Pub Date : 2024-09-03DOI: 10.1093/ecco-jcc/jjae041
Sarita Shrestha, Judith S Brand, Mehdi Osooli, Carl Eriksson, Ida Schoultz, Johan Askling, Tine Jess, Scott Montgomery, Ola Olén, Jonas Halfvarson
Background and aims: Register-based research suggests a shared pathophysiology between inflammatory bowel disease [IBD] and spondyloarthritis [SpA], but the role of familial [genetic and environmental] factors in this shared susceptibility is largely unknown. We aimed to compare the risk of SpA in first-degree relatives [FDRs] and spouses of IBD patients with FDRs and spouses of matched, population-based, reference individuals.
Methods: We identified 147 080 FDRs and 25 945 spouses of patients with incident IBD [N = 39 203] during 2006-2016, and 1 453 429 FDRs and 258 098 spouses of matched reference individuals [N = 390 490], by linking nationwide Swedish registers and gastrointestinal biopsy data. Study participants were followed 1987-2017. Cox regression was used to estimate hazard ratios [HRs] of SpA.
Results: During follow-up, 2430 FDRs of IBD patients [6.5/10 000 person-years] and 17 761 FDRs of reference individuals [4.8/10 000 person-years] were diagnosed with SpA, corresponding to an HR of 1.35 [95% CI:1.29, 1.41]. In subgroup analyses, the increased risk of SpA was most pronounced in FDRs of Crohn's disease patients [HR = 1.44; 95% CI:1.34,1.5 6] and of IBD patients aged <18 years at diagnosis [HR = 1.46; 95% CI: 1.27, 1.68]. IBD patients' spouses also had a higher SpA rate than reference individuals' spouses, but the difference was less pronounced [4.3 vs 3.5/10 000 person-years; HR = 1.22; 95% CI:1.09, 1.37]. No subgroup-specific risk pattern was identified among spouses.
Conclusions: The observed shared familial risks between IBD and SpA support shared genetic factors in their pathogenesis. However, spouses of IBD patients were also at increased risk for SpA, reflecting the influence of environmental exposures or similarities in health-seeking patterns.
{"title":"Spondyloarthritis in First-Degree Relatives and Spouses of Patients with Inflammatory Bowel Disease: A Nationwide Population-based Cohort Study from Sweden.","authors":"Sarita Shrestha, Judith S Brand, Mehdi Osooli, Carl Eriksson, Ida Schoultz, Johan Askling, Tine Jess, Scott Montgomery, Ola Olén, Jonas Halfvarson","doi":"10.1093/ecco-jcc/jjae041","DOIUrl":"10.1093/ecco-jcc/jjae041","url":null,"abstract":"<p><strong>Background and aims: </strong>Register-based research suggests a shared pathophysiology between inflammatory bowel disease [IBD] and spondyloarthritis [SpA], but the role of familial [genetic and environmental] factors in this shared susceptibility is largely unknown. We aimed to compare the risk of SpA in first-degree relatives [FDRs] and spouses of IBD patients with FDRs and spouses of matched, population-based, reference individuals.</p><p><strong>Methods: </strong>We identified 147 080 FDRs and 25 945 spouses of patients with incident IBD [N = 39 203] during 2006-2016, and 1 453 429 FDRs and 258 098 spouses of matched reference individuals [N = 390 490], by linking nationwide Swedish registers and gastrointestinal biopsy data. Study participants were followed 1987-2017. Cox regression was used to estimate hazard ratios [HRs] of SpA.</p><p><strong>Results: </strong>During follow-up, 2430 FDRs of IBD patients [6.5/10 000 person-years] and 17 761 FDRs of reference individuals [4.8/10 000 person-years] were diagnosed with SpA, corresponding to an HR of 1.35 [95% CI:1.29, 1.41]. In subgroup analyses, the increased risk of SpA was most pronounced in FDRs of Crohn's disease patients [HR = 1.44; 95% CI:1.34,1.5 6] and of IBD patients aged <18 years at diagnosis [HR = 1.46; 95% CI: 1.27, 1.68]. IBD patients' spouses also had a higher SpA rate than reference individuals' spouses, but the difference was less pronounced [4.3 vs 3.5/10 000 person-years; HR = 1.22; 95% CI:1.09, 1.37]. No subgroup-specific risk pattern was identified among spouses.</p><p><strong>Conclusions: </strong>The observed shared familial risks between IBD and SpA support shared genetic factors in their pathogenesis. However, spouses of IBD patients were also at increased risk for SpA, reflecting the influence of environmental exposures or similarities in health-seeking patterns.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140190522","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}
Pub Date : 2024-09-03DOI: 10.1093/ecco-jcc/jjad213
Mina Hassan-Zahraee, Zhan Ye, Li Xi, Elizabeth Dushin, Julie Lee, Jacek Romatowski, Jaroslaw Leszczyszyn, Silvio Danese, William J Sandborn, Christopher Banfield, Jeremy D Gale, Elena Peeva, Randy S Longman, Craig L Hyde, Kenneth E Hung
Background and aims: Ritlecitinib, an oral JAK3/TEC family kinase inhibitor, was well-tolerated and efficacious in the phase 2b VIBRATO study in participants with moderate-to-severe ulcerative colitis [UC]. The aim of this study was to identify baseline serum and microbiome markers that predict subsequent clinical efficacy and to develop noninvasive serum signatures as potential real-time noninvasive surrogates of clinical efficacy after ritlecitinib.
Methods: Tissue and peripheral blood proteomics, transcriptomics, and faecal metagenomics were performed on samples before and after 8 weeks of oral ritlecitinib induction therapy [20 mg, 70 mg, 200 mg, or placebo once daily, N = 39, 41, 33, and 18, respectively]. Linear mixed models were used to identify baseline and longitudinal protein markers associated with efficacy. The combined predictivity of these proteins was evaluated using a logistic model with permuted efficacy data. Differential expression of faecal metagenomics was used to differentiate responders and nonresponders.
