for optimizing outcomes in CD patients requiring bowel resection surgery.

Pooled data from this meta-analysis demonstrated significantly decreased rates of skin/soft tissue and intra-abdominal infections following intestinal surgery for Crohn's disease after preoperative treatment with exclusive enteral nutrition.

Effectiveness and safety of prophylactic anticoagulation among hospitalized patients with inflammatory bowel disease.

ABSTRACT: Hospitalized patients with inflammatory bowel disease (IBD) are at increased risk of venous thromboembolism (VTE). We aimed to evaluate the effectiveness and safety of prophylactic anticoagulation compared with no anticoagulation in hospitalized patients with IBD. We conducted a retrospective cohort study using a hospital-based database. We included patients with IBD who had a length of hospital stay ≥2 days between 1 January 2016 and 31 December 2019. We excluded patients who had other indications for anticoagulation, users of direct oral anticoagulants, warfarin, therapeutic-intensity heparin, and patients admitted for surgery. We defined exposure to prophylactic anticoagulation using charge codes. The primary effectiveness outcome was VTE. The primary safety outcome was bleeding. We used propensity score matching to reduce potential differences between users and nonusers of anticoagulants and Cox proportional-hazards regression to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The analysis included 56 194 matched patients with IBD (users of anticoagulants, n = 28 097; nonusers, n = 28 097). In the matched sample, prophylactic use of anticoagulants (vs no use) was associated with a lower rate of VTE (HR, 0.62; 95% CI, 0.41-0.94) and with no difference in the rate of bleeding (HR, 1.05; 95% CI, 0.87-1.26). In this study of hospitalized patients with IBD, prophylactic use of heparin was associated with a lower rate of VTE without increasing bleeding risk compared with no anticoagulation. Our results suggest potential benefits of prophylactic anticoagulation to reduce the burden of VTE in hospitalized patients with IBD.

AGA Clinical Practice Update on Diet and Nutritional Therapies in Patients With Inflammatory Bowel Disease: Expert Review.

DESCRIPTION: Diet plays a critical role in human health, but especially for patients with inflammatory bowel disease (IBD). Guidance about diet for patients with IBD are often controversial and a source of uncertainty for many physicians and patients. The role of diet has been investigated as a risk factor for IBD etiopathogenesis and as a therapy for active disease. Dietary restrictions, along with the clinical complications of IBD, can result in malnutrition, an underrecognized condition among this patient population. The aim of this American Gastroenterological Association (AGA) Clinical Practice Update (CPU) is to provide best practice advice statements, primarily to clinical gastroenterologists, covering the topics of diet and nutritional therapies in the management of IBD, while emphasizing identification and treatment of malnutrition in these patients. We provide guidance for tailored dietary approaches during IBD remission, active disease, and intestinal failure. A healthy Mediterranean diet will benefit patients with IBD, but may require accommodations for food texture in the setting of intestinal strictures or obstructions. New data in Crohn's disease supports the use of enteral liquid nutrition to help induce remission and correct malnutrition in patients heading for surgery. Parenteral nutrition plays a critical role in patients with IBD facing acute and/or chronic intestinal failure. Registered dietitians are an essential part of the interdisciplinary team approach for optimal nutrition assessment and management in the patient population with IBD. METHODS: This expert review was commissioned and approved by the AGA Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the CPU Committee and external peer review through standard procedures of Gastroenterology. The best practice advice statements were drawn from reviewing existing literature combined with expert opinion to provide practical advice on the role of diet and nutritional therapies in patients with IBD. Because this was not a systematic review, formal rating of the quality of evidence or strength of the presented considerations was not performed. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Unless there is a contraindication, all patients with IBD should be advised to follow a Mediterranean diet rich in a variety of fresh fruits and vegetables, monounsaturated fats, complex carbohydrates, and lean proteins and low in ultraprocessed foods, added sugar, and salt for their overall health and general well-being. No diet has consistently been found to decrease the rate of flares in adults with IBD. A diet low in red and processed meat may reduce ulcerative colitis flares, but has not been found to reduce relapse in Crohn's disease. BEST PRACTICE ADVICE 2: Patients with IBD who have symptomatic intestinal strictures may not tolerate fibrous, plant-based foods (ie, raw fruits and vegetables) due to their texture. An emphasis on careful chewing and cooking and processing of fruits and vegetables to a soft, less fibrinous consistency may help patients with IBD who have concomitant intestinal strictures incorporate a wider variety of plant-based foods and fiber in their diets. BEST PRACTICE ADVICE 3: Exclusive enteral nutrition using liquid nutrition formulations is an effective therapy for induction of clinical remission and endoscopic response in Crohn's disease, with stronger evidence in children than adults. Exclusive enteral nutrition may be considered as a steroid-sparing bridge therapy for patients with Crohn's disease. BEST PRACTICE ADVICE 4: Crohn's disease exclusion diet, a type of partial enteral nutrition therapy, may be an effective therapy for induction of clinical remission and endoscopic response in mild to moderate Crohn's disease of relatively short duration. BEST PRACTICE ADVICE 5: Exclusive enteral nutrition may be an effective therapy in malnourished patients before undergoing elective surgery for Crohn's disease to optimize nutritional status and reduce postoperative complications. BEST PRACTICE ADVICE 6: In patients with IBD who have an intra-abdominal abscess and/or phlegmonous inflammation that limits ability to achieve optimal nutrition via the digestive tract, short-term parenteral nutrition may be used to provide bowel rest in the preoperative phase to decrease infection and inflammation as a bridge to definitive surgical management and to optimize surgical outcomes. BEST PRACTICE ADVICE 7: We suggest the use of parenteral nutrition for high-output gastrointestinal fistula, prolonged ileus, short bowel syndrome, and for patients with IBD with severe malnutrition when oral and enteral nutrition has been trialed and failed or when enteral access is not feasible or contraindicated. BEST PRACTICE ADVICE 8: In patients with IBD and short bowel syndrome, long-term parenteral nutrition should be transitioned to customized hydration management (ie, intravenous electrolyte support and/or oral rehydration solutions) and oral intake whenever possible to decrease the risk of developing long-term complications. Treatment with glucagon-like peptide-2 agonists can facilitate this transition. BEST PRACTICE ADVICE 9: All patients with IBD warrant regular screening for malnutrition by their provider by means of assessing signs and symptoms, including unintended weight loss, edema and fluid retention, and fat and muscle mass loss. When observed, more complete evaluation for malnutrition by a registered dietitian is indicated. Serum proteins are no longer recommended for the identification and diagnosis of malnutrition due to their lack of specificity for nutritional status and high sensitivity to inflammation. BEST PRACTICE ADVICE 10: All patients with IBD should be monitored for vitamin D and iron deficiency. Patients with extensive ileal disease or prior ileal surgery (resection or ileal pouch) should be monitored for vitamin B12 deficiency. BEST PRACTICE ADVICE 11: All outpatients and inpatients with complicated IBD warrant co-management with a registered dietitian, especially those who have malnutrition, short bowel syndrome, enterocutaneous fistula, and/or are requiring more complex nutrition therapies (eg, parenteral nutrition, enteral nutrition, or exclusive enteral nutrition), or those on a Crohn's disease exclusion diet. We suggest that all newly diagnosed patients with IBD have access to a registered dietitian. BEST PRACTICE ADVICE 12: Breastfeeding is associated with a lower risk for diagnosis of IBD during childhood. A healthy, balanced, Mediterranean diet rich in a variety of fruits and vegetables and decreased intake of ultraprocessed foods have been associated with a lower risk of developing IBD.

