Charting human development using a multi-endodermal organ atlas and organoid models.

Organs are composed of diverse cell types that traverse transient states during organogenesis. To interrogate this diversity during human development, we generate a single-cell transcriptome atlas from multiple developing endodermal organs of the respiratory and gastrointestinal tract. We illuminate cell states, transcription factors, and organ-specific epithelial stem cell and mesenchyme interactions across lineages. We implement the atlas as a high-dimensional search space to benchmark human pluripotent stem cell (hPSC)-derived intestinal organoids (HIOs) under multiple culture conditions. We show that HIOs recapitulate reference cell states and use HIOs to reconstruct the molecular dynamics of intestinal epithelium and mesenchyme emergence. We show that the mesenchyme-derived niche cue NRG1 enhances intestinal stem cell maturation in vitro and that the homeobox transcription factor CDX2 is required for regionalization of intestinal epithelium and mesenchyme in humans. This work combines cell atlases and organoid technologies to understand how human organ development is orchestrated.

Mapping the adult human esophagus in vivo and in vitro.

Many esophageal diseases can arise during development or throughout life. Therefore, well-characterized in vitro models and detailed methods are essential for studying human esophageal development, homeostasis and disease. Here, we (1) create an atlas of the cell types observed in the normal adult human esophagus; (2) establish an ancestrally diverse biobank of in vitro esophagus tissue to interrogate homeostasis and injury; and (3) benchmark in vitro models using the adult human esophagus atlas. We created a single-cell RNA sequencing reference atlas using fresh adult esophagus biopsies and a continuously expanding biobank of patient-derived in vitro cultures (n=55 lines). We identify and validate several transcriptionally distinct cell classes in the native human adult esophagus, with four populations belonging to the epithelial layer, including basal, epibasal, early differentiating and terminally differentiated luminal cells. Benchmarking in vitro esophagus cultures to the in vivo reference using single-cell RNA sequencing shows that the basal stem cells are robustly maintained in vitro, and the diversity of epithelial cell types in culture is dependent on cell density. We also demonstrate that cultures can be grown in 2D or as 3D organoids, and these methods can be employed for modeling the complete epithelial layers, thereby enabling in vitro modeling of the human adult esophagus.

Long-Term Effectiveness and Durability of COVID-19 Vaccination Among Patients With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: COVID-19 vaccination prevents severe disease in most patients with inflammatory bowel disease (IBD), but immunosuppressive medications can blunt serologic response. We followed adults with IBD for >1 year post-COVID-19 vaccination to describe factors associated with SARS-CoV-2 infection after vaccination, evaluate for a protective SARS-CoV-2 antibody level, characterize SARS-CoV-2 antibody persistence, and identify factors associated with humoral immune response durability. METHODS: Using a prospective cohort of COVID-19 immunized adults with IBD, we analyzed factors associated with SARS-CoV-2 infection after vaccination. We evaluated for an association between SARS-CoV-2 antibody level 12 weeks postvaccination and subsequent SARS-CoV-2 infection and assessed for a threshold of protection using receiver-operating characteristic curve analysis. We then conducted a separate analysis evaluating factors associated with persistence of SARS-CoV-2 antibodies 52 weeks postimmunization. RESULTS: Almost half (43%) of 1869 participants developed COVID-19 after vaccination, but most infections were mild, and <1% required hospitalization. Older age and corticosteroid use were associated with a decreased risk of SARS-CoV-2 infection postvaccination (50-59 years of age vs 18-29 years of age: adjusted hazard ratio, 0.57; 95% confidence interval, 0.44-0.74; steroid users vs nonusers: adjusted hazard ratio, 0.58; 95% confidence interval, 0.39-0.87). Most (98%) participants had detectable antibody levels at 52 weeks postvaccination. Antibody levels at 12 weeks and number of vaccine doses were positively associated with higher antibody levels at 52 weeks, while anti-tumor necrosis factor α therapy was negatively associated. CONCLUSIONS: COVID-19 vaccination generates an effective and durable protective response for the vast majority of adults with IBD, including vulnerable populations such as corticosteroid users and older individuals. Patients with IBD benefit from COVID-19 booster vaccination.

Insurer-Mandated Medication Utilization Barriers are Associated With Decreased Insurance Satisfaction and Adverse Clinical Outcomes: An Inflammatory Bowel Disease Partners Survey.

