Journal of Crohn's & colitis最新文献

{"title":"Ulcerative Colitis Severity Classification and Localized Extent (UC-SCALE): An Artificial Intelligence Scoring System for a Spatial Assessment of Disease Severity in Ulcerative Colitis.","authors":"Benjamin Gutierrez-Becker, Stefan Fraessle, Heming Yao, Jerome Luscher, Rafal Girycki, Bartosz Machura, Janusz Czornik, Jaroslaw Goslinsky, Marek Pitura, Steven Levitte, Josep Arús-Pous, Emily Fisher, Daniela Bojic, David Richmond, Amelie E Bigorgne, Marco Prunotto","doi":"10.1093/ecco-jcc/jjae187","DOIUrl":"10.1093/ecco-jcc/jjae187","url":null,"abstract":"<p><strong>Background and aims: </strong>Validated scoring methods such as the Mayo Clinic Endoscopic Subscore (MCES) evaluate ulcerative colitis (UC) severity at the worst colon segment, without considering disease extent. We present the Ulcerative Colitis Severity Classification and Localized Extent (UC-SCALE) algorithm, which provides a comprehensive and automated evaluation of endoscopic severity and disease extent in UC.</p><p><strong>Methods: </strong>Ulcerative Colitis Severity Classification and Localized Extent consists of 3 main elements: (1) a quality filter selecting readable images (frames) from colonoscopy videos, (2) a scoring system assigning an MCES to each readable frame, and (3) a camera localization algorithm assigning each frame to a location within the colon. Ulcerative Colitis Severity Classification and Localized Extent was trained and tested using 4326 sigmoidoscopy videos from phase III Etrolizumab clinical trials.</p><p><strong>Results: </strong>The high agreement between UC-SCALE and central reading at the level of the colon section (𝜅 = 0.80), and the agreement between central and local reading (𝜅 = 0.84), suggested a similar inter-rater agreement between UC-SCALE and experienced readers. Furthermore, UC-SCALE correlated with disease activity markers such calprotectin, C-reactive protein and patient-reported outcomes, Physician Global Assessment and Geboes Histologic scores (rs 0.40-0.55, ps < 0.0001). Finally, the value of using UC-SCALE was demonstrated by assessing individual endoscopic severity between baseline and induction.</p><p><strong>Conclusions: </strong>Our fully automated scoring system enables accurate, objective, and localized assessment of endoscopic severity in UC patients. In addition, we provide a topological representation of the score as a marker of disease severity that correlates highly with clinical metrics. Ulcerative Colitis Severity Classification and Localized Extent reproduces central reading and holds promise to enhance disease severity evaluation in both clinical trials and everyday practice.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142808904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diverse Phenotypes, Consistent Treatment: A Study of 30 997 South Asian and White Inflammatory Bowel Disease Patients Using the UK Inflammatory Bowel Disease BioResource.","authors":"Sharmili Balarajah, Laura Martinez-Gili, James Leslie Alexander, Benjamin Harvey Mullish, Robert William Perry, Jia V Li, Julian Roberto Marchesi, Miles Parkes, Timothy Robin Orchard, Lucy Charlotte Hicks, Horace Richard Timothy Williams","doi":"10.1093/ecco-jcc/jjae186","DOIUrl":"10.1093/ecco-jcc/jjae186","url":null,"abstract":"<p><strong>Background: </strong>Studies in the UK and North America have suggested a distinct disease profile in South Asians compared to that of White populations. Disparities in the medical and surgical management of IBD in minority ethnic groups (including Black Americans and Asians) in the US have been shown, while data from Europe, including the UK, have been lacking. This study sought to evaluate South Asian (SA) and White (WH) inflammatory bowel disease (IBD) phenotypes, and to explore treatment approach variations between these cohorts in the UK using the IBD BioResource database.</p><p><strong>Design: </strong>Differences between WH and SA IBD patients were analysed using demographic, phenotypic and outcome data. Drug utilisation patterns and surgical outcomes were assessed in propensity score-matched (PSM) cohorts with multivariable logistic regression, Cox regression and Kaplan-Meier analysis.