Journal of Crohn's & colitis最新文献

{"title":"Histology in Inflammatory Bowel Disease: A Redundant Tool or a Valuable Prognostic Marker?","authors":"Matthias Lenfant, Gert De Hertogh, João Sabino","doi":"10.1093/ecco-jcc/jjaf064","DOIUrl":"10.1093/ecco-jcc/jjaf064","url":null,"abstract":"","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144063683","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":"Long-term disease course of ulcerative colitis in a prospective European population-based inception cohort-an Epi-IBD cohort study.","authors":"Mads Damsgaard Wewer, Søren Lophaven, Peter L Lakatos, Lorant Gonczi, Riina Salupere, Hendrika Adriana Linda Kievit, Kári Rubek Nielsen, Jóngerð Midjord, Viktor Domislovic, Željko Krznarić, Natalia Pedersen, Jens Kjeldsen, Jonas Halfvarson, Shaji Sebastian, Adrian Goldis, Naila Arebi, Pia Oksanen, Anders Neumann, Vibeke Andersen, Konstantinos H Katsanos, Anastasios Koukoudis, Svetlana Turcan, Pierre Ellul, Juozas Kupcinskas, Gediminas Kiudelis, Mathurin Fumery, Ioannis P Kaimakliotis, Renata D'Inca, Silvia Lombardini, Vicent Hernandez, Alberto Fernandez, Ebbe Langholz, Pia Munkholm, Johan Burisch","doi":"10.1093/ecco-jcc/jjaf089","DOIUrl":"10.1093/ecco-jcc/jjaf089","url":null,"abstract":"<p><strong>Background and aims: </strong>The Epi-IBD cohort is a population-based inception cohort of patients with inflammatory bowel disease from 22 European centers. The aim was to assess the 10-year disease course of patients with ulcerative colitis (UC) across Europe.</p><p><strong>Methods: </strong>Patients were followed prospectively from the time of diagnosis in 2010 and 2011, with a uniform collection of data to the end of 2020. Associations between covariates and colectomy, progression to extensive disease, and hospitalization were analyzed separately by multivariable Cox regression analyses in a propensity-score-matched subpopulation to address regional differences.</p><p><strong>Results: </strong>A total of 873 UC patients were recruited (Eastern Europe: 196 [22.4%], Western Europe: 677 [77.5%]). The 10-year crude rate for the use of advanced therapy was comparable in Eastern (13%) and Western Europe (16%) (P > 0.9), and the median time from diagnosis until initiation of advanced treatment was similar, at 3 years. The need for colectomy remained comparable in Eastern and Western Europe, with a 10-year crude rate of 4% and 6% (Cox: P = 0.6), respectively. Likewise, disease progression to extensive disease (10-year rate: 17%, Cox: P = 0.06) and hospitalization (10-year rate: 23%, Cox: P = 0.2) were comparable across Europe. The use of advanced therapy and the early use of corticosteroids were both associated with an increased risk of colectomy (Cox: both P < 0.05).</p><p><strong>Conclusions: </strong>While the introduction of advanced therapies for UC has transformed the therapeutic landscape, their impact on colectomy rates, disease progression, and hospitalizations remains modest. Our findings highlight the need for continued innovation in UC treatment and the importance of individualized and targeted care to achieve optimal long-term outcomes.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210518","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":"Cancer incidence in patients with ulcerative colitis naïve to or treated with thiopurine and targeted therapies-a cohort study 2007 to 2022 with comparison to the general population.","authors":"Åsa H Everhov, Johan Askling, Jonas Söderling, Jonas Halfvarson, Julia Eriksson, Karin E Smedby, Jonas F Ludvigsson, Henrik Toft Sørensen, Ola Olén","doi":"10.1093/ecco-jcc/jjaf091","DOIUrl":"10.1093/ecco-jcc/jjaf091","url":null,"abstract":"<p><strong>Background: </strong>Cancer incidence data including absolute risk differences are needed for clinical risk communication to patients receiving modern-day treatments for ulcerative colitis (UC).