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Introduction: Rapidity of effect of advanced therapies for patients with Crohn's disease (CD) can be an essential decision parameter; however, comparative evaluation is lacking. We aimed to compare early response for advanced CD therapies in a network meta-analysis (NMA)., Methods: We searched systematically MEDLINE, Embase, and CENTRAL up to 19 February 2024, for randomised controlled trials. The co-primary outcomes were induction of clinical remission (Crohn's Disease Activity Index (CDAI) ≤150) and clinical response (≥100-point reduction in CDAI) within the first 6 weeks of treatment. We incorporated any assessment within this time point in a Bayesian random-effects NMA following PRISMA-NMA guidance (PROSPERO ID: CRD42022368509)., Results: Twenty-five studies, comprising 7414 patients, were included. Infliximab combined with azathioprine or monotherapy ranked highest for induction of clinical remission within 6 weeks and was significantly superior to certolizumab, ustekinumab, guselkumab, vedolizumab, and upadacitinib. However, superiority over risankizumab 600 mg and adalimumab 160/80 mg was non-significant. Accordingly, infliximab in combination with azathioprine and guselkumab 600 mg ranked highest in the corresponding analysis of clinical response with no statistical significance demonstrated. Among bio-exposed patients, none of whom received infliximab, upadacitinib, and risankizumab induced the highest clinical responses. On the other hand, vedolizumab, certolizumab, and ustekinumab ranked lowest across the analyses., Conclusions: We found infliximab to be ranked highest and superior to all other agents but risankizumab and adalimumab, demonstrating the highest probability of early induction of remission. Upadacitinib and risankizumab induced the highest clinical responses in bio-exposed patients. However, infliximab was not investigated in this population., (© 2024 John Wiley & Sons Ltd.)

Innate immune activity fuels intestinal inflammation in Crohn's disease (CD), an inflammatory bowel disease. Identification and targeting of new molecular regulators of the innate activity are warranted to control the disease. Inhibitor of apoptosis proteins (IAPs) regulate both cell survival and inflammatory signaling. We investigated the effects of IAP inhibition by second mitochondria-derived activator of caspases (SMAC) mimetics (SMs) on innate responses and cell death to pathogen-associated molecular patterns in peripheral blood mononuclear cells (PBMCs) and monocytes. IAPs inhibited lipopolysaccharide (LPS)-induced expression of proinflammatory interleukin (IL)-1β, IL-6. Likewise, LPS (but not muramyl dipeptide or Escherichia coli) induced TNF-α was inhibited in CD and control PBMCs. The SM effect was partially reversed by inhibition of receptor-interacting serine/threonine-protein kinase 1 (RIPK1). The effect was mainly cell death independent. Thus, IAP inhibition by SMs leads to reduced production of proinflammatory cytokines and may be considered in the efforts to develop new therapeutic strategies to control CD., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Inflammatory bowel disease (IBD) is a chronic intestinal disorder, with two main types: Crohn's disease (CD) and ulcerative colitis (UC), whose molecular pathology is not well understood. The majority of IBD-associated SNPs are located in non-coding regions and are hard to characterize since regulatory regions in IBD are not known. Here we profile transcription start sites (TSSs) and enhancers in the descending colon of 94 IBD patients and controls. IBD-upregulated promoters and enhancers are highly enriched for IBD-associated SNPs and are bound by the same transcription factors. IBD-specific TSSs are associated to genes with roles in both inflammatory cascades and gut epithelia while TSSs distinguishing UC and CD are associated to gut epithelia functions. We find that as few as 35 TSSs can distinguish active CD, UC, and controls with 85% accuracy in an independent cohort. Our data constitute a foundation for understanding the molecular pathology, gene regulation, and genetics of IBD.

