Active Crohn's Disease Research Articles

Model-based Investigation of Inadequate Efficacy of Tesnatilimab, an Anti- Natural Killer Group 2 Member D (NKG2D) Monoclonal Antibody, in Moderately to Severely Active Crohn's Disease.

Tesnatilimab is a human immunoglobulin G4 isotype monoclonal antibody that blocks the natural killer group 2 member D (NKG2D) receptor and prevent the downstream signaling of proinflammatory cytokines and cytotoxic mediators. Subcutaneous tesnatilimab was investigated in a phase 2 randomized, double-blind, placebo-controlled trial in patients with moderately to severely active Crohn's disease (CD). While the proof-of-concept Part I of the study demonstrated significant treatment effects, Part II (dose-ranging) revealed unexpected lack of dose-response and a modest degree of clinical benefit for treatment groups. To inform further drug development, population pharmacokinetic (PopPK) modeling and exposure-response (E-R) analyses were planned and performed. A one-compartment PopPK model with first-order absorption and parallel linear and non-linear elimination pathways was established for tesnatilimab in CD patients. No clinically significant covariates were identified and overall consistent PK was observed between Part I and Part II patients. Receptor occupancy data suggested full occupancy of the peripheral blood NKG2D receptors and target engagement at all tested dose levels. Pooled Part I and Part II data showed a positive efficacy E-R relationship, however, this was driven by data from Part I. Part II only analysis did not show an apparent efficacy E-R relationship. No important covariates were identified in efficacy E-R analyses, overall and in various subpopulations. No apparent E-R relationships were observed for the investigated safety endpoints. The PopPK and E-R analysis indicated that the inadequate efficacy of tesnatilimab in CD was unlikely due to insufficient drug exposure and target engagement. This article is protected by copyright. All rights reserved.

Targeting IL23p19 using risankizumab for the management of moderate-to-severely active Crohn's disease

Targeting Th17-mediated inflammatory pathways through inhibition of interleukin (IL)-23 has emerged as an important therapeutic mechanism for patients with inflammatory bowel disease. Ustekinumab, a monoclonal antibody blocking both IL-12 and IL-23, was the first agent approved by Health Canada with this mechanism of action, initially for Crohn’s disease (CD) in 2016 and subsequently for ulcerative colitis (UC) in 2020. Over the past decade, there has been increasing attention focused on selectively blocking IL-23, as the key activator of pathogenic Th17 inflammatory cells. Several monoclonal antibodies that target the unique p19 subunit of IL-23 (IL23p19 antagonists) have been developed for psoriasis and psoriatic arthritis, where IL-23 specific blockade results in substantially greater efficacy compared to targeting IL-12/23. The first IL23p19 antagonist, risankizumab, has recently been approved in Canada for the treatment of moderate-to-severely active CD. Here, we describe the mechanism of action of risankizumab and how it differentiates from ustekinumab; review the pivotal clinical trial data that demonstrates the ability of risankizumab to achieve relevant clinical and endoscopic endpoints in both biologic treatment naïve and exposed patients; and summarize key safety data that helps inform decisions about the benefit-risk profile of this novel therapy.

Insight into gut dysbiosis of patients with inflammatory bowel disease and ischemic colitis.

The collection of whole microbial communities (bacteria, archaea, fungi, and viruses) together constitutes the gut microbiome. Diet, age, stress, host genetics, and diseases cause increases or decreases in the relative abundance and diversity of bacterial species (dysbiosis). We aimed to investigate the gut microbial composition at different taxonomic levels of healthy controls (HCs) with active Crohn's disease (CD), ulcerative colitis (UC), and ischemic colitis (IC) using culture- and non-culture-based approaches and identify biomarkers to discriminate CD, UC, or IC. We determined the specific changes in the gut microbial profile using culture-independent (16S rRNA gene amplicon sequencing) as well as culture-based (culturomic) approaches. Biomarkers were validated using quantitative Real-Time PCR (qPCR). In both methods, bacterial diversity and species richness decreased in disease-associated conditions compared with that in HCs. Highly reduced abundance of Faecalibacterium prausnitzii and Prevotella sp. and an increased abundance of potentially pathogenic bacteria such as Enterococcus faecium, Enterococcus faecalis, and Escherichia coli in all CD, UC, or IC conditions were observed. We noted a high abundance of Latilactobacillus sakei in CD patients; Ligilactobacillus ruminis in UC patients; and Enterococcus faecium, Escherichia coli, and Enterococcus faecalis in IC patients. Highly reduced abundance of Faecalibacterium prausnitzii in all cases, and increased abundance of Latilactobacillus sakei and Enterococcus faecium in CD, Ligilactobacillus ruminis and Enterococcus faecium in UC, and Enterococcus faecium, Escherichia coli, and Enterococcus faecalis in IC could be biomarkers for CD, UC, and IC, respectively. These biomarkers may help in IBD (CD or UC) and IC diagnosis.

