Faculty Bibliography

BACKGROUND & AIMS/OBJECTIVE:Restorative proctocolectomy with ileal pouch-anal anastomosis is a surgical procedure in patients with ulcerative colitis refractory to medical therapies. Pouchitis, the most common complication, is inflammation of the pouch of unknown etiology. To define how the intestinal immune system is distinctly organized during pouchitis, we analyzed tissues from patients with and without pouchitis and from patients with ulcerative colitis using single-cell RNA sequencing (scRNA-seq). METHODS:We examined pouch lamina propria CD45+ hematopoietic cells from intestinal tissues of ulcerative colitis patients with (n=15) and without an ileal pouch-anal anastomosis (n=11). Further in silico meta-analysis was performed to generate transcriptional interaction networks and identify biomarkers for patients with inflamed pouches. RESULTS:In addition to tissue-specific signatures, we identified a population of IL1B/LYZ+ myeloid cells and FOXP3/BATF+ T cells that distinguish inflamed tissues which we further validated in other single cell RNA-seq datasets from IBD patients. Cell type specific transcriptional markers obtained from single-cell RNA-sequencing was used to infer representation from bulk RNA sequencing datasets, which further implicated myeloid cells expressing IL1B and S100A8/A9 calprotectin as interacting with stromal cells, and Bacteroidiales and Clostridiales bacterial taxa. We found that non-responsiveness to anti-integrin biologic therapies in ulcerative colitis patients was associated with the signature of IL1B+/LYZ+ myeloid cells in a subset of patients. CONCLUSIONS:Features of intestinal inflammation during pouchitis and ulcerative colitis are similar, which may have clinical implications for the management of pouchitis. scRNA-seq enables meta-analysis of multiple studies, which may facilitate the identification of biomarkers to personalize therapy for IBD patients.

OBJECTIVE:The objective of this study was to determine if dual-energy computed tomography enterography (DECTE)-obtained iodine density can predict medical management change or surgery in Crohn disease patients. METHODS:The most active-appearing bowel segment on DECTE in 21 Crohn disease patients was retrospectively interrogated with prototype software determining the percentage of bowel wall (I) in specified ranges. Patients were categorized into 3 groups after DECTE: (1) no management change, (2) outpatient medication change, and (3) inpatient admission or surgery. Crohn's disease activity index was calculated. Group 3's percentage iodine density of >3 mg/mL and Crohn's disease activity index were compared with group 1/2. Crohn's disease activity index and percentage iodine density of >2 mg/mL were compared for groups 2/3 versus group 1 patients. RESULTS:There were 5 group 1, 6 group 2, and 10 group 3 patients. Group 3 patients had higher frequency of iodine density >3 mg/mL (27%) compared with groups 1/2 patients (12.6%) (P < 0.05). Crohn's disease activity index was similar (P = 0.98). Groups 2/3 patients had 60.5% iodine density of >2 mg/mL, whereas group 1 patients had 31.7% iodine density of >2 mg/mL (P < 0.05). Crohn's disease activity index was similar (P = 0.12). CONCLUSIONS:Iodine density from DECTE may predict medical or surgical Crohn disease management.

BACKGROUND:Several routes of fecal microbiota transplantation (FMT) administration are available for treating recurrent Clostridioides difficile infections (CDI), the most recent of which are capsules. AIM/OBJECTIVE:To assess the efficacy of colonoscopy, capsule, enema, and nasogastric tube (NGT) FMT for the treatment of recurrent CDI. METHODS:We reported clinical outcomes of colonoscopy, capsule, enema, and NGT FMT for the treatment of recurrent CDI according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. During January 2000 to January 2018, three databases were searched: PubMed, EMBASE, and CINAHL. Primary outcome was overall cure rate which was assessed using a random effects model; secondary outcomes included adverse effects as well as subgroup analyses comparing donor relationship, sample preparation, and study design. RESULTS:0%). On subgroup analysis of colonoscopy FMT, sample preparation methods had comparable cure rates: fresh 94.9% compared to 94.5%. Similarly, cure rates were unaffected by donor relationship: mixed 94.5% compared to unrelated donor 95.7%. CONCLUSION/CONCLUSIONS:CDI cure rates with FMT performed with colonoscopy are superior to enema and NGT FMT, while those with FMT with colonoscopy and capsule are comparable.

