bluuebunny/crossref_metadata_2025 huggingface dataset:
IMPROVEMENT IN BOWEL URGENCY IS ASSOCIATED WITH STOOL FREQUENCY AND RECTAL BLEEDING REMISSION AT 12 AND 52 WEEKS IN PATIENTS WITH MODERATELY-TO-SEVERELY ACTIVE ULCERATIVE COLITIS
Authors: Long Millie , Gisbert Javier , McGinnis Kim , Ferrante Marc , Rogler Gerhard , Sapin Christophe , Hunter Theresa , Milata Joe , Navabi Seyedehsan
Published: January 2023

INTRODUCTION

Mirikizumab, an anti-IL23p19 antibody, has demonstrated safety and efficacy versus placebo across clinical remission, symptomatic remission, and endoscopic and histologic endpoints in patients with moderately-to-severely active ulcerative colitis (UC) in a Phase 3, double-blind, 12-week induction study (LUCENT-1/NCT03518086) and 40-week maintenance study (LUCENT-2/NCT03524092). Here, we examine the relationship between bowel urgency (BU) clinically meaningful improvement (CMI) and BU remission with rectal bleeding (RB) remission and stool frequency (SF) remission (Table 1 for definitions).

METHODS

Patients in LUCENT-1 (N=1281) were randomly assigned 3:1 to receive intravenous mirikizumab 300mg or placebo every four weeks (Q4W) for a total of 12 weeks. Patients who achieved clinical response to mirikizumab by Week 12 of LUCENT-1 (N=544) were re-randomized 2:1 to subcutaneous mirikizumab 200mg or placebo Q4W for 40 weeks in LUCENT-2 (maintenance study). Patients recorded their BU severity in the previous 24 hours using an 11-point Urgency Numeric Rating Scale (UNRS; 0=no urgency to 10=worst possible urgency) in an electronic daily diary. Weekly scores were averaged for patients with at least 4 of 7 days of complete diary data. BU remission was defined as UNRS score of 0 or 1, and BU CMI was defined as ≥3-point decrease in UNRS score compared to baseline. For patients who achieved clinical response at the end of induction, analyses were repeated for the end of maintenance at Week 40 (for 52 weeks of continuous treatment). Patients with UNRS<3 at baseline were not included in this analysis.

RESULTS

A total of 1087 patients reported a baseline UNRS score ≥3. Patients achieving BU CMI had significantly higher rates of RB remission and SF remission at both Week 12 and Week 40 compared with patients not achieving these outcomes (all p<0.001, Table 1, Figure 1). Similarly, at Week 12 and Week 40, patients achieving BU remission had significantly higher rates of achieving RB remission and SF remission compared to those who did not achieve BU remission (all p<0.001, Table 1, Figure 1).

CONCLUSION

A higher proportion of patients enrolled in LUCENT-1 and -2 who achieved BU CMI and BU remission achieved RB remission and SF remission. These results support that the symptom of bowel urgency is an important marker of UC disease activity that is related to and distinct from other commonly accepted symptoms of active UC.
LONGITUDINAL MONITORING OF INFLAMMATORY BOWEL DISEASE ACTIVITY USING WEARABLE DEVICES THROUGH INFLAMMATORY MARKERS IN SWEAT
Authors: Hirten Robert , Lin Kai-chun , Whang Jessica , Shahub Sarah , Sardesai Abha , Helmus Drew , Muthukumar Sriram , Sands Bruce , Prasad Shalini
Published: January 2023

BACKGROUND

Current methods to monitor inflammatory bowel disease (IBD) activity, such as colonoscopy, blood and stool markers, or imaging, are suboptimal and rely on single timepoint assessments that are inconvenient, expensive, or invasive. Wearable devices are a highly scalable mobile health technology that can non-invasively, continuously, and accurately monitor several physiological parameters that have been linked to flare in IBD. We performed a pilot feasibility study in subjects with IBD of a wearable device to monitor sweat-based inflammatory markers.

METHODS

Eligible participants were aged ≥ 18 years, diagnosed with IBD, admitted to the Mount Sinai Hospital for an IBD-related admission and had an elevated CRP (>5 mg/L). The sweat sensing device was worn by subjects to continuously measure the inflammatory markers C-reactive protein (CRP), tumor necrosis factor (TNF)α, and interleukin-6 (IL-6). The immunoassay on the sweat sensor was developed by immobilizing a specific capture probe antibody to capture CRP, TNFα and IL-6 in sweat. Data were transmitted from the device via Bluetooth to the cloud server. Sensor response was measured using impedance spectroscopy. Serum samples were collected daily. To evaluate the relationship between inflammatory markers in the sweat and serum, the Pearson correlation coefficient was calculated between longitudinal sweat measurements and serum CRP, TNFα and IL-6 levels. This was calculated for each subject with 2 or more consecutive serum values. The coefficient of variation was then calculated for each inflammatory marker.

RESULTS

A total of 16 subjects were enrolled. The sweat sensor device demonstrated the ability to measure in sweat CRP in the range of 525 to 1175.38 pg/ml, IL-6 in the range of 0.45 to 3.14 pg/ml, and TNFα in the range of 10.22 to 11.32 pg/ml. These measurements were correlated to their serum levels which were in the range of 2,200,000 to 12,7800,000 ug/ml for CRP, 0.68 to 31.66 pg/ml for IL-6, and 0.15 to 15.01 pg/ml for TNFα. The Pearson correlation coefficients between sweat and serum readings for CRP, IL-6 and TNFα are presented in Table 1. The coefficient of variation for CRP is 16.2% (mean 33,6863.14; standard deviation [std] 54,654.71), IL-6 is 19.5% (mean 33.23; std 7.06), and TNFα is 16.3% (mean 2.37; std 0.39). Figure 1 demonstrates temporal serum and sweat trends in a participant.