An essential role of adenosine deaminase acting on RNA 1 in coeliac disease mucosa.

Type I interferons (IFNs) are highly expressed in the gut mucosa of celiac disease (CD) gut mucosa and stimulates immune response prompted by gluten ingestion, but the processes that maintain the production of these inflammatory molecules are not well understood. Adenosine deaminase acting on RNA 1 (ADAR1), an RNA-editing enzyme, plays a crucial role in inhibiting self or viral RNAs from activating auto-immune mediated responses, most notably within the type-I IFN production pathway. The aim of this study was to assess whether ADAR1 could contribute to the induction and/or progression of gut inflammation in patients with celiac disease. ADAR1 expression was assessed by Real time PCR and Western blotting in duodenal biopsy taken from inactive and active celiac disease (CD) patients and normal controls (CTR). To analyze the role of ADAR1 in inflamed CD mucosa, lamina propria mononuclear cells (LPMC) were isolated from inactive CD and ADAR1 was silenced in with a specific antisense oligonucleotide (AS) and then incubated with a synthetic analogue of viral dsRNA (poly I:C). IFN-inducing pathways (IRF3, IRF7) in these cells were evaluated with Western blotting and inflammatory cytokines were evaluated with flow cytometry. Lastly, the role of ADAR1 was investigated in a mouse model of poly I:C-driven small intestine atrophy. Reduced ADAR1 expression was seen in duodenal biopsies compared to inactive CD and normal controls. Ex vivo organ cultures of duodenal mucosal biopsies, taken from inactive CD patients, stimulated with a peptic-tryptic digest of gliadin displayed a decreased expression of ADAR1. ADAR1 silencing in LPMC stimulated with a synthetic analogue of viral dsRNA strongly boosted the activation of IRF3 and IRF7 and the production of type-I IFN, TNF-α and IFN-γ. Administration of ADAR1 antisense but not sense oligonucleotide to mice with poly I:C-induced intestinal atrophy, significantly increased gut damage and inflammatory cytokines production. These data show that ADAR1 is an important regulator of intestinal immune homeostasis and demonstrate that defective ADAR1 expression could provide to amplifying pathogenic responses in CD intestinal mucosa.

Efficacy of short-chain polypeptide-based EEN formulas in alleviating intestinal injury in children with Crohn's disease: a single-center study in China.

Short-chain polypeptides are composed of three to nine amino acids, which can be absorbed by the intestinal tract without digestive enzymes and ATP energy. Crohn's disease (CD) is a chronic non-specific disease derived from inflammation and damage of the gastrointestinal tract. In this study, we aim to investigate the effect of short-chain polypeptide-based exclusive enteral nutrition (EEN) formulas on intestinal injury in Chinese children with active CD. From January 2013 to January 2019, a total of 84 consecutive children with a diagnosis of Crohn's disease (CD) in the Department of Pediatric Gastroenterology, Children's Hospital of Nanjing Medical University, were divided into mild and moderate-to-severe active CD groups. Each group was further divided into two subgroups: drug group and short-chain polypeptide plus drug group. Tests were carried out on the levels of intestinal fatty acid binding protein (I-FABP) in the blood, fecal calprotectin (FC), and occludin protein in the intestinal mucosa 1 day before treatment and 8 weeks after treatment. Endoscopic and histopathological observations were detected to compare the changes in intestinal injury in children with active CD. After 8 weeks of treatment, the SES-CD scores and Chiu scores of the ileocecal area and terminal ileum of children with mild active CD and the ileocecal area of children with moderate-to-severe active CD in short-chain polypeptide plus drug group were significantly lower than those in the drug group. The OD value of occludin in the terminal ileum and ileocecal area of children with mild active CD and the ileocecal area of children with moderate-to-severe active CD after short-chain polypeptide-based EEN formulas and drug treatment was significantly higher than those in the drug group (p < 0.05). Meanwhile, the levels of FC and I-FABP were significantly decreased (p < 0.05). The results showed that short-chain polypeptide-based EEN formulas effectively alleviate intestinal injury in children with active CD.