Background: Ustekinumab has been recently approved for the treatment of moderately to severely active ulcerative colitis (UC). The registry trials for ustekinumab in UC demonstrated efficacy and safety, but data on real-world outcomes are limited. We describe the effectiveness and safety of ustekinumab in patients with UC from 2 US tertiary inflammatory bowel disease centers. Methods: Patients with moderately to severely active UC treated with ustekinumab at NYU Langone Health (New York, New York) and University of Chicago Medical Center (Chicago, Illinois) between January 2016 and March 2020 were retrospectively included. The primary outcome was clinical remission at 3 and 12 months, defined as a partial Mayo score of ≤2, with a combined rectal bleeding and stool frequency subscore of ≤1. Results: Sixty-six UC patients were included. Ninety-two percent of patients had prior exposure to biologics or tofacitinib. Forty-three percent and 45% of patients achieved clinical remission by 3 and 12 months, respectively. Anti-TNF nonresponse and endoscopic Mayo score of 3 were negative predictors of clinical remission. Thirty-three percent of those followed for a year achieved concurrent endoscopic and histologic healing, which was significantly associated with lower partial Mayo score (P < 0.01) and lower stool frequency (P = 0.02). Serious adverse events occurred in 4 (6%) patients (3 UC exacerbations, 1 vasculitis). Conclusions: In this cohort of mostly biologic-refractory UC patients, treatment with ustekinumab achieved remission in nearly half of them at 12 months, and was associated with an overall favorable safety profile. These results are modestly better than the pivotal trials.

Pouchitis is the most common complication in patients who have undergone restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA). Up to 81% of IPAA patients experience pouchitis, with 40% of patients presenting within the first year of surgery. Common risk factors include genetic mutations, extensive colitis, rheumatologic disorders, and primary sclerosing cholangitis. Currently, there are no medications with approved indications for pouchitis. As such, the conventional treatment of pouchitis is entirely off-label. This paper is intended to be a practical and up-to-date review of available therapies used for the management of pouchitis. The mainstay of treatment for acute pouchitis remains antibiotics, but newer therapeutics have also shown promise in the treatment of chronic pouchitis. Common lifestyle considerations that may play a role in pouchitis are also reviewed.

BACKGROUND & AIMS:We created and validated a clinical decision support tool (CDST) to predict outcomes of vedolizumab therapy for ulcerative colitis (UC). METHODS:We performed logistic regression analyses of data from the GEMINI 1 trial, from 620 patients with UC who received vedolizumab induction and maintenance therapy (derivation cohort), to identify factors associated with corticosteroid-free remission (full Mayo score of 2 or less, no subscore above 1). We used these factors to develop a model to predict outcomes of treatment, which we called the vedolizumab CDST. We evaluated the correlation between exposure and efficacy. We validated the CDST in using data from 199 patients treated with vedolizumab in routine practice in the United States from May 2014 through December 2017. RESULTS:Absence of exposure to a tumor necrosis factor (TNF) antagonist (+3 points), disease duration of 2 y or more (+3 points), baseline endoscopic activity (moderate vs severe) (+2 points), and baseline albumin concentration (+0.65 points per 1 g/L) were independently associated with corticosteroid-free remission during vedolizumab therapy. Patients in the derivation and validation cohorts were assigned to groups of low (CDST score, 26 points or less), intermediate (CDST score, 27-32 points), or high (CDST score, 33 points or more) probability of vedolizumab response. We observed a statistically significant linear relationship between probability group and efficacy (area under the receiver operating characteristic curve, 0.65), as well as drug exposure (P < .001) in the derivation cohort. In the validation cohort, a cutoff value of 26 points identified patients who did not respond to vedolizumab with high sensitivity (93%); only the low and intermediate probability groups benefited from reducing intervals of vedolizumab administration due to lack of response (P = .02). The vedolizumab CDST did not identify patients with corticosteroid-free remission during TNF antagonist therapy. CONCLUSIONS:We used data from a trial of patients with UC to develop a scoring system, called the CDST, which identified patients most likely to enter corticosteroid-free remission during vedolizumab therapy, but not anti-TNF therapy. We validated the vedolizumab CDST in a separate cohort of patients in clinical practice. The CDST identified patients most likely to benefited from reducing intervals of vedolizumab administration due to lack of initial response. ClinicalTrials.gov no: NCT00783718.

Background: This study evaluated the prevalence of adjunctive pharmacotherapies use among ileal pouch-anal anastomosis (IPAA) patients. Methods: The IBD Partners database was queried to compare IPAA patients with and without pouch-related symptoms (PRS). Within the cohort of patients with PRS, patient reported outcomes were compared among opioid, nonsteroidal anti-inflammatory drug (NSAID), and probiotic users. Results: There were no differences in patient reported outcomes based on NSAID or probiotic usage. Opioid users reported increased bowel frequency, urgency, poor general well-being, abdominal pain, and depression (P < 0.05 for all variables). Conclusions: In IPAA patients with PRS, opioid use, but not NSAIDs or probiotics, was associated with a higher burden of PRS.