CONCLUSION

Longitudinally collected sweat CRP, IL-6 and TNFα, measured using a wearable device, correlate with serum measurements. This work is the first demonstration of continuous, non-invasive methods to longitudinally monitor inflammatory markers in sweat, and suggests the feasibility of using a non-invasive sweat-sensing wearable device to monitor IBD disease activity.
ANALYSIS OF THE GENETIC EXPRESSION OF COLON CANCER GENETIC BIOMARKERS ON INFLAMMATORY BOWEL DISEASE ON BLOOD AND BIOPSY SAMPLES
Authors: Martinez Evelyn Calderon , Zevallos-Delgado Christian , Joseph Maria
Published: January 2023

INTRODUCTION

Inflammatory bowel disease (IBD) is an immune-mediated inflammatory condition of the gastrointestinal tract. Its incidence rose steadily in the last century and the estimated incidence is approximately 2.5 million in Europe and 1.5 million in North America [1]. This condition can be associated with an increased risk of cardiovascular diseases, infections, and cancer [2] The risk of colorectal cancer (CRC) is approximately 2- to 3-fold higher for IBD patients than in the general population. [2] Malignancies are the second most common cause of mortality after cardiovascular disease in patients with IBD. [3] Several genetic biomarkers have been studied as prognostic factors, such as BRAF, CEACAM5, SMAD4, APC, MLH1 (part of the Microsatellite instability prognosis factors), and KRAS.

OBJECTIVE

The aim of this study was to determine the gene expression of CRC genetic biomarkers in IBD patients' peripheral blood and biopsy samples.

METHODOLOGY

The gene expression data was retrieved from the Gene Expression Omnibus (peripheral blood: GSE186507 and colon biopsies: GSE193677). This data was submitted by Argmann et al, a study that included healthy control patients (n=243), UC (n=421), and CD (n=243). The biopsy samples were obtained from the ileum, colon, and rectum. Several CRC biomarkers were retrieved from the literature. We compared the expression of these biomarkers between the groups in both, blood samples and the different sites of biopsies using T-test (UC vs control, CD vs control, and UC vs CD).

RESULTS

The analysis showed a significant difference in some CRC gene biomarkers between IBD patients and the control group in peripheral blood and the different locations where the biopsies were obtained. MLH1 was more expressed in IBD patients compared with healthy patients in the cecum (CD vs control p=8e-06; CD vs UC p= 0.00046), left colon (CD vs UC p= 0.02), right colon (UC vs control p=0.022; CD vs UC p=0.0053), sigmoid colon (UC vs control p=0.037; CD vs UC p=0.028), and rectum (CD vs control p=5e-10, CD vs UC p= 1.2e-13). In the case of the blood samples, the gene expression of SMAD4 (p = 0.03) CEACAM5 (p= 0.02), KRAS (p= 0.0005), and MLH1 (p= 0.0002) was significantly higher in IBD patients compared with control group.
THE EFFECTS OF BIOLOGIC AND SMALL MOLECULE INHIBITOR THERAPY ON THE MUCOSAL IMMUNE SYSTEM IN ULCERATIVE COLITIS
Authors: Briggs Kristi , Tam Ada , Housseau Franck , Melia Joanna , Pardoll Drew
Published: January 2023

Ulcerative colitis (UC) is a subtype of inflammatory bowel disease (IBD) that causes relapsing and remitting inflammation in the colon and rectum. Numerous treatment options are available for patients with UC including biologics and small molecule inhibitors that target the immune system. Although these therapies have dramatically improved options for patients with IBD, there remains a modest ceiling for their overall efficacy. Currently there are no biomarkers that can guide treatment decisions in patients with UC. Some studies have reported certain molecules or immune populations that are associated with treatment resistance or as predictors of treatment response. However, their clinical utility have yet to be fully determined because there is a paucity of longitudinal studies examining the direct effects of current biologics and small molecule inhibitors approved for UC on the immune biology of the colon mucosa. In this study, we perform longitudinal immune phenotyping using flow cytometry in patients with UC before and after therapy. Colon biopsy tissue was taken prior to treatment from 10 UC patients who were then followed and repeat biopsies were obtained from the same patients after 6-12 months of treatment. Tissue was analyzed using high dimensional flow cytometry with a panel of 24 markers of both lymphoid and myeloid lineages. Pre-treatment samples with inflammation correlated with higher populations of CD4+ T cells and CD4+ FOXP3 regulatory T cells also positive for TIGIT and GITR. Inflammation also corresponded with the presence of a CD33+ HLA-DR- population classically known as myeloid-derived suppressor cells (MDSC). Overall, therapy significantly decreased immune cell infiltration in the colon, most notably in B and T cell populations. However, certain treatments increased the MDSC population along with the stromal compartment of non-immune cells. A comprehensive analysis of the populations present during active inflammation and the treatment-induced changes in mucosal immunity will help identify biomarkers to predict response to therapy. In addition, examining the interplay between immune cells and the surrounding stroma can may lead to important findings that improve our understanding of each drug’s mechanism and efficacy. Future experiments with single cell RNA and T cell receptor sequencing on the same patients will identify effects of biologic therapy on the T cell repertoire and interactions between immune, epithelial, and stromal cells in the colonic mucosa. With the advent of novel sequencing and immune profiling assays, we now have the ability to harness the power of precision medicine to make more informed therapeutic decisions for IBD patients that improve clinical outcomes.
A NEW MODEL TO STUDY INTESTINAL FIBROSIS USING IPSC-DERIVED HUMAN EPITHELIAL AND MESENCHYMAL CELLS FROM CROHN’S DISEASE PATIENTS
Authors: Valencia Christian Wong , Patel Shachi , Bay Olivia , Estrada Hannah , Casero David , Targan Stephan , Barrett Robert
Published: January 2023