Visceral Adiposity Independently Predicts Time to Flare in Inflammatory Bowel Disease but Body Mass Index Does Not.

BACKGROUND: Obesity is associated with progression of inflammatory bowel disease (IBD). Visceral adiposity may be a more meaningful measure of obesity compared with traditional measures such as body mass index (BMI). This study compared visceral adiposity vs BMI as predictors of time to IBD flare among patients with Crohn's disease and ulcerative colitis. METHODS: This was a retrospective cohort study. IBD patients were included if they had a colonoscopy and computed tomography (CT) scan within a 30-day window of an IBD flare. They were followed for 6 months or until their next flare. The primary exposure was the ratio of visceral adipose tissue to subcutaneous adipose tissue (VAT:SAT) obtained from CT imaging. BMI was calculated at the time of index CT scan. RESULTS: A total of 100 Crohn's disease and 100 ulcerative colitis patients were included. The median age was 43 (interquartile range, 31-58) years, 39% had disease duration of 10 years or more, and 14% had severe disease activity on endoscopic examination. Overall, 23% of the cohort flared with median time to flare 90 (interquartile range, 67-117) days. Higher VAT:SAT was associated with shorter time to IBD flare (hazard ratio of 4.8 for VAT:SAT ≥1.0 vs VAT:SAT ratio <1.0), whereas higher BMI was not associated with shorter time to flare (hazard ratio of 0.73 for BMI ≥25 kg/m2 vs BMI <25 kg/m2). The relationship between increased VAT:SAT and shorter time to flare appeared stronger for Crohn's than for ulcerative colitis. CONCLUSIONS: Visceral adiposity was associated with decreased time to IBD flare, but BMI was not. Future studies could test whether interventions that decrease visceral adiposity will improve IBD disease activity.

An increased ratio of visceral to subcutaneous adipose tissue was associated with a shorter time to flare in patients with both Crohn's and ulcerative colitis. Conversely, increased body mass index was not associated with a shorter time to flare in inflammatory bowel disease patients.

Real-world Evidence Comparing Tofacitinib and Vedolizumab in Anti-TNF-experienced Patients With Ulcerative Colitis.

