Journal of Crohn's & colitis最新文献

{"title":"Orofacial granulomatosis associated with Crohn's disease: clinical phenotype and response to biologics and Janus kinase inhibitor therapy in a large multi-center cohort.","authors":"Robert D Lees, Priyanka Patel, Gregory Young, Lauren Beck, Angelica Molinillo Marin, Daniel Parkinson, Laetitia Pele, Miles Parkes, Jeremy Sanderson, Cameron Herbert, Esther Hullah, Christopher A Lamb, Joel Mawdsley, Richard Ally Speight","doi":"10.1093/ecco-jcc/jjag139","DOIUrl":"10.1093/ecco-jcc/jjag139","url":null,"abstract":"<p><strong>Background & aims: </strong>Orofacial granulomatosis (OFG) is strongly associated with Crohn's disease (CD). The CD phenotype associated with OFG is poorly defined, and there is little evidence regarding treatment. We aimed to characterize OFG-associated CD phenotypes and evaluate the response of OFG to advanced therapies in the largest cohort described to date.</p><p><strong>Methods: </strong>We conducted a retrospective cohort study of patients with OFG and CD from two UK centers, derived from patient records compiled since 2008. Phenotypic characteristics were compared with a CD control cohort of 1609 individuals without OFG from the NIHR IBD-BioResource. Clinical response to biologic/Janus kinase inhibitor (JAKi) therapies was assessed.</p><p><strong>Results: </strong>A total of 117 patients were included. Compared with controls, OFG was associated with earlier CD diagnosis (<17 years: 43% vs 22%, P < .001), increased ileocolonic disease (61% vs 41%, P < .001), perianal disease (46% vs 35%, P = .012), and upper gastrointestinal disease (21% vs 8%, P < .001). Clinical remission was achieved in 29 of 53 (55%) prescribed infliximab and 35 of 59 (59%) prescribed adalimumab, with frequent dose escalation. Remission was achieved with ustekinumab, risankizumab, and upadacitinib in 14 of 25 (56%), 6 of 12 (50%), and 3 of 5 (60%), respectively in biologic-experienced patients. Higher anti-TNF drug levels were associated with higher odds of achieving treatment response (adalimumab OR 1.14 per 1 µg/mL increase, P = .049; infliximab OR 1.27, P = .047).</p><p><strong>Conclusions: </strong>OFG is associated with a distinct CD phenotype characterized by frequent UGI and perianal involvement. Advanced therapies, including anti-TNF, anti-IL23, and JAKi therapies, are effective, with evidence supporting dose optimization.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":"20 9","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13594358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149019219","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":"Follow-up duration and tuberculosis do not modify the comparative safety of JAK inhibitors in ulcerative colitis.","authors":"Antoine Meyer, Aurélien Amiot","doi":"10.1093/ecco-jcc/jjag142","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjag142","url":null,"abstract":"","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":"20 9","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148993275","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":"Isolated perianal fistulizing Crohn's disease in contemporary clinical practice: a multicenter ECCO-CONFER cohort study.","authors":"Kumarini Basnayake, Deloshaan Subhaharan, David Drobne, Parakkal Deepak, Sami Samaan, Alessia La Mantia, Olga Maria Nardone, Justin R Howard, Francisco López Romero-Salazar, Pablo Ramírez Alcázar, Andrea Centritto, Bram Verstockt, Catherine Reenaers, Luke Hanna, Simone Saibeni, Rafal Filip, Melissa Hale, Daniela Pugliese, Edoardo Vincenzo Savarino, Davide Giuseppe Ribaldone, Jeroen Geldof, Magdalena Gawron-Kiszka, Cristina Bezzio, Anna Gojdičová, Edyta Zagórowicz, Aranzazu Jauregui-Amezaga, Thilini Basnayake, Stefano Festa, James L Alexander, Rachel Cooney, Tim Raine","doi":"10.1093/ecco-jcc/jjag130","DOIUrl":"10.1093/ecco-jcc/jjag130","url":null,"abstract":"<p><strong>Background and aims: </strong>Isolated perianal fistulizing Crohn's disease (IPFCD) is an uncommon presentation of Crohn's disease with an uncertain natural history. We aimed to characterize contemporary diagnostic strategies, management approaches, and long-term outcomes, including progression to luminal Crohn's disease.