INTRODUCTION

Intestinal fibrosis is a serious complication of Crohn's disease (CD) and is caused by the excess deposition of extracellular matrix protein. There are no therapies to prevent or treat this and surgical intervention remains the only treatment option. Numerous cell types, including intestinal epithelial and mesenchymal cells, are implicated in this but research efforts are impaired by a lack of in vitro models. Human intestinal organoids (HIOs), derived from induced pluripotent stem cells (iPSCs), are comprised of both of these cell types; therefore iPSC-derived HIOs represent an approach in which an unlimited number of patient specific cells could be generated for such models. Our goal was to confirm the feasibility of using iPSC-derived epithelial and mesenchymal cells from CD patients to model intestinal fibrosis

METHODS

iPSCs from CD patients with and without fibrotic complications were directed to form HIOs. As iPSC-derived HIOs contain epithelial and mesenchymal cells, the organoids were dissociated to generate purified cultures of epithelial-only HIOs (eHIOs) and mesenchymal cells. Both cell types were cultured with TNFα and TGFβ, and responses were assayed after 8, 24 and 48 hrs. Further assessment on the transcriptomic profile of the cultures was conducted using the Nanostring nCounter Fibrosis Panel.

RESULTS

Mesenchymal cells treated with TNFα for 48 hrs showed a significant increase in MMP9 expression, whereas TGFβ elicited an upregulation in COL1A1 and COL5A1. Further analysis via Nanostring identified the upregulation of numerous other fibrosis-related genes in response to TNFα stimulation, mainly: CCL2, IL6, MMP7, and MMP9. In eHIO cultures, after 24 hrs of cytokine exposure, we detected a significant upregulation in EMT (NCAD, VIM, and SNAI2) and fibrosis genes (COL1A1, COL5A1, and MMP9), mainly in response to TGFβ and the combination TNFα/TGFβ. Nanostring further identified a total of 121 differentially expressed genes, mostly in response to these treatments, particularly: CCL2, IL11, MMP9, MMP10. Overall, Nanostring analysis found an upregulation in pathways associated with ECM production and remodeling, immunomodulation, and ligands associated with EMT and cell migration.

CONCLUSION

We have successfully generated a system to assay intestinal fibrosis in a patient-specific manner using iPSC-derived epithelial and mesenchymal cells from CD patients. Our model elicited a reliable and reproducible response to inflammatory and fibrogenic stimuli, measured by the differential expression of key fibrosis-associated genes. Future studies will focus on a broader analysis of these data via RNA-seq to investigate a potential fibrogenic phenotype and to identify novel genes/pathways that may play in role in the pathophysiology of intestinal fibrosis in CD.
CREATINE KINASE EXPRESSION IS PROTECTIVE IN A MOUSE COLITIS MODEL
Authors: Hall Caroline , Lanis Jordi , Dowdell Alexander , Murphy Emily , Colgan Sean
Published: January 2023

BACKGROUND

We have previously identified a loss of expression of creatine pathway proteins in mucosal tissue samples from inflammatory bowel disease patients. This is important as creatine is vital to ATP buffering in energetically active cells. The goal of this study was to determine the impact of decreased creatine kinase (CK) expression on mucosal inflammation by utilizing a whole body CK Brain and CK Mitochondrial knockout mouse (CKB/MitKO) in the dextran sulfate sodium (DSS) model of acute colitis.

METHODS

CKB/MitKO and matched controls were administered 1.5% DSS in drinking water for 5 days and assessed by body weight loss, disease activity index, mucosal permeability, histology and inflammatory cytokine production by Mesoscale analysis. In subsequent experiments, interferon-γ (IFN-γ) was given by intraperitoneal injection during the DSS experiment. We also analyzed transcriptional differences between CKB/MitKO and controls using a transcription factor array and western blot. Finally, we evaluated the impact of CK on the regulation of IFN-γ and transcriptional regulation of IFN-γ production in immune cells by flow cytometry.

RESULTS

Loss of CKB/Mit did not result in detectable baseline inflammation or barrier dysfunction in CKB/MitKO mice as compared to controls. However, in the setting of the chemical irritant DSS, CKB/MitKO mice had significantly increased weight loss, disease activity, intestinal permeability, histologic inflammation and decreased colon length. While control mice treated with DSS had significant increases in mucosal IFN-γ, the CKB/MitKO mice had strikingly absent mucosal protein concentrations of IFN-γ. Although IFN-γ is commonly considered a pro-inflammatory cytokine, it has also been shown to help promote inflammatory resolution. Therefore, we proceeded to add back IFN-γ in DSS experiments and we identified significant protection from weight loss and histologic damage with the addition of IFN-γ. We went on to identify transcription factor differences between CKB/MitKO and control splenocytes that revealed a >40-fold increase in the hypoxia responsive factor, HIF-1a, in CKB/MitKO splenocytes. We confirmed a causative relationship between HIF-1 expression and IFN-γ by treating mouse splenocytes with a HIF stabilizer and identified that HIF stabilization results in a reduction of IFN-γ production by CD4+ and CD8+ T cells.