X-linked lymphoproliferative disease type 2 (XLP-2, OMIM 300635) is a primary immunodeficiency caused by the loss of X chromosome-linked inhibitor of apoptosis (XIAP), the X-linked inhibitor of apoptosis gene at Xq25. XLP-2 individuals are susceptible to several specific and potentially fatal infections, such as Epstein-Barr virus (EBV). Children with XIAP-related XLP-2 may present with either familial hemophagocytic lymphohistiocytosis, often triggered in response to EBV infection, or with a treatment-refractory severe pediatric form of inflammatory bowel disease (IBD) that might be diagnosed as Crohn disease. However, this monogenic cause of IBD is distinct from adult Crohn disease (a polygenic and multifactorial disease) in its etiology and responsiveness to therapy. XLP-2 and the associated IBD symptoms are managed by a reduced-intensity conditioning regimen with an allogeneic hematopoietic stem cell transplantation that causes resolution of gastrointestinal symptoms. Exome sequencing has enabled identification of XIAP-deficient diseased individuals and has altered their morbidity by providing potentially lifesaving strategies in a timely and effective manner. Here, we summarize XLP-2 IBD treatment history and patient morbidity/mortality since its original identification in 2006. Since XLP-2 is rare, cases are probably undergiagnosed or misdiagnosed. Consideration of XLP-2 in children with severe symptoms of IBD can prevent serious morbidities and mortality, avoid unnecessary procedures, and expedite specific targeted therapy.Genet Med 19 2, 133-143.

Genetic variations in the autophagic pathway influence genetic predispositions to Crohn disease. Autophagy, the major lysosomal pathway for degrading and recycling cytoplasmic material, constitutes an important homeostatic cellular process. Of interest, single-nucleotide polymorphisms in ATG16L1 (autophagy-related 16-like 1 [S. cerevisiae]), a key component in the autophagic response to invading pathogens, have been associated with an increased risk of developing Crohn disease. The most common and well-studied genetic variant of ATG16L1 (rs2241880; leading to a T300A conversion) exhibits a strong association with risk for developing Crohn disease. The rs2241880 variant plays a crucial role in pathogen clearance, resulting in imbalanced cytokine production, and is linked to other biological processes, such as the endoplasmic reticulum stress/unfolded protein response. In this review, we focus on the importance of ATG16L1 and its genetic variant (T300A) within the elementary biological processes linked to Crohn disease.

Aims: Inflammation is considered to play a role in the development of atrial fibrillation (AF). Hence inflammatory bowel disease (IBD) may be associated with AF. We therefore examined the incidence of AF and stroke in patients with IBD., Methods and Results: From Danish nationwide registries 1996-2011, we identified 24 499 patients with new-onset IBD and 236 275 age- and sex-matched controls. Poisson regression analyses with continuously updated covariates were used to estimate incidence rate ratios (IRRs) of AF and stroke. Disease activity stages of flare (new disease activity), persistent activity, and remission were defined by corticosteroid prescriptions, IBD hospital admissions, and biological treatment. Inflammatory bowel disease patients had a mean age of 43.9 years, 53.9% were women, and mean follow-up was 6.8 years. Among IBD patients, 685 had AF and 549 had a stroke, corresponding to incidence rates per 1000 person-years of 4.16 vs. 2.70 for AF and 3.33 vs. 2.44 for stroke, compared with matched controls. Overall IBD-associated risk of AF corresponded to IRR 1.26 (1.16-1.36), but was driven by increased AF incidence during IBD flares [IRR 2.63 (2.26-3.06)] and persistent activity [IRR 2.06 (1.67-2.55)], whereas no increased AF risk was observed in remission periods [IRR 0.97 (0.88-1.08)]. Likewise increased stroke risk was exclusively found during active IBD [IRRs: 1.57 (1.27-1.93), 1.71 (1.32-2.21), and 1.04 (0.93-1.15) for flares, persistent activity, and remission, respectively]., Conclusion: Active IBD is associated with increased risk of AF and stroke. These findings may be relevant to clinical practice.

Crohn's disease (CD) is one of main disease entities under the umbrella term chronic inflammatory bowel disease. The etiology of CD involves alterations in genetic, microbiological, and immunological factors. This review is devoted to the role of the bacterial wall compound muramyl dipeptide (MDP) for the activation of inflammatory pathways involved in the pathogenesis of CD. The importance of this molecule is underscored by the fact that (1) MDP, which is found in most Gram-negative and -positive bacteria, is able to trigger several immunological responses in the intestinal system, and (2) that alterations in several mediators of the MDP response including-but not restricted to-nucleotide oligomerization domain 2 (NOD2) are associated with CD. The normalization of MDP signaling is one of several important factors that influence the intestinal inflammatory response, a fact which emphasizes the pathogenic importance of MDP signaling for the pathogenesis of CD. The important aspects of NOD2 and non-NOD2 mediated effects of MDP for the development of CD are highlighted, as well as how alterations in these pathways might translate into the development of new therapeutic strategies.