Results: Peripheral blood serum proteomics identified four baseline serum markers [LTA, CCL21, HLA-E, MEGF10] predictive of modified clinical remission [MR], endoscopic improvement [EI], histological remission [HR], and integrative score of tissue molecular improvement. In responders, 37 serum proteins significantly changed at Week 8 compared with baseline [false discovery rate of <0.05]; of these, changes in four [IL4R, TNFRSF4, SPINK4, and LAIR-1] predicted concurrent EI and HR responses. Faecal metagenomics analysis revealed baseline and treatment response signatures that correlated with EI, MR, and tissue molecular improvement.
Conclusions: Blood and microbiome biomarkers stratify endoscopic, histological, and tissue molecular responses to ritlecitinib, which may help guide future precision medicine approaches to UC treatment. ClinicalTrials.gov NCT02958865.
{"title":"Baseline Serum and Stool Microbiome Biomarkers Predict Clinical Efficacy and Tissue Molecular Response After Ritlecitinib Induction Therapy in Ulcerative Colitis.","authors":"Mina Hassan-Zahraee, Zhan Ye, Li Xi, Elizabeth Dushin, Julie Lee, Jacek Romatowski, Jaroslaw Leszczyszyn, Silvio Danese, William J Sandborn, Christopher Banfield, Jeremy D Gale, Elena Peeva, Randy S Longman, Craig L Hyde, Kenneth E Hung","doi":"10.1093/ecco-jcc/jjad213","DOIUrl":"10.1093/ecco-jcc/jjad213","url":null,"abstract":"<p><strong>Background and aims: </strong>Ritlecitinib, an oral JAK3/TEC family kinase inhibitor, was well-tolerated and efficacious in the phase 2b VIBRATO study in participants with moderate-to-severe ulcerative colitis [UC]. The aim of this study was to identify baseline serum and microbiome markers that predict subsequent clinical efficacy and to develop noninvasive serum signatures as potential real-time noninvasive surrogates of clinical efficacy after ritlecitinib.</p><p><strong>Methods: </strong>Tissue and peripheral blood proteomics, transcriptomics, and faecal metagenomics were performed on samples before and after 8 weeks of oral ritlecitinib induction therapy [20 mg, 70 mg, 200 mg, or placebo once daily, N = 39, 41, 33, and 18, respectively]. Linear mixed models were used to identify baseline and longitudinal protein markers associated with efficacy. The combined predictivity of these proteins was evaluated using a logistic model with permuted efficacy data. Differential expression of faecal metagenomics was used to differentiate responders and nonresponders.</p><p><strong>Results: </strong>Peripheral blood serum proteomics identified four baseline serum markers [LTA, CCL21, HLA-E, MEGF10] predictive of modified clinical remission [MR], endoscopic improvement [EI], histological remission [HR], and integrative score of tissue molecular improvement. In responders, 37 serum proteins significantly changed at Week 8 compared with baseline [false discovery rate of <0.05]; of these, changes in four [IL4R, TNFRSF4, SPINK4, and LAIR-1] predicted concurrent EI and HR responses. Faecal metagenomics analysis revealed baseline and treatment response signatures that correlated with EI, MR, and tissue molecular improvement.</p><p><strong>Conclusions: </strong>Blood and microbiome biomarkers stratify endoscopic, histological, and tissue molecular responses to ritlecitinib, which may help guide future precision medicine approaches to UC treatment. ClinicalTrials.gov NCT02958865.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139033118","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}
Pub Date : 2024-08-30DOI: 10.1093/ecco-jcc/jjae132
Maria Francesca Nanì, Ester Pagano, Paola De Cicco, Giuseppe Lucariello, Fabio Cattaneo, Francesca Paola Tropeano, Donatella Cicia, Rebecca Amico, Federica Raucci, Giuseppe Ercolano, Francesco Maione, Maria Michela Rinaldi, Fabiana Esposito, Rosario Ammendola, Gaetano Luglio, Raffaele Capasso, Alexandros Makriyannis, Stefania Petrosino, Francesca Borrelli, Barbara Romano, Angelo A Izzo
Background and aims: Intestinal fibrosis, a frequent complication of inflammatory bowel disease, is characterized by stricture formation with no pharmacological treatment to date. N-acylethanolamine acid amidase (NAAA) is responsible of acylethanolamides (AEs, e.g., palmitoylethanolamide and oleoylethanolamide) hydrolysis. Here, we investigated NAAA and AEs signalling in gut fibrosis.
Methods: NAAA and AEs signalling were evaluated in human intestinal specimens from stenotic Crohn's diseases (CD) patients. Gut fibrosis was induced by TNBS, monitored by colonoscopy and unascertained by qRT-PCR, histological analyses, and confocal microscopy. Immune cells were analysed in mesenteric lymph nodes by FACS. Colonic fibroblasts were cultured in conditioned media derived from polarized or not bone marrow-derived macrophages (BMDM). IL-23 signalling was evaluated by qRT-PCR, ELISA, FACS, and western blot in BMDM and in lamina propria CX3CR1+ cells.
Results: In ileocolonic human CD strictures, increased transcript expression of NAAA was observed with a decrease of its substrates OEA and PEA. NAAA inhibition reduced intestinal fibrosis in vivo, as revealed by decrease in inflammatory parameters, collagen deposition and fibrosis genes, including epithelial to mesenchymal transition. More in-depth studies revealed modulation of the immune response related to IL-23 following NAAA inhibition. The antifibrotic actions of NAAA inhibition are mediated by Mφ and M2 macrophages that indirectly affect fibroblast collagenogenesis. NAAA inhibitor AM9053 normalized IL-23 signalling in BMDM and in lamina propria CX3CR1+ cells.