</p><p><strong>Methods: </strong>We linked nationwide Swedish health registers and assessed incident cancers in patients with UC in 2007-2022. We computed age-stratified incidence rates (IRs), IR differences, and hazard ratios (HRs) in a naïve cohort with no immunomodulatory treatment, and in cohorts treated with thiopurine or targeted therapies. General population comparator subjects were matched (by age, sex, calendar year, and area of residence) to each treatment cohort. We used a once-exposed-always-exposed design.</p><p><strong>Results: </strong>We identified 63 925 patients with UC in partly overlapping cohorts and 593 072 comparators with a total follow-up time of 5 800 089 years (median 8.1 years). The IRs were elevated compared to the general population in naïve patients: 2.7 extra cancer cases per 1000 person-years (HR: 1.12, 95% CI, 1.09-1.16), in thiopurine-treated patients: 3.4 extra cases (HR: 1.48;1.37-1.61), tumor necrosis factor inhibitor (TNFi)-treated: 2.7 extra cases (HR: 1.41;1.24-1.62), Thiopurine + TNFi-treated: 2.42 extra cases (HR: 1.44;1.19-1.75), vedolizumab-treated: 2.88 extra cases (HR: 1.27;0.90-1.79). The IR differences were not significantly increased in patients treated with ustekinumab 0.57 (HR: 0.87;0,39-1.93) and tofacitinib -0.69 (HR: 0.84;0.25-2.77). Across all treatment groups, the IR differences compared to the general population were highest in patients ≥ 60 years. The differences were driven by colorectal cancer, hepatobiliary cancer, lymphoma, and basal cell skin carcinoma.</p><p><strong>Conclusions: </strong>Elevated cancer incidence was observed in patients with UC amounting to around 3 extra cases of cancer per 1000 years. Cancer risks varied more among groups defined by age than by treatment.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210574","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":"Spatial immune profiling of Crohn's disease fistula carcinomas-defining a distinct cancer subtype.","authors":"Malte Lehmann, Daniela Paclik, Adrian Huck, Alexander Arnold, Clemens Kurth-Stavenhagen, Michael Vieth, Christoph Treese, Anja A Kühl, Britta Siegmund","doi":"10.1093/ecco-jcc/jjaf086","DOIUrl":"10.1093/ecco-jcc/jjaf086","url":null,"abstract":"<p><strong>Background and aims: </strong>Fistula formation is a common and debilitating complication in Crohn's disease (CD). CD-associated fistula carcinomas (Fi-Cas), though rare, pose diagnostic and prognostic challenges. This study aims to identify disease-defining immune cell subsets in CD-associated Fi-Cas.</p><p><strong>Methods: </strong>The study included tissue samples from 10 CD patients with Fi-Cas, 7 with CD-associated fistulas, and 6 with sporadic colorectal cancer (CRC). The main tumor (MT), infiltration front, and non-involved areas were analyzed in tumor samples. A 36-marker panel was employed to define the immune landscape using imaging mass cytometry. Samples were processed, stained, and analyzed for immune cell compositions, cell-cell interactions, and spatial microenvironments.</p><p><strong>Results: </strong>The immune infiltrate in Fi-Cas shared similarities with both CD fistulas and CRC. Fi-Ca samples exhibited high levels of neutrophils, B cells, and CD163high macrophages. CRC MT samples showed an increased presence of intraepithelial CD8+ lymphocytes and CD163low macrophages. Cleaved Caspase-3 levels were highest in CRC MT samples, correlating positively with CD163low macrophages and cytotoxic T cells. In contrast, Fi-Ca MT samples showed a negative correlation between cleaved Caspase-3 and cytotoxic T cells. Analysis of cellular microenvironments and dimensionality reduction clustering based on immune cell frequencies indicated Fi-Cas to exhibit a mixture of immune cell characteristics from both CD fistulas and CRC.</p><p><strong>Conclusions: </strong>The immune landscape of CD-associated Fi-Cas exhibits features of both CD fistulas and CRC, suggesting a complex pathogenesis influenced by chronic inflammation. Our data suggest that Fi-Cas represent a unique cancer subtype, that requires further analysis to develop targeted therapeutic strategies.