Crohn's disease and breast cancer: a literature review of the mechanisms and treatment.

This is a literature review describes Crohn's disease (CD) concomitant with breast cancer and summarizes possible common pathogenic mechanisms shared by the two diseases involving the IL-17 and NF-κB signaling pathways. Inflammatory cytokines including TNF-α and Th17 cells in CD patients can induce activation of the ERK1/2, NF-κB and Bcl-2 pathways. Hub genes are involved in the generation of cancer stem cells (CSCs) and are related to inflammatory mediators, including CXCL8, IL1-β and PTGS2, which promote inflammation and breast cancer growth, metastasis, and development. CD activity is highly associated with altered intestinal microbiota processes, including secretion of complex glucose polysaccharides by Ruminococcus gnavus colonies; furthermore, γ-proteobacteria and Clostridium are associated with CD recurrence and active CD, while Ruminococcaceae, Faecococcus and Vibrio desulfuris are associated with CD remission. Intestinal microbiota disorder promotes breast cancer occurrence and development. Bacteroides fragilis can produce toxins that induce breast epithelial hyperplasia and breast cancer growth and metastasis. Gut microbiota regulation can also improve chemotherapy and immunotherapy efficacy in breast cancer treatment. Intestinal inflammation can affects the brain through the brain-gut axis, which activates the hypothalamic‒pituitary‒adrenal (HPA) axis to induce anxiety and depression in patients; these effects can inhibit the antitumor immune responses of the immune system and promote breast cancer occurrence in patients with CD. There are few studies on the treatment of patients with CD concomitant with breast cancer, but published studies show three main strategies: new biological agents combined with breast cancer treatment methods, intestinal fecal bacteria transplantation, and dietary treatment.

Analysis of Circulating Food Antigen-Specific T-Cells in Celiac Disease and Inflammatory Bowel Disease.

To demonstrate and analyze the specific T-cell response following barrier disruption and antigen translocation, circulating food antigen-specific effector T-cells isolated from peripheral blood were analyzed in patients suffering from celiac disease (CeD) as well as inflammatory bowel disease (IBD). We applied the antigen-reactive T-cell enrichment (ARTE) technique allowing for phenotypical and functional flow cytometric analyses of rare nutritional antigen-specific T-cells, including the celiac disease-causing gliadin (gluten). For CeD, patient groups, including treatment-refractory cases, differ significantly from healthy controls. Even symptom-free patients on a gluten-free diet were distinguishable from healthy controls, without being previously challenged with gluten. Moreover, frequency and phenotype of nutritional antigen-specific T-cells of IBD patients directly correlated to the presence of small intestinal inflammation. Specifically, the frequency of antigen specific T-cells as well as pro-inflammatory cytokines was increased in patients with active CeD or Crohn's disease, respectively. These results suggest active small intestinal inflammation as key for the development of a peripheral food antigen-specific T-cell response in Crohn's disease and celiac disease.