BACKGROUND: Antitumor necrosis factor (anti-TNF) inhibitors are first-line treatment among patients with ulcerative colitis (UC). With time, patients tend to lose response or become intolerant, necessitating switching to small cell biologics such as tofacitinib or vedolizumab. In this real-world study of a large, geographically diverse US population of TNF-experienced patients with UC, we evaluated the effectiveness and safety of newly initiating treatment with tofacitinib vs vedolizumab. METHODS: We conducted a cohort study using secondary data from a large US insurer (Anthem, Inc.). Our cohort included patients with UC newly initiating treatment with tofacitinib or vedolizumab. Patients were required to have evidence of treatment with anti-TNF inhibitors in the 6 months prior to cohort entry. The primary outcome was treatment persistence >52 weeks. Additionally, we evaluated the following secondary outcomes as additional measures of effectiveness and safety: (1) all-cause hospitalization; (2) total abdominal colectomy; (3) hospitalization for infection; (4) hospitalization for malignancy; (5) hospitalization for cardiac events; and (6) hospitalization for thromboembolic events. We used fine stratification by propensity scores to control for confounding by demographics, clinical factors, and treatment history at baseline. RESULTS: Our primary cohort included 168 new users of tofacitinib and 568 new users of vedolizumab. Tofacitinib was associated with lower treatment persistence (adjusted risked ratio, 0.77; 95% CI, 0.60 -0.99). Differences in secondary measures of effectiveness or safety between tofacitinib initiators vs vedolizumab initiators were not statistically significant (all-cause hospitalization, adjusted hazard ratio, 1.23; 95% CI, 0.83-1.84; total abdominal colectomy, adjusted HR, 1.79; 95% CI, 0.93-3.44;and hospitalization for any infection, adjusted HR, 1.94; 95% CI, 0.83-4.52). DISCUSSION: Ulcerative colitis patients with prior anti-TNF experience initiating tofacitinib demonstrated lower treatment persistence compared with those initiating vedolizumab. This finding is in contrast to other recent studies suggesting superior effectiveness of tofacitinib. Ultimately, head-to-head randomized, controlled trials that focus on directly measured end points may be needed to best inform clinical practice.

Anti-TNF-experienced patients with UC initiating vedolizumab demonstrated higher treatment persistence compared with those initiating tofacitinib in this real-world evaluation of comparative effectiveness. Ultimately, head-to-head randomized trials that focus on directly measured end points are needed to best inform clinical practice.

Corticosteroids but not Anti-TNF Are Associated With Increased COVID-19 Complications in Patients With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Immunosuppressed individuals are at higher risk for COVID-19 complications, yet data in patients with inflammatory bowel disease (IBD) are limited. We evaluated the risk of COVID-19- severe sequelae by medication utilization in a large cohort of patients with IBD. METHODS: We conducted a retrospective cohort study utilizing insurance claims data between August 31, 2019, and August 31, 2021.We included IBD patients identified by diagnosis and treatment codes. Use of IBD medications was defined in the 90 days prior to cohort entry. Study outcomes included COVID-19 hospitalization, mechanical ventilation, and inpatient death. Patients were followed until the outcome of interest, outpatient death, disenrollment, or end of study period. Due to the aggregate nature of available data, we were unable to perform multivariate analyses. RESULTS: We included 102 986 patients (48 728 CD, 47 592 UC) with a mean age of 53 years; 55% were female. Overall, 412 (0.4%) patients were hospitalized with COVID-19. The incidence of hospitalization was higher in those on corticosteroids (0.6% vs 0.3%; P < .0001; 13.6 per 1000 person-years; 95% confidence interval [CI], 10.8-16.9) and lower in those receiving anti-tumor necrosis factor α therapy (0.2% vs 0.5%; P < .0001; 3.9 per 1000 person-years; 95% CI, 2.7-5.4). Older age was associated with increased hospitalization with COVID-19. Overall, 71 (0.07%) patients required mechanical ventilation and 52 (0.05%) died at the hospital with COVID-19. The proportion requiring mechanical ventilation (1.9% vs 0.05%; P < .0001; 3.9 per 1000 person-years; 95% CI, 2.5-5.9) was higher among users of corticosteroids. CONCLUSIONS: Among patients with IBD, those on corticosteroids had more hospitalizations and mechanical ventilation with COVID-19. Anti-tumor necrosis factor α therapy was associated with a decreased risk of hospitalization. These findings reinforce previous guidance to taper and/or discontinue corticosteroids in IBD.

Validation of the bowel urgency numeric rating scale in patients with Crohn's disease: results from a mixed methods study.

PURPOSE: Bowel urgency (BU) is an important symptom of Crohn's disease (CD), however there is no patient-reported outcome (PRO) scale validated in this population to assess BU severity. Here we evaluated the content validity and psychometric properties of the Urgency Numeric Rating Scale (NRS). METHOD: Qualitative interviews were conducted with moderate-to-severe CD participants to confirm importance and relevance of BU in this population, cognitively debrief the Urgency NRS, and explore score interpretation and CD remission. A quantitative web survey study was conducted to explore the measurement properties of the urgency NRS. RESULTS: Qualitative Interview: 34 of 35 participants reported BU. It was most bothersome for 44%, 47% reported it daily, 18% with every bowel movement. BU had a severe impact on daily activities, causing many participants to stay home more than preferred. Patients confirmed the relevance, appropriateness, comprehensibility of the item, recall period, response options, and instructions of the Urgency NRS. Small reductions on the Urgency NRS score reflected meaningful improvements. Quantitative survey: The study sample comprised 76 participants (65.8% female). Mean Urgency NRS score was 4.7 (SD 2.26; N = 76) at Week 1, with no floor/ceiling effect. Test-retest reliability was acceptable. Construct and known-groups validity against selected PROs were overall strong and within ranges hypothesized a priori. CONCLUSION: The Urgency NRS is a valid and reliable instrument to assess BU severity in CD.