Conclusions: Our findings provide new insights into the pathophysiological mechanism of intestinal fibrosis and identify NAAA as a promising target for the development of therapeutic treatments to alleviate CD fibrosis.
背景和目的:肠纤维化是炎症性肠病的一种常见并发症,其特征是狭窄的形成,迄今为止尚无药物治疗方法。N-酰乙醇胺酸酰胺酶(NAAA)负责酰乙醇酰胺(AEs,如棕榈酰乙醇酰胺和油酰乙醇酰胺)的水解。在此,我们研究了NAAA和AEs在肠道纤维化中的信号传导:方法:在狭窄性克罗恩病(CD)患者的人体肠道标本中评估 NAAA 和 AEs 信号。TNBS诱导肠道纤维化,结肠镜监测,qRT-PCR、组织学分析和共聚焦显微镜检测。通过 FACS 分析肠系膜淋巴结中的免疫细胞。结肠成纤维细胞在来自极化或非极化骨髓源性巨噬细胞(BMDM)的条件培养基中培养。通过 qRT-PCR、ELISA、FACS 和 Western 印迹对 BMDM 和固有层 CX3CR1+ 细胞中的 IL-23 信号进行评估:结果:在回结肠人类 CD 狭窄处,观察到 NAAA 的转录表达增加,其底物 OEA 和 PEA 的表达减少。抑制NAAA可减少体内肠道纤维化,这体现在炎症参数、胶原沉积和纤维化基因(包括上皮细胞向间充质转化)的减少。更深入的研究显示,抑制NAAA后,与IL-23有关的免疫反应发生了改变。NAAA抑制剂的抗纤维化作用是由Mφ和M2巨噬细胞介导的,它们间接影响了成纤维细胞胶原蛋白的生成。NAAA抑制剂AM9053可使BMDM和固有层CX3CR1+细胞中的IL-23信号正常化:我们的研究结果为了解肠纤维化的病理生理机制提供了新的视角,并确定了NAAA是开发缓解CD纤维化治疗方法的一个有前景的靶点。
{"title":"Pharmacological inhibition of N-Acylethanolamine acid amidase (NAAA) mitigates intestinal fibrosis through modulation of macrophage activity.","authors":"Maria Francesca Nanì, Ester Pagano, Paola De Cicco, Giuseppe Lucariello, Fabio Cattaneo, Francesca Paola Tropeano, Donatella Cicia, Rebecca Amico, Federica Raucci, Giuseppe Ercolano, Francesco Maione, Maria Michela Rinaldi, Fabiana Esposito, Rosario Ammendola, Gaetano Luglio, Raffaele Capasso, Alexandros Makriyannis, Stefania Petrosino, Francesca Borrelli, Barbara Romano, Angelo A Izzo","doi":"10.1093/ecco-jcc/jjae132","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae132","url":null,"abstract":"<p><strong>Background and aims: </strong>Intestinal fibrosis, a frequent complication of inflammatory bowel disease, is characterized by stricture formation with no pharmacological treatment to date. N-acylethanolamine acid amidase (NAAA) is responsible of acylethanolamides (AEs, e.g., palmitoylethanolamide and oleoylethanolamide) hydrolysis. Here, we investigated NAAA and AEs signalling in gut fibrosis.</p><p><strong>Methods: </strong>NAAA and AEs signalling were evaluated in human intestinal specimens from stenotic Crohn's diseases (CD) patients. Gut fibrosis was induced by TNBS, monitored by colonoscopy and unascertained by qRT-PCR, histological analyses, and confocal microscopy. Immune cells were analysed in mesenteric lymph nodes by FACS. Colonic fibroblasts were cultured in conditioned media derived from polarized or not bone marrow-derived macrophages (BMDM). IL-23 signalling was evaluated by qRT-PCR, ELISA, FACS, and western blot in BMDM and in lamina propria CX3CR1+ cells.</p><p><strong>Results: </strong>In ileocolonic human CD strictures, increased transcript expression of NAAA was observed with a decrease of its substrates OEA and PEA. NAAA inhibition reduced intestinal fibrosis in vivo, as revealed by decrease in inflammatory parameters, collagen deposition and fibrosis genes, including epithelial to mesenchymal transition. More in-depth studies revealed modulation of the immune response related to IL-23 following NAAA inhibition. The antifibrotic actions of NAAA inhibition are mediated by Mφ and M2 macrophages that indirectly affect fibroblast collagenogenesis. NAAA inhibitor AM9053 normalized IL-23 signalling in BMDM and in lamina propria CX3CR1+ cells.</p><p><strong>Conclusions: </strong>Our findings provide new insights into the pathophysiological mechanism of intestinal fibrosis and identify NAAA as a promising target for the development of therapeutic treatments to alleviate CD fibrosis.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142116572","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}
Pub Date : 2024-08-30DOI: 10.1093/ecco-jcc/jjae131
Dominik Roth, Miriam M Düll, Ludwig J Horst, Aylin Lindemann, Xenia Malzer, Kristina Koop, Sebastian Zundler, Marcel Vetter, André Jefremow, Raja Atreya, Carol Geppert, Sören Weidemann, Maximilian J Waldner, Peter Dietrich, Claudia Günther, Luis E Munoz, Martin Herrmann, Alexander Scheffold, Markus F Neurath, Jürgen Siebler, Christoph Schramm, Andreas E Kremer, Moritz Leppkes
Objective: Recently, autoantibodies directed against the epithelial adhesion protein integrin αVβ6 have been identified which strongly associate with ulcerative colitis (UC). We aimed to elucidate whether anti-integrin αVβ6 (anti- αVβ6) is present in primary sclerosing cholangitis (PSC), its associated inflammatory bowel disease or other cholestatic liver diseases and their persistence after proctocolectomy.