INTRODUCTION: Insurer-mandated barriers to timely initiation of advanced therapies used to treat inflammatory bowel disease (IBD) have been shown to worsen clinical outcomes and increase healthcare utilization, yet rarely alter the medication ultimately prescribed. METHODS: We conducted a survey within the IBD Partners longitudinal cohort to evaluate the frequency and patient-reported impacts of medication utilization barriers on insurance satisfaction and clinical outcomes. Barriers included medication denials, prior authorizations, and forced medication switches. Variables associated with insurance satisfaction, measured on a 1-7 Likert scale, were identified. The association between insurance-related barriers and downstream clinical outcomes (surgery, corticosteroid requirement, and disease activity) were evaluated. RESULTS: Two thousand seventeen patients (age 45 [interquartile range 34-58] years, 73% female) were included. Seventy-two percent experienced an insurer-mandated barrier, most commonly prior authorizations (51%). Fifteen percent were denied an IBD medication by their insurer, 22% experienced an insurance-related gap in therapy, and 8% were forced by their insurer to switch from an effective medication. Insurance satisfaction was negatively associated with medication denials, prior authorization-related delays, gaps in therapy, and high-deductible health plan coverage. In the year following the initial survey, several insurance barriers were linked to negative downstream clinical outcomes, including prior authorizations associated with corticosteroid rescue (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.25-4.00), forced medication switches associated with continued disease activity (OR 3.28, 95% CI 1.56-6.89), and medication denials associated with IBD-related surgery (OR 8.92, 95% CI 1.97-40.39). DISCUSSION: These data illustrate the frequency and negative impacts of insurer-mandated medication barriers on patients with IBD, including decreased insurance satisfaction and negative downstream clinical outcomes.

Legalization of Cannabis Does Not Reduce Opioid Prescribing in Patients With Inflammatory Bowel Disease: A Difference-in-Difference Analysis.

INTRODUCTION: Cannabis may provide inflammatory bowel disease (IBD) patients with an alternative to opioids for pain. METHODS: We conducted a difference-in-difference analysis using MarketScan. Changes over time in rates of opioid prescribing were compared in states with legalized cannabis to those without. RESULTS: We identified 6,240 patients with IBD in states with legalized cannabis and 79,272 patients with IBD in states without legalized cannabis. The rate of opioid prescribing decreased over time in both groups and were not significantly different (attributed differential = 0.34, confidence interval -13.02 to 13.70, P = 0.96). DISCUSSION: Opioid prescribing decreased from 2009 to 2016 among patients with IBD in both states with legalized and state without legalized cannabis, similar to what has been observed nationally across a variety of diseases. Cannabis legalization was not associated with a lower rate of opioid prescribing for patients with IBD.

Changes in Therapy Are Not Associated With Increased Remission in Patients With Crohn's Disease of the Pouch.

INTRODUCTION: There is a paucity of data on the real-world effectiveness of therapies in patients with Crohn's disease of the pouch. METHODS: This was a prospective multicenter study evaluating the primary outcome of remission at 12 months of therapy for Crohn's disease of the pouch. RESULTS: One hundred thirty-four patients were enrolled. Among the 77 patients with symptoms at baseline, 35 (46.7%) achieved remission at 12 months. Of them, 12 (34.3%) changed therapy. There was no significant association between therapy patterns and remission status. DISCUSSION: Approximately 50% with symptoms at enrollment achieved clinical remission at 12 months, most of whom did so without a change in therapy.

Effectiveness of Upadacitinib for Patients With Acute Severe Ulcerative Colitis: A Multicenter Experience.

INTRODUCTION: A significant proportion of patients with acute severe ulcerative colitis (ASUC) require colectomy. METHODS: Patients with ASUC treated with upadacitinib and intravenous corticosteroids at 5 hospitals are presented. The primary outcome was 90-day colectomy rate. Secondary outcomes included frequency of steroid-free clinical remission, adverse events, and all-cause readmissions. RESULTS: Of the 25 patients with ASUC treated with upadacitinib, 6 (24%) patients underwent colectomy, 15 (83%) of the 18 patients with available data and who did not undergo colectomy experienced steroid-free clinical remission (1 patient did not have complete data), 1 (4%) patient experienced a venous thromboembolic event, while 5 (20%) patients were readmitted. DISCUSSION: Upadacitinib along with intravenous corticosteroids may be an effective treatment for ASUC.