Update on Endoscopic Dysplasia Surveillance in Inflammatory Bowel Disease.

As medical management of inflammatory bowel disease makes great advances, most patients with inflammatory bowel disease will have long life expectancies without need for total colectomy. With prolonged disease duration, however, there is increased risk of dysplasia leading to colorectal cancer. Multiple consensus and guideline documents have been published over the last decade with recommendations to optimize early detection and management of dysplastic lesions. Endoscopic technology has improved tremendously, even over the past few years. Previously invisible dysplasia has become visible in most cases with advanced imaging technologies that now allow for much clearer and more detailed mucosal inspection. New tools to facilitate endoscopic resection of visible lesions have also enabled patients to avoid colectomy, with resulting need to continue colon surveillance. There are limited or conflicting data leading to inconsistent recommendations regarding the need for random biopsies, the preferred endoscopic imaging technique, and surveillance intervals after resection of dysplasia. Similarly, there remains significant variability in the application of guidelines into daily practice and availability of and training with advanced imaging technologies. Here, we present a narrative review of which patients are at highest risk for dysplasia, the current guidelines on surveillance colonoscopy, factors affecting optimal mucosal visualization, enhanced imaging techniques, standardized reporting terminologies for surveillance colonoscopy, endoscopic management of dysplasia, indications for colectomy, and briefly on future potential technologies to assist in dysplasia detection.

Comparing Patient-Reported Outcomes Among Anti-TNF Experienced Patients With Ulcerative Colitis Initiating Vedolizumab Versus Tofacitinib.

Background: Primary and secondary nonresponse to anti-tumor necrosis factor (TNF) therapy is common in patients with ulcerative colitis (UC), yet limited research has compared the effectiveness of subsequent biological therapy. Objective: We sought to compare the effectiveness of vedolizumab and tofacitinib in anti-TNF experienced patients with UC, focusing on patient-prioritized patient-reported outcomes (PROs). Methods: We conducted a prospective cohort study nested within the Crohn's & Colitis Foundation's IBD Partners and SPARC IBD initiatives. We identified anti-TNF experienced patients with UC initiating vedolizumab or tofacitinib and analyzed PROs reported approximately 6 months later (minimum 4 months, maximum 10 months). Co-primary outcomes were Patient Reported Outcome Measurement Information System (PROMIS) domains of Fatigue and Pain Interference. Secondary outcomes included PRO2, treatment persistence, and need for colectomy. Results: We compared 72 vedolizumab initiators and 33 tofacitinib initiators. At follow-up, Pain Interference (P = .04), but not Fatigue (P = .53) was lower among tofacitinib initiators. A trend toward higher Social Role Satisfaction was not significant. The remainder of secondary outcomes (PRO2, treatment persistence, colectomy) did not differ between treatment groups. Conclusions: Among anti-TNF experienced patients with UC, Pain Interference 4-10 months after treatment initiation was lower among tofacitinib users as compared with vedolizumab users. Many, but not all, secondary endpoints and subanalyses also favored tofacitinib. Future studies with larger sample sizes are needed to further evaluate these findings.

Utilization of Treat-to-Target Monitoring Colonoscopy After Treatment Initiation in the US-Based Study of a Prospective Adult Research Cohort With Inflammatory Bowel Disease.

INTRODUCTION: Endoscopic healing has been associated with improved long-term clinical outcomes in inflammatory bowel disease (IBD) and is a recommended target for treatment. Evidence is limited regarding real-world uptake and patterns of treat-to-target monitoring to assess endoscopic healing after treatment initiation. We aimed to estimate the proportion of patients in the Study of a Prospective Adult Research Cohort with IBD (SPARC IBD) who received colonoscopy in the 3-15 months after starting a new IBD treatment. METHODS: We identified SPARC IBD patients who initiated a new biologic (infliximab, adalimumab, certolizumab pegol, golimumab, vedolizumab, and ustekinumab) or tofacitinib. We estimated the proportion of patients who received colonoscopies in the 3-15 months after IBD treatment initiation and described use by patient subgroups. RESULTS: Among 1,708 eligible initiations from 2017 to 2022, the most common medications were ustekinumab (32%), infliximab (22%), vedolizumab (20%), and adalimumab (16%). The median patient age was 38 years, with 66% Crohn's disease; 55% were female, and 12% were non-White. In the 3-15 months after medication initiation, 49.3% (95% confidence interval 46.2%-52.5%) of initiations were followed by a colonoscopy. Colonoscopy use was similar between ulcerative colitis and Crohn's disease, but was higher among male patients, those older than 40 years, and those who received colonoscopy within 3 months of initiation. Colonoscopy use varied between study sites, from 26.6% (15.0%-38.3%) to 63.2% (54.5%-72.0%). DISCUSSION: Approximately half of SPARC IBD patients received colonoscopy in the 3-15 months after initiation to a new IBD treatment, suggesting a low uptake of treat-to-target colonoscopy for the assessment of mucosal healing in real-world clinical practice. The variation in colonoscopy use between study sites suggests a lack of consensus and a need for more robust evidence around whether or not the practice of routine monitoring colonoscopy is associated with improved patient outcomes.