Design: We detected anti- αVβ6 by an enzyme-linked immunosorbent assay in sera collected at two German tertiary centers, including healthy controls (N=62), UC (N=36), Crohn's disease (CD, N=65), PSC-IBD (78 samples from N=41 patients), PSC without IBD (PSC, 41 samples from N=18 patients), primary biliary cholangitis (PBC, N=24), autoimmune hepatitis (AIH, N=32), secondary sclerosing cholangitis (SSC, N=12) and metabolic dysfunction-associated steatotic liver disease (MASLD, N=24). Additionally, sera after proctocolectomy were studied (44 samples / N= 10 patients). Immunofluorescent analyses were performed in tissue samples from liver, large bile duct from surgical resections and colon of PSC patients.
Results: Anti- αVβ6 occurred in 91% of UC, 17% of CD, 73% of PSC-IBD, 39% of PSC, 4% of PBC, 14% of AIH, and 0% of healthy controls, SSC or MASLD. Integrin αVβ6 is selectively expressed in disease-associated epithelia of both bile duct and colon. Anti- αVβ6 levels correlate moderately with intestinal disease activity in PSC-IBD, but only weakly with biliary disease.
Conclusion: Anti- αVβ6 frequently occur in patients suffering from PSC, especially in PSC-IBD. Anti- αVß6 levels positively correlate to IBD activity in PSC-IBD, but may also occur in the absence of clinically manifest IBD in PSC.
{"title":"Integrin αVß6 - autoantigen and driver of epithelial remodeling in colon and bile ducts in primary sclerosing cholangitis and inflammatory bowel disease.","authors":"Dominik Roth, Miriam M Düll, Ludwig J Horst, Aylin Lindemann, Xenia Malzer, Kristina Koop, Sebastian Zundler, Marcel Vetter, André Jefremow, Raja Atreya, Carol Geppert, Sören Weidemann, Maximilian J Waldner, Peter Dietrich, Claudia Günther, Luis E Munoz, Martin Herrmann, Alexander Scheffold, Markus F Neurath, Jürgen Siebler, Christoph Schramm, Andreas E Kremer, Moritz Leppkes","doi":"10.1093/ecco-jcc/jjae131","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae131","url":null,"abstract":"<p><strong>Objective: </strong>Recently, autoantibodies directed against the epithelial adhesion protein integrin αVβ6 have been identified which strongly associate with ulcerative colitis (UC). We aimed to elucidate whether anti-integrin αVβ6 (anti- αVβ6) is present in primary sclerosing cholangitis (PSC), its associated inflammatory bowel disease or other cholestatic liver diseases and their persistence after proctocolectomy.</p><p><strong>Design: </strong>We detected anti- αVβ6 by an enzyme-linked immunosorbent assay in sera collected at two German tertiary centers, including healthy controls (N=62), UC (N=36), Crohn's disease (CD, N=65), PSC-IBD (78 samples from N=41 patients), PSC without IBD (PSC, 41 samples from N=18 patients), primary biliary cholangitis (PBC, N=24), autoimmune hepatitis (AIH, N=32), secondary sclerosing cholangitis (SSC, N=12) and metabolic dysfunction-associated steatotic liver disease (MASLD, N=24). Additionally, sera after proctocolectomy were studied (44 samples / N= 10 patients). Immunofluorescent analyses were performed in tissue samples from liver, large bile duct from surgical resections and colon of PSC patients.</p><p><strong>Results: </strong>Anti- αVβ6 occurred in 91% of UC, 17% of CD, 73% of PSC-IBD, 39% of PSC, 4% of PBC, 14% of AIH, and 0% of healthy controls, SSC or MASLD. Integrin αVβ6 is selectively expressed in disease-associated epithelia of both bile duct and colon. Anti- αVβ6 levels correlate moderately with intestinal disease activity in PSC-IBD, but only weakly with biliary disease.</p><p><strong>Conclusion: </strong>Anti- αVβ6 frequently occur in patients suffering from PSC, especially in PSC-IBD. Anti- αVß6 levels positively correlate to IBD activity in PSC-IBD, but may also occur in the absence of clinically manifest IBD in PSC.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142116570","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}
Pub Date : 2024-08-30DOI: 10.1093/ecco-jcc/jjae139
Ingrid Jurickova, Benjamin W Dreskin, Elizabeth Angerman, Erin Bonkowski, Jack Nguyen, Richard Villarreal, Kentaro Tominaga, Kentaro Iwasawa, Tzipi Braun, Takanori Takebe, Michael A Helmrath, Yael Haberman, James M Wells, Lee A Denson
Background and aims: We previously identified small molecules predicted to reverse an ileal gene signature for future Crohn's Disease (CD) strictures. Here we used a new human intestinal organoid (HIO) model system containing macrophages to test a lead candidate, eicosatetraynoic acid (ETYA).
Methods: Induced pluripotent stem cell lines (iPSC) were derived from CD patients and differentiated into macrophages and HIOs. Macrophages and macrophage:HIO co-cultures were exposed to lipopolysaccharide (LPS) with and without ETYA pre-treatment. Cytospin and flow cytometry characterized macrophage morphology and activation markers, and RNA sequencing defined the global pattern of macrophage gene expression. TaqMan Low Density Array, Luminex multiplex assay, immunohistologic staining, and sirius red polarized light microscopy were performed to measure macrophage cytokine production and HIO pro-fibrotic gene expression and collagen content.