</p><p><strong>Methods: </strong>We conducted a retrospective multicenter cohort study across 25 centers within the ECCO-CONFER network. Adult patients with IPFCD and no evidence of luminal Crohn's disease at baseline were included. The primary outcome was progression to luminal Crohn's disease. Secondary outcomes included clinical and radiological fistula response and patterns of medical and surgical management. Time-to-event analyses were performed using Kaplan-Meier methods.</p><p><strong>Results: </strong>A total of 121 patients were included with a median follow-up of 76 months (IQR 46-118). Diagnostic pathways were heterogeneous, with most patients undergoing colonoscopy (91.7%) and pelvic magnetic resonance imaging (63.6%), alongside variable use of additional modalities. Management was intensive, with 76.9% receiving biologic therapies and 85.1% undergoing combined medical-surgical treatment. Complete clinical remission was achieved in 57% of patients, while radiological healing was observed in 46.4%. During follow-up, 42 (34.7%) patients developed luminal Crohn's disease. Median progression-free survival was 145.6 months, with a median time to luminal diagnosis of 110 months (IQR 40-152). No consistent predictors of progression were identified.</p><p><strong>Conclusions: </strong>Approximately one-third of patients with IPFCD developed luminal Crohn's disease over long-term follow-up, typically after several years. However, many patients remain free of intestinal involvement, reflecting a heterogenous disease course and highlighting the need for standardized evaluation and improved risk stratification.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":"20 9","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13568819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148946289","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":"Targeting epithelial IFN-I signaling restores barrier integrity in anti-TNF refractory Crohn's disease.","authors":"Safina Gadeock, Mikayla King, D Brent Polk, Andrew J Highton, Shujun Fan, Claudia Campbell, Michael Schultz, Roslyn A Kemp","doi":"10.1093/ecco-jcc/jjag140","DOIUrl":"10.1093/ecco-jcc/jjag140","url":null,"abstract":"<p><strong>Background and aims: </strong>Type I interferons (IFN-Is) are central regulators of intestinal epithelial homeostasis, yet their role in driving epithelial dysfunction and therapeutic non-response in Crohn's disease (CD) remains poorly defined. Here, we investigated epithelial tumor necrosis factor (TNF)-IFN-I crosstalk as a previously unrecognized contributor to anti-TNF non-response in CD.</p><p><strong>Methods: </strong>We analyzed human intestinal biopsies, single-cell RNA sequencing data from CD donors, and used murine TNFR1-deficient and patient-derived organoids exposed to inflammatory cytokines and clinically relevant treatments.</p><p><strong>Results: </strong>Colonic epithelia from anti-TNF non-responders (NR-CD) showed enrichment of IFN-I genes associated with epithelial stress, impaired regeneration, and inflammatory cytokine production. Using patient-derived and murine TNFR1-deficient organoids, we demonstrated that TNF signaling sustains epithelial IFN-I responses linked to immune regulation and antiviral pathways, establishing a mechanistic connection between chronic TNF signaling and epithelial barrier failure. Low-dose butyrate (0.1 mM) suppressed cytokine-induced IFN-I genes and enhanced epithelial turnover in non-IBD and responder CD (R-CD) organoids but did not rescue the apoptosis and defective repair characteristic of NR-CD organoids. Notably, anti-IFN-I antibody treatment selectively attenuated IFN-I signaling and restored epithelial integrity in NR-CD organoids, identifying epithelial IFN-I blockade as a novel therapeutic rescue strategy for anti-TNF refractory disease.</p><p><strong>Conclusions: </strong>TNF-IFN-I crosstalk drives epithelial dysfunction in CD. Elevated epithelial IFN-I genes distinguish anti-TNF non-responders and underlie differential therapeutic responses. Together, this work supports integration of epithelial IFN-I gene expression and patient-derived ex vivo functional testing into treatment decisions for CD patients.