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145237","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":"The effectiveness of second- and-third-line biologics in perianal Crohn's disease-a multicenter propensity score-matched study.","authors":"Uria Shani, Monica State, Radu Bogdan Mateescu, Ana-Maria Davidoiu, Lucian Negreanu, Isabel Silva, Fernando Magro, Charlie W Lees, Nikolas Plevris, Xavier Roblin, Sílvia Castellet-Farrús, Yago Gonzalez Lama, Shanshan Wang, Carolina Abad, Nicola Imperatore, Milan Lukas, Gabriela Vojtechova, Offir Ukashi, Shomron Ben-Horin, Stephane Nancey, Edoardo Savarino, Kamila Stawczyk-Eder, Piotr Eder, Alexandros Toskas, Nikolaos Kamperidis, Naila Arebi, Bernadett Farkas, Klaudia Farkas, Barbora Pipek, Premysl Falt, Konstantinos Karmiris, Pinelopi Nikolaou, Zeljko Krznaric, Marko Brinar, Frank Hoentjen, Lisa van Lierop, Manuel Barreiro-de Acosta, Marta Zaborowska, Edyta Zagorowicz, Daniela Pugliese, Giuseppe Cuccia, Marie Truyens, Uri Kopylov","doi":"10.1093/ecco-jcc/jjaf099","DOIUrl":"10.1093/ecco-jcc/jjaf099","url":null,"abstract":"<p><strong>Background and aims: </strong>Anti-tumor necrosis factor-α inhibitors (anti-TNFs) are the established treatment for perianal Crohn's disease (pCD), but relapse and non-response are common. Data on second- and third-line biologics are limited. We present the first direct comparison of second- and third-line biologics in pCD patients with active perianal disease previously treated with first-line anti-TNFs.</p><p><strong>Methods: </strong>A multicenter retrospective cohort study included adult patients with pCD who failed first-line anti-TNF. The primary outcome was clinical perianal response, with secondary outcomes of radiological response (magnetic resonance imaging or transrectal ultrasound) and healing, and clinical remission. Propensity score matching (PSM) was used to adjust for baseline differences.</p><p><strong>Results: </strong>A total of 486 pCD patients from 23 IBD centers were included, with 333/486 (68.5%) and 216/263 (82.1%) matched by PSM in the second and third-line treatment groups, respectively. In the second-line group, 62/78 (79.5%) of ustekinumab (UST)-treated patients achieved clinical perianal response, compared to 46/78 (58.9%) with vedolizumab (VDZ) (OR 4.47, 95% CI, 1.94-10.28, P < .001) and 38/78 (48.7%) with anti-TNFs (OR 5.29, 95% CI, 2.39-11.71, P < .001). In the third-line group, 38/49 (77.6%) of UST-treated patients achieved clinical perianal response, compared to 29/49 (59.2%) with VDZ (OR 9.96, 95% CI, 2.6-38.4, P < .001) and 27/49 (55.1%) with anti-TNFs (OR 12.03, 95% CI, 2.99-48.47, P < .001). UST-treated patients also had higher radiological response rates than VDZ (OR 3.28, 95% CI, 1.07-10.07, P = .038).</p><p><strong>Conclusion: </strong>In pCD patients failing anti-TNFs as first-line treatment, ustekinumab may be more effective than vedolizumab or another anti-TNF as second or third-line therapy.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259714","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":"Epithelial genetic muscarinic receptor 3 ablation induces sex-specific modulation of colonic intestinal progenitor cells and response to intestinal injury.","authors":"Mohab Ragab, Jessica Wieland, Caroline Waldherr Avila de Melo, Tatiana Agibalova, Anastasia Ermolova, Niklas Durner, Anneke Hempel, Fabian Heindl, H Carlo Maurer, Katja Steiger, Klaus-Peter Janssen, Markus Tschurtschenthaler, Timothy C Wang, Michael Quante, Roland M Schmid, Moritz Middelhoff","doi":"10.1093/ecco-jcc/jjaf038","DOIUrl":"10.1093/ecco-jcc/jjaf038","url":null,"abstract":"<p><strong>Background & aims: </strong>Epithelial muscarinic acetylcholine receptor subtype 3 (M3R) signaling modulates intestinal stem and progenitor cell function, yet its impact on colonic homeostasis remains unclear. Hence, this study explores the sex-specific effects of epithelial genetic M3R ablation and muscarinic receptor agonism on murine colonic Lgr5-EGFP+ progenitor cells and epithelial homeostasis.