Results: iPSC-derived macrophages exhibited morphology similar to primary macrophages and expressed inflammatory macrophage cell surface markers including CD64 and CD68. LPS-stimulated macrophages expressed a global pattern of gene expression enriched in CD ileal inflammatory macrophages and matrisome secreted products, and produced cytokines and chemokines including CCL2, IL1B, and OSM implicated in refractory disease. ETYA suppressed CD64 abundance and pro-fibrotic gene expression pathways in LPS stimulated macrophages. Co-culture of LPS-primed macrophages with HIO led to up-regulation of fibroblast activation genes including ACTA2 and COL1A1, and an increase in HIO collagen content. ETYA pre-treatment prevented pro-fibrotic effects of LPS-primed macrophages.
Conclusions: ETYA inhibits pro-fibrotic effects of LPS-primed macrophages upon co-cultured HIO. This model may be used in future untargeted screens for small molecules to treat refractory CD.
{"title":"Eicosatetraynoic Acid Regulates Pro-Fibrotic Pathways in an Induced Pluripotent Stem Cell Derived Macrophage:Human Intestinal Organoid Model of Crohn's Disease.","authors":"Ingrid Jurickova, Benjamin W Dreskin, Elizabeth Angerman, Erin Bonkowski, Jack Nguyen, Richard Villarreal, Kentaro Tominaga, Kentaro Iwasawa, Tzipi Braun, Takanori Takebe, Michael A Helmrath, Yael Haberman, James M Wells, Lee A Denson","doi":"10.1093/ecco-jcc/jjae139","DOIUrl":"10.1093/ecco-jcc/jjae139","url":null,"abstract":"<p><strong>Background and aims: </strong>We previously identified small molecules predicted to reverse an ileal gene signature for future Crohn's Disease (CD) strictures. Here we used a new human intestinal organoid (HIO) model system containing macrophages to test a lead candidate, eicosatetraynoic acid (ETYA).</p><p><strong>Methods: </strong>Induced pluripotent stem cell lines (iPSC) were derived from CD patients and differentiated into macrophages and HIOs. Macrophages and macrophage:HIO co-cultures were exposed to lipopolysaccharide (LPS) with and without ETYA pre-treatment. Cytospin and flow cytometry characterized macrophage morphology and activation markers, and RNA sequencing defined the global pattern of macrophage gene expression. TaqMan Low Density Array, Luminex multiplex assay, immunohistologic staining, and sirius red polarized light microscopy were performed to measure macrophage cytokine production and HIO pro-fibrotic gene expression and collagen content.</p><p><strong>Results: </strong>iPSC-derived macrophages exhibited morphology similar to primary macrophages and expressed inflammatory macrophage cell surface markers including CD64 and CD68. LPS-stimulated macrophages expressed a global pattern of gene expression enriched in CD ileal inflammatory macrophages and matrisome secreted products, and produced cytokines and chemokines including CCL2, IL1B, and OSM implicated in refractory disease. ETYA suppressed CD64 abundance and pro-fibrotic gene expression pathways in LPS stimulated macrophages. Co-culture of LPS-primed macrophages with HIO led to up-regulation of fibroblast activation genes including ACTA2 and COL1A1, and an increase in HIO collagen content. ETYA pre-treatment prevented pro-fibrotic effects of LPS-primed macrophages.</p><p><strong>Conclusions: </strong>ETYA inhibits pro-fibrotic effects of LPS-primed macrophages upon co-cultured HIO. This model may be used in future untargeted screens for small molecules to treat refractory CD.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142116569","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}
Pub Date : 2024-08-30DOI: 10.1093/ecco-jcc/jjae128
Remo Panaccione, Christopher Ma, Vipul Jairath, Axel Dignass, Namita Joshi, Ryan Clark, Jenny Griffith, Kristina Kligys, Monika Semwal, Zachary Smith, Dominic Mitchell, Dominic Nunag, Marc Ferrante
Background: Endoscopic remission has emerged as an important treatment target in Crohn's disease (CD) and has been associated with improvement in long-term outcomes. We examined the relationship between achievement of endoscopic remission and hospitalizations using pooled 52-week Phase III risankizumab and upadacitinib maintenance trials for patients with moderate-to-severely active CD.
Methods: Included patients received maintenance therapy after achieving a clinical response following a 12-week induction with risankizumab or upadacitinib. Endoscopic remission defined as a Simple Endoscopic Score for CD no greater than 4 with at least a 2-point reduction versus induction baseline and no subscore greater than 1. All subsequent hospitalization events were recorded until completion of the maintenance trial or discontinuation. Exposure-adjusted negative binomial regression models were estimated to assess the relationship between post-induction endoscopic remission and long-term hospitalization, controlling for demographics, clinical variables, and treatment arm.
Results: Post-induction hospitalization rates were lower in patients who achieved endoscopic remission at the end of the induction period. In multivariable models, post-induction endoscopic remission was independently associated with an IRR of 0.45 (95% CI [0.22-0.95], p=0.036) and 0.71 (95% CI [0.44-1.14], p=0.156) for long-term disease-related and all-cause hospitalizations, respectively.
Conclusions: Week 12 endoscopic remission is independently associated with reducing 52-week disease-related hospitalizations. However, achieving this stringent endpoint within 12 weeks of therapy may be challenging. Endoscopic response may be a more realistic early endoscopic target in the post-induction timeframe. Additional research is needed to evaluate early achievement of alternative endoscopic endpoints in CD.