Mezinárodní zkušenosti s dietou pro Crohnovu chorobu založenou na vyloučení konkrétních potravin (CDED) s parciální enterální výživou (PEN)

The role of dietary intervention in the induction of remission of Crohn’s disease (CD) has been confirmed again by the recent ECCO (European Crohn’s and Colitis Organization) and ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition) guidelines. Exclusive enteral nutrition (EEN) should be the method of choice in induction of remission of active luminal CD in children. Steroids should be reserved for situations when intolerance or infectivity of EEN is present. The main limitations of EEN consist of its monotony and palatability. In search for a safe and at least similarly effective diet, Crohn’s disease exclusion diet (CDED) was developed. The number of published data regarding its safety and efficacy has increased significantly since the publication of the first randomized controlled trial in 2019. CDED seems, to be safe and its efficacy is very promising. It seems that CDED could be used in three scenarios: as a monotherapy, as a part of complex treatment and as rescue therapy in cases of loss of response. The use of CDED is promising but further research for evaluation of its efficacy, including the necessity of using partial enteral nutrition, on larger patient cohorts is required. Keywords Crohn’s disease, exclusive enteral nutrition, steroids, Crohn’s Disease Exclusion Diet (CDED), adherence

Fecal transplantation for treatment of inflammatory bowel disease.

Fecal transplantation for treatment of inflammatory bowel disease.

Role of prebiotics, probiotics, and synbiotics in management of inflammatory bowel disease: Current perspectives.

Experimental evidence supports the fact that changes in the bowel microflora due to environmental or dietary factors have been investigated as implicating factors in the etiopathogenesis of inflammatory bowel disease (IBD). The amassing knowledge that the inhabited microbiome regulates the gut physiology and immune functions in IBD, has led researchers to explore the effectiveness of prebiotics, probiotics, and synbiotics in treating IBD. This therapeutic approach focuses on restoring the dynamic balance between the microflora and host defense mechanisms in the intestinal mucosa to prevent the onset and persistence of intestinal inflammation. Numerous microbial strains and carbohydrate blends, along with their combinations have been examined in experimental colitis models and clinical trials, and the results indicated that it can be an attractive therapeutic strategy for the suppression of inflammation, remission induction, and relapse prevention in IBD with minimal side effects. Several mechanisms of action of probiotics (for e.g., Lactobacillus species, and Bifidobacterium species) have been reported such as suppression of pathogen growth by releasing certain antimicrobial mediators (lactic and hydrogen peroxide, acetic acid, and bacteriocins), immunomodulation and initiation of an immune response, enhancement of barrier activity, and suppression of human T-cell proliferation. Prebiotics such as lactulose, lactosucrose, oligofructose, and inulin have been found to induce the growth of certain types of host microflora, resulting in an enriched enteric function. These non-digestible food dietary components have been reported to exert anti-inflammatory effects by inhibiting the expression of tumor necrosis factor-α-related cytokines while augmenting interleukin-10 levels. Although pro-and prebiotics has established their efficacy in healthy subjects, a better understanding of the luminal ecosystem is required to determine which specific bacterial strain or combination of probiotics and prebiotics would prove to be the ideal treatment for IBD. Clinical trials, however, have given some conflicting results, requiring the necessity to cite the more profound clinical effect of these treatments on IBD remission and prevention. The purpose of this review article is to provide the most comprehensive and updated review on the utility of prebiotics, probiotics, and synbiotics in the management of active Crohn's disease and ulcerative colitis/pouchitis.

Changes in the gut mycobiome in pediatric patients in relation to the clinical activity of Crohn's disease

Numerous studies have shown that in Crohn's disease (CD), the gut microbiota is of great importance in the induction and maintenance of inflammation in the gastrointestinal tract. Until recently, studies have focused almost exclusively on bacteria in the gut. Lately, more attention has been paid to the role of intestinal fungi. To study the gut mycobiome analysis of pediatric patients with CD (in different stages of disease activity) compared to healthy children. Fecal samples were collected from patients: With active, newly diagnosed CD (n = 50); active but previously diagnosed and treated CD (n = 16); non-active CD and who were in clinical remission (n = 39) and from healthy volunteers (n = 40). Fungal DNA was isolated from the samples. Next, next generation sequencing (MiSeq, Illumina) was performed. The composition of mycobiota was correlated with clinical and blood parameters. Candida spp. were overrepresented in CD patients, while in the control group, the most abundant genus was Saccharomyces. In CD patients, the percentage of Malassezia was almost twice that of the control (P < 0.05). In active CD patients, we documented a higher abundance of Debaryomyces hansenii (D. hansenii) compared to the non-active CD and control (P < 0.05) groups. Moreover, statistically significant changes in the abundance of Mycosphaerella, Rhodotorula, and Microidium were observed. The analyses at the species level and linear discriminant analysis showed that in each group it was possible to distinguish a specific species characteristic of a given patient population. Moreover, we have documented statistically significant correlations between: D. hansenii and patient age (negative); C. zeylanoides and patient age (positive); C. dubliniensis and calprotectin (positive); C. sake and calprotectin (positive); and C. tropicalis and pediatric CD activity index (PCDAI) (positive). Mycobiome changes in CD patients, and the positive correlation of some species with calprotectin or PCDAI, give strong evidence that fungi may be of key importance in the development of CD.