CONCLUSIONS

CK is an essential energetic regulator. Using CK knockout mice we have identified an important role for CK in regulating IFN-γ production, mediated at least in part by HIF stabilization. These findings support a novel role for CK in tissue protection by immune regulation during acute colitis. Better understanding the role of energetics and the creatine pathway in particular may provide novel therapeutic options in inflammatory bowel disease.
EXCESS DIETARY SUGAR ALTERS COLONOCYTE METABOLISM AND IMPAIRS THE EARLY PROLIFERATIVE RESPONSE TO DAMAGE
Authors: Burr Ansen , Ji Junyi , Ozler Kadir , Mentrup Heather , Eskiocak Onur , Cumberland Rachel , Menk Ashley , Zhang Xiaoyi , Overacre-Delgoffe Abigail , Rittenhouse Natalie , Marshall Chris , Cooper Vaughn , Poholek Amanda , Delgoffe Greg , Beyaz Semir , Hand Timothy
Published: January 2023

The colonic epithelium requires continuous renewal by crypt resident intestinal stem cells (ISCs) and transit amplifying (TA) cells to maintain barrier integrity, especially after inflammatory damage. An important regulator of ISC and TA cell function is dietary metabolites which can affect their proliferative capacity. Over the last 150 years, the diet of high-income countries contains increasing amounts of simple sugars, such as sucrose, but whether excess sugar affects the function of ISCs and TA cells directly is unknown. We used a combination of 3-dimensional colonoids and a mouse model of colon damage/repair (DSS colitis) to demonstrate the direct effect of sugar on the transcriptional, metabolic, and regenerative functions of crypt ISCs and TA cells. We demonstrate that high sugar conditions directly limit murine and human colonoid development, which is associated with a reduction in the expression of proliferative and key stem cell gene signatures. Further, high-glucose conditions led to the accumulation of glycolytic metabolite pyruvate in colonoids, with a concomitant decrease in ATP, suggesting impaired glycolytic fuel metabolism. Treatment of colonoids with DCA, which forces pyruvate into the TCA cycle, restored their growth, ATP levels, and the expression of proliferation and stem cell gene signatures. Similarly, DSS treatment of mice fed a high sugar diet led to massive irreparable damage that was independent of the colonic microbiota and its metabolites. Metabolic analyses of crypt cells from high-sucrose-fed mice revealed increased glycolytic potential without a commensurate increase in aerobic respiration. Rather, epithelium from high-sucrose-fed mice has increased mitochondrial content, without increased levels of ATP, further demonstrating impaired oxidative phosphorylation and fuel metabolism. Finally, we demonstrated impaired proliferative potential of ISCs and reduced number of TA direct daughter cells in high-sucrose-fed mice with DSS damage. Taken together, our results indicate that short-term, excess dietary sucrose can directly modulate intestinal crypt cell metabolism and inhibit ISC/TA cell regenerative proliferation. This knowledge may inform diets that better support the treatment of acute intestinal injury, as is seen in patients with an acute flare of Ulcerative Colitis.
STRUCTURAL MODIFICATIONS OF BUTYRATE REVEAL TEMPLATES FOR INTESTINAL EPITHELIAL HIF STABILIZERS
Authors: Ornelas Alfredo , Wang Ruth , Countess Jake , Colgan Sean
Published: January 2023

Microbiota-derived short chain fatty acids, particularly butyrate (BA), show multiple beneficial influences on health. In the colon, BA ranges from 10-20 mM and up to 99% is utilized as a metabolic fuel by the mucosa. BA plays a key role in epithelial barrier regulation, reduces inflammation, and regulates cell growth and differentiation. There are multiple mechanisms by which BA contributes to gut health, many due to its regulatory capacity for gene expression. Our group reported (PMID: 34190032) a direct influence of BA on the stabilization of the transcription factor hypoxia-inducible factor (HIF). It is known that HIF stabilization is essential for appropriate mucosal barrier regulation and the coordination of regenerative capacity in the intestine. However, BA is constantly metabolized limiting its HIF stabilization effect. This observation led to the design and investigation of BA-mimicking compounds that stabilize HIF, but may not be involved in metabolism. We hypothesize that structural modifications of BA yield analogues that stabilize HIF with better efficacy and a longer biological half-life. A library of BA derivatives was screened in search of a non-endogenous analogue with higher potency and/or longer half-life for HIF stabilization. In vitro screenings at physiologically-relevant concentrations (5 mM) were performed using intestinal epithelial cell lines (T84 and CaCO2) in normoxia to determine HIF-1a protein abundance. Various analogues stabilized HIF, with 4-mercapto-butyrate (MBA) being the most promising candidate. The best analogues were validated through the induction of classic HIF gene targets, including BNIP3 and CAIX by q-PCR. MBA exhibited higher induction of these targets compared to BA. Time-course studies revealed that MBA exhibits significantly longer half-life as observed in the stabilization of HIF and induction of gene targets for up to 72 h compared to BA (24 h). Loss of gene induction was observed in MBA treated cells expressing lentiviral shRNA against HIF1b (HIF1b KD), supporting a HIF-dependent transcription. Furthermore, it’s been widely reported that BA enhances epithelial barrier, primarily through HIF coordinated barrier protection. Among several other BA derivatives, MBA enhanced and prolonged epithelial barrier function in intestinal epithelial cells. In vivo studies in C57BL/6 mice explored the induction of HIF targets in tissue and specifically erythropoietin (EPO) in circulation following administration of BA and MBA at similar doses. These studies revealed that induction of EPO with a single dose of MBA exceeded that of native BA. In colonic and kidney tissue, GLUT1 and BNIP3 were moderately induced in vivo. Thus, a non-endogenous BA derivative (MBA) stabilizes HIF at higher potency and longer half-life than native BA and will be used as a template for the development of HIF stabilizing agents.
IRE1α-XBP1 CONTROLS GROUP 3 INNATE LYMPHOID CELLS IN INFLAMMATORY BOWEL DISEASE
Authors: Cao Siyan , Colonna Marco
Published: January 2023

BACKGROUNDS

Group 3 innate lymphoid cells (ILC3s) recently emerged as important regulators and potential drug targets for IBD. However, the response of ILC3s to environmental stimuli during intestinal inflammation remains elusive. IRE1α-XBP1 is the most conserved pathway of the endoplasmic reticulum stress response that plays an important role in intestinal homeostasis. IRE1α mediates the alternative splicing of Xbp1 mRNA to produce a potent transcription factor XBP1s. Our preliminary data suggested that IRE1-XBP1 is induced during the activation of intestinal ILC3s.