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. Changes in liver enzymes, lipids, hemoglobin (Hb), absolute neutrophil count (ANC), and absolute lymphocyte count (ALC) have been observed during 8-wk induction and 52-wk maintenance therapy with tofacitinib in patients (pts) with UC [1]. Monitoring of select parameters is recommended in pts treated with tofacitinib per product labeling [2].
METHOD(S): Changes from baseline in liver enzymes, lipids, ANC, ALC, and Hb were investigated in pts with UC treated with tofacitinib in an ongoing Phase 3, open-label, long-term extension (OLE) study (NCT01470612; data as of May 2019, database not locked). Pts who completed or demonstrated treatment failure in OCTAVE Sustain, or were non-responders after completing OCTAVE Induction 1 or 2, were eligible for the OLE study. Pts in remission at the end of OCTAVE Sustain received tofacitinib 5 mg twice daily (BID); all other pts received tofacitinib 10 mg BID in the OLE study. Proportions of pts with laboratory values meeting protocol discontinuation criteria (Table), proportions of pts with investigator-defined treatment-emergent adverse events (TEAEs) of hyper-lipidemia, and proportions of pts with an addition of or change in lipid-lowering agent (LLA), were also evaluated.
RESULT(S): Changes from OLE study baseline in liver enzymes, lipids, ANC, ALC, and Hb at Months 36 and 48, and the proportion of pts meeting protocol discontinuation criteria, are presented (Table). Findings were generally similar to the previously presented Sep 2018 data cut, which focused on Month 36 [3]. Hyperlipidemia TEAEs occurred in 2.3% and 1.3% of pts treated with tofacitinib 5 and 10 mg BID, respectively. Furthermore, 9.7% and 6.8% of pts treated with tofacitinib 5 and 10 mg BID, respectively, had a new LLA added, and 2.9% and 1.8% of pts treated with tofacitinib 5 and 10 mg BID, respectively, had their LLA dose increased.
CONCLUSION(S): No major changes from OLE study baseline were observed with tofacitinib in laboratory parameters recommended for monitoring up to Month 48. Proportions of pts meeting protocol discontinuation criteria for liver enzymes, ANC, ALC, or Hb, with hyperlipidemia TEAEs, or with a change in LLA, were low. Due to OLE study dose assignment, pt baseline remission status differs across treatment arms

BACKGROUND:Ileal pouch-anal anastomosis is a common surgical procedure in patients with an initial diagnosis of ulcerative colitis or indeterminate colitis. Tobacco smoking has been associated with protection from onset of ulcerative colitis. Smoking has been reported to be both a protective factor and a risk factor for the development of pouchitis. AIM/OBJECTIVE:To examine the influence of smoking on the risk of pouchitis. METHODS:We identified 15 studies evaluating smoking as a risk factor for developing pouchitis in ulcerative colitis or indeterminate colitis patients with a history of ileal pouch-anal anastomosis in a systematic search performed from inception through May 4, 2020. A meta-analysis was then performed using a random-effects model to generate risk ratios (RR) and 95% confidence intervals (CI). RESULTS: = 78.5%). CONCLUSIONS:Smoking, past or present, is not associated with an increased risk for the development of pouchitis in patients with ulcerative colitis or indeterminate colitis.

INTRODUCTION: Hospitalization for flare of inflammatory bowel disease (IBD) is associated with significant morbidity and healthcare costs. We aimed to examine the relationship between IBD severity at presentation and adverse outcomes in patients hospitalized with flare. Additionally, we aimed to create and validate a predictive model for length of stay (LOS) using markers of disease severity.
METHOD(S): We conducted a retrospective cohort study of IBD patients hospitalized with flare at two urban academic medical centers. We collected demographic and IBD-related data including the presence of Clostridioides difficile and markers of disease severity at presentation. The primary outcome was a composite of adverse inpatient IBD outcomes, including LOS >7 days, anti-TNF administration, and surgery. The data was split into training (70%) and validation (30%) samples. Employing variables of disease severity, models (including logistic regression, Classification and Regression Tree (CART), and Random Forest (RF) modeling techniques) were created to predict LOS >7 days using the training sample. These models were adjusted for surgery and anti-TNF administration, and their performance was subsequently validated.
RESULT(S): A total of 187 IBD patients hospitalized with flare were included (Table 1). The composite primary outcome was achieved in 71 patients (38%) with 51 (27%) hospitalized for >7 days. In univariate analyses, C-reactive protein and C. difficile positivity correlated with anti-TNF administration and surgery (Table 2). Adjusting for anti-TNF administration and surgery, tachycardia (OR 1.07; 95% CI 1.05-1.10), hypotension (1.07; 1.03-1.11), hypoalbuminemia (2.87; 1.81-4.74), leukocytosis (1.17; 1.09-1.27), anemia (1.10; 1.05-1.15) and C. difficile posi-tivity (2.63; 1.27-5.47) were predictive of prolonged LOS (Table 2). In multivariate analyses, tachycardia predicted the primary composite outcome of all adverse effects (OR 1.07; 95% CI 1.03-1.11). C. difficile positivity (OR 4.33; 95% CI 1.36-14.9), hypoalbuminemia (3.25; 1.29-9.01), and tachycardia (1.11; 1.06-1.16) predicted prolonged LOS (.7 days). The CART and RF models had acceptable accuracy, sensitivity, and specificity for predicting LOS >7 days (Table 3).
CONCLUSION(S): C. difficile positivity, hypoalbuminemia, and tachycardia at presentation predicted prolonged length of stay in a multicenter cohort of IBD patients hospitalized with flare. CART and Random Forest models perform well in predicting prolonged length of stay in these patients