</p><p><strong>Results: </strong>30,997 eligible patients were included. UC was the predominant disease subtype in SA (p<0.001). SA were younger at diagnosis (p<0.001), had a male preponderance (p<0.001), and were less likely to have a smoking history at diagnosis. The SA CD phenotype differed from WH, with less ileal (SA 30.3%, WH 38.4%, p=0.008) and stricturing (SA 16.9%, WH 25.6%, p<0.001) disease, but more perianal disease (SA 38.5%, WH 32.2%, p=0.009). More SA UC patients had extensive disease (SA 41.7%, WH 34.1%, p<0.001). In PSM cohorts, comparing treatments, there were no differences in 5-aminosalicylate, corticosteroid, thiopurine, anti-TNF or vedolizumab use. Survival analysis in matched cohorts showed no difference in time to surgery (CD) or colectomy (UC), and SA ethnicity was not associated with a difference in risk of surgery/colectomy.</p><p><strong>Conclusion: </strong>Demographic and phenotypic differences exist between UK SA and WH IBD patients, highlighting distinct ethnicity-related variance, and the need for a research focus on under-represented populations. In comparing matched SA and WH patients, no disparity in medical and surgical IBD therapy in UK healthcare has been demonstrated: treatment is consistent regardless of ethnicity.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11737890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142808897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preventable Predictive Factors of Post-colonoscopy Colorectal Cancer in Inflammatory Bowel Disease.","authors":"Elena De Cristofaro, Irene Marafini, Roberto Mancone, Mariasofia Fiorillo, Martina Franchin, Adelaide Mattogno, Benedetto Neri, Francesca Zorzi, Giovanna Del Vecchio Blanco, Livia Biancone, Emma Calabrese, Diana Giannarelli, Giovanni Monteleone","doi":"10.1093/ecco-jcc/jjae115","DOIUrl":"10.1093/ecco-jcc/jjae115","url":null,"abstract":"<p><strong>Background and aim: </strong>Post-colonoscopy colorectal cancer [PCCRC] is a colorectal cancer [CRC] diagnosed after a colonoscopy in which no cancer was detected [index colonoscopy]. Although the overall cumulative rates of PCCRC are low in both the general population and inflammatory bowel disease [IBD] patients, the overall incidence of PCCRC in IBD is greater than that documented in the general population. This study aimed to identify the index colonoscopy-related factors and patients' characteristics influencing IBD-associated PCCRC development.</p><p><strong>Methods: </strong>We carried out an observational, retrospective study in which IBD-associated PCCRCs were diagnosed between 2010 and 2023. The PCCRC group was compared with a control cohort of IBD patients without CRC, matched 1:1 by several demographic and clinical features as well as characteristics of index colonoscopy, to minimise selection bias.</p><p><strong>Results: </strong>Among 61 CRCs identified, 37 [61%] were PCCRC. Twelve of the 37 [32%] PCCRC were diagnosed within 12 months after the previous negative colonoscopy, 15 [41%] within 12-36 months, and 10 [27%] within 36-60 months. In the multivariate analysis, the inadequate bowel preparation of the index colonoscopy (odds ratio [OR]: 5.9; 95% confidence interval [CI]: 11.1-31.4) and the presence of high-risk factors for CRC [OR: 24.03; 95% CI: 3.1-187.8] were independently associated with PCCRC. Conversely, prior exposure to immunosuppressors or biologics [OR: 0.17; 95% CI: 0.03-0.83] and random biopsies sampling at index colonoscopy [OR: 0.19; 95% CI: 0.04-0.85] were inversely associated with PCCRC.</p><p><strong>Conclusions: </strong>More than 50% of CRCs in our population were PCCRC. PCCRCs were associated with previous inadequate cleansing and occurred more frequently in high-risk patients.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141753671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic Poor Sleep is Associated with Increased Disease Activity in Patients with Ulcerative Colitis: Prospective Observational Study in Japan.","authors":"Hideaki Oyama, Rintaro Moroi, Atsushi Sakuma, Yusuke Shimoyama, Hiroshi Nagai, Takeo Naito, Hisashi Shiga, Yoichi Kakuta, Yoshitaka Kinouchi, Atsushi Masamune","doi":"10.1093/ecco-jcc/jjae116","DOIUrl":"10.1093/ecco-jcc/jjae116","url":null,"abstract":"<p><strong>Background and aim: </strong>Although sleep disorders are associated with the pathogenesis of inflammatory bowel disease, the causal relationship is unclear. Therefore, in this study we aimed to clarify the causal relationship between them.