Aim: To use microarray-based miRNA profiling of colonic mucosal biopsies from patients with ulcerative colitis (UC), Crohn's disease (CD), and controls in order to identify new potential miRNA biomarkers in inflammatory bowel disease., Methods: Colonic mucosal pinch biopsies from the descending part were obtained endoscopically from patients with active UC or CD, quiescent UC or CD, as well as healthy controls. Total RNA was isolated and miRNA expression assessed using the miRNA microarray Geniom Biochip miRNA Homo sapiens (Febit GmbH, Heidelberg, Germany). Data analysis was carried out by principal component analysis and projection to latent structure-discriminant analysis using the SIMCA-P+12 software package (Umetrics, Umea, Sweden). The microarray data were subsequently validated by quantitative real-time polymerase chain reaction (qPCR) performed on colonic tissue samples from active UC patients (n = 20), patients with quiescent UC (n = 19), and healthy controls (n = 20). The qPCR results were analyzed with Mann-Whitney U test. In silico prediction analysis were performed to identify potential miRNA target genes and the predicted miRNA targets were then compared with all UC associated susceptibility genes reported in the literature., Results: The colonic mucosal miRNA transcriptome differs significantly between UC and controls, UC and CD, as well as between UC patients with mucosal inflammation and those without. However, no clear differences in the transcriptome of patients with CD and controls were found. The miRNAs with the strongest differential power were identified (miR-20b, miR-99a, miR-203, miR-26b, and miR-98) and found to be up-regulated more than a 10-fold in active UC as compared to quiescent UC, CD, and controls. Two miRNAs, miR-125b-1* and let-7e*, were up-regulated more than 5-fold in quiescent UC compared to active UC, CD, and controls. Four of the seven miRNAs (miR-20b, miR-98, miR-125b-1*, and let-7e*) were validated by qPCR and found to be specifically upregulated in patients with UC. Using in silico analysis we found several predicted pro-inflammatory target genes involved in various pathways, such as mitogen-activated protein kinase and cytokine signaling, which are both key signaling pathways in UC., Conclusion: The present study provides the first evidence that miR-20b, miR-98, miR-125b-1*, and let-7e* are deregulated in patients with UC. The level of these miRNAs may serve as new potential biomarkers for this chronic disease.

Use of the immunomodulators thiopurines and methotrexate (MTX) in the treatment of inflammatory bowel disease (IBD), i.e., Crohn's disease and ulcerative colitis (UC), is considered to be good clinical practice. However, despite being administered to a considerable number of IBD patients over the years, questions remain about the most rational treatment regimens of azathioprine (AZA), 6-mercaptopurine (6-MP), and MTX, and results from a range of recent studies necessitate increased attention to how to optimize the use of these immunomodulators. First and foremost, it is of utmost importance to define the subgroup of IBD patients in need of immunomodulators, including those in need of combination therapy with biologic agents, especially because some side effects may be rather severe. Second, colorectal cancer is observed more often in IBD patients than in the background population. However, a recent nationwide Dutch study pointed to a preventive effect of thiopurines. Finally, the need for an appropriate approach to the discontinuation of immunomodulators is emphasized. Since controversy continues regarding the most appropriate use of immunomodulators, this paper is focusing on pharmacokinetics, pharmacogenetics, and therapeutic blood testing, as well as the occurrence of adverse events, when using AZA, 6-MP, and MTX in an attempt to determine a more up-to-date and rational treatment regimen in IBD., (© The Author(s) 2013.)