Expression analysis of IL-2, TBX21 and SOCS1 in peripheral blood cells of celiac disease patients reveals the diagnostic potential of IL-2.

Celiac disease (CD) is a chronic immune-mediated enteropathy and a cytokine network is involved in its pathogenesis. Interleukin-2 (IL-2) has a key role in the adaptive immune pathogenesis of CD and has been reported to be one of the earliest cytokines to be elicited after gluten exposure by CD patients. This study aimed at investigating the expression level of IL-2 and functionally related genes SOCS1 and TBX21 in active and treated CD patients compared to controls. Peripheral blood (PB) samples were collected from 40 active CD (ACD), 100 treated CD, and 100 healthy subjects. RNA was extracted, cDNA was synthesized and mRNA expression levels of the desired genes were investigated by Real-time PCR. The gene-gene interaction network was also constructed by GeneMANIA. Our results showed a higher PB mRNA expression of IL-2 in ACD patients compared to controls (p = 0.001) and treated CD patients (p˂0.0001). The mRNA expression level of TBX21 was also significantly up-regulated in ACD patients compared to controls (P = 0.03). SOCS1 mRNA level did not differ between active and treated CD patients and controls (p˃0.05) but showed a significant correlation with the patient's aphthous stomatitis symptom (r = 0.37, p = 0.01). ROC curve analysis suggested that the use of IL-2 levels can reach a high specificity and sensitivity in discriminating active CD patients. The PB level of IL-2 has the potential to be introduced as a diagnostic biomarker for CD. Larger cohort studies, including pediatric patients, are needed to achieve more insights in this regard.

Predicting Crohn's disease severity in the colon using mixed cell nucleus density from pseudo labels.

Crohn's disease (CD) is a debilitating inflammatory bowel disease with no known cure. Computational analysis of hematoxylin and eosin (H&E) stained colon biopsy whole slide images (WSIs) from CD patients provides the opportunity to discover unknown and complex relationships between tissue cellular features and disease severity. While there have been works using cell nuclei-derived features for predicting slide-level traits, this has not been performed on CD H&E WSIs for classifying normal tissue from CD patients vs active CD and assessing slide label-predictive performance while using both separate and combined information from pseudo-segmentation labels of nuclei from neutrophils, eosinophils, epithelial cells, lymphocytes, plasma cells, and connective cells. We used 413 WSIs of CD patient biopsies and calculated normalized histograms of nucleus density for the six cell classes for each WSI. We used a support vector machine to classify the truncated singular value decomposition representations of the normalized histograms as normal or active CD with four-fold cross-validation in rounds where nucleus types were first compared individually, the best was selected, and further types were added each round. We found that neutrophils were the most predictive individual nucleus type, with an AUC of 0.92 ± 0.0003 on the withheld test set. Adding information improved cross-validation performance for the first two rounds and on the withheld test set for the first three rounds, though performance metrics did not increase substantially beyond when neutrophils were used alone.

Development and Validation of the Glasgow Exclusive Enteral Nutrition Index of Compliance.