METHODS

We generated conditional knockout Ire1αflox/flox,Rorc-Cre (Ire1αΔRorc) mice with Ire1α deleted in ILC3s. Intestinal infections were induced by Citrobacter rodentium and Clostridium difficile. In the acute phase of C. rodentium and C. difficile infection, IL-22 secreted by ILC3s, but not adaptive immune cells, is crucial for the host defense. Dextran sodium sulfate (DSS) was given in drinking water to induce colitis. We recruited patients with active Crohn’s disease (CD) and collected ileal biopsies during routine colonoscopy before starting a new biologic therapy. Mucosal immune cells were isolated from tissue samples for analysis of ILC3s by flow cytometry.

RESULTS

In murine intestinal ILC3s, the activity of IRE1α-XBP1 follows a robust 24h circadian rhythm which parallels that of clock genes and cytokines including IL-22 and IL-17A. IRE1α-XBP1 in intestinal ILC3s is further activated in response to inflammation/infection in mice and in patients with IBD compared to healthy controls. The IRE1α-XBP1 activation in stimulated ILC3s requires mitochondrial reactive oxygen species. Using the Ire1αΔRorc mice, we demonstrate that IRE1α-XBP1 is critical for cytokine expression by ILC3s. XBP1s binds to the promoters of Il-22 and Il-17a in activated ILC3s. Ire1αΔRorc mice loss the rhythmic expression of Il-22 and Il-17a by ILC3s in the gut. Additionally, Ire1αΔRorc mice are highly vulnerable to C. rodentium and C. difficile infection as well as DSS-induced colitis (Figure 1). The Ire1αΔRorc mice exhibit reduced IL-22 and IL-17A in ILC3s and impaired epithelial barrier function with diminished expression of mucins and antimicrobial peptides. The susceptibilities of Ire1αΔRorc mice to infections and colitis are rescued by injection of recombinant IL-22. Importantly, the frequency of ILC3s expressing XBP1s in ileal mucosa from CD patients positively correlates with response to therapies (Figure 2).

CONCLUSIONS

IRE1α-XBP1 controls ILC3s by activating IL-22 and IL-17A that are crucial for intestinal barrier function. Loss of IRE1α-XBP1 in ILC3s impairs the optimal and rhythmic expression of protective cytokines and renders the mice more susceptible to intestinal infections and colitis. Moreover, XBP1s in mucosal ILC3s may become a useful marker to predict response to therapies in CD patients.
SINGLE CENTER EXPERIENCE WITH UPADACITINIB FOR REFRACTORY PEDIATRIC INFLAMMATORY BOWEL DISEASE
Authors: Bergstein Suzannah , Spencer Elizabeth
Published: January 2023

BACKGROUND

Upadactinib (UPA) was recently approved for ulcerative colitis (UC) for patients 18 and older, and there is promising data for its use in adult Crohn’s disease (CD). It is currently also approved for use in atopic dermatitis (AD) down to the age of 12, but doses used are lower than in inflammatory bowel disease (IBD). There is currently no data on its use for pediatric IBD; we present here a case series of patients ≤18 years on UPA.

METHODS

We identified ≤18yo patients who were started on UPA for the indication of IBD +/- AD and completed ≥58 days of therapy at a single, US center. Data, with relevant descriptive statistics, were gathered on demographics, disease subtype, Montreal classification, indication for UPA, time on UPA, number of biologic failures, tofacitinib use, concomitant biologic use, adverse events, and clinical and biomarker remission (8-16 week clinical remission: HBI <5, pMS <3; 2-6 month CRP normalization).

RESULTS

12 patients (Median age at UPA start: 16.5y, Interquartile Range [IQR]: 4; 67% female) completed 8 or more weeks (Median [IQR] days: 118 [80]) of UPA (Table 1). Two-thirds of patients had CD. A quarter of patients (25%) had concomitant AD. All patients were diagnosed <17 years, with 67% patients diagnosed below or at the age of ten. The majority of patients (75%) had failed three or more biologics. UPA was used as monotherapy in 50% of patients. Four patients were exposed to and had a partial response to tofacitinib. The majority of patients (75%) had clinically active disease at UPA start. Most patients (83%) were induced with 45 mg, one patient was induced with 30mg, and one patient initiated 15mg as part of AD protocol, later increasing to 30mg. Out of the 12 total patients, 11/12 (92%) were in clinical remission between 8-16 weeks of therapy; in the subset of patients ≤17 years, 6/7 (86%) were in clinical remission. Nine patients had CRP levels measured 2-6 months after initiating UPA treatment; 8/9 (89%) of these patients achieved CRP normalization during this time. No serious adverse events occurred; one patient, who was on UPA monotherapy, developed recurrent styes that responded to hot compresses and antibiotic ointment. Joint involvement (sacroiliitis, arthritis, arthralgias) at the start of their treatment occurred in 3 patients; all of these patients had resolution of joint pain by 8 or more weeks. All patients had previously received vaccination for varicella; no patients were vaccinated for zoster, including the 5 who were 18 years of age.