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":"20 9","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149009564","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":"Piezo1 in intestinal epithelial cells plays a critical role in the mechanobiological positive feedback underlying intestinal fibrosis.","authors":"Xinghuang Liu, Ruohang He, Zhiyue Xu, Xiaochuan Dong, Dongke Wang, Jie Chen, Biqiang Zhu, Jun Song, Xiaohua Hou, Tao Bai","doi":"10.1093/ecco-jcc/jjag103","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjag103","url":null,"abstract":"<p><strong>Background and aims: </strong>Intestinal fibrosis involves extracellular matrix stiffening. Piezo1, a mechanosensitive ion channel highly expressed in intestinal epithelial cells (IECs), may sense this change. We investigated whether IEC Piezo1 drives fibrosis and explored the underlying mechanobiological mechanism.</p><p><strong>Methods: </strong>Dextran sulfate sodium (DSS)-induced fibrosis models, inflammatory bowel disease (IBD) patient samples, and IEC-specific Piezo1 knockout (Piezo1ΔIEC) mice were used. RNA-sequencing, Seahorse assays, and stiffness-gradient hydrogels (1-10 kPa) were applied to assess Piezo1 function, oxidative phosphorylation (OXPHOS), reactive oxygen species (ROS), epithelial-mesenchymal transition (EMT) of IECs, and the anti-fibrosis effect of vitamin C.</p><p><strong>Results: </strong>Piezo1 expression was significantly upregulated in IECs from fibrotic regions of both DSS model mice and IBD patients. IEC Piezo1 deficiency alleviated DSS-induced intestinal fibrosis without substantially altering chronic inflammation or fibroblast activation/proliferation. Piezo1 deficiency suppressed the partial EMT phenotype in IECs, as evidenced by preserved E-cadherin and Claudin-1 expression. RNA-sequencing and functional assays revealed enhanced OXPHOS activity in Piezo1-deficient IECs. In vitro, matrix stiffness of 4 kPa (mimicking fibrotic tissue) activated Piezo1, increased intracellular Ca2+ and ROS accumulation, and induced EMT. Knockout of Piezo1 or treatment with vitamin C prevented these stiffness-induced changes. Oral administration of high-dose vitamin C in vivo reduced intestinal fibrosis and suppressed IEC EMT.</p><p><strong>Conclusions: </strong>Piezo1 plays a critical role in the sensing of pathological extracellular matrix stiffness in intestinal fibrosis, driving an ROS-EMT axis that promotes disease progression. Targeting Piezo1 or its downstream ROS pathway, for instance with vitamin C, represents a potential therapeutic strategy for intestinal fibrosis.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":"20 9","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889837","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":"Self-expandable metal stents versus endoscopic balloon dilatation for the treatment of strictures in Crohn's disease: a retrospective long-term follow-up of the ProtDilat study, an open label, multicenter, randomized trial.","authors":"Carme Loras, Pablo Ruiz-Ramírez, Joan B Gornals, Vicente Sanchiz, Eduard Brunet-Mas, Eva Iglesias, Jesús Barrio, Beatriz Sicilia, Carmen Dueñas, José Ramón Foruny, María Dolores Martín-Arranz, David Busquets, Elena Cerrillo, Natalia García-Morales, David Monfort, Francisco Pérez-Roldán, Eva Pijoan, Begoña González, José Reyes, Gisela Torres, Elisabet Maristany Bosch, Marta Maia Bosca-Watts, Jordi Guardiola, Albert Martín-Cardona, Maria Esteve","doi":"10.1093/ecco-jcc/jjag112","DOIUrl":"10.1093/ecco-jcc/jjag112","url":null,"abstract":"<p><strong>Background: </strong>At 1-year of follow-up, the ProtDilat trial indicated that endoscopic balloon dilatation (EBD) was more effective than self-expandable metal stents (SEMSs) for treating Crohn's disease (CD) strictures. We aimed to assess the long-term outcomes of ProtDilat participants, focusing on surgery-free rates, factors related to surgery, and endoscopic retreatment.</p><p><strong>Methods: </strong>We retrospectively collected data on medical treatment, endoscopic-surgical interventions, and smoking status. The primary outcome was the percentage of patients who remained free of surgery at the end of follow-up.