Unlabelled: CCX282-B, also called vercirnon, is a specific, orally-administered chemokine receptor CCR9 antagonist that regulates migration and activation of inflammatory cells in the intestine. This randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of CCX282-B in 436 patients with Crohn's disease. Crohn's Disease Activity Index (CDAI) scores were 250-450 and C-reactive protein >7.5 mg/L at study entry. In addition to stable concomitant Crohn's medication (85% of subjects), subjects received placebo or CCX282-B (250 mg once daily, 250 mg twice daily, or 500 mg once daily) for 12 weeks. They then received 250 mg CCX282-B twice daily, open-label, through week 16. Subjects who had a clinical response (a ≥ 70 point drop in CDAI) at week 16 were randomly assigned to groups given placebo or CCX282-B (250 mg, twice daily) for 36 weeks. Primary endpoints were clinical response at Week 8 and sustained clinical response at Week 52. During the 12-week Induction period, the clinical response was highest in the group given 500 mg CCX282-B once daily. Response rates at week 8 were 49% in the placebo group, 52% in the group given CCX282-B 250 mg once daily (odds ratio [OR] = 1.12; p = .667 vs placebo), 48% in the group given CCX282-B 250 mg twice daily (OR = 0.95; p = .833), and 60% in the group given CCX282-B 500 mg once daily (OR = 1.53; p = .111). At week 12, response rates were 47%, 56% (OR = 1.44; p = .168), 49% (OR = 1.07; p = .792), and 61% (OR = 1.74; p = .039), respectively. At the end of the Maintenance period (week 52), 47% of subjects on CCX282-B were in remission, compared to 31% on placebo (OR = 2.01; p = .012); 46% showed sustained clinical responses, compared to 42% on placebo (OR = 1.14; p = .629). CCX282-B was well tolerated. Encouraging results from this clinical trial led to initiation of Phase 3 clinical trials in Crohn's disease., Trial Registration: ClinicalTrials.gov NCT00306215.

Introduction of biological agents for the treatment of Crohn's disease (CD) has led to a transformation of the treatment paradigm. Several biological compounds have been approved for patients with CD refractory to conventional treatment: infliximab, adalimumab and certolizumab pegol (and natalizumab in several countries outside the European Union). However, despite the use of biologics for more than a decade, questions still remain about the true efficacy and the best treatment regimens - especially about when to discontinue treatment. Furthermore, a need for optimizing treatment with biologics still exists, as 20-40% of patients with CD (depending on selection criteria) do not have any relevant response to the current biological agents (i.e. primary failures). A better patient selection might maximize the clinical outcome while minimizing the complications associated with this type of therapy. However, the clinical tools capable of identifying such patients are still unavailable, and the trough level strategy may help the clinician to optimize therapy and to avoid loss of response and/or immunogenicity (i.e. a low but measurable antibody level exists just before the periodic administration of the biological agent). On the other hand, peak levels and average levels should not exceed concentrations associated with increased toxicity. Randomized, controlled studies focusing on trough levels and antibodies towards the biological agent in routine clinical situations may add important pieces to the puzzle for a more rational treatment algorithm of CD patients. In some situations, the risks (i.e. immunogenicity, serious infections and the promotion of neoplasia) may, however, not outweigh the benefits of biological treatment., (Copyright © 2012 S. Karger AG, Basel.)

Background and Purpose of Study: Extensive copy number variation is observed for the DEFA1A3 gene encoding alpha-defensins 1-3. The objective of this study was to determine the involvement of alpha-defensins in colonic tissue from Crohn's disease (CD) patients and the possible genetic association of DEFA1A3 with CD., Methods: Two-hundred and forty ethnic Danish CD patients were included in the study. Reverse transcriptase PCR assays determined DEFA1A3 expression in colonic tissue from a subset of patients. Immunohistochemical analysis identified alpha-defensin peptides in colonic tissue. Copy number of DEFA1A3 and individual alleles, DEFA1 and DEFA3, were compared with those for controls, by use of combined real-time quantitative PCR and pyrosequencing, and correlated with disease location., Results: Inflammatory-dependent mRNA expression of DEFA1A3 (P < 0.001), and the presence of alpha-defensin peptides, were observed in colonic tissue samples. Higher DEFA1A3 gene copy number (CD: mean copy number, 7.2 vs. controls 6.7; P < 0.001) and individual DEFA1 alleles (CD mean copy number 5.6 vs. controls 5.1; P < 0.01) were associated with CD, with strong association with colonic location (P < 0.001)., Conclusions: Alpha-defensins are involved in the inflammation of CD, with local mRNA and peptide expression. In combination with the findings that a high DEFA1A3 copy number is significantly linked to CD, these results suggest that a high DEFA1A3 copy number might be important in hindering the normal inflammatory response in CD, particularly colonic CD.

