Faculty Bibliography

BACKGROUND:Sacroiliitis is an inflammatory arthritis of the sacroiliac joints and is associated with inflammatory bowel disease (IBD). Yet, sacroiliitis often goes undiagnosed in IBD, and the clinical association between IBD disease activity and sacroiliitis is not well established. Patients with Crohn's disease (CD) often receive magnetic resonance enterography (MRE) to assess disease activity, affording clinicians the opportunity to evaluate for the presence of sacroiliitis. We aimed to identify the prevalence and disease characteristics associated with sacroiliitis in CD patients undergoing MRE. METHODS:All CD patients undergoing MRE for any indication between 2014 and 2018 at an IBD referral center were identified. The MREs were reviewed for the presence of sacroiliitis based on bone marrow edema (BME) and structural lesions. We analyzed demographics, IBD characteristics, clinical and endoscopic disease activity, and management between CD patients with and without sacroiliitis. RESULTS:Two hundred fifty-eight patients with CD underwent MRE during the study period. Overall, 17% of patients had MR evidence of sacroiliitis, of whom 73% demonstrated bone marrow edema. Female gender, back pain, and later age of CD diagnosis were associated with sacroiliitis (P = 0.05, P < 0.001, P = 0.04, respectively). Disease location and CD therapy were not associated with sacroiliitis on MRE. Clinical, endoscopic, and radiographic disease activity were not associated with sacroiliitis on MRE. CONCLUSION/CONCLUSIONS:Sacroiliitis is a common comorbid condition in CD. With limited clinical clues and disease characteristics to suggest sacroiliitis, physicians may utilize MRE to identify sacroiliitis, especially in CD patients with back pain.

GOALS AND BACKGROUND/OBJECTIVE:Ustekinumab (UST) is a monoclonal antibody inhibitor of IL-12/IL-23 approved for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). We conducted a meta-analysis to compare rates of adverse events (AEs) in randomized controlled trials (RCTs) of UST for all indications. STUDY/METHODS:A systematic search was performed of MEDLINE, Embase, and PubMed databases through November 2019. Study inclusion included RCTs comparing UST to placebo or other biologics in patients aged 18 years or older with a diagnosis of an autoimmune condition. RESULTS:Thirty RCTs with 16,068 patients were included in our analysis. Nine thousand six hundred and twenty-six subjects were included in the UST vs placebo analysis. There was no significant difference in serious or mild/moderate AEs between UST and placebo with an OR of 0.83 (95% CI 0.66, 1.05) and 1.08 (95% CI 0.99, 1.18), respectively, over a median follow-up time of 16 weeks. In a sub-analysis of CD and UC trials, no difference in serious or mild/moderate AEs in UST versus placebo was seen. CONCLUSIONS:UST was not associated with an increase in short-term risk of AEs.

BACKGROUND:We aimed to characterize patients with inflammatory bowel disease (IBD) and novel coronavirus disease 2019 (COVID-19). METHODS:We performed a case series of patients with IBD and confirmed or highly suspected COVID-19 to assess rates of severe outcomes. RESULTS:We identified 83 patients with IBD with confirmed (54%) or highly suspected (46%) COVID-19. The overall hospitalization rate was 6%, generally comprising patients with active Crohn's disease or older men with comorbidities, and 1 patient expired. DISCUSSION/CONCLUSIONS:In this series of patients with IBD, severe outcomes of COVID-19 were rare and comparable to similarly aged individuals in the general population.

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.

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.

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.

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. Following 8 weeks of tofacitinib 10 mg twice daily (BID) in OCTAVE Induction 1&2, modest and reversible increases in serum lipid levels were reported in patients with UC, which were associated with reduced C-reactive protein (CRP) levels [1].
METHOD(S): OCTAVE Induction 1&2 (NCT01465763; NCT01458951) were 2 identical, 8-week, Phase 3 studies in which patients with moderately to severely active UC received tofacitinib 10 mg BID or placebo (total n = 1,139). In this post hoc analysis of the pooled induction studies, we assessed changes from baseline (CFB) in lipid levels (total cholesterol [total-c], high-density lipo-protein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c]) at Week 8 by responder and remitter status in patients who received tofacitinib 10 mg BID or placebo; analysis of variance was performed to estimate differences for responders or remitters vs non-responders. The association between CFB in lipid levels and CFB in CRP levels (log-transformed), by responder and remitter status, was assessed using a linear regression model at Week 8 in patients who received tofacitinib 10 mg BID.
RESULT(S): Increases in lipid levels from baseline to Week 8 were observed in responders, non-responders, and remitters (Table), which were greater with tofacitinib 10 mg BID vs placebo. There were significantly greater increases from baseline in total-c, HDL-c, and LDL-c for responders vs non-responders (all P < 0.0001), and in total-c and HDL-c for remitters vs non-responders (both P # 0.0001) in patients who received tofacitinib 10 mg BID (Table). Significant differences in lipid levels by responder and remitter status were not reported with placebo (data not shown). In patients who received tofacitinib 10 mg BID, linear regression modeling showed a significant association between CFB in total-c, HDL-c, and LDL-c and CFB in CRP in responders and non-responders, and between CFB in total-c and HDL-c and CFB in CRP in remitters (all P < 0.01) (Table).
CONCLUSION(S): These data suggest an association between increases in lipid levels and tofacitinib responder and remitter status. Further research is necessary to determine if increases in lipid levels can be used as a surrogate marker of reduced inflammation, and to establish lipid levels as potential predictors of patient outcomes to tofacitinib treatment

INTRODUCTION: Current guidelines recommend preoperative risk stratification to guide postoperative prophylactic biologic therapy for the prevention of Crohn's disease (CD) recurrence1. Few data have corroborated the quantified risk of postoperative recurrence (POR) and validated the proposed risk stratification. We aimed to assess the impact of biologic therapy on POR based on guideline-recommended risk stratification.
METHOD(S): CD patients who underwent an ileocolic resection from 1992-2019 were identified at two tertiary referral centers. Patients were stratified into cohorts with high-risk features (smoking, age < 30 years, and >=2 prior surgeries) and low-risk features (nonsmokers, age >50 years, resection length < 10 cm, and disease duration < 10 years). POR, defined as endoscopic (Rutgeerts . i1) or radiographic evidence of disease at least >6 months after surgery, was compared between groups. Recurrence-free survival analysis using Cox proportional hazard modeling and Kaplan-Meier curves were used to estimate POR and the impact of biologic prophylaxis.
RESULT(S): A total of 950 patients with ileocolic resection for CD were included (mean age 37.9, 47%): 785 (82.6%) high-risk and 165 (17.4%) low-risk patients. In the high-risk group, the majority (58.2%) received biologic prophylaxis (43.4% anti-TNF, 7.1% vedolizumab, and 7.8% ustekinumab) while 41.8% had no therapy. In contrast, 60% of low-risk patients had no therapy while 40% received biologic prophylaxis (32.7% anti-TNF, 8% vedolizumab, and 2.4% ustekinumab). In the high-risk group, biologic prophylaxis was significantly associated with earlier POR compared to no therapy (P < 0.001). In the low-risk group, there was no significant difference between biologic and no therapy in time to POR (P = 0.10; Figure 1). When assessing specific risk factors on multivariable analysis, >=2 prior surgeries was the only independent risk factor for POR (P < 0.05) (Table 1).
CONCLUSION(S): The risk stratification proposed for POR in current guidelines may have limited utility in predicting disease recurrence. Low-risk individuals are unlikely to benefit from postoperative biologic prophylaxis. Multiple prior surgeries is the strongest risk factor for POR and these patients may benefit from postoperative biologic prophylaxis