Real-World Evidence Comparing Vedolizumab and Ustekinumab in Antitumor Necrosis Factor-Experienced Patients With Crohn's Disease.

INTRODUCTION: Many patients with Crohn's disease (CD) lose response or become intolerant to antitumor necrosis factor (TNF) therapy and subsequently switch out of class. We compared the effectiveness and safety of ustekinumab to vedolizumab in a large, geographically diverse US population of TNF-experienced patients with CD. METHODS: We conducted a retrospective cohort study using longitudinal claims data from a large US insurer (Anthem, Inc.). We identified patients with CD initiating vedolizumab or ustekinumab with anti-TNF treatment in the prior 6 months. Our primary outcome was treatment persistence for >52 weeks. Secondary outcomes included (i) all-cause hospitalization, (ii) hospitalization for CD with surgery, (iii) hospitalization for CD without surgery, and (iv) hospitalization for infection. Propensity score fine stratification was used to control for demographic and baseline clinical characteristics and prior treatments. RESULTS: Among 885 new users of ustekinumab and 490 new users of vedolizumab, we observed no difference in treatment persistence (adjusted risk ratio 1.09 [95% confidence interval 0.95-1.25]). Ustekinumab was associated with a lower rate of all-cause hospitalization (adjusted hazard ratio 0.73 [0.59-0.91]), nonsurgical CD hospitalization (adjusted hazard ratio 0.58 [0.40-0.83]), and hospitalization for infection (adjusted hazard ratio 0.56 [0.34-0.92]). DISCUSSION: This real-world comparative effectiveness study of anti-TNF-experienced patients with CD initiating vedolizumab or ustekinumab showed similar treatment persistence rates beyond 52 weeks, although secondary outcomes such as all-cause hospitalizations, nonsurgical CD hospitalizations, and hospitalizations for infection favored ustekinumab initiation. We, therefore, advocate for individualized decision making in this medically refractory population, considering patient preference and other factors such as cost and route of administration.

Association Between Bariatric Surgery and Alcohol Use-Related Hospitalization and All-Cause Mortality in a Veterans Affairs Cohort.

Importance: Bariatric surgery procedures, in particular Roux-en-Y gastric bypass (RYGB), have been associated with subsequent alcohol-related complications. However, previous studies lack data to account for changes in body mass index (BMI) or alcohol use over time, which are key potential confounders. Objective: To evaluate the association between RYGB, sleeve gastrectomy, or gastric banding on subsequent alcohol use disorder (AUD)-related hospitalization and all-cause mortality as compared with referral to a weight management program alone. Design, Setting, and Participants: This cohort study included 127 Veterans Health Administration health centers in the US. Patients who underwent RYGB, sleeve gastrectomy, or gastric banding or who were referred to MOVE!, a weight management program, and had a BMI (calculated as weight in kilograms divided by height in meters squared) of 30 or greater between January 1, 2008, and December 31, 2021, were included in the study. Exposures: RYGB, sleeve gastrectomy, or gastric banding or referral to the MOVE! program. Main Outcomes and Measures: The primary outcome was time to AUD-related hospitalization from the time of bariatric surgery or MOVE! referral. The secondary outcome was time to all-cause mortality. Separate propensity scores were created for each pairwise comparison (RYGB vs MOVE! program, RYGB vs sleeve gastrectomy, sleeve gastrectomy vs MOVE!). Sequential Cox regression approaches were used for each pairwise comparison to estimate the relative hazard of the primary outcome in unadjusted, inverse probability treatment weighting (IPTW)-adjusted (generated from the pairwise logistic regression models), and IPTW-adjusted approaches with additional adjustment for time-updating BMI and categorical Alcohol Use Disorders Identification Test-Concise scores. Results: A total of 1854 patients received RYGB (median [IQR] age, 53 [45-60] years; 1294 men [69.8%]), 4211 received sleeve gastrectomy (median [IQR] age, 52 [44-59] years; 2817 men [66.9%]), 265 received gastric banding (median [IQR] age, 55 [46-61] years; 199 men [75.1%]), and 1364 were referred to MOVE! (median [IQR] age, 59 [49-66] years; 1175 men [86.1%]). In IPTW Cox regression analyses accounting for time-updating alcohol use and BMI, RYGB was associated with an increased hazard of AUD-related hospitalization vs MOVE! (hazard ratio [HR], 1.70; 95% CI, 1.20-2.41; P = .003) and vs sleeve gastrectomy (HR, 1.98; 95% CI, 1.55-2.53; P < .001). There was no significant difference between sleeve gastrectomy and MOVE! (HR, 0.76; 95% CI, 0.56-1.03; P = .08). While RYGB was associated with a reduced mortality risk vs MOVE! (HR, 0.63; 95% CI, 0.49-0.81; P < .001), this association was mitigated by increasing alcohol use over time. Conclusions and Relevance: This cohort study found that RYGB was associated with an increased risk of AUD-related hospitalizations vs both sleeve gastrectomy and the MOVE! program. The mortality benefit associated with RYGB was diminished by increased alcohol use, highlighting the importance of careful patient selection and alcohol-related counseling for patients undergoing this procedure.