Humoral immune response and safety of SARS-CoV-2 vaccination in very early onset inflammatory bowel disease.

Children with very early onset inflammatory bowel disease (VEO-IBD) may respond differently to coronavirus disease 2019 (COVID-19) immunization compared to healthy children or other patients with IBD. We recruited children with VEO-IBD <6 years of age and younger following receipt of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Demographics, IBD characteristics, medication use, adverse events (AEs) and IBD exacerbations were collected. Blood draws (optional) were obtained for measurement of antireceptor binding domain (RBD) IgG antibodies following vaccination. Of 41 participants, none required emergency department visit or hospitalization due to AE, and only one experienced IBD exacerbation. Detectable antibody was present in 19/19 participants who provided blood sample; 6/7 participants (86%) had durable humoral response 12 months postvaccination. Children with VEO-IBD experience robust humoral immune response to COVID-19 immunization. Severe AEs were rare. These findings provide reassurance that children with VEO-IBD respond well and safely to SARS-CoV-2 vaccination.

Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials.

BACKGROUND: There is a great unmet need for advanced therapies that provide rapid, robust, and sustained disease control for patients with ulcerative colitis. We assessed the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. METHODS: This phase 3, multicentre, randomised, double-blind, placebo-controlled clinical programme consisted of two replicate induction studies (U-ACHIEVE induction [UC1] and U-ACCOMPLISH [UC2]) and a single maintenance study (U-ACHIEVE maintenance [UC3]). The studies were conducted across Europe, North and South America, Australasia, Africa, and the Asia-Pacific region at 199 clinical centres in 39 countries (UC1), 204 clinical centres in 40 countries (UC2), and 195 clinical centres in 35 countries (UC3). Patients aged 16-75 years with moderately to severely active ulcerative colitis (Adapted Mayo score 5-9; endoscopic subscore 2 or 3) for at least 90 days were randomly assigned (2:1) to oral upadacitinib 45 mg once daily or placebo for 8 weeks (induction studies). Patients who achieved clinical response following 8-week upadacitinib induction were re-randomly assigned (1:1:1) to upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 52 weeks (maintenance study). All patients were randomly assigned using web-based interactive response technology. The primary endpoints were clinical remission per Adapted Mayo score at week 8 (induction) and week 52 (maintenance). The efficacy analyses in the two induction studies were based on the intent-to-treat population, which included all randomised patients who received at least one dose of treatment. In the maintenance study, the primary efficacy analyses reported in this manuscript were based on the first 450 (planned) clinical responders to 8-week induction therapy with upadacitinib 45 mg once daily. The safety analysis population in the induction studies consisted of all randomised patients who received at least one dose of treatment; in the maintenance study, this population included all patients who received at least one dose of treatment as part of the primary analysis population. These studies are registered at ClinicalTrials.gov, NCT02819635 (U-ACHIEVE) and NCT03653026 (U-ACCOMPLISH). FINDINGS: Between Oct 23, 2018, and Sept 7, 2020, 474 patients were randomly assigned to upadacitinib 45 mg once daily (n=319) or placebo (n=155) in UC1. Between Dec 6, 2018, and Jan 14, 2021, 522 patients were randomly assigned to upadacitinib 45 mg once daily (n=345) or placebo (n=177) in UC2. In UC3, a total of 451 patients (21 from the phase 2b study, 278 from UC1, and 152 from UC2) who achieved a clinical response after 8 weeks of upadacitinib induction treatment were randomly assigned again to upadacitinib 15 mg (n=148), upadacitinib 30 mg (n=154), and placebo (n=149) in the primary analysis population. Statistically significantly more patients achieved clinical remission with upadacitinib 45 mg (83 [26%] of 319 patients in UC1 and 114 [34%] of 341 patients in UC2) than in the placebo group (seven [5%] of 154 patients in UC1 and seven [4%] of 174 patients; p<0·0001; adjusted treatment difference 21·6% [95% CI 15·8-27·4] for UC1 and 29·0% [23·2-34·7] for UC2). In the maintenance study, clinical remission was achieved by statistically significantly more patients receiving upadacitinib (15 mg 63 [42%] of 148; 30 mg 80 [52%] of 154) than those receiving placebo (18 [12%] of 149; p<0·0001; adjusted treatment difference 30·7% [21·7-39·8] for upadacitinib 15 mg vs placebo and 39·0% [29·7-48·2] for upadacitinib 30 mg vs placebo). The most commonly reported adverse events in UC1 were nasopharyngitis (15 [5%] of 319 in the upadacitinib 45 mg group vs six [4%] of 155 in the placebo group), creatine phosphokinase elevation (15 [4%] vs three [2%]), and acne (15 [5%] vs one [1%]). In UC2, the most frequently reported adverse event was acne (24 [7%] of 344 in the upadacitinib 45 mg group vs three [2%] of 177 in the placebo group). In both induction studies, serious adverse events and adverse events leading to discontinuation of treatment were less frequent in the upadacitinib 45 mg group than in the placebo group (serious adverse events eight [3%] vs nine (6%) in UC1 and 11 [3%] vs eight [5%] in UC2; adverse events leading to discontinuation six [2%] vs 14 [9%] in UC1 and six [2%] vs nine [5%] in UC2). In UC3, the most frequently reported adverse events (≥5%) were worsening of ulcerative colitis (19 [13%] of 148 in the upadacitinib 15 mg group vs 11 [7%] of 154 in the upadacitinib 30 mg group vs 45 [30%] of 149 in the placebo group), nasopharyngitis (18 [12%] vs 22 [14%] vs 15 [10%]), creatine phosphokinase elevation (nine [6%] vs 13 [8%] vs three [2%]), arthralgia (nine [6%] vs five [3%] vs 15 [10%]), and upper respiratory tract infection (seven [5%] vs nine [6%] vs six [4%]). The proportion of serious adverse events (ten [7%] vs nine [6%] vs 19 [13%]) and adverse events leading to discontinuation (six [4%] vs ten [6%] vs 17 [11%]) was lower in both upadacitinib groups than in the placebo group. Events of cancer, adjudicated major adverse cardiac events, or venous thromboembolism were reported infrequently. There were no treatment-related deaths. INTERPRETATION: Upadacitinib demonstrated a positive efficacy and safety profile and could be an effective treatment option for patients with moderately to severely active ulcerative colitis. FUNDING: AbbVie.

Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Crohn's Disease.

BACKGROUND: Mirikizumab is a humanized monoclonal antibody targeting interleukin 23p19 with demonstrated efficacy in psoriasis and ulcerative colitis. We investigated the safety and efficacy of mirikizumab in patients with moderate-to-severe Crohn's disease (CD). METHODS: Patients (N = 191) were randomized (2:1:1:2) to receive placebo (PBO), 200, 600, or 1000 mg mirikizumab, administered intravenously (IV) every 4 weeks. Patients who received mirikizumab and achieved ≥1 point improvement in Simple Endoscopic Score-CD at Week 12 (rerandomized maintenance cohort) were rerandomized to continue their induction IV treatment (combined IV groups [IV-C]) or receive 300 mg mirikizumab subcutaneously (SC) every 4 weeks. Nonrandomized maintenance cohort included endoscopic nonimprovers (1000 mg) and PBO patients (PBO/1000 mg) who received 1000 mg mirikizumab IV from Week 12. The primary objective was to evaluate superiority of mirikizumab to PBO in inducing endoscopic response (50% reduction from baseline in Simple Endoscopic Score-CD) at Week 12. RESULTS: At Week 12, endoscopic response was significantly higher by the predefined 2-sided significance level of 0.1 for all mirikizumab groups compared with PBO (200 mg: 25.8%, 8/31, 95% confidence interval [CI], 10.4-41.2, P = .079; 600 mg: 37.5%, 12/32, 95% CI, 20.7-54.3, P = .003; 1000 mg: 43.8%, 28/64, 95% CI, 31.6-55.9, P < .001; PBO: 10.9 %, 7/64, 95% CI, 3.3-18.6). Endoscopic response at Week 52 was 58.5% (24/41) and 58.7% (27/46) in the IV-C and SC groups, respectively. Frequencies of adverse events (AE) in the mirikizumab groups were similar to PBO. Through Week 52, frequencies of treatment-emergent AEs were similar across all groups. Frequencies of serious AE and discontinuations due to AE were higher in the nonrandomized maintenance cohort. CONCLUSION: Mirikizumab effectively induced endoscopic response after 12 weeks in patients with moderate-to-severe CD and demonstrated durable efficacy to Week 52. A detailed summary can be found in the Video Abstract. ClinicalTrials.gov, Number: NCT02891226.