</p><p><strong>Results: </strong>Eighty participants were included (39 SEMS, 41 EBD); 39 were women and the median age was 45 years (IQR: 38-55). Over a 7-year follow-up (median 77 months; IQR 61-84), 31.5% (25/80) of patients required surgery, with a median time to surgery of 30.6 months (IQR 6.4-55.2). Surgery-protective factors were no-intensification of medical therapy (HR 0.22 [0.08-0.58]), EBD treatment (HR 0.26 [0.10-0.68]), and single endoscopic treatment (HR 0.33 [0.15-0.74]). Among the 55 patients who avoided surgery, the median number of endoscopic treatments was two. Notably, 36.3% (29/80) required neither surgery nor endoscopic retreatment. Among the 53 patients (20 SEMS vs 33 EBD) with successful initial endoscopic treatment in the ProtDilat, the long-term effectiveness (free of surgery and endoscopic retreatment) was 45% and 57.6% respectively (P = .374). Treatment-related adverse events occurred in 8.75% (7/80) of endoscopic cases vs 36% (9/25) of surgical cases (P = .003), with a severity (AGREE/Clavien-Dindo ≥ 3) of 38% (3/8) vs 84% (10/12), respectively (P = .011).</p><p><strong>Conclusions: </strong>Endoscopic approaches (especially EBD) are effective long-term therapies for avoiding surgery and requiring few endoscopic treatments. Stable medical management and single EBD therapy were independently associated with a lower likelihood of surgery during follow-up. Our findings also highlight the higher frequency and severity of adverse events associated with surgical intervention compared to endoscopic management.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":"20 9","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13588575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003238","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":"Real-world effectiveness and safety of risankizumab induction and maintenance therapy in pediatric patients with Crohn's disease: a multicenter retrospective analysis.","authors":"Elizabeth A Spencer, Quentin Buck, Lauren V Collen, Ronen Stein, Tyler Babinski, Dror S Shouval, Firas Rinawi, Richard K Russell, Eyal Zifman, Chani Topf-Olivestone, Christos Tzvinikos, Mordechai Slae, Raffi Lev-Tzion, Dan Turner, Marla C Dubinsky, Amit Assa","doi":"10.1093/ecco-jcc/jjag134","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjag134","url":null,"abstract":"<p><strong>Background & aims: </strong>Risankizumab is approved for adults with Crohn's disease (CD); pediatric data are limited. We evaluated real-world effectiveness, durability, safety, and dosing in children with CD.</p><p><strong>Methods: </strong>Retrospective, global multicenter cohort of patients <18 years initiating risankizumab monotherapy (2022-2025). The outcomes were primary: corticosteroid-free clinical remission (CFR, wPCDAI < 12.5) post-induction (Week 12) among those with clinically active (wPCDAI ≥ 12.5) disease at start; secondary: clinical response (decrease wPCDAI ≥ 17.5-points), C-reactive protein (CRP) remission (<5 mg/L), CFR + CRP remission, intestinal ultrasound (IUS) remission, CFR at Weeks 30/54, therapy durability, and safety.</p><p><strong>Results: </strong>Of the 96 (median age 15 [IQR: 13-16] years; 51% male; 70% ileocolonic; 38% prior ustekinumab) started on risankizumab, 68 (71%) had active disease at start. Nearly all (93/96, 97%) received the adult induction regimen-3 < 30 kg received a median 383 mg/m² (IQR: 339-397). Post-induction CFR was achieved in 28/68 (41%), clinical response in 37/68 (54%), and combined CFR + CRP in 22/68 (32%). Week 30 and 54 CFR were attained in 34/68 (50%) and 34/68 (50%), respectively. In the full cohort, median follow-up was 53.5 weeks (IQR: 47-60); 86/96 (90%) remained on risankizumab. Durability was greater with post-induction CFR (log-rank P = .008; Cox HR 0.21, 95% CI 0.06-0.75; P = .02). Lower baseline ESR predicted higher odds of post-induction CFR (OR 0.97 per mm/h; 95% CI 0.94-0.99; P = .01). No serious safety events occurred.</p><p><strong>Conclusions: </strong>In this multicenter pediatric cohort, risankizumab induced meaningful clinical and biomarker improvement with durable remission and a favorable safety profile, supporting risankizumab as an effective option for children with CD.