CONCLUSION

No new safety signals were seen during induction dosing of UPA in teenage patients with IBD. In this very refractory group, nearly all patients achieved clinical & biomarker remission. Further study on the effectiveness and safety of UPA needs to be performed in pediatric patients.
AN ASSESSMENT OF HEALTHCARE PROFESSIONAL KNOWLEDGE REGARDING INVESTIGATIONAL STEM CELL THERAPIES FOR PATIENTS WITH CROHN’S PERIANAL FISTULA: A US MULTISPECIALITY EDUCATIONAL NEEDS SURVEY
Authors: Salinas Greg , Belcher Emily , Cazzetta Susan , Nazarey Pradeep , Stacy Sylvie
Published: January 2023

BACKGROUND

Crohn’s perianal fistulas (CPFs) are a common complication in patients with Crohn’s disease. Stem cell therapies are under investigation for the treatment of CPF; however, understanding amongst healthcare professionals (HCPs) is unknown and their educational needs have not been assessed. This study aimed to assess HCP familiarity with stem cells, their potential application in treating CPF and factors that may influence their use.

METHODS

An online educational needs survey was developed and distributed to HCPs, including gastroenterology and colorectal surgery specialists and primary care physicians (PCPs). Questions focused on the types of stem cells showing promise in treating CPF, their proposed mechanism(s) of action and familiarity with stem cell therapies. Factors influencing HCP treatment decisions regarding stem cell use in patients with CPF were also assessed. Results were reported using descriptive statistics.

RESULTS

Overall, 433 HCPs completed the survey, including: 151 PCPs; 127 gastroenterologists (GEs); 78 colorectal surgeons (CRSs); 63 GE nurse practitioners/physician assistants (NPs/PAs); and 14 CRS NPs/PAs. Uncertainty regarding the mechanism(s) of stem cell action for perianal fistula (PF) healing was reported in more than half of the surveyed PCPs and GE NPs/PAs (52% and 54%, respectively) and under half of the surveyed GEs, CRSs and CRS NPs/PAs (39%, 35% and 43%, respectively). Excluding GEs (42%), most HCPs (PCPs: 67%; CRS NP/NPAs: 64%; GE NP/NPAs: 60%; CRSs: 55%) were unsure about which stem cell types had shown promise in treating CPF. Regarding stem cell use in CPF, gastroenterology and colorectal surgery specialists considered clinical trial outcomes, particularly the success rate of PF healing and the safety profile of stem cells reported in clinical trials, as the most significant factors influencing decisions to use an approved stem cell therapy, with mean (standard deviation; SD) scores on a five-point scale of 4.2 (0.8) and 4.3 (0.7) for the success rate of PF healing and 4.1 (0.8) and 4.2 (0.8) for the safety profile, respectively. For PCPs, the success rate of PF healing reported in clinical trials and cost/insurance coverage were considered the most significant factors, with mean (SD) scores of 4.1 (0.8) and 4.0 (1.0), respectively.

CONCLUSIONS

HCPs would benefit from more information and education on stem cell therapies for CPF, notably on the types of stems cells and mechanism(s) that lead to PF healing. Effective communication of stem cell clinical efficacy and safety data, alongside information on the cost/insurance coverage of stem cell therapy are all required to inform recommendations on the use of stem cells for treating patients with CPF.
MANAGEMENT STRATEGIES FOR OBESITY VARY IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE
Authors: Dave Sonya , Beniwal-Patel Poonam
Published: January 2023

INTRODUCTION

Obesity among patients with inflammatory bowel disease (IBD) is increasing with prevalence of 15-40%. Studies have shown that obesity may have poor prognostic implications on IBD treatment and outcomes. There is lack of data focused on the management of obesity in IBD patients. This study’s primary aim was to evaluate whether patients with obesity and IBD have similar rates of obesity management compared to non-IBD obese patients with and without nonalcoholic fatty liver disease (NAFLD).

METHODS

This is a single-center retrospective study of 400 obese (body mass index > 30 kg/m2) adult patients seen in a primary care clinic between March 2019 and August 2021. Four cohorts, each with 100 patients, were studied. The 4-level cohort analysis included patients with ulcerative colitis and obesity (UC-O), Crohn’s disease and obesity (CD-O), NAFLD and obesity (NAFLD-O), and a control group of patients with obesity only. The 3-level cohort analysis combined UC-O and CD-O and compared this cohort to the NAFLD-O and obesity-only cohorts. Obesity management data collected included: if obesity was documented (OD) in the medical record’s problem list, dietician referral, pharmacologic therapy, and bariatric surgery referral. One-way ANOVA was used to compare numeric variables and chi-squared was used for categorical variables. Logistic regression models were used for primary outcomes.

RESULTS

Baseline characteristics of BMI, age, gender, and race were similar among patients in the 4-level and 3-level cohort analyses (Tables 1 and 2). Across both analyses, NAFLD-O patients had the highest prevalence of OD (79% p<0.001) and 2.61 higher odds of OD than the control (p =0.003). NAFLD-O patients also had the highest prevalence of dietician referrals (69%, p=0.01). CD-O patients had the highest prevalence of pharmacologic intervention (17%, p=0.01). UC-O patients were less likely to be referred to a dietician (OR=0.55, p=0.03) while CD-O patients were more likely to have pharmacologic management (OR=3.21, p=0.02). Secondary outcomes of comparisons of IBD-specific variables between UC-O and CD-O revealed significant differences as well (Table 3).