Treatment adherence is key to the efficacy of exclusive enteral nutrition [100% EN] in active Crohn's disease [CD], but there are no biomarkers to objectively estimate this. We explored faecal parameters as biomarkers of compliance with 100% EN, and subsequently developed and validated the Glasgow Exclusive Enteral Nutrition Index of Compliance [GENIE]. Healthy adults replaced all [100% EN] or part [85% EN, 50% EN, 20% EN] of their diet with a formula for 7 days. Faecal pH, water content, short chain fatty acids, and branched chain fatty acids [BCFAs] were measured before [D0] and after [D7] each intervention. Optimal biomarkers and threshold values were derived using receiver operating characteristic curve analyses and machine learning to develop the GENIE. The GENIE was then validated in 30 CD children, during and after 100% EN. In all, 61 adults were recruited. D7 faecal pH and the ratios of BCFAs to either acetate or butyrate performed the best to differentiate between patients on 100% EN from <100% EN. Two models were generated; one included faecal metabolites (Laboratory GENIE, L-GENIE; sensitivity, specificity, and positive predictive value [PPV] of 88%, 94%, and 92%) and a second one [Clinical Genie, C-GENIE] which considers only faecal pH [sensitivity, specificity, and PPV of 84%, 86%, and 81%]. Validation of GENIE in CD children found that C-GENIE outperformed L-GENIE, producing a sensitivity, specificity, and PPV of 85%, 88%, and 88%, respectively. GENIE can help predict adherence to 100% EN and may complement current conventional dietary assessment.

Subcutaneous Infliximab Monotherapy Versus Combination Therapy with Immunosuppressants in Inflammatory Bowel Disease: A Post Hoc Analysis of a Randomised Clinical Trial

Whether benefits and risks of intravenous (IV) infliximab combotherapy with immunosuppressants versus infliximab monotherapy apply to subcutaneous (SC) infliximab is unknown. This post hoc analysis of a pivotal randomised CT-P13 SC 1.6 trial aimed to compare SC infliximab monotherapy with combotherapy in inflammatory bowel disease (IBD). Biologic-naïve patients with active Crohn's disease or ulcerative colitis received CT-P13 IV 5 mg/kg at Week (W) 0 and 2 (dose-loading phase). At W6, patients were randomised (1:1) to receive CT-P13 SC 120 or 240 mg (patients <80 or ≥80 kg) every 2 weeks until W54 (maintenance phase), or to continue CT-P13 IV every 8 weeks until switching to CT-P13 SC from W30. The primary endpoint-non-inferiority of trough serum concentrations-was assessed at W22. We report a post hoc analysis comparing pharmacokinetic, efficacy, safety and immunogenicity outcomes up to W54 for patients randomised to CT-P13 SC, stratified by concomitant immunosuppressant use. Sixty-six patients were randomised to CT-P13 SC (37 monotherapy, 29 combotherapy). At W54, there were no significant differences in the proportions of patients achieving target exposure (5 µg/mL; 96.6% monotherapy vs 95.8% combotherapy; p > 0.999) or meeting efficacy or biomarker outcomes including clinical remission (62.9% vs 74.1%; p = 0.418). Monotherapy and combotherapy groups had comparable immunogenicity (anti-drug antibodies [ADAs]: 65.5% vs 48.0% [p = 0.271], neutralising antibodies [in ADA-positive patients]: 10.5% vs 16.7% [p = 0.630], respectively). Pharmacokinetics, efficacy and immunogenicity were potentially comparable between SC infliximab monotherapy and combotherapy in biologic-naïve IBD patients. ClinicalTrials.gov: NCT02883452.

The Association Between Depression and Activity of Inflammatory Bowel Disease

Background: The association between depression and inflammatory bowel disease (IBD) has been reported worldwide. Objectives: We aimed to investigate the prevalence of active and inactive IBD depression and its associated risk factors among patients with depression and IBD. Materials &amp; Methods: In this cross-sectional study, demographic data and clinical characteristics of 156 IBD patients referred to Razi Hospital, Rasht City, Iran, were recorded from 2015 to 2016. The Beck depression inventory (BDI) was administered to all patients, and their scores were classified as no, mild, moderate, and severe depression. Modified Truelove and Witts severity index (MTWSI) for ulcerative colitis (UC) and Harvey Bradshaw severity index (HBSI) for Crohn’s disease (CD) were used to quantitate IBD activity as active UC (scored ≥10) and active CD (scored ≥7). Results: About 35.9% of the patients (n=56) had depression. Patients with active IBD had significantly higher BDI scores than those with inactive IBD (14.41±10.34 vs 10.14±10.28, respectively, P=0.011). Except for income (P=0.001), no significant associations were detected between IBD status and other background variables (P&gt;0.05). No patients in either active or inactive IBD groups had cancers. Based on the severity of depression, the patients were grouped as follows: 64.1% had no depression, 30.1% had mild depression, 5.8% had moderate depression, and 0.0% had severe depression. However, significant positive associations were seen between an increase in depression severity and having autoimmune diseases, a lower education level, and a history of IBD-related surgeries. Conclusion: It seems that patients with active IBD are more depressed than inactive IBD patients.