</p><p><strong>Methods: </strong>We administered the Pittsburgh Sleep Questionnaire to participants during regular visits to evaluate their sleep condition, and prospectively observed the participants. Participants were divided into poor sleep and non-poor sleep groups according to their first and second questionnaire scores. We compared inflammatory bowel disease relapse rates between the two groups.</p><p><strong>Results: </strong>The study population included 139 patients with inflammatory bowel disease, including 60 with chronic poor sleep. Disease relapse rate was significantly higher in the poor sleep group than in the non-poor sleep group [28.3% vs 8.9%; p = 0.0033]. Ulcerative colitis relapse rate was significantly higher in the poor sleep group than in the non-poor sleep group [34.5% vs 10.3%, p = 0.031]. Multivariate analysis identified chronic poor sleep as a clinical factor that affected inflammatory bowel disease relapse (odds ratio [OR] = 6.69, 95% confidence interval [CI]: 2.23-20.0, p = 0.0007] and ulcerative colitis relapse [OR = 8.89, 95% CI: 1.57-50.2, p = 0.014]. The Kaplan - Meier curve showed significantly lower cumulative treatment retention rates in the poor sleep group than in the non-poor sleep group [all patients, p = 0.0061; ulcerative colitis, p = 0.025].</p><p><strong>Conclusions: </strong>Concomitant chronic poor sleep may have a negative influence on the disease activity in patients with inflammatory bowel disease, particularly in those with ulcerative colitis.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141763572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improvement in serum eosinophilia is observed in clinical responders to ustekinumab but not adalimumab in inflammatory bowel disease.","authors":"Emily C L Wong, Parambir S Dulai, John K Marshall, Vipul Jairath, Walter Reinisch, Neeraj Narula","doi":"10.1093/ecco-jcc/jjaf006","DOIUrl":"10.1093/ecco-jcc/jjaf006","url":null,"abstract":"<p><strong>Introduction: </strong>In inflammatory bowel disease (IBD), the number of eosinophils increases in the lamina propria of the intestinal tract, but their specific patho-mechanistic role remains unclear. Elevated blood eosinophil counts in active IBD suggest their potential as biomarkers for predicting response to biological therapies. This study evaluates blood eosinophil count trends and their predictive value for clinical response and endoscopic improvement in patients with IBD receiving ustekinumab or adalimumab induction therapy.</p><p><strong>Methods: </strong>Participant-level data from phase 3 and 4 clinical trials (UNIFI, SEAVUE, VARSITY) evaluating ustekinumab and adalimumab for moderate-severe Crohn's disease (CD) and ulcerative colitis (UC) were used. The primary outcome was clinical response, defined by reductions in disease activity scores. Eosinophil counts were compared between responders and non-responders at multiple time points using t-tests. Logistic regression assessed the odds of achieving a clinical response based on baseline eosinophil counts.</p><p><strong>Results: </strong>Among patients treated with ustekinumab for UC, responders had significantly higher baseline eosinophil counts compared to non-responders (0.21 × 109/L vs 0.18 × 109/L, P = .042). By week 8, responders showed a greater absolute (-0.07 × 109/L vs -0.01 × 109/L, P < .001) and percent decline (-33.33% vs -5.55%, P = .027) in eosinophil counts. In CD, ustekinumab responders also had higher baseline eosinophil counts and showed significant reductions by week 8. However, no significant differences in eosinophil counts were observed among CD patients treated with adalimumab or UC patients treated with vedolizumab.</p><p><strong>Conclusion: </strong>Eosinophil reduction was identified as a marker for early response to ustekinumab in both UC and CD, but not adalimumab. No difference was observed among UC patients treated with vedolizumab either. Targeting the IL-12/IL-23 pathway may be more effective in managing eosinophil-associated inflammation in IBD.