</p><p><strong>Methods: </strong>Genetic ablation of M3R was achieved using Vil-Cre × M3R fl/fl mice. The effects on Lgr5-expressing progenitor cells, epithelial homeostasis, and response to intestinal injury were assessed, with attention to sex-specific differences. Effects of cholinergic and muscarinic agonism on epithelial cell homeostasis were evaluated employing murine and human colonoids.</p><p><strong>Results: </strong>Genetic epithelial ablation of the M3R employing Vil-Cre × M3R fl/fl mice interestingly resulted in the prominent reduction in Lgr5-expressing progenitor cells in male tissues, contrasting an expansion of Lgr5-expressing cells in female colonic epithelia. This difference was abrogated in young female Vil-Cre × M3R fl/fl mice, which harbor reduced circulating sex hormone levels. Genetic M3R ablation further induced changes to epithelial differentiation. Importantly, male Vil-Cre × M3R fl/fl mice developed severe inflammation following induction of acute experimental colitis, which did almost not affect female Vil-Cre × M3R fl/fl mice. Moreover, sex-specific effects of modulations of cholinergic and muscarinic signaling on epithelial cells could be corroborated in murine and human colonoids.</p><p><strong>Conclusions: </strong>Our data reveal sex differences in the modulation of intestinal, colonic epithelial cells by cholinergic, muscarinic signaling and highlight the potential for therapeutic strategies targeting cholinergic receptor signaling in colonic inflammatory diseases.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12138776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574955","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":"Impact of immunomodulating medication on maternal Tdap vaccination-induced antibodies in infants.","authors":"Jantien W Wieringa, Mirjam J Esser, Gerco den Hartog, M Alina Nicolaie, Lyanne W Rövekamp, Esther G J Rijntjes-Jacobs, Ron H T van Beek, Gerdien A Tramper-Stranders, Marjan Kuijer, Maarten M Immink, Nicoline A T van der Maas, Nynke Y Rots, Gertjan J A Driessen","doi":"10.1093/ecco-jcc/jjaf090","DOIUrl":"10.1093/ecco-jcc/jjaf090","url":null,"abstract":"<p><strong>Background and aims: </strong>Current international guidelines on inflammatory bowel disease (IBD) advise to continue immunomodulating medication during pregnancy. Data on the effect of this medication on maternal Tdap (Tetanus-Diphtheria-acellular pertussis) vaccination and transfer of antibodies to the infant are scarce.</p><p><strong>Methods: </strong>Pregnant women with IBD receiving various immunomodulating medications and their infants were prospectively recruited in the Pregnancy Exposure to TNF alpha inhibitors and Immunological effect (PETIT) study cohort from 16 hospitals in the Netherlands between December 2018 and March 2023. All women were offered maternal Tdap vaccination according to the Dutch National Immunization Program. IgG concentrations against all Tdap components were measured at birth (maternal and cord blood) and at 2 months of age in the infant, preceding active immunization. We compared geometrical mean concentrations (GMCs) in IBD mother-infant pairs with healthy control mother-infant pairs.</p><p><strong>Results: </strong>Geometrical mean concentrations of antibodies against all Tdap components were significantly higher in 135 maternally vaccinated mothers and their infants compared with 25 unvaccinated IBD women-infant pairs treated with immunomodulating medication during pregnancy, at all timepoints. However, GMC against pertactin (PRN) was significantly lower in vaccinated IBD mother-infant pairs compared to healthy vaccinated control mother-infant pairs, particularly in mothers treated with anti-tumor necrosis factor alpha and their infants.</p><p><strong>Conclusions: </strong>Maternal Tdap vaccination in women with IBD receiving immunomodulating medication during pregnancy results in significantly higher Tdap-antibody concentrations in their infants compared to infants of unvaccinated IBD mothers, although GMC was lower for PRN compared to healthy controls. These results support current recommendations to advise maternal Tdap vaccination in pregnant women receiving immunomodulating medication.