Comparison of gastrointestinal ultrasound with capsule endoscopy in patients with small bowel Crohn's disease

ObjectiveWe aimed to investigate the association between gastrointestinal ultrasound (GIUS) and capsule endoscopy (CE) in assessing disease activity in patients with small bowel Crohn's disease (CD).MethodsMedical records of 74 patients with small bowel CD who were treated at our hospital between January 2020 and March 2022 were retrospectively reviewed, including 50 men and 24 women. All patients underwent both GIUS and CE within one week after their admissions. The Simple Ultrasound Scoring of Crohn's Disease (SUS‐CD) and Lewis score were used to assess disease activity during GIUS and CE, respectively. P &lt; 0.05 was considered as statistically significant.ResultsThe area under the receiver operating characteristic curve (AUROC) of SUS‐CD was 0.90 (95% confidence interval [CI] 0.81–0.99; P &lt; 0.001). And the diagnostic accuracy of GIUS was 79.7%, with a sensitivity of 93.6%, a specificity of 81.8%, a positive predictive value of 96.7%, a negative predictive value of 69.2% in predicting active small bowel CD. Furthermore, the agreement between GIUS and CE was assessed using Spearman's correlation analysis and SUS‐CD was correlated with Lewis score (r = 0.82, P &lt; 0.001)ConclusionOur findings demonstrate a strong correlation between GIUS and CE in assessing the disease activity in patients with CD affecting the small intestine.

Tissue and Circulating MicroRNA-31, MicroRNA-200b, and MicroRNA-200c Reflects Disease Activity in Crohn‘s Disease Patients: Results from the BIOMIR Study

MicroRNAs (miR) have altered expression in multiple autoimmune disorders including inflammatory bowel disease. The aim of the study was to assess the tissue and circulating miR-31, miR-200b, and miR-200c expression levels as potential biomarkers for intestinal disease activity in patients with Crohn's disease (CD). The study included 45 patients with histopathological confirmed CD and active disease (defined as fecal calprotectin >50 μg/g and Simple Endoscopic Score (SES) of CD >3), and 21 subjects as controls for the validation cohort. Demographic and clinical data, biomarkers (fecal calprotectin), endoscopy data, the expression levels of miR-31, miR-200b, and miR-200c in tissue and serum were assessed (by RT-PCR). Receiver operating characteristic analysis was performed to assess the miR-31, miR-200b, and miR-200c expression levels as potential biomarkers for active CD. Mean fecal calprotectin was 1540±890 μg/g. Mean SES-CD was 8.9±4.2. Tissue and circulating miR- 31 were significantly correlated with fecal calprotectin (r=0.81, r=0.83, p<0.01) and with SES-CD (r=0.82, r=0.79, p<0.01). The expression level of miR-31 was significantly upregulated in CD tissue cases compared to the control tissue samples (6.24±1.57 vs. 3.70±1.44; p <0.01). Similarly, serum miR-31 expression levels in CD patients were significantly upregulated compared to the control serum samples (0.78±0.42 vs. -2.07±1.00; p<0.01). The expression levels of tissue miR-200b and miR-200c were significantly upregulated in CD tissue cases compared to the control tissue samples (-5.25±0.93 vs. -4.69±0.80, p=0.03 for miR-200b, and -0.86±0.96 vs. 0.39±0.66, p<0.01 for miR-200c). Similarly, serum miR-200b and miR-200c expression levels in CD patients were significantly upregulated compared to the control serum samples (p < 0.05). Receiver operating characteristic analysis revealed that the expression levels of the selected miRNAs could help to discriminate active CD patients from healthy controls with very good specificity and sensitivity. Tissue and circulating miR-31, miR-200b, and miR-200c reflect disease activity in CD patients and can be used as biomarkers for active disease.