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11760988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subcutaneous Infliximab Cutoff Points in Patients With Inflammatory Bowel Disease: Data From the ENEIDA Registry.","authors":"Marisa Iborra, Berta Caballol, Alejandro Garrido, José María Huguet, Francisco Mesonero, Ángel Ponferrada, Lara Arias García, Marta Maia Boscá Watts, Samuel J Fernández Prada, Eduard Brunet Mas, Ana Gutiérrez Casbas, Elena Cerrillo, Ingrid Ordás, Lucía Ruiz, Irene García de la Filia, Jaime Escobar Ortiz, Beatriz Sicilia, Elena Ricart, Eugeni Domènech, Pilar Nos","doi":"10.1093/ecco-jcc/jjae127","DOIUrl":"10.1093/ecco-jcc/jjae127","url":null,"abstract":"<p><strong>Background and aims: </strong>Switching from intravenous infliximab (IV-IFX) to subcutaneous biosimilar infliximab (SC-IFX) has been shown to safely maintain clinical remission and increase drug levels in patients with Crohn's disease (CD) and ulcerative colitis (UC). The aim of this study was to evaluate long-term outcomes after switching from IV-IFX to SC-IFX, including the drug concentration thresholds for maintaining remission and other predictors for loss of response after the switch.</p><p><strong>Methods: </strong>This multicenter observational study involved CD and UC patients who were in clinical remission for at least 24 weeks and were scheduled to switch from IV-IFX to SC-IFX.</p><p><strong>Results: </strong>Two hundred and twenty patients were included (74 UC [34%] and 146 CD [66%]). IV-IFX was administered for 52.5 months (range 25-89). Before switch, 106 (49%) patients were receiving intensified IV-IFX. While SC-IFX levels significantly increased following the switch from IV-IFX to SC-IFX, clinical parameters, C-reactive protein, and fecal calprotectin remained unchanged during follow-up. SC-IFX levels were significantly higher in patients receiving the standard IV-IFX dose than in those receiving the intensified dose. Immunomodulatory therapy at baseline and perianal disease had no effect on IFX trough levels, whereas higher body mass index was associated with increased levels. The suggested optimal SC-IFX cutoff concentration for clinical and biochemical remissions based on receiver operating characteristic analysis was 12.2 μg/mL (area under the curve [AUC]: 0.62) at Week 12 and 13.2 μg/mL (AUC: 0.57) at Week 52. Drug persistence was 92% at Week 52, with a good safety profile.</p><p><strong>Conclusions: </strong>Switching from IV-IFX to SC-IFX safely maintains long-term remission in patients with CD and UC. In maintenance, the optimal cutoff point associated with remission was 12-13 μg/mL.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to: Autophagy Reduces the Degradation and Promotes Membrane Localization of Occludin to Enhance the Intestinal Epithelial Tight Junction Barrier against Paracellular Macromolecule Flux.","authors":"","doi":"10.1093/ecco-jcc/jjae196","DOIUrl":"10.1093/ecco-jcc/jjae196","url":null,"abstract":"","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to: European Crohn's and Colitis Guidelines on Sexuality, Fertility, Pregnancy, and Lactation.","authors":"","doi":"10.1093/ecco-jcc/jjae195","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae195","url":null,"abstract":"","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HLA-DQA1*05 Associates With Anti-Tumor Necrosis Factor Immunogenicity and Low Adalimumab Trough Concentrations in Inflammatory Bowel Disease Patients From the SERENE Ulcerative Colitis and Crohn's Disease Studies.","authors":"Mark Reppell, Xiuwen Zheng, Ingeborg Dreher, Jonas Blaes, Elina Regan, Tobias Haslberger, Heath Guay, Valerie Pivorunas, Nizar Smaoui","doi":"10.1093/ecco-jcc/jjae129","DOIUrl":"10.1093/ecco-jcc/jjae129","url":null,"abstract":"<p><strong>Background and aims: </strong>Anti-tumor necrosis factor (anti-TNF) therapies are commonly prescribed treatments for Crohn's disease (CD) and ulcerative colitis (UC). Many patients treated with anti-TNF therapy eventually develop anti-drug antibodies (ADAs). Understanding the factors associated with immunogenicity in anti-TNF-treated patients can help guide treatment. The Humira SERENE studies were Phase 3 trials investigating adalimumab induction regimens in CD and UC patients.