Prospective Cohort Study to Investigate the Safety of Preoperative Tumor Necrosis Factor Inhibitor Exposure in Patients With Inflammatory Bowel Disease Undergoing Intra-abdominal Surgery.

BACKGROUND & AIMS: Whether preoperative treatment of inflammatory bowel disease (IBD) with tumor necrosis factor inhibitors (TNFis) increases the risk of postoperative infectious complications remains controversial. The primary aim of this study was to determine whether preoperative exposure to TNFis is an independent risk factor for postoperative infectious complications within 30 days of surgery. METHODS: We conducted a multicenter prospective observational study of patients with IBD undergoing intra-abdominal surgery across 17 sites from the Crohn's & Colitis Foundation Clinical Research Alliance. Infectious complications were categorized as surgical site infections (SSIs) or non-SSIs. Current TNFi exposure was defined as use within 12 weeks of surgery, and serum was collected for drug-level analyses. Multivariable models for occurrence of the primary outcome, any infection, or SSI were adjusted by predefined covariates (age, sex, preoperative steroid use, and disease type), baseline variables significantly associated (P < .05) with any infection or SSI separately, and TNFi exposure status. Exploratory models used TNFi exposure based on serum drug concentration. RESULTS: A total of 947 patients were enrolled from September 2014 through June 2017. Current TNFi exposure was reported by 382 patients. Any infection (18.1% vs 20.2%, P = .469) and SSI (12.0% vs 12.6%, P = .889) rates were similar in patients currently exposed to TNFis and those unexposed. In multivariable analysis, current TNFi exposure was not associated with any infection (odds ratio, 1.050; 95% confidence interval, 0.716-1.535) or SSI (odds ratio, 1.249; 95% confidence interval, 0.793-1.960). Detectable TNFi drug concentration was not associated with any infection or SSI. CONCLUSIONS: Preoperative TNFi exposure was not associated with postoperative infectious complications in a large prospective multicenter cohort.

Characteristics of Facilities With Early and Rapid Ustekinumab Adoption for Patients With Inflammatory Bowel Disease.

INTRODUCTION: To examine which facility characteristics, including teamwork, are associated with early or rapid inflammatory bowel disease-related ustekinumab adoption. METHODS: We examined the association between ustekinumab adoption and the characteristics of 130 Veterans Affairs facilities. RESULTS: Mean ustekinumab adoption increased by 3.9% from 2016 to 2018 and was higher in urban compared with rural facilities (ß = 0.03, P = 0.033) and among facilities with more teamwork (ß = 0.11, P = 0.041). Compared with nonearly adopters, early adopters were more likely be high-volume facilities (46% vs 19%, P = 0.001). DISCUSSION: Facility variation in medication adoption provides an opportunity for improving inflammatory bowel disease care through targeted dissemination strategies to improve medication uptake.

Humoral Immune Response and Safety of SARS-CoV-2 Vaccination in Pediatric Inflammatory Bowel Disease.

INTRODUCTION: Children with inflammatory bowel disease (IBD) may respond differently to COVID-19 immunization as compared with healthy children or adults with IBD. Those younger than 12 years receive a lower vaccine dose than adults. We sought to describe the safety and humoral immune response to COVID-19 vaccine in children with IBD. METHODS: We recruited children with IBD, ages 5-17 years, who received ≥ 2 doses of the BNT162b2 vaccine by a direct-to-patient outreach and at select sites. Patient demographics, IBD characteristics, medication use, and vaccine adverse events were collected. A subset of participants had quantitative measurement of anti-receptor binding domain IgG antibodies after 2-part immunization. RESULTS: Our study population included 280 participants. Only 1 participant required an ED visit or hospitalization because of an adverse event. Of 99 participants who underwent anti-receptor binding domain IgG antibody measurement, 98 had a detectable antibody, with a mean antibody level of 43.0 µg/mL (SD 67) and a median of 22 µg/mL (interquartile range 12-38). In adjusted analyses, older age ( P = 0.028) and antitumor necrosis factor monotherapy compared with immunomodulators alone ( P = 0.005) were associated with a decreased antibody level. Antibody response in patients treated with antitumor necrosis factor combination vs monotherapy was numerically lower but not significant. DISCUSSION: Humoral immune response to COVID-19 immunization in children with IBD was robust, despite a high proportion of this pediatric cohort being treated with immunosuppressive agents. Severe vaccine-related AEs were rare. Overall, these findings provide a high level of reassurance that pediatric patients with IBD respond well and safely to SARS-CoV-2 vaccination.