DISCUSSION

This is the first study investigating differences in treatments offered for obesity in IBD. With emerging evidence that obesity likely plays a role in IBD pathogenesis, timely identification and treatment is crucial. Significant differences in management of IBD patients with obesity highlight the need for increased awareness among healthcare providers. Our findings that CD-O patients had a higher rate of corticosteroid, immunomodulator, anti-TNF, anti-interleukin use, and IBD surgery compared to UC-O patients suggests that obesity may contribute to the pathogenesis of CD more so than UC. Further studies are needed to determine which obesity therapies are most effective in the IBD population.
THE INTERPLAY OF IBD AND DEPRESSION IN INPATIENT LENGTH OF STAY, COST, AND COMPLICATIONS
Authors: Dong Rachel , Chang Patrick , Zhang Bing
Published: January 2023

BACKGROUND

Many patients with inflammatory bowel disease (IBD) also have symptoms of depression. Both IBD and depression are associated with high healthcare utilization. In this cross-sectional study of population-based data, we sought to better characterize the impact of comorbid depression on hospitalizations of IBD patients.

METHODS

We used the 2016-2018 National Inpatient Sample (NIS) from the United States Department of Health and Human Services to identify hospitalizations with IBD and depression using ICD-10 codes. ICD-10 codes also identified confirmed complications of IBD, such as rectal bleed, fistula, abscess, or intestinal obstruction. Hospitalizations for suicidal intent were excluded from our analysis. Health outcomes including length of stay (LOS), total cost, and complications of IBD were compared between IBD patients with and without depression. Patients with confirmed discharges were captured and survival curves were compared for time to discharge. Statistical analysis was performed using STATA, including two-sample t-testing and logistic regression (significance, p<0.01).

RESULTS

Over three years, 129,011 hospitalizations for IBD were isolated. Of these, 2,124 hospitalizations (1.65%) were recognized to have both IBD and depression. Lengths of hospitalization for IBD patients with depression were longer than those without (mean LOS [95% CI]: 7.52 [7.06-7.98] vs. 5.28 [5.24-5.32], p<0.001) (Figure 1). Despite this, total cost of hospitalizations for IBD patients with depression was lower compared to IBD patients without depression ($mean [95% CI]: $47,841 [43,720-51,963] vs. $53,544 [53,023-54,065], p=0.008). Additionally, odds of hospitalization with IBD complication were lower in admissions coded for IBD with depression compared to without (OR [95% CI]: 0.52 [0.45, 0.61], p<0.001). On sub-analysis, hospitalizations of IBD patients with depression in partial or full remission had lower length of stay than hospitalizations of IBD with ongoing depression (mean LOS [95% CI]: 4.84 [3.90-5.79] vs. 7.52 [7.06-7.98], p<0.001) (Figure 2).

CONCLUSIONS

While IBD patients with depression demonstrated lengthier hospitalizations compared to IBD patients without depression, the higher inpatient cost and complications from the latter group may reflect diagnostic, procedural, or surgical management of active disease. While major limitations of this administrative database include identification of hospitalizations instead of individual patients, as well as possibly underreporting or lower recognition of depression during hospitalization, our findings suggest that management of comorbid depression may reduce the length of stay in hospitalized patients with IBD.
THE RELATIONSHIP BETWEEN SELF-REPORTED SLEEP, WRIST ACTIGRAPHY, AND SYMPTOMS AMONG ADULTS WITH INFLAMMATORY BOWEL DISEASE (IBD)
Authors: Winders Samantha , Yoo Linda , Clark-Snustad Kindra , Jacobs Jeffrey , Barahimi Mitra , Heitkemper Margaret , Lee Scott D , Kamp Kendra
Published: January 2023

BACKGROUND

Recently, there has been a growing recognition of the bidirectional link between sleep and inflammation. Several studies have reported the prevalence of sleep disturbances in those with Inflammatory Bowel Disease (IBD) and found poor sleep has the potential to increase the risk of disease relapse. Additionally, sleep loss may adversely affect cognitive performance, mental health, metabolism, and pain perception. While previous research has indicated potential associations between sleep and symptoms commonly reported in IBD, few studies use objective measures of sleep. Wrist actigraphy can objectively and non-invasively measure sleep-wake cycles and has been found feasible for use in the IBD population. This study aimed to examine the relationship between self-reported sleep, wrist actigraphy, and symptoms among adults with IBD.

METHODS

Participants with IBD (ages 18-55) completed demographic and sleep questionnaires, a 28-day symptom diary, and wore a wrist actigraph for up to 15 days. Sleep questionnaires were the Pittsburgh Sleep Quality Index (PSQI), Patient-Reported Outcomes Measurement Information System (PROMIS) sleep disturbance, and PROMIS sleep-related impairment. Participants rated symptoms on a 4-point Likert scale, including gastrointestinal-related symptoms such as abdominal pain, diarrhea, bloating, constipation, fatigue, and extraintestinal symptoms, including anxiety, depression, and stress. Data analysis included descriptive statistics and Pearson correlations.

RESULTS

Twenty-five participants (Crohn’s Disease=18; Ulcerative Colitis=7) were included. The mean age was 33.5 (SD 8.3) years of age, 60% were female, 92% were White, 88% were non-Hispanic or Latino, and 36% had active endoscopic disease. Most (64%) participants had poor quality sleep (PSQI global ≥ 5). In contrast, the averages for onset latency, efficiency, wake after sleep onset (WASO), and total sleep time were all within normal values at 17.4 min (SD 26.7), 84.2% (SD 7.5), 48.7 min (SD 27.3), and 435.8 min (69.2), respectively. PROMIS sleep disturbance was significantly correlated with abdominal pain (r=0.56), bloating (r=0.43), constipation (r=0.46), fatigue (r=0.50), and stress (r=0.42). PROMIS sleep-related impairment was significantly correlated with bloating (r=0.47), constipation (r=0.50), fatigue (r=0.60), depression (r=0.42), and stress (r=0.46). Onset latency was significantly correlated with anxiety (r=0.41) and stress (r=0.42). Sleep time was significantly correlated with fatigue (r=0.42).