背景:内镜缓解已成为克罗恩病(CD)的一个重要治疗目标,并与长期预后的改善有关。我们对中度至重度活动性克罗恩病患者进行了为期 52 周的利桑珠单抗和乌达替尼维持治疗 III 期试验,研究了内镜缓解与住院治疗之间的关系:纳入的患者在使用利桑珠单抗或高达替尼进行为期 12 周的诱导治疗并获得临床应答后接受维持治疗。内镜下缓解的定义是:CD简单内镜评分不超过4分,与诱导基线相比至少降低2分,且没有子评分超过1分。在控制人口统计学、临床变量和治疗组的情况下,对暴露调整负二项回归模型进行了估计,以评估诱导后内镜缓解与长期住院之间的关系:结果:在诱导期结束时获得内镜缓解的患者诱导后住院率较低。在多变量模型中,诱导后内镜缓解与长期疾病相关住院和全因住院的IRR分别为0.45(95% CI [0.22-0.95],p=0.036)和0.71(95% CI [0.44-1.14],p=0.156):结论:第12周内镜治疗缓解与减少52周疾病相关住院率密切相关。结论:第12周内镜下缓解与减少52周疾病相关住院率密切相关。然而,在治疗12周内达到这一严格终点可能具有挑战性。内镜反应可能是诱导后更现实的早期内镜目标。还需要进行更多的研究来评估 CD 早期实现其他内镜终点的情况。
{"title":"Achievement of Endoscopic Remission After Induction Reduces Hospitalization Burden in Crohn's Disease: Findings From a Pooled Post Hoc Analysis of Risankizumab and Upadacitinib Phase III Trials.","authors":"Remo Panaccione, Christopher Ma, Vipul Jairath, Axel Dignass, Namita Joshi, Ryan Clark, Jenny Griffith, Kristina Kligys, Monika Semwal, Zachary Smith, Dominic Mitchell, Dominic Nunag, Marc Ferrante","doi":"10.1093/ecco-jcc/jjae128","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae128","url":null,"abstract":"<p><strong>Background: </strong>Endoscopic remission has emerged as an important treatment target in Crohn's disease (CD) and has been associated with improvement in long-term outcomes. We examined the relationship between achievement of endoscopic remission and hospitalizations using pooled 52-week Phase III risankizumab and upadacitinib maintenance trials for patients with moderate-to-severely active CD.</p><p><strong>Methods: </strong>Included patients received maintenance therapy after achieving a clinical response following a 12-week induction with risankizumab or upadacitinib. Endoscopic remission defined as a Simple Endoscopic Score for CD no greater than 4 with at least a 2-point reduction versus induction baseline and no subscore greater than 1. All subsequent hospitalization events were recorded until completion of the maintenance trial or discontinuation. Exposure-adjusted negative binomial regression models were estimated to assess the relationship between post-induction endoscopic remission and long-term hospitalization, controlling for demographics, clinical variables, and treatment arm.</p><p><strong>Results: </strong>Post-induction hospitalization rates were lower in patients who achieved endoscopic remission at the end of the induction period. In multivariable models, post-induction endoscopic remission was independently associated with an IRR of 0.45 (95% CI [0.22-0.95], p=0.036) and 0.71 (95% CI [0.44-1.14], p=0.156) for long-term disease-related and all-cause hospitalizations, respectively.</p><p><strong>Conclusions: </strong>Week 12 endoscopic remission is independently associated with reducing 52-week disease-related hospitalizations. However, achieving this stringent endpoint within 12 weeks of therapy may be challenging. Endoscopic response may be a more realistic early endoscopic target in the post-induction timeframe. Additional research is needed to evaluate early achievement of alternative endoscopic endpoints in CD.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142116567","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}
Pub Date : 2024-08-29DOI: 10.1093/ecco-jcc/jjae136
Maria Jose Temido, Sailish Honap, Silvio Danese, Vipul Jairath, Fernando Magro, Francisco Portela, Laurent Peyrin-Biroulet
Although randomized controlled trials (RCTs) are the gold standard for investigating the efficacy and safety of interventions, they present major operational challenges due to their complexity, time-consuming nature, and high costs. To address some of these difficulties, RCTs nested in cohorts (RCTsNC) have been developed to enable patient enrolment and randomization from existing databases. RCTsNC is an emerging trial design, which has been successfully utilized across several medical disciplines but not inflammatory bowel disease (IBD). This narrative review outlines the principles of RCTsNC and discusses the numerous advantages it affords for IBD, including harnessing longer-term longitudinal data for safety and efficacy assessment, and enhanced recruitment and follow up processes. Leveraging pre-existing cohorts and their organizational structures improves patient acceptance and is more economical compared to traditional randomized trials. Observational data for IBD, derived from research (cohort and case-control studies) and non-research sources (electronic health records and registries), provides access to comprehensive records for a large number of IBD patients. It permits researchers to address knowledge gaps in IBD where traditional RCTs have had a limited role, such as specific sub-populations typically excluded from pivotal trials, or assessing the effect of environmental exposures on disease course. This review also details caveats of this study design that include the risk of selection bias and constraints related to comparisons with placebo. In conclusion, RCTsNC offers a promising opportunity IBD research given the challenges of the current IBD RCT landscape.