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":"20 9","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13626131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149120797","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":"Evaluating sonographic response and remission in inflammatory bowel disease: aligning intestinal ultrasound assessment with STRIDE-II timelines.","authors":"Ashish R Srinivasan, Shintaro Sagami, Andrew Nguyen, Rebecca L Smith, Abhinav Vasudevan, Stuart A Taylor","doi":"10.1093/ecco-jcc/jjag132","DOIUrl":"10.1093/ecco-jcc/jjag132","url":null,"abstract":"<p><strong>Background and aims: </strong>The diagnostic accuracy of intestinal ultrasound (IUS) is established; however, guidance on the timing and interpretation of sonographic response and remission in inflammatory bowel disease (IBD) remains limited. This review synthesizes current evidence to define expected response and remission kinetics in Crohn's disease (CD) and ulcerative colitis (UC) across STRIDE-II aligned reassessment timepoints.</p><p><strong>Methods: </strong>A structured narrative review was undertaken of studies published up to August 31, 2025 evaluating longitudinal IUS changes following initiation of medical therapy in patients with CD and UC. Outcomes were synthesized across early (<3 months), intermediate (3-6 months), and longer-term (6-12 months) reassessment intervals aligned with STRIDE-II timelines.</p><p><strong>Results: </strong>In CD, sonographic response was reported in approximately 51%-66% of patients by 12 weeks, while remission was reported in 14%-37%. At 3-6 months, response was reported in approximately 36%-38%, while remission was reported in 12%-38%. Longer-term response and remission were reported in approximately 36%-57% and 24%-42%, respectively, at 48-56 weeks. In UC, response was reported in 57%-77% and remission in 45%-64% by weeks 8-12 in selected cohorts. However, traditional IUS response and remission estimates beyond this early treatment phase remain limited in UC. Direct comparisons between studies was limited by heterogeneity in outcome definitions, reassessment timepoints, therapy class, and disease characteristics.</p><p><strong>Conclusion: </strong>IUS is a practical, non-invasive tool for monitoring therapeutic response in IBD. The optimal timing of reassessment is likely to vary according to therapy-specific time to response, IBD subtype, disease phenotype, and bowel segment. Standardization of definitions and reassessment timelines remain central to integrating IUS into treat-to-target models of IBD care.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":"20 9","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149043084","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":"Bridging preclinical and clinical efficacy of SIK2/SIK3 inhibition in inflammatory bowel disease through integrated murine, patient-derived models, and phase 2a trial-based analyses.","authors":"Lorenzo Giorio, Steve De Vos, Maikel Luis Colli, Didier Merciris, Eva Vissers, Tommaso Innocenti, Fabrice Kolb, Marc Ferrante, João Guedelha Sabino, Séverine Vermeire, Kaline Arnauts, Bram Verstockt","doi":"10.1093/ecco-jcc/jjag133","DOIUrl":"10.1093/ecco-jcc/jjag133","url":null,"abstract":"<p><strong>Background and aims: </strong>Translational attrition remains a major obstacle in inflammatory bowel disease (IBD) drug development due to limited concordance between conventional preclinical models and patient responses. In this study we aimed to evaluate the activity of the selective salt-inducible kinase 2/3 (SIK2/3) inhibitor GLPG3970 across complementary experimental platforms, including murine colitis, patient-derived intestinal organoids, and ex vivo mucosal biopsies, and compared these findings with transcriptional data from a UC-phase 2 study.</p><p><strong>Methods: </strong>Therapeutic efficacy of GLPG3970 (20 mg/kg) was assessed in the murine CD4 + CD25- T-cell transfer colitis model. Epithelial-intrinsic responses were investigated in ulcerative colitis (UC) patient-derived intestinal organoids (n = 5). In parallel, mucosal biopsies from UC (n = 10) and Crohn's disease (CD; n = 10) patients were treated ex vivo with GLPG3970 (60 µM) or tofacitinib (10 µM) for 24 h. Treatment-induced transcriptional signatures were compared with bulk RNA sequencing data from patients enrolled in a short 6-week UC-phase 2 study (GLPG3970 n = 21, placebo n = 10; NCT04577794).