Adherent-invasive Escherichia coli (AIEC) are reported to inhabit the gut mucosa in Crohn's disease (CD), however, little is known about the importance of host factors for the interplay between AIEC and the human gut. To examine if differences in bacterial adhesion patterns are disease associated, the AIEC-prototype strain LF82 was evaluated for its ability to adhere to ileal and colonic biopsies from CD and healthy controls (HC). Moreover, the efficacy of the non-pathogenic E. coli Nissle 1917 (ECN) in averting LF82 adhesion to ileal mucosa was assessed. Similar numbers of LF82 adhered to biopsies from CD and HC. A significantly greater LF82 attachment to ileal versus colonic mucosa was found in HC (P < 0.01), however, not in CD. ECN did not reduce the adhesion of LF82 to ileal specimens in CD or HC. These results show that enhanced bacterial adhesion ability is unlikely to play any significant role in CD, thus implying that other host protective factors may be impaired in CD. Further, exclusion of LF82 attachment by ECN co-incubation does not appear to represent a relevant treatment regimen., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The complex and yet unknown etiology of Crohn's disease (CD) might consist of various disease endophenotypes, each of which represent their own pathogenesis. This review focuses on the disease endophenotype linked to polymorphisms in the nucleotide-binding oligomerization domain containing 2 (NOD2) protein and on the importance of established adherent-invasive E. coli (AIEC) in ileal mucosa. To date, there are several reports pointing to the implications of NOD2 polymorphisms in epithelial and immunological responses against microbes, but the pathological significance of NOD2 mutations in CD is not yet clarified. The enhanced number of pathogenic E. coli in the ileal mucosa of CD as compared to healthy controls may result from a genetically based failure in one of the intestinal bacteria sensing systems, like NOD2, making the ileal epithelium more prone to colonization with microbes harboring specific properties such as AIEC. Increasing the focus on defining subgroups of patients with similar disease initiations, mechanisms of action, and manifestations in CD may be pivotal for the development and implementation of future individualized treatment strategies of benefit for the single patient at an early stage., (Copyright © 2011 Crohn's & Crohn's & Colitis Foundation of America, Inc.)

A systematic review to evaluate the efficacy of 5-aminosalicylates for induction of remission or clinical response in patients with mild to moderately active Crohn's disease is described. The effect of either high (3 to 4.5 g/day) or low dose (1 to 2 g/day) 5-aminosalicylic acid was similar to that of placebo. Overall, sulfasalazine was not superior to placebo and was inferior to glucocorticoids for the treatment of mild to moderately active Crohn's disease. Neither published nor unpublished data support any use of 5-aminosalicylates for the treatment of Crohn's disease.

We here present a method based on qRT-PCR to quantify E. coli LF82 in intestinal human samples. Two different primer-probe sets were designed to detect LF82, and a third to target total E. coli. The assay showed high robustness and specificity for detection of LF82 in the presence of intestinal tissue., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Sensing of muramyl dipeptide (MDP) is impaired in Crohn's disease (CD) patients with disease-linked variants of the CARD15 (caspase activation and recruitment domain 15) gene. Animal studies suggest that normal CARD15 signalling prevents inflammatory bowel disease, and may be important for disease development in CD. However, only a small fraction of CD patients carry the disease linked CARD15 variants. The aim of this study was thus to investigate if changes could be found in CARD15 signalling in patients without disease associated CARD15 variants., Methodology/principal Findings: By mapping the response to MDP in peripheral monocytes obtained from CD patients in remission not receiving immunosuppresives, an impaired response to MDP was found in patients without disease linked CARD15 variants compared to control monocytes. This impairment was accompanied by a decreased activation of IkappaB kinase alpha/beta (IKKalpha/beta), the initial step in the nuclear factor kappaB (NFkappaB) pathway, whereas activation of mitogen-activated protein (MAP)-kinases was unaffected. MDP additionally stimulates the inflammasome which is of importance for processing of cytokines. The inflammasome was constitutively activated in CD, but unresponsive to MDP both in CD and control monocytes., Conclusions/significance: These results suggest that inhibited MDP-dependent pathways in CD patients not carrying the disease-associated CARD15 variants might be of importance for the pathogenesis of CD. The results reveal a dysfunctional immune response in CD patients, not able to sense relevant stimuli on the one hand, and on the other hand possessing constitutively active cytokine processing.