Supratherapeutic Infliximab Levels Do Not Predict Risk of Short-term Complications in Adults With Crohn's Disease.

BACKGROUND: It is uncertain if higher infliximab trough levels (TLs) confer a greater risk of infectious/noninfectious complications (IC/NIC). We aimed to assess the risk of IC and NIC in patients with different TLs. METHODS: We retrospectively evaluated a cohort of Crohn's disease (CD) patients treated with infliximab who underwent therapeutic drug monitoring (TDM), at a tertiary inflammatory bowel disease center, between January 1, 2010, and December 1, 2019. TDM was defined as checking of infliximab trough and antibody levels within a 48-hour period before administration. Patients with a minimum of 3-month assessment pre-TDM and post-TDM were included. In the case of multiple TDMs, the highest TL was considered, and patients were distributed across 4 predefined TL groups (A: <5 µg/mL, B: 5 to 10 µg/mL, C: 10 to 15 µg/mL, and D: ≥15 µg/mL). Rates of IC and NIC during the 3-month prior and following TDM were compared across the groups. In addition, duration of exposure, in terms of months up to TDM, was collected to analyze differences in rates of IC and NIC. RESULTS: Our study included 341 CD patients (median age: 35 y, 58% men). IC and NIC occurred in 52 (15%) and 30 (9%) patients, respectively. Rates of IC and NIC were similar across the 4 TL groups ( P =0.9 and 0.7, respectively for IC and NIC). On multivariable analysis, exposure to infliximab >40 months (as determined by receiver operating characteristic curve analysis) was associated with decreased odds for IC (adjusted odds ratio=0.51, P =0.04), but not NIC (adjusted odds ratio=0.72, P =0.46). CONCLUSIONS: In this large CD cohort, there was no association between infliximab TL and risk of short-term IC or NIC. Interestingly, a shorter duration of exposure predicted higher rates of IC. This supports the safety of targeting higher infliximab TLs when necessary and greater vigilance during the early stages of treatment.

Successful Dietary Therapy in Paediatric Crohn's Disease is Associated with Shifts in Bacterial Dysbiosis and Inflammatory Metabotype Towards Healthy Controls.

BACKGROUND AND AIMS: Nutritional therapy with the Crohn's Disease Exclusion Diet + Partial Enteral Nutrition [CDED+PEN] or Exclusive Enteral Nutrition [EEN] induces remission and reduces inflammation in mild-to-moderate paediatric Crohn's disease [CD]. We aimed to assess if reaching remission with nutritional therapy is mediated by correcting compositional or functional dysbiosis. METHODS: We assessed metagenome sequences, short chain fatty acids [SCFA] and bile acids [BA] in 54 paediatric CD patients reaching remission after nutritional therapy [with CDED + PEN or EEN] [NCT01728870], compared to 26 paediatric healthy controls. RESULTS: Successful dietary therapy decreased the relative abundance of Proteobacteria and increased Firmicutes towards healthy controls. CD patients possessed a mixture of two metabotypes [M1 and M2], whereas all healthy controls had metabotype M1. M1 was characterised by high Bacteroidetes and Firmicutes, low Proteobacteria, and higher SCFA synthesis pathways, and M2 was associated with high Proteobacteria and genes involved in SCFA degradation. M1 contribution increased during diet: 48%, 63%, up to 74% [Weeks 0, 6, 12, respectively.]. By Week 12, genera from Proteobacteria reached relative abundance levels of healthy controls with the exception of E. coli. Despite an increase in SCFA synthesis pathways, remission was not associated with increased SCFAs. Primary BA decreased with EEN but not with CDED+PEN, and secondary BA did not change during diet. CONCLUSION: Successful dietary therapy induced correction of both compositional and functional dysbiosis. However, 12 weeks of diet was not enough to achieve complete correction of dysbiosis. Our data suggests that composition and metabotype are important and change quickly during the early clinical response to dietary intervention. Correction of dysbiosis may therefore be an important future treatment goal for CD.

Modeling Optimal Clinical Thresholds for Elective Abdominal Hernia Repair in Patients With Cirrhosis.