</p><p><strong>Results: </strong>GLPG3970 reduced disease activity and restored goblet cell-associated mucus production in the T-cell transfer model. In patient-derived intestinal organoids, SIK2/SIK3 inhibition enhanced epithelial mucus secretion. Ex vivo exposure of IBD biopsies elicited anti-inflammatory transcriptional and proteomic responses, revealing disease- and treatment-specific signatures. Notably, GLPG3970-induced signatures in ex vivo biopsies closely aligned with treatment-responsive gene expression changes observed in the UC-phase 2 study.</p><p><strong>Conclusions: </strong>Integrated analyses across murine, patient-derived, and clinical trial datasets demonstrate conserved immune-epithelial responses to SIK2/SIK3 inhibition by GLPG3970. These findings support the value of patient-relevant experimental platforms to assess target engagement and therapeutic activity prior to clinical testing, strengthening translational alignment in IBD drug development.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":"20 9","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148946029","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":"Upadacitinib treatment in pediatric Crohn's disease: 52-week outcomes of an international multicenter retrospective cohort study from the pediatric IBD Porto Group of ESPGHAN.","authors":"Elizabeth A Spencer, Shlomi Cohen, Marla C Dubinsky, David L Suskind, Katarina Mitrova, Ondrej Hradsky, Máire A Conrad, Judith R Kelsen, Malgorzata Sladek, Pai-Jui Yeh, Christos Tzivinikos, Paul Henderson, Magdalena Wlazlo, Lukas Hackl, Dror S Shouval, Natalia Mouratidou, Matteo Bramuzzo, Darja Urlep, Christine Olbjørn, Miriam D'Orsi, Anna-Maria Schneider, Gemma Pujol-Muncunill, Leora Gotesdyner, Ben Kang, Marco Gasparetto, Christine Rungø, Claudio Romano, Erasmo Miele, Kaija-Leena Kolho, Iva Hojsak, Lorenzo Norsa, Firas Rinawi, Naire Sansotta, Ramit Magen Rimon, Maya Granot, Luca Scarallo, Eunice Trindade, Marta Velasco Rodríguez-Belvís, Dan Turner, Anat Yerushalmy-Feler","doi":"10.1093/ecco-jcc/jjag125","DOIUrl":"10.1093/ecco-jcc/jjag125","url":null,"abstract":"<p><strong>Background and aims: </strong>Data on upadacitinib maintenance therapy in pediatric Crohn's disease (CD) are scarce. We aimed to evaluate the effectiveness, safety, and dosing of upadacitinib as maintenance therapy in pediatric CD.</p><p><strong>Methods: </strong>Children treated with upadacitinib for maintenance of remission of active CD from 35 centers affiliated with the Porto Group of ESPGHAN were included in this retrospective cohort study. Data on demographic, clinical, laboratory, endoscopic, and imaging findings and on adverse events (AEs) were recorded over 52 weeks of follow-up.</p><p><strong>Results: </strong>A total of 120 children were included (91 receiving upadacitinib as monotherapy and 29 as combination advanced therapy, mean age 15.4 ± 2.5 years). Prior to upadacitinib induction, 119/120 (99%) children had been treated with biologic therapies, 104 (87%) with two or more biologics and 98 (82%) had failed both vedolizumab and ustekinumab. Clinical remission and corticosteroid-free clinical remission (CFR) were observed after upadacitinib induction in 77 (64%) and 72 (60%) children, respectively. By week 52, 74 (62%) children achieved both clinical remission and CFR, and CFR was sustained in 66 (55%) children. CFR with normal C-reactive protein levels was achieved in 50% of children and CFR with fecal calprotectin levels <150 µg/g was achieved in 33% of children by week 52. Fifty-three (44%) children sustained AEs, two of which were serious (severe acne and intestinal perforation). The most frequent AEs were acne (n = 23), hyperlipidemia (n = 18), and infections (n = 14).</p><p><strong>Conclusion: </strong>Upadacitinib is an effective maintenance therapy for refractory pediatric CD. Effectiveness should be weighed against the potential risks of AEs.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":"20 9","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149019253","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}