Background: The development and course of Crohn's disease (CD) is related to both genetic and environmental factors. Smoking has been found to exacerbate the course of CD by increasing the risk of developing fistulas and strictures as well as the need for surgery, possibly because of an interaction between smoking or nicotine on macrophage function and the intestinal microvasculature. Several genes are involved in the pathogenesis of CD, and in this study the gene expression differences of the descending colonic mucosa were investigated in CD (smokers or never smokers) and controls (smokers or never smokers)., Aim: To identify any difference in gene expression of the descending colonic mucosa between smoking and never-smoking CD patients (and controls) by determining genetic expression profiles from microarray analysis., Methods: Fifty-seven specimens were obtained by routine colonoscopy from the included material: CD smokers (n = 28) or never-smokers (n = 14) as compared to fifteen healthy controls (8 smokers and 7 never-smokers). RNA was isolated and gene expression assessed with Affymetrix GeneChip Human Genome U133 Plus 2.0. Data were analyzed by principal component analysis (PCA), Wilcoxon rank sum test and multiple linear regressions. Real-time (RT) PCR was subsequently applied to verify microarray results., Results: The PCA analysis showed no intrinsic clustering of smokers versus never-smokers. However, when Wilcoxon rank sum test corrected with Q values were performed, six known genes were significantly expressed differently in the inflamed CD smokers as compared to the inflamed CD never-smokers: ring finger protein 138 (RNF138), metalothionein 2A (MT2A) and six transmembrane epithelial antigen of the prostate 3 (STEAP3), SA hypertension-associated homolog, PGM2L1 and KCNJ2. The subsequent RT-PCR-analyses verified, however, that only RNF138, MT2A and STEAP3 were significantly up-regulated in CD smokers in specimens with inflammatory activity of the descending colon., Conclusions: The present study demonstrates that the genes, RNF138, MT2A, and STEAP3 are differently expressed in the inflamed descending colon of smoking versus never-smoking CD patients, which might be of relevance for the poorer clinical course among CD smokers. Many gastroenterologists are still not totally aware of the benefits of smoking cessation in relation to CD, and do not put much effort into getting the patients to quit, therefore more information on the negative effects of smoking, seems warranted.

The transmural inflammation characteristic of Crohn's disease predisposes patients to the formation of fistulas. Up to 50% of patients with Crohn's disease are affected by fistulas, which is a major problem given the considerable morbidity associated with this complication. Appropriate treatment of fistulas requires knowledge of specific pharmacological and surgical therapies. Treatment options depend on the severity of symptoms, fistula location, the number and complexity of fistula tracts, and the presence of rectal complications. Internal fistulas, such as ileoileal or ileocecal fistulas, are mostly asymptomatic and do not require intervention. By contrast, perianal fistulas can be painful and abscesses may develop that require surgical drainage with or without seton placement, transient ileostomy, or in severe cases, proctectomy. This Review describes the epidemiology and pathology of fistulizing Crohn's disease. Particular focus is given to external and perianal fistulas, for which treatment options are well established. Available therapeutic options, including novel therapies, are discussed. Wherever possible, practical and evidence-based treatment regimens for Crohn's disease-associated fistulas are provided.

Familial disposition and mutations in the Caspase Recruitment Domain 15 (CARD15) have been associated with an increased risk for Crohn's disease (CD). This study investigated whether these risk factors correlate with colonic gene expression profiles generated by DNA-microarray technology. Tissue specimens from descending colon were obtained during colonoscopy from 45 CD patients (18 from areas with inflammation and 27 from noninflamed areas). Gene profiling analysis was performed using the Human Genome U133 Plus 2.0 GeneChip Array. Patients were classified according to their CARD15 status. Hybridization data were analyzed with dChip software. Nine patients with either one or two CARD15 mutations had no differentially expressed genes, compared to 36 patients with wild- type CARD15. There was only one differentially expressed EST between 8 patients who had familial disposition for inflammatory bowel disease (IBD) and 36 who did not, but hierarchical cluster analysis did not show group homogeneity. We conclude that gene expression profiling of mucosal biopsies from the descending colon of patients with CD could not be correlated with CARD15 status or with familial disposition for IBD.