Fecal calprotectin level is nonlinearly associated with GI pathogen detection in patients with and without inflammatory bowel disease.

Fecal calprotectin (FCP) is used to monitor inflammatory bowel disease (IBD) activity and can also be elevated in gastrointestinal infections. Our study's objective was to quantify the relationship between FCP levels and lab-confirmed infections in people with and without IBD. We performed a cross-sectional study at a tertiary-care center of all encounters during which FCP and gastrointestinal pathogen polymerase-chain reaction (GI PCR) panel testings were conducted. Using non-parametric tests and quantile regression, we compared the FCP levels by IBD status and pathogen detection. There were 3,347 encounters with FCP and GI PCR testings from 2,780 unique individuals between 1 August 2016 and 17 February 2022. Overall, 54.4% had IBD (n = 1,819). Pathogens were detected in 744 encounters (22.2%), and the detection rate did not differ by IBD status. Median FCP without IBD was significantly elevated when a pathogen was detected (64 vs 41 mg/kg, P = 0.0003, normal ≤50.0 mg/kg), but FCP with IBD was not significantly elevated when a pathogen was detected (299 vs 255 mg/kg, P = 0.207). In quantile regression adjusted for age and IBD, pathogen detection was only significantly associated with higher FCP in the lower two quartiles, though IBD remained significantly associated with higher FCP at all levels (P > 0.001). Pathogen detection by GI PCR is associated with elevated FCP, though this relationship is nonlinear and varies by IBD status. Our findings indicate that FCP may be an adjunct to, but not a substitute for, stool pathogen testing.

In-hospital management of inflammatory bowel disease.

PURPOSE OF REVIEW: The management of hospitalized patients with inflammatory bowel disease (IBD) is complex. Despite considerable therapeutic advancements in outpatient ulcerative colitis and Crohn's disease management, the in-hospital management continues to lag with suboptimal outcomes. The purpose of this review is to provide a brief overview of our approach to managing patients hospitalized with acute severe ulcerative colitis (ASUC) and Crohn's disease-related complications, followed by a summary of emerging evidence for new management approaches. RECENT FINDINGS: ASUC has seen the emergence of well validated prognostic models for colectomy as well as the development of novel treatment strategies such as accelerated infliximab dosing, Janus kinase inhibitor therapy, and sequential therapy, yet the rate of colectomy for steroid-refractory ASUC has not meaningfully improved. Crohn's disease has seen the development of better diagnostic tools, early Crohn's disease-related complication stratification and identification, as well as better surgical techniques, yet the rates of hospitalization and development of Crohn's disease-related complications remain high. SUMMARY: Significant progress has been made in the in-hospital IBD management; however, both the management of ASUC and hospitalized Crohn's disease remain a challenge with suboptimal outcomes. Critical knowledge gaps still exist, and dedicated studies in hospitalized patients with IBD are needed to address them.