Perfusion Computed Tomography May Help in Discriminating Gastrointestinal Tuberculosis and Crohn’s Disease

Gastrointestinal tuberculosis (GITB) and Crohn's disease (CD) are close mimics. This prospective study aimed to evaluate the diagnostic performance of perfusion computed tomography (CT) in differentiating GITB from CD. Consecutive patients with ileocaecal thickening underwent perfusion CT of the ileocaecal region between January 2019 and July 2020. Two radiologists (blinded to the final diagnosis) independently assessed blood flow (BF), blood volume (BV), mean transit time (MTT), and permeability at perfusion CT. These parameters were compared among the patients with GITB as well as active and inactive CD. Receiver operating characteristic curves were utilized for determining the diagnostic performance of perfusion CT. Interclass correlation coefficient and Bland-Altman analysis were performed to compare the observations of the two radiologists. During the study period, 34 patients underwent perfusion CT. Eight patients had diagnoses other than intestinal tuberculosis or CD. Thus, 26 patients (mean age 36 ± 14 years, 18 males) with GITB (n = 11), active CD (n = 6), and inactive CD (n = 9) were evaluated. BF, MTT, and permeability showed significant differences among the groups, while BV did not differ significantly among the groups. BF and permeability had 100% sensitivity and 100% specificity, while MTT had 61.5-100% sensitivity and 70-100% specificity for differentiating GITB from active CD and active from inactive CD. The interclass correlation coefficient for perfusion CT parameters was 0.88-1. Perfusion CT is a novel imaging technique that can improve the diagnostic performance of differentiating tuberculosis from CD.

A Phase 2b, Randomised, Double-blind, Placebo-controlled, Parallel-arm, Multicenter Study Evaluating the Safety and Efficacy of Tesnatilimab in Patients with Moderately to Severely Active Crohn's Disease.

Tesnatilimab, a monoclonal antibody targeting NKG2D, was evaluated in Crohn's disease [CD] patients who had failed or were intolerant to biologic or conventional therapy. TRIDENT was a phase 2b, two-part, randomised, double-blind, placebo-controlled, parallel-arm, multicenter study. In Part 1 [proof of concept], 145 patients who were biologic intolerant or refractory [Bio-IR] or had not failed biologic therapy [Bio-NF] were randomised in a 1:1 ratio to placebo subcutaneously [SC] or tesnatilimab 400 mg SC. In Part 2 [dose ranging], 243 Bio-IR and Bio-NF patients were randomised in a 1:1:1:1:1 ratio to placebo, tesnatilimab [50 mg, 150 mg, 400 mg], or intravenous infusion of ustekinumab ~6 mg/kg at Week 0 and 90 mg SC at Weeks 8 and 16. The primary endpoint was mean change from baseline in Crohn's Disease Activity Index [CDAI] at Week 8 [Part 1] and Week 12 [Part 2]. Clinical and endoscopic remission/response were evaluated. Efficacy analyses were also assessed by NKG2D and MICB single nucleotide polymorphism [SNP] status [SNP-positive means positive in at least one of two SNPs]. Safety events were summarised. In Part 1, mean change from baseline in CDAI score was significantly greater with tesnatilimab vs placebo at Week 8 [-103.6 vs -60.0; p < 0.01]. In Part 2, no dose-response signal was detected. Mean changes from baseline in CDAI at Week 12 were -93.2, -72.2, and -84.3 for low, middle, and high doses of tesnatilimab, respectively, vs -59.2 for placebo and -148.8 for ustekinumab. Similar reductions from baseline in CDAI score were observed in patients receiving tesnatilimab, regardless of SNP status. Clinical remission rates were greater with tesnatilimab than placebo in Parts 1 and 2, whereas endoscopic response rates were greater with tesnatilimab only in Part 1. No unexpected safety events occurred. Tesnatilimab was well tolerated. The efficacy of tesnatilimab in patients with CD was significant for the primary endpoint in Part 1; however, no dose-response signal was detected for the primary endpoint in Part 2. Based on these inconsistent findings, tesnatilimab was not considered an effective treatment for patients with CD and no further development is planned. NCT02877134.