{"title":"Nested Randomized Controlled Trials in Large Databases: An Opportunity for Inflammatory Bowel Disease?","authors":"Maria Jose Temido, Sailish Honap, Silvio Danese, Vipul Jairath, Fernando Magro, Francisco Portela, Laurent Peyrin-Biroulet","doi":"10.1093/ecco-jcc/jjae136","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae136","url":null,"abstract":"<p><p>Although randomized controlled trials (RCTs) are the gold standard for investigating the efficacy and safety of interventions, they present major operational challenges due to their complexity, time-consuming nature, and high costs. To address some of these difficulties, RCTs nested in cohorts (RCTsNC) have been developed to enable patient enrolment and randomization from existing databases. RCTsNC is an emerging trial design, which has been successfully utilized across several medical disciplines but not inflammatory bowel disease (IBD). This narrative review outlines the principles of RCTsNC and discusses the numerous advantages it affords for IBD, including harnessing longer-term longitudinal data for safety and efficacy assessment, and enhanced recruitment and follow up processes. Leveraging pre-existing cohorts and their organizational structures improves patient acceptance and is more economical compared to traditional randomized trials. Observational data for IBD, derived from research (cohort and case-control studies) and non-research sources (electronic health records and registries), provides access to comprehensive records for a large number of IBD patients. It permits researchers to address knowledge gaps in IBD where traditional RCTs have had a limited role, such as specific sub-populations typically excluded from pivotal trials, or assessing the effect of environmental exposures on disease course. This review also details caveats of this study design that include the risk of selection bias and constraints related to comparisons with placebo. In conclusion, RCTsNC offers a promising opportunity IBD research given the challenges of the current IBD RCT landscape.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142116571","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}
Background: Ulcerative colitis (UC) is one of the most important risk factors for developing colitis-associated cancer (CAC). Persistent DNA damage increases CAC risk and has been observed in patients with UC. We aimed to identify the regulatory role of RAD50, a DNA double-strand breaks (DSBs) sensor, in UC progression to CAC.
Methods: DSBs and RAD50 expression in IBD and CAC cell and mouse models were assessed. Mice with intestinal epithelial RAD50 deletion (RAD50IEC-KO) were used to examine the role of RAD50 in colitis and CAC.
Results: Along with the increased γ-H2AX expression in colitis and CAC models, RAD50 expression reduced in human IBD and CAC as well as in mouse models. Furthermore, RAD50IEC-KO sensitizes mice to dextran sulfate sodium (DSS)-induced acute and chronic experimental colitis. RNA-seq analyses revealed that RAD50 activated the cytokine-cytokine receptor response, which was amplified through the JAK-STAT pathway. RAD50 directly interacts with STAT3 and subsequently inhibits its phosphorylation, which may disrupt the IL-6-JAK1/2-STAT3-IL-6 feed-forward loop. Pharmacological STAT3 inhibition relieves colitis in RAD50IEC-KO mice. Severe DSBs, increased cell proliferation, and extended inflammatory response were identified in RAD50-deficienct cells, which promoted azoxymethane (AOM)-DSS-induced colon tumor development in RAD50IEC-KO mice.
Conclusion: RAD50 exerts anti-IL-6-related inflammatory effects in colitis and suppresses CAC. Increasing RAD50 level in colon tissues may be promising for treating patients with UC and CAC.
{"title":"Deficiency in epithelium RAD50 aggravates UC via IL-6-mediated JAK1/2-STAT3 signaling and promotes development of colitis-associated cancer in mice.","authors":"Jie Zhang, Mengli Yu, Tiantian Zhang, Xin Song, Songmin Ying, Zhe Shen, Chaohui Yu","doi":"10.1093/ecco-jcc/jjae134","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae134","url":null,"abstract":"<p><strong>Background: </strong>Ulcerative colitis (UC) is one of the most important risk factors for developing colitis-associated cancer (CAC). Persistent DNA damage increases CAC risk and has been observed in patients with UC. We aimed to identify the regulatory role of RAD50, a DNA double-strand breaks (DSBs) sensor, in UC progression to CAC.</p><p><strong>Methods: </strong>DSBs and RAD50 expression in IBD and CAC cell and mouse models were assessed. Mice with intestinal epithelial RAD50 deletion (RAD50IEC-KO) were used to examine the role of RAD50 in colitis and CAC.</p><p><strong>Results: </strong>Along with the increased γ-H2AX expression in colitis and CAC models, RAD50 expression reduced in human IBD and CAC as well as in mouse models. Furthermore, RAD50IEC-KO sensitizes mice to dextran sulfate sodium (DSS)-induced acute and chronic experimental colitis. RNA-seq analyses revealed that RAD50 activated the cytokine-cytokine receptor response, which was amplified through the JAK-STAT pathway. RAD50 directly interacts with STAT3 and subsequently inhibits its phosphorylation, which may disrupt the IL-6-JAK1/2-STAT3-IL-6 feed-forward loop. Pharmacological STAT3 inhibition relieves colitis in RAD50IEC-KO mice. Severe DSBs, increased cell proliferation, and extended inflammatory response were identified in RAD50-deficienct cells, which promoted azoxymethane (AOM)-DSS-induced colon tumor development in RAD50IEC-KO mice.</p><p><strong>Conclusion: </strong>RAD50 exerts anti-IL-6-related inflammatory effects in colitis and suppresses CAC. Increasing RAD50 level in colon tissues may be promising for treating patients with UC and CAC.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142116568","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}
Pub Date : 2024-08-29DOI: 10.1093/ecco-jcc/jjae122
David Laharie, Lucine Vuitton, Arnaud Bourreille, Yoram Bouhnik, Jean-Frédéric Colombel, Edouard Louis, Mathurin Fumery, Charlotte Mailhat, Jean-Yves Mary, Laurent Peyrin-Biroulet
The Groupe d'Etude sur les Affections Inflammatoires Digestives (GETAID) was founded in Paris in 1983 by Professor R Modigliani and colleagues. From the beginning, the aim of this international (France, Belgium and Switzerland), multicentre, French-speaking group was to address clinical questions raised by patients or physicians in their daily practice or the inflammatory bowel diseases community, by focusing on clinical research on treatments through randomised controlled trials, prospective cohorts and cross-sectional studies, quantifying the severity of various facets of the disease when necessary for these studies. This approach very innovative has contributed to the advancement of knowledge in inflammatory bowel diseases by publishing more than 120 original articles in peer-reviewed journals throughout the GETAID 40-year history, most of them in top publications in gastroenterology and hepatology journals. In this paper, we will see what GETAID's contribution has been over the last four decades, review reasons for success and forthcoming challenges.