An Assessment of Comparative Medication Durability in Inflammatory Bowel Disease Patients With and Without Co-morbid Psoriasis, Rheumatoid Arthritis, and/or Enteropathic Arthritis.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk for many co-morbid diseases. However, little is known about durability of IBD medications in patients with co-morbid diseases. AIMS: Determine medication durability in IBD patients with and without psoriasis, rheumatoid arthritis, and/or enteropathic arthropathy. METHODS: All patients with at least three ICD-9 or 10 diagnoses for IBD were included in the cohort. The risk factors of interest were a co-morbid diagnosis of psoriasis (IBD-Ps), rheumatoid arthritis (IBD-RA), and/or enteropathic arthritis (IBD-EA). Medication durability was defined as days of medication use, calculated using order start and stop dates from the electronic medical record. Significant differences were tested using the Wilcoxon rank sum test for continuous variables and Fisher's exact test or Pearson's Chi-squared test, as appropriate, for categorical variables. Boxplots were constructed for graphical interpretation of results. RESULTS: In the psoriasis group, there were 481 patients with 831 medication exposures [131 IBS-Ps (16%), 700 IBD only (84%)]. The median days of medication use were numerically higher in the IBD-Ps group for all therapies [anti-TNF: 1109 vs 861 (p = 0.17); anti-IL-12/23: 984 vs 834 (p = 0.33); JAKi: 682 vs 230 (p = 0.13)], anti-TNF/IM: 370 vs 202 (p = 0.57), except anti-integrin therapy [214 vs 470 (p = 0.08)]. When restricting to UC only, patients with co-morbid again Ps had a significantly shorter duration on anti-integrin therapy (84 vs 456 days, p = 0.02). While not reaching statistical significance, there was a distinctly longer medication duration on JAKi therapy (910 vs 317, p = 0.10). When restricting to patients with CD only, no results reached statistical significance though there was a trend towards longer anti-TNF durability in CD-Ps (1340 vs 1000 days, p = 0.098). There were no differences in medication durability in IBD-RA or IBD-EA patients. DISCUSSION: Larger studies investigating medication durability of JAKi and anti-integrin therapy in IBD patients with psoriasis would be beneficial given noteworthy trends towards increased and decreased durability, respectively.

Efficacy and Safety of Dual Targeted Therapy for Partially or Non-responsive Inflammatory Bowel Disease: A Systematic Review of the Literature.

BACKGROUND: Dual targeted therapy (DTT) has emerged as an attractive therapeutic option for select patients with active inflammatory bowel disease (IBD) who are unable to achieve remission with biologic or small molecule monotherapy. We conducted a systematic review of specific DTT combinations in patients with IBD. METHODS: We conducted a systematic search of MEDLINE, EMBASE, Scopus, CINAHL Complete, Web of Science Core Collection, and Cochrane Library to identify articles related to the use of DTT for the treatment of Crohn Disease (CD) or ulcerative colitis (UC) published before February 2021. RESULTS: Twenty-nine studies were identified comprising 288 patients started on DTT for partially or non-responsive IBD. We identified 14 studies with 113 patients receiving anti-tumor necrosis factor (TNF) and anti-integrin therapies (i.e., vedolizumab and natalizumab), 12 studies with 55 patients receiving vedolizumab and ustekinumab, nine studies with 68 patients receiving vedolizumab and tofacitinib, five studies with 24 patients receiving anti-TNF therapy and tofacitinib, six studies with 18 patients receiving anti-TNF therapy and ustekinumab, and three studies with 13 patients receiving ustekinumab and tofacitinib. CONCLUSION: DTT is a promising approach to improve IBD treatment for patients with incomplete responses to targeted monotherapy. Larger prospective clinical studies are needed to confirm these findings as is additional predictive modeling to identify the patient subgroups most likely to require and benefit from this approach.

Ultrasound shear wave elastography in pediatric stricturing small bowel Crohn disease: correlation with histology and second harmonic imaging microscopy.

BACKGROUND: Preclinical animal as well as small exploratory ex vivo and in vivo human studies have suggested that bowel wall shear wave speed (SWS) measurements may be a noninvasive biomarker of intestinal damage. OBJECTIVE: To evaluate the relationships between bowel wall stiffness, measured using ultrasound shear wave elastography (SWE), and intestinal fibrosis and smooth muscle hypertrophy as determined by (1) histology and (2) second harmonic imaging microscopy (SHIM) in surgically resected ileal strictures from pediatric Crohn disease patients. MATERIALS AND METHODS: Nineteen pediatric Crohn disease patients with symptomatic ileal strictures underwent research ultrasound examinations before surgical resection between December 2017 and September 2020. Two-dimensional SWE was performed through the area of the most severe stenosis, with measurements obtained from the bowel wall at the 9:00, 12:00 and 3:00 o'clock locations with 0%, 10% and 20% abdominal strain. Overall right lower quadrant stiffness also was documented. Median bowel wall and overall right lower quadrant SWS measurements were correlated with bowel wall histological scores of inflammation, fibrosis and smooth muscle proliferation as well as SHIM collagen signal. RESULTS: Diagnostic ultrasound SWE imaging was obtained from 18 participants. The median age was 16.8 years. There were negative correlations between histological mucosal active inflammation and both bowel wall SWS with 10% abdominal strain (r=-0.50, P = 0.04) and overall right lower quadrant SWS with 20% abdominal strain (r=-0.69, P = 0.002). There were positive correlations between histological muscularis propria inner layer smooth muscle hypertrophy and both median bowel wall SWS with 10% abdominal strain (r = 0.72, P = 0.002) and overall right lower quadrant SWS with 20% abdominal strain (r = 0.71, P = 0.002). There were no associations between ultrasound stiffness metrics and bowel wall SHIM collagen measurements. CONCLUSION: Bowel wall and overall right lower quadrant ultrasound stiffness measurements correlate with mucosal active inflammation and muscularis propria smooth muscle hypertrophy in pediatric stricturing ileal Crohn disease, but not with intestinal fibrosis.