</p><p><strong>Methods: </strong>We imputed alleles for 7 HLA genes in 1100 patients from the SERENE CD and SERENE UC trials. We then tested these alleles for association with time to immunogenicity. Subsequently, we tested loci significantly associated with immunogenicity for their association with patients who had consistently low drug serum concentrations.</p><p><strong>Results: </strong>This study replicated the association of HLA-DQA1*05 with time to immunogenicity (hazard ratio [HR] 1.42, p = 2.22E-06). Specifically, HLA-DQA1*05:05 was strongly associated (HR 1.76, p = 2.02E-10) and we detected a novel association represented by HLA-DRB1*01:02 (HR 3.16, p = 2.92E-07). Carriage of HLA-DQA1*05:05 and HLA-DRB1*01:02 was associated with patients who experienced consistently low adalimumab trough concentrations (HLA-DQA1*05:05: odds ratio [OR] 1.98, p = 0.0049; HLA DRB1*01:02: OR 7.06, p = 7.44E-05).</p><p><strong>Conclusions: </strong>We found a significant association between alleles at genes in the human HLA locus and the formation of adalimumab immunogenicity and low adalimumab drug serum concentrations in large clinical studies of CD and UC patients. This work extends previous findings in CD to UC and directly shows a genetic association in patients with low drug concentrations. This work builds on existing literature to suggest that genetic screening could be a useful tool for clinicians concerned with patient anti-TNF immunogenicity.</p><p><strong>Clinical trial registration numbers: </strong>SERENE CD (NCT02065570), SERENE UC (NCT02065622).</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142006192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Impact of Peptidyl Arginine Deiminase 4-Dependent Neutrophil Extracellular Trap Formation on the Early Development of Intestinal Fibrosis in Crohn's Disease.","authors":"Gabriele Dragoni, Bo-Jun Ke, Lucia Picariello, Saeed Abdurahiman, Elisabetta Ceni, Francesca Biscu, Tommaso Mello, Simone Polvani, Tommaso Innocenti, Valérie Spalart, Stefano Milani, André D'Hoore, Gabriele Bislenghi, Stefano Scaringi, Bram Verstockt, Gert De Hertogh, Kimberly Martinod, Andrea Galli, Gianluca Matteoli, Séverine Vermeire","doi":"10.1093/ecco-jcc/jjae121","DOIUrl":"10.1093/ecco-jcc/jjae121","url":null,"abstract":"<p><strong>Background and aims: </strong>During early phases of inflammation, activated neutrophils extrude neutrophil extracellular traps (NETs) in a peptidyl arginine deiminase 4 (PAD4)-dependent manner, aggravating tissue injury and remodeling. In this study, we investigated the potential pro-fibrotic properties and signaling of NETs in Crohn's disease (CD).</p><p><strong>Methods: </strong>NETs and activated fibroblasts were labeled on resected ileum from CD patients by multiplex immunofluorescence staining. NETs-treated human primary intestinal fibroblasts were analyzed by bulk RNA sequencing to uncover cell signaling pathways, and by high-throughput imaging to assess collagen production and migratory activity. Consequentially, TLR2/NF-κB pathway was evaluated by transfection of CCD-18Co fibroblasts with an NF-κB-luciferase reporter plasmid, incorporating C29 to block TLR2 signaling. A chronic dextran sulfate sodium (DSS) mouse model was used to define the specific role of PAD4 deletion in neutrophils (MRP8-Cre, Pad4fl/fl).</p><p><strong>Results: </strong>Immunofluorescence showed spatial colocalization of NETs and activated fibroblasts in ileal ulcerations of CD patients. Transcriptomic analysis revealed upregulation of pro-fibrotic genes and activation of Toll-like receptor signaling pathways in NETs-treated fibroblasts. NETs treatment induced fibroblast proliferation, diminished migratory capability, and increased collagen release. Transfection experiments indicated a substantial increase in an NF-κB expression with NETs, whereas C29 led to decreased expression and release of collagen. In line, a significant reduction in collagen content was observed in the colon of MRP8-Cre, Pad4fl/fl mice subjected to chronic DSS colitis.</p><p><strong>Conclusions: </strong>NETs potentially serve as an initial stimulus for pathological activation of fibroblasts within the intestine via the TLR2/NF-κB pathway. Given their early involvement in inflammation, inhibition of PAD4 might offer a strategy to modulate both inflammation and fibrogenesis in CD.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}