Objective: Responses and adverse events to medication vary greatly among patients with Crohn's disease (CD). The aim of this study was to investigate whether global gene expression profiles could predict such responses and possible side effects., Material and Methods: Tissue specimens from the descending colon were obtained from 32 CD patients (in 18 patients from areas without inflammation and in 14 patients from inflamed areas). Gene profiling was done using the Affymetrix Human Genome U133 Plus 2.0 GeneChip array. Hybridization data were analyzed with dChip software., Results: There were no differentially expressed genes between six patients who responded well to azathioprine and four who did not. No differences were found between 12 patients with adverse events to azathioprine and 9 patients who tolerated this drug. Sixteen patients who were not glucocorticoid-dependent had no differentially expressed genes as compared with 15 glucocorticoid-dependent patients. Six patients who responded well to infliximab had only one differentially expressed gene as compared to four patients who did not., Conclusions: DNA microarray analyses did not show differentially expressed genetic profiles from colonic mucosal cells obtained from groups of patients classified according to therapeutic criteria.

Objective: A global gene expression profile of non-inflamed colonic mucosal cells from patients with Crohn's disease (CD) and of colonic mucosal cells from controls was performed., Material and Methods: Tissue specimens from macroscopically non-inflamed descending colon were obtained colonoscopically from 33 CD patients and from 17 control subjects. All controls and 10 CD patients were medication-free at the time of colonoscopy. The Human Genome U133 Plus 2.0 GeneChip Array was used for gene profiling. Hybridization data were analysed with dChip software. Results were confirmed by real-time reverse transcriptase polymerase chain reaction (RT-PCR). Protein product expression of selected genes was assessed by immunohistochemistry using the Envision+ visualization technique., Results: The expression profile was not homogeneous with the statistical cut-point settings applied. In comparison with controls, it was found that 19 CD patients had three differentially expressed genes, two of them related to the innate immune system: dual oxidase 2 on chromosome 15 (DUOX2, fold change 4.1) and lipocalin 2 on chromosome 9 (LCN2, fold change 3.1). The third gene, regenerating islet-derived 1 alpha (REG1A, fold change 3.9), codes for a mitogenic protein; this could not be confirmed by RT-PCR. Medication-free patients had no differentially expressed genes as compared with controls. Immunohistochemistry indicated that these proteins were produced by epithelial cells (REG1A, LCN2) and leucocytes (DUOX2 and LCN2)., Conclusions: As compared with controls, non-inflamed colonic mucosal cells contain two up-regulated genes related to the innate immune system. Up-regulation of these genes, known to be induced by microorganisms, suggests either increased microflora antigenicity or an altered function in mucosal barrier defence.

Inflammatory bowel disease (IBD) is characterized by the increased survival of lamina propria leucocytes and ulcerations and an increased epithelial leakiness that compromise the barrier function of the epithelial lining. Deregulated apoptosis seems to be a major cause of the impaired barrier function and of leucocyte survival. This review focuses on the regulation of epithelial and leucocyte apoptosis in the IBD colon. Furthermore, the implications for present and future therapeutic strategies are discussed.

This review focuses on the potential pathogenic role of microorganisms in relation to inflammatory bowel diseases, i.e. Crohn's disease and ulcerative colitis. Pathogenic microorganism such as Mycobacterium paratuberculosis, measles and mumps viruses, Epstein-Barr virus, and Listeria monocytogenes are discussed, as well as involvement of the normal intestinal flora. Furthermore, the influence of microorganisms in experimental animal colitis models is discussed. The available results are inconclusive, but there seems to be basis for proposing the hypothesis that the inflammation in inflammatory bowel disease reflects an immune imbalance with loss of tolerance for normally harmless antigens in the mucosal microflora.