Importance: Patients with cirrhosis have increased risk of postoperative mortality. Several models have been developed to estimate this risk; however, current risk estimation scores cannot compare surgical risk with the risk of not operating. Objective: To identify clinical optimal thresholds to favor operative or nonoperative management for a common cirrhosis surgical scenario, the symptomatic abdominal hernia. Design, Setting, and Participants: This was a Markov cohort decision analytical modeling study evaluating elective surgery vs nonoperative management for a symptomatic abdominal hernia in a patient with cirrhosis. Transition probabilities and utilities were derived from the literature and from data using an established cirrhosis cohort in the Veterans Health Administration. Participants included patients who were referred to a surgery clinic for a symptomatic abdominal hernia. Data were obtained from patients diagnosed with cirrhosis between January 1, 2008 and December 31, 2018. Data were analyzed from January 1 to May 1, 2022. Main Outcomes and Measures: Expected quality-adjusted life-years (QALYs) were estimated for each pathway and iterated over baseline model for end-stage liver disease-sodium (MELD-Na) scores ranging from 6 to 25. Markov models were cycled over a 5-year time horizon. Results: A total 2740 patients with cirrhosis (median [IQR] age, 62 [56-66] years; 2699 [98.5%] men) were referred to a surgery clinic for a symptomatic abdominal hernia; 1752 patients (63.9%) did not receive surgery. The median (IQR) follow-up was 42.1 (25.3-70.0) months. Using this cohort to estimate the mortality risk of operative and nonoperative pathways, an initial MELD-Na threshold of 21.3 points, below which surgery was associated with maximized QALYs was identified. Nonoperative management was associated with increased QALYs above this MELD-Na threshold. Although more patients experienced death with a surgical treatment decision across all initial MELD-Na values, this was counterbalanced by increased time spent in a resolved hernia state associated with increased utility. Model results were sensitive to the probability of hernia recurrence and hernia incarceration and utility decrement in the symptomatic hernia state. Conclusions and Relevance: This decision analytical model study found that elective surgical treatment for a symptomatic abdominal hernia was favored even in the setting of relatively high MELD-Na scores. Patient symptoms, hernia-specific characteristics, and surgeon and center expertise may potentially impact the optimal strategy, emphasizing the importance of shared decision-making.

Ustekinumab versus adalimumab for induction and maintenance therapy in biologic-naive patients with moderately to severely active Crohn's disease: a multicentre, randomised, double-blind, parallel-group, phase 3b trial.

BACKGROUND: Active-comparator trials are important to inform patient and physician choice. We aimed to evaluate the efficacy and safety of monotherapy with either ustekinumab or adalimumab in biologic-naive patients with moderately to severely active Crohn's disease. METHODS: We conducted a randomised, double-blind, parallel-group, active-comparator, phase 3b trial (SEAVUE) at 121 hospitals or private practices in 18 countries. We included biologic-naive patients aged 18 years or older with moderately to severely active Crohn's disease and a Crohn's Disease Activity Index (CDAI) score of 220-450, who had not responded to or were intolerant to conventional therapy (or were corticosteroid dependent) and had at least one ulcer of any size at baseline endoscopic evaluation. Eligible patients were randomly assigned (1:1; via an interactive web response system) to receive ustekinumab (approximately 6 mg/kg intravenously on day 0, then 90 mg subcutaneously once every 8 weeks) or adalimumab (160 mg on day 0, 80 mg at 2 weeks, then 40 mg once every 2 weeks, subcutaneously) through week 56. Study treatments were administered as monotherapy and without dose modifications. Patients, investigators, and study site personnel were masked to treatment group assignment. The primary endpoint was the proportion of patients who were in clinical remission (CDAI score <150) at week 52 in the intention-to-treat population (ie, all patients who were randomly assigned to a treatment group). This trial is registered with ClinicalTrials.gov, NCT03464136, and EudraCT, 2017-004209-41. FINDINGS: Between June 28, 2018, and Dec 12, 2019, 633 patients were assessed for eligibility and 386 were enrolled and randomly assigned to receive ustekinumab (n=191) or adalimumab (n=195). 29 (15%) of 191 patients in the ustekinumab group and 46 (24%) of 195 in the adalimumab group discontinued study treatment before week 52. There was no significant difference between the ustekinumab and adalimumab groups in the occurrence of the primary endpoint; at week 52, 124 (65%) of 191 patients in the ustekinumab group versus 119 (61%) of 195 in the adalimumab group were in clinical remission (between-group difference 4%, 95% CI -6 to 14; p=0·42). Safety for both groups was consistent with previous reports. Serious infections were reported in four (2%) of 191 patients in the ustekinumab group and five (3%) of 195 in the adalimumab group. No deaths occurred through week 52 of the study. INTERPRETATION: Both ustekinumab and adalimumab monotherapies were highly effective in this population of biologic-naive patients, with no difference in the primary outcome between the drugs. FUNDING: Janssen Scientific Affairs.

Comparative Effectiveness of Surveillance Colonoscopy Intervals on Colorectal Cancer Outcomes in a National Cohort of Patients with Inflammatory Bowel Disease.