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201248","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":"Histologic and Endoscopic Findings Are Highly Correlated in a Prospective Cohort of Patients With Inflammatory Bowel Diseases.","authors":"Federica Di Vincenzo, Maria A Quintero, Joao M Serigado, Tulay Koru-Sengul, Rose Marie Killian, Julio Poveda, Jonathan England, Oriana Damas, David Kerman, Amar Deshpande, Maria T Abreu","doi":"10.1093/ecco-jcc/jjae141","DOIUrl":"10.1093/ecco-jcc/jjae141","url":null,"abstract":"<p><strong>Background and aims: </strong>The advantages of endoscopic vs histologic assessments of inflammation in inflammatory bowel disease remain unclear. We compared endoscopic and histologic inflammation in a prospective cohort. Furthermore, in patients with discordant findings, we compared the ability of endoscopy vs histology to predict disease course.</p><p><strong>Methods: </strong>Ulcerative colitis (UC) or Crohn's disease (CD) patients underwent routine colonoscopies with intestinal biopsies, which included ratings of inflammation severity. Tetrachoric correlation analysis between the endoscopic and histologic inflammation ratings was performed. In postsurgical CD patients, major adverse outcomes (MAOs) were recorded.</p><p><strong>Results: </strong>The analysis included 749 patients (60.2% CD patients), with 2807 biopsied segments. We found high concordance between endoscopist and pathologist inflammation ratings (0.84, 95% confidence interval, 0.81-0.87, p < 0.0001). Only 12.5% of biopsied segments exhibited microscopic inflammation without endoscopic inflammation. Neo-terminal ileum (neo-TI) biopsies exhibited the highest discordance; UC colonic biopsies had the highest concordance. Postsurgical CD patients who completed the 48-month follow-up (n = 138) were included in the survival analysis. The probability of MAO-free survival was significantly higher in patients with a Rutgeerts score of i0 at baseline than in those with higher scores. Microscopic inflammation in the neo-TI did not predict a higher risk of MAOs (p = 1.00).</p><p><strong>Conclusions: </strong>In a real-world setting, endoscopic inflammation predicted histologic inflammation with high accuracy. In patients with a Rutgeerts score of i0, microscopic inflammation in neo-TI biopsies did not predict more aggressive disease behavior over the next 4 years. These results have implications for the design of clinical trials, suggesting the use of endoscopic healing as an endpoint.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12187366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911163","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":"Differential effects of tofacitinib on macrophage activation contribute to lack of response in ulcerative colitis patients.","authors":"Elisa Melón-Ardanaz, Marisol Veny, Ana M Corraliza, Victoria Gudiño, Alba Garrido-Trigo, Ángela Sanzo-Machuca, Marc Buendia, Miriam Esteller, Lisseth Robbins-Moreno, Maite Rodrigo, M Carme Masamunt, Ángel Giner, Marta Gallego, Ingrid Ordás, Agnès Fernández-Clotet, Berta Caballol, Ángel Corbí, Bram Verstockt, Severine Vermeire, Julian Panés, Elena Ricart, Azucena Salas","doi":"10.1093/ecco-jcc/jjaf076","DOIUrl":"10.1093/ecco-jcc/jjaf076","url":null,"abstract":"<p><strong>Background and aims: </strong>Tofacitinib, a Janus kinase inhibitor, is approved for the treatment of moderate-to-severe ulcerative colitis. Nonetheless, 40-60% of patients will not respond adequately. The mechanisms underlying responses to tofacitinib remain unknown.</p><p><strong>Methods: </strong>We applied single-cell and/or bulk RNA analysis to biopsies (n = 23 and 63, respectively) from ulcerative colitis patients (n = 31) before and after tofacitinib treatment. Response was assessed using endoscopic and clinical criteria. In vitro-derived macrophages and primary intestinal fibroblasts were used to validate our findings.