CONCLUSION

This study highlights sleep disturbances are prevalent in those with IBD and significantly correlated with both GI and extraintestinal symptoms. Future work is needed to explore these relationships further and the potential benefit of sleep interventions in this population.
TRENDS AND RELATED FACTORS OF QUALITY OF LIFE IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE
Authors: Kim Sihyun , Yoon Hyuk , Jun Yu Kyung
Published: January 2023

INTRODUCTION

Inflammatory bowel disease(IBD) affects health-related quality of life(HRQoL). The short inflammatory bowel disease questionnaire(SIBDQ), measuring physical, social, and emotional status(score 10-70, poor to good HRQoL), is known to be well correlated to HRQoL of IBD patients.

AIM/METHODS

We aimed to evaluate factors that impact IBD patients' HRQoL. This prospective study included a cohort of patients with ulcerative colitis(UC) and Crohn’s disease(CD). IBD patients completed a SIBDQ questionnaire at enrollment and 20% of those patients completed a second SIBDQ questionnaire at follow-up. Data were analyzed using multiple linear regression analysis and Pearson’s correlation.

RESULTS

A total of 1,058 patients with IBD(UC 68%, CD 32%) were included. A SIBDQ score was median 52(IQR: 44-58). The first and follow-up SIBDQ score were not significantly different between UC and CD patients (p=0.243 and p=0.893, respectively). The distributions of SIBDQ change were as follows: decrease over 10%: 28%, -10% < change < 10%: 29%, increase over 10%: 43%. In UC patients, significant factors that negatively associated with SIBDQ score, were physician’s global assessment(r=-3.562, p<0.001), corticosteroids use(r=-5.478, p<0.001), fecal calprotectin level(r=-2.313, p=0.008), presence of joint symptoms(r=-2.925, p=0.017). In CD patients, significant factors that negatively associated with SIBDQ score, were Crohn's disease activity index score(r=-0.035, p=0.009), level of abdominal pain(r=-3.400, p=0.013) and presence of skin symptoms(r=-3.842, p=0.016). Factors that associated with SIBDQ score in both UC and CD patients were stool frequency(r=-2.913, p<0.001 in UC patients; r=-2.347, p=0.014 in CD patients).

CONCLUSION

SIBDQ questionnaire shows that IBD patients' HRQoL was mainly affected by the patient-reported outcome. However, it was also influenced by biochemical markers and extraintestinal symptoms depending on the specific type of IBD.
EICOSATETRAYNOIC ACID REGULATES PRO-FIBROTIC PATHWAYS IN AN INDUCED PLURIPOTENT STEM CELL DERIVED MACROPHAGE:HUMAN INTESTINAL ORGANOID MODEL OF ILEAL CROHN’S DISEASE
Authors: Dreskin Benjamin , Jurickova Ingrid , Angerman Elizabeth , Bonkowski Erin , Denson Lee
Published: January 2023

INTRODUCTION

Biologics targeting TNF are the mainstay of therapy for children with Crohn’s Disease (CD). However, a subset of patients do not respond, progressing to intestinal fibrosis requiring surgical resection. Prior studies have defined an ileal gene expression module linked to future strictures, and identified small molecules which may reverse this gene signature and suppress fibroblast activation. In the current study we developed a pre-clinical model system and tested a lead candidate, eicosatetraynoic acid (ETYA), a Peroxisome Proliferator-Activated Receptor (PPAR) agonist and arachidonic acid metabolism inhibitor.

METHODS

Peripheral blood samples were collected from pediatric CD patients and induced pluripotent stem cell (iPSC) lines were generated. iPSC were differentiated into human intestinal organoids (HIOs) and macrophage-like cells. Macrophage:HIO co-cultures were exposed to lipopolysaccharide (LPS) with and without eicosatetraynoic acid (ETYA) pre-treatment. Flow cytometry and cytospin characterized macrophage activation markers and morphology. Co-culture populations were harvested, and RNA and conditioned media were isolated for downstream analysis. TaqMan Low Density Array, Luminex multiplex assay, immunohistologic staining, and sirius red polarized light microscopy were performed to quantify measures of inflammation and fibrosis, and to test whether introduction of ETYA abated any of these inflammatory or fibrotic changes.

RESULTS

iPSC-derived macrophages exhibited morphology similar to primary macrophages, and expressed inflammatory macrophage cell surface markers including CD68 (Fig. 1A). LPS-stimulated iPSC-derived macrophages expressed a global pattern of gene expression by RNA sequencing enriched in CD ileal inflammatory macrophages (ToppCell Atlas, p=4.397E-117), and produced cytokines and chemokines implicated in refractory disease (Fig. 1B). Co-culture of LPS-primed macrophages with HIO led to up-regulation of the fibroblast activation genes ACTA2 and COL1A1 (Fig. 2). Under these conditions, HIO collagen content measured by sirius red staining and polarized light microscopy was increased (Fig. 2). ETYA pre-treatment prevented these pro-fibrotic effects of LPS-primed macrophages upon HIO gene expression and collagen content. However, LPS induction of macrophage IL1B, TNF, and OSM production was not suppressed by ETYA, suggesting an alternative mechanism of action upon HIO fibroblast activation and collagen content in the co-culture system.

CONCLUSIONS

ETYA inhibits effects of LPS-primed macrophages upon HIO pro-fibrotic gene expression and collagen production. This was not associated with an effect of ETYA upon macrophage inflammatory cytokine production. Future studies will test alternate pathways including PPAR activation and arachidonic acid metabolism which may mediate this response.