BACKGROUND & AIMS: Surveillance colonoscopy is recommended to reduce colorectal cancer (CRC)-related morbidity and mortality in patients with inflammatory bowel disease (IBD). The comparative effectiveness of varying colonoscopy intervals on CRC outcomes among patients with IBD is unknown. METHODS: We performed a retrospective cohort study of patients with confirmed CRC within a cohort of 77,824 patients with IBD during 2000 to 2015 in the National Veterans Health Administration. We examined the association between colonoscopy surveillance intervals on CRC stage, treatment, or all-cause and cancer-specific mortality. The interval of colonoscopy prior to CRC diagnosis was categorized as those performed within <1 year, 1 to 3 years, 3 to 5 years, or none within 5 years. RESULTS: Among 566 patients with CRC-IBD, most (69.4%) did not have colonoscopy within 5 years prior to CRC diagnosis, whereas 9.7% had colonoscopy within 1 year prior to diagnosis, 17.7% within 1 to 3 years, and 3.1% between 3 and 5 years. Compared with no surveillance, colonoscopy within 1 year (adjusted odds ratio, 0.40; 95% confidence interval [CI], 0.20-0.82), and 1 to 3 years (adjusted odds ratio, 0.56; 95% CI, 0.32-0.98) were less likely to be diagnosed at late stage. Regardless of IBD type and duration, colonoscopy within 1 year was associated with a lower all-cause mortality (adjusted hazard ratio, 0.56; 95% CI, 0.36-0.88). CONCLUSIONS: In a national cohort of patients with CRC-IBD, colonoscopy within 3 years prior to CRC diagnosis was associated with early tumor stage at diagnosis, and colonoscopy within 1 year was associated with a reduced all-cause mortality compared with no colonoscopy. Our findings support colonoscopy intervals of 1 to 3 years in patients with IBD to reduce late-stage CRC and all-cause mortality.

Delays Related to Prior Authorization in Inflammatory Bowel Disease.

BACKGROUND: Delays in advancing to biologic therapies are associated with adverse outcomes in inflammatory bowel disease (IBD). Insurer-mandated prior authorizations have been linked to prolonged medication initiation times. We hypothesized that prior authorizations are associated with prolonged biologic initiation time and increased IBD-related healthcare utilization among children with IBD. METHODS: We performed a retrospective cohort study of 190 pediatric patients with IBD initiating biologics at a tertiary care hospital to measure the association between prior authorization, biologic initiation time (physician recommendation to first dose), and healthcare utilization (hospitalization, surgery, or emergency department visit). Demographic, insurance, and disease severity-related covariables were collected. Multivariable linear regression was used to measure the association between prior authorization and biologic initiation time. Propensity score methods were used to measure the associations between prior authorization and IBD-related healthcare utilization within 180 days and corticosteroid dependence at 90 days, with adjustment for insurance type, demographics, and disease severity-related characteristics. RESULTS: Median biologic initiation time was 21 days. Prior authorization and complicated prior authorizations (requiring appeal, step therapy, or peer-to-peer review) were associated with 10.2-day (95% confidence interval [CI] 8.2 to 12.3) and 24.6-day (95% CI 16.4 to 32.8) increases in biologic initiation time, respectively. Prior authorizations increased the likelihood of IBD-related healthcare utilization within 180 days by 12.9% (95% CI 2.5 to 23.4) and corticosteroid dependence at 90 days by 14.1% (95% CI 3.3 to 24.8). CONCLUSIONS: Prior authorizations are associated with prolonged biologic initiation time and increased IBD-related healthcare utilization. Minimizing prior authorization-related delays may expedite biologic delivery and reduce the risk of IBD-related healthcare utilization.

IOIBD Recommendations for Clinical Trials in Ulcerative Proctitis: The PROCTRIAL Consensus.

BACKGROUND & AIMS: Clinical trials evaluating biologics and small molecules in patients with ulcerative colitis are predominantly excluding ulcerative proctitis. The objective of the Definition and endpoints for ulcerative PROCtitis in clinical TRIALs initiative was to develop consensus statements for definitions, inclusion criteria, and endpoints for the evaluation of ulcerative proctitis in adults. METHODS: Thirty-five international experts held a consensus meeting to define ulcerative proctitis, and the endpoints to use in clinical trials. Based on a systematic review of the literature, statements were generated, discussed, and approved by the working group participants using a modified Delphi method. Consensus was defined as at least 75% agreement among voters. RESULTS: The group agreed that the diagnosis of ulcerative proctitis should be made by ileocolonoscopy and confirmed by histopathology, with the exclusion of infections, drug-induced causes, radiation, trauma, and Crohn's disease. Ulcerative proctitis was defined as macroscopic extent of lesions limited to 15 cm distance from the anal verge in adults. Primary and secondary endpoints were identified to capture response of ulcerative proctitis to therapy. A combined clinical and endoscopic primary endpoint for the evaluation of ulcerative proctitis disease activity was proposed. Secondary endpoints that should be evaluated include endoscopic remission, histologic remission, mucosal healing, histologic endoscopic mucosal improvement, disability, fecal incontinence, urgency, constipation, and health-related quality of life. CONCLUSIONS: In response to the need for guidance on the design of clinical trials in patients with ulcerative proctitis, the Definition and end points for ulcerative PROCtitis in clinical TRIALs consensus provides recommendations on the definition and endpoints for ulcerative proctitis clinical trials.