Recent significant advances have been made in the treatment of chronic inflammatory diseases with initiation of the era of biologics. However, an unmet medical need still exists for novel targeted therapies. Compared with biologics, Janus kinase inhibitors (JAKis) are a new drug class of orally administered small molecules that have been shown to efficiently modulate complex cytokine-driven inflammation in preclinical models and human studies. Unfortunately, serious adverse effects have been reported with the first introduced pan-JAKi, tofacitinib. Here, we review tyrosine kinase 2 (TYK2) signaling in the pathophysiology of inflammatory bowel disease (IBD), examine mechanisms of action of selective TYK2 inhibitors (TYK2is), and discuss the potential for these inhibitors in efforts to balance benefits and harms. Tyrosine kinase 2 (TYK2), which is part of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, is implicated in the pathophysiology of various immune-mediated inflammatory diseases, including inflammatory bowel disease (IBD). Different nonspecific JAK inhibitors suppress various cytokine signals but display serious side effects, such as bone marrow suppression, risk of serious infections (particularly shingles), and thromboembolism. TYK2 contains a JAK homology 2 (JH2) pseudokinase domain that acts as a regulator of its JH1 kinase domain responsible for receptor activation. Recently, a TYK2-specific inhibitor, deucravacitinib, that binds allosterically to the JH2 domain and prevents receptor-mediated activation, has been developed. Deucravacitinib and other TYK2 inhibitors are currently being tested in Phase II studies for both ulcerative colitis and Crohn disease. Although data on adverse events in IBD are still scarce, no serious infections or thrombotic events have been reported. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) has been linked to adverse cardiovascular events, but a relation to heart failure (HF) is uncertain. We investigated the IBD-associated risk of HF in a nationwide setting.A total of 5 436 647 Danish citizens, with no history of IBD or HF, were included on January 1, 1997, and followed up until first hospitalization for HF, death, or December 31, 2011. Of these subjects, 23 681 developed IBD for which disease activity was determined continuously throughout the study. The risk of hospitalization for HF was estimated with a Poisson regression model adjusting for comorbidity and cardiovascular pharmacotherapy as time-dependent covariates. During a mean follow-up of 11.8 years in the reference population and 6.4 years in the IBD group, hospitalization for HF occurred in 553 subjects with IBD and 171 405 in the reference population. Patients with IBD had a 37% increased risk of hospitalization for HF (incidence rate ratio, 1.37; 95% confidence interval, 1.26-1.49) compared with the reference population. IBD activity-specific analyses showed markedly increased risk of HF hospitalization during flares (incidence rate ratio, 2.54; 95% confidence interval, 2.13-3.04) and persistent activity (incidence rate ratio, 2.73; 95% confidence interval, 2.25-3.33) but not in IBD remission (incidence rate ratio, 1.04; 95% confidence interval, 0.94-1.16).In a nationwide cohort, IBD was associated with an increased risk of hospitalization for HF, and this risk was strongly correlated to periods of active disease. The mechanisms underlying this finding warrant further studies. [ABSTRACT FROM AUTHOR]

Objective . Intercellular adhesion molecule-1 (ICAM-1) is important in ulcerative colitis (UC) by mediating the arrest and further migration of neutrophils. In vitro studies have shown that colonocytes from chronically inflamed colon and cultured colon cancer cells are capable of expressing ICAM-1. The aim of this study was to assess the ICAM-1 expression in human colonic tissue representing UC, Crohn's disease (CD), adenomas, and adenocarcinomas, with special attention to the epithelium. Material and methods . Formalin-fixed and paraffin-embedded tissue from the archives of the Department of Pathology of Rigshospitalet University of Copenhagen was examined. Colonic tissue from 10 patients with UC, 10 with CD, 32 adenomas, 27 adenocarcinomas, and 10 lymph node metastases were included. The expression of ICAM-1 was assessed by using the EnVision + technique (DakoCytomation). Results . Endothelial ICAM-1 was up-regulated in areas with dense lymphocyte infiltration and near crypt abscesses and ulcerations. Ulcerations were covered by a continuous layer of macrophages and epithelial cells expressing ICAM-1. Similar observations were made in the case of adenomas and adenocarcinomas, but in adenocarcinomas the epithelial ICAM-1 was more diffuse and not related solely to sites of surface destruction. Conclusions . In the colon, endothelial cells, macrophages, and epithelial cells are in certain conditions capable of expressing ICAM-1. Although the ICAM-1 expression was related to both the degree and the nature of inflammation, the data indicate increased susceptibility of cancer cells to express ICAM-1. Epithelial and macrophage ICAM-1 might be involved in the immune surveillance and the first-line defense of the diseased colon. [ABSTRACT FROM AUTHOR]