A Care Coordination Intervention Improves Symptoms But Not Charges in High-Risk Patients With Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with substantial symptom burden, variability in clinical outcomes, and high direct costs. We sought to determine if a care coordination-based strategy was effective at improving patient symptom burden and reducing healthcare costs for patients with IBD in the top quintile of predicted healthcare utilization and costs. METHODS: We performed a randomized controlled trial to evaluate the efficacy of a patient-tailored multicomponent care coordination intervention composed of proactive symptom monitoring and care coordinator-triggered algorithms. Enrolled patients with IBD were randomized to usual care or to our care coordination intervention over a 9-month period (April 2019 to January 2020). Primary outcomes included change in patient symptom scores throughout the intervention and IBD-related charges at 12 months. RESULTS: Eligible IBD patients in the top quintile for predicted healthcare utilization and expenditures were identified. A total of 205 patients were enrolled and randomized to our intervention (n = 100) or to usual care (n = 105). Patients in the care coordinator arm demonstrated an improvement in symptoms scores compared with usual care (coefficient, -0.68, 95% confidence interval, -1.18 to -0.18; P = .008) without a significant difference in median annual IBD-related healthcare charges ($10,094 vs $9080; P = .322). CONCLUSIONS: In this first randomized controlled trial of a patient-tailored care coordination intervention, composed of proactive symptom monitoring and care coordinator-triggered algorithms, we observed an improvement in patient symptom scores but not in healthcare charges. Care coordination programs may represent an effective value-based approach to improve symptoms scores without added direct costs in a subgroup of high-risk patients with IBD. (ClinicalTrials.gov, Number: NCT04796571).

Biomarkers for the Prediction and Diagnosis of Fibrostenosing Crohn's Disease: A Systematic Review.

BACKGROUND AND AIMS: Intestinal strictures are a common complication of Crohn's disease (CD). Biomarkers of intestinal strictures would assist in their prediction, diagnosis, and monitoring. Herein we provide a comprehensive systematic review of studies assessing biomarkers that may predict or diagnose CD-associated strictures. METHODS: We performed a systematic review of PubMed, EMBASE, ISI Web of Science, Cochrane Library, and Scopus to identify citations pertaining to biomarkers of intestinal fibrosis through July 6, 2020, that used a reference standard of full-thickness histopathology or cross-sectional imaging or endoscopy. Studies were categorized based on the type of biomarker they evaluated (serum, genetic, histopathologic, or fecal). RESULTS: Thirty-five distinct biomarkers from 3 major groups were identified: serum (20 markers), genetic (9 markers), and histopathology (6 markers). Promising markers include cartilage oligomeric matrix protein, hepatocyte growth factor activator, and lower levels of microRNA-19-3p (area under the curves were 0.805, 0.738, and 0.67, respectively), and multiple anti-flagellin antibodies (A4-Fla2 [odds ratio, 3.41], anti Fla-X [odds ratio, 2.95], and anti-CBir1 [multiple]). Substantial heterogeneity was observed and none of the markers had undergone formal validation. Specific limitations to acceptance of these markers included failure to use a standardized definition of stricturing disease, lack of specificity, and insufficient relevance to the pathogenesis of intestinal strictures or incomplete knowledge regarding their operating properties. CONCLUSIONS: There is a lack of well-defined studies on biomarkers of intestinal stricture. Development of reliable and accurate biomarkers of stricture is a research priority. Biomarkers can support the clinical management of CD patients and aid in the stratification and monitoring of patients during clinical trials of future antifibrotic drug candidates.