{"title":"The GETAID: 40 years of a family story in IBD.","authors":"David Laharie, Lucine Vuitton, Arnaud Bourreille, Yoram Bouhnik, Jean-Frédéric Colombel, Edouard Louis, Mathurin Fumery, Charlotte Mailhat, Jean-Yves Mary, Laurent Peyrin-Biroulet","doi":"10.1093/ecco-jcc/jjae122","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae122","url":null,"abstract":"<p><p>The Groupe d'Etude sur les Affections Inflammatoires Digestives (GETAID) was founded in Paris in 1983 by Professor R Modigliani and colleagues. From the beginning, the aim of this international (France, Belgium and Switzerland), multicentre, French-speaking group was to address clinical questions raised by patients or physicians in their daily practice or the inflammatory bowel diseases community, by focusing on clinical research on treatments through randomised controlled trials, prospective cohorts and cross-sectional studies, quantifying the severity of various facets of the disease when necessary for these studies. This approach very innovative has contributed to the advancement of knowledge in inflammatory bowel diseases by publishing more than 120 original articles in peer-reviewed journals throughout the GETAID 40-year history, most of them in top publications in gastroenterology and hepatology journals. In this paper, we will see what GETAID's contribution has been over the last four decades, review reasons for success and forthcoming challenges.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142116573","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}
Pub Date : 2024-08-26DOI: 10.1093/ecco-jcc/jjae133
Olga Maria Nardone, Giulio Calabrese, Luisa Bertin, Alexander C Ford, Fabiana Castiglione, Fabiana Zingone, Edoardo Savarino, Brigida Barberio
Background & aim: Patients with inflammatory bowel disease (IBD) may experience symptoms of sexual dysfunction (SD). However, the magnitude of this problem remains uncertain. Therefore, we performed a systematic review and meta-analysis to assess the prevalence of SD in adult patients with IBD.
Methods: MEDLINE EMBASE, EMBASE Classic (from inception to 9th April 2024) were searched to identify observational studies reporting the prevalence of SD in adult patients with IBD based on validated screening instruments. Data were extracted, and pooled prevalence (PP), odds ratios (OR), and 95% confidence intervals (CIs) were calculated.
Results: Of 1017 citations evaluated, 18 articles fulfilled eligibility criteria, containing 2,694 patients with IBD recruited from 13 different countries. The PP of SD in IBD patients was 50.6% (95% CI=40.8%-60.5%; I2=96.3%) with an OR=2.94 (95% CI=1.99-4.35, I2=73.4) compared to healthy controls. When we considered UC or CD separately, the PP of SD was 64.8% (95% CI=45.1%-82.1%; I2=88.8%) in patients with UC, and 58.3% (95% CI=36.0%-79.0%; I2=95.3%) in patients with CD. In the subgroup analysis based on sex, the PP of SD was higher in females with IBD than in males (62.7% vs 34.0%; OR=3.99, 95% CI=2.80-5.68; I2=61.7%,). Furthermore, the PP of SD was higher in patients with active disease than patients with inactive disease (75.1% vs 34.2%; OR=9.65, 95% CI=1.02-91.33, I2=95.5%).
Conclusion: We demonstrated high prevalence of SD in IBD patients, especially in women. Encouraging gastroenterologists to screen for, and treat, these disorders with a holistic approach might improve quality of life of patients with IBD.
{"title":"Prevalence of Sexual Dysfunction In Inflammatory Bowel Disease: Systematic Review and Meta-Analysis.","authors":"Olga Maria Nardone, Giulio Calabrese, Luisa Bertin, Alexander C Ford, Fabiana Castiglione, Fabiana Zingone, Edoardo Savarino, Brigida Barberio","doi":"10.1093/ecco-jcc/jjae133","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae133","url":null,"abstract":"<p><strong>Background & aim: </strong>Patients with inflammatory bowel disease (IBD) may experience symptoms of sexual dysfunction (SD). However, the magnitude of this problem remains uncertain. Therefore, we performed a systematic review and meta-analysis to assess the prevalence of SD in adult patients with IBD.</p><p><strong>Methods: </strong>MEDLINE EMBASE, EMBASE Classic (from inception to 9th April 2024) were searched to identify observational studies reporting the prevalence of SD in adult patients with IBD based on validated screening instruments. Data were extracted, and pooled prevalence (PP), odds ratios (OR), and 95% confidence intervals (CIs) were calculated.</p><p><strong>Results: </strong>Of 1017 citations evaluated, 18 articles fulfilled eligibility criteria, containing 2,694 patients with IBD recruited from 13 different countries. The PP of SD in IBD patients was 50.6% (95% CI=40.8%-60.5%; I2=96.3%) with an OR=2.94 (95% CI=1.99-4.35, I2=73.4) compared to healthy controls. When we considered UC or CD separately, the PP of SD was 64.8% (95% CI=45.1%-82.1%; I2=88.8%) in patients with UC, and 58.3% (95% CI=36.0%-79.0%; I2=95.3%) in patients with CD. In the subgroup analysis based on sex, the PP of SD was higher in females with IBD than in males (62.7% vs 34.0%; OR=3.99, 95% CI=2.80-5.68; I2=61.7%,). Furthermore, the PP of SD was higher in patients with active disease than patients with inactive disease (75.1% vs 34.2%; OR=9.65, 95% CI=1.02-91.33, I2=95.5%).</p><p><strong>Conclusion: </strong>We demonstrated high prevalence of SD in IBD patients, especially in women. Encouraging gastroenterologists to screen for, and treat, these disorders with a holistic approach might improve quality of life of patients with IBD.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142057670","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}