</p><p><strong>Results: </strong>Forty percent of patients responded to tofacitinib. Responders exhibited higher baseline JAK-STAT activity, while non-responders had increased baseline NF-kB pathway activation. Response was associated with significant changes in the abundance and/or activation of immune, epithelial, and stromal cells and the downregulation of S100A9, FCGR3A, MMP12 in resident macrophages. In contrast, non-responders showed a significant increase in the number and activation of macrophages and fibroblasts following tofacitinib treatment, including upregulation of MMP9, IL1B, IL6, CXCL1, CXCL8, and S100A9 compared to baseline. In monocyte-derived macrophages tofacitinib drove the hyperactivation of macrophages in response to lipopolysaccharide, but not TNF or IFNγ. This effect is dependent on the inhibition of IL-10 signaling, which is abundantly induced in response to LPS, but not to TNF or IFNγ. In contrast, cultured fibroblasts, which produced no IL-10 regardless of the stimuli, showed no hyperactivation when pre-treated with tofacitinib.</p><p><strong>Conclusions: </strong>We conclude that resistance to tofacitinib is mediated by the hyperactivation of myeloid cells and we identify IL-10-dependent macrophages as one cellular subset contributing to this resistance.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055942","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":"Gene-Environment Interactions in Inflammatory Bowel Disease: A Systematic Review of Human Epidemiologic Studies.","authors":"Jingjing Bai, Dianne Gelien Bouwknegt, Rinse Karel Weersma, Gerard Dijkstra, Kimberley Wilhelmina Johanna van der Sloot, Eleonora Anna Margaretha Festen","doi":"10.1093/ecco-jcc/jjaf061","DOIUrl":"10.1093/ecco-jcc/jjaf061","url":null,"abstract":"<p><strong>Background and aims: </strong>Complex gene-environment interaction (GXE) for inflammatory bowel disease (IBD) remains elusive. This systematic review aims to summarize the current evidence of GXE in IBD.</p><p><strong>Methods: </strong>PubMed, EMBASE, Web of Science, and Scopus were systematically searched from inception through April 30, 2024, to identify publications examining the interaction effect of genetic variants and environmental factors in IBD. All eligible studies were graded using STREGA guideline.</p><p><strong>Results: </strong>Four thousand eight hundred thirty-three publications were identified and screened, resulting in 39 eligible studies, and 17 studies reported statistically significant interactions. NOD2-smoking interaction was most frequently investigated and showed variant-specific effect at rs2066847 regarding the risk of Crohn's disease. Gene-smoking interactions were further identified in other IBD risk genes (ATG16L1, IL23R, and CALM3), detoxification genes (GSTP1 and HMOX1), smoking-associated genes (CHRNA3, CHRNA5, PPP1R3C, and BDNF), and the inflammatory cytokine (IL1B) through a candidate gene approach. Immunochip-wide interaction analyses yielded 64 smoking interacting variants. Gene-diet interactions were observed across multiple nutritional measures, including fatty acid intake with CYP4F3 and FADS2, serum selenium with SEPHS1 and SEPSECS, potassium intake with IL21, alcohol consumption with IL12B, heme iron intake with FCGR2A, and serum vitamin D with VDR.</p><p><strong>Conclusions: </strong>Current evidence indicated that the IBD risk conferred by environmental factors can vary among the individuals carrying certain genetic variants. Further efforts, including genome wide environment interaction studies and genotype-based nutrition/lifestyle clinical trials, are needed to unravel the missing heritability influenced by environmental exposures and to construct personalized recommendations of lifestyle/dietary modification based on an individual genetic background.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":"19 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217953","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}