Pub Date : 2024-05-04DOI: 10.1093/ecco-jcc/jjae061
David A Muñiz Pedrogo, Cynthia L Sears, Joanna M P Melia
The risk of colorectal cancer (CRC) is increased in patients with inflammatory bowel disease (IBD), particularly in extensive ulcerative colitis (UC) and Crohn’s colitis. Gut microbiota have been implicated in the pathogenesis of CRC via multiple mechanisms, including the release of reactive oxygen species and genotoxins, and induction of inflammation as well as activation of the immune response. Gut microbiota can enhance their carcinogenic and pro-inflammatory properties by organizing into biofilms, potentially making them more resistant to the host’s immune system and to antibiotics. Colonic biofilms have the capacity to invade colonic tissue and accelerate tumorigenesis in tumor-prone models of mice. In the context of IBD, the prevalence of biofilms has been estimated to be up to 95%. Although the relationship between chronic inflammation and molecular mediators that contribute to IBD-associated CRC is well established, the role of gut microbiota and biofilms in this sequence is not fully understood. Because CRC can still arise in the absence of histologic inflammation, there is a growing interest in identifying chemopreventive agents against IBD-associated CRC. 5-aminosalicylates, commonly used in the treatment of UC, have antimicrobial and anti-carcinogenic properties that might have a role in the chemoprevention of CRC via the inhibition or modulation of carcinogenic gut microbiota and potentially biofilm formation. Whether biologics and other IBD-targeted therapies can decrease the progression towards dysplasia and CRC via mechanisms independent of inflammation is still unknown. Further research is warranted to identify potential new microbial targets of therapy for chemoprevention of dysplasia and CRC in IBD.
{"title":"Colorectal cancer in inflammatory bowel disease: a review of the role of gut microbiota and bacterial biofilms in disease pathogenesis","authors":"David A Muñiz Pedrogo, Cynthia L Sears, Joanna M P Melia","doi":"10.1093/ecco-jcc/jjae061","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae061","url":null,"abstract":"The risk of colorectal cancer (CRC) is increased in patients with inflammatory bowel disease (IBD), particularly in extensive ulcerative colitis (UC) and Crohn’s colitis. Gut microbiota have been implicated in the pathogenesis of CRC via multiple mechanisms, including the release of reactive oxygen species and genotoxins, and induction of inflammation as well as activation of the immune response. Gut microbiota can enhance their carcinogenic and pro-inflammatory properties by organizing into biofilms, potentially making them more resistant to the host’s immune system and to antibiotics. Colonic biofilms have the capacity to invade colonic tissue and accelerate tumorigenesis in tumor-prone models of mice. In the context of IBD, the prevalence of biofilms has been estimated to be up to 95%. Although the relationship between chronic inflammation and molecular mediators that contribute to IBD-associated CRC is well established, the role of gut microbiota and biofilms in this sequence is not fully understood. Because CRC can still arise in the absence of histologic inflammation, there is a growing interest in identifying chemopreventive agents against IBD-associated CRC. 5-aminosalicylates, commonly used in the treatment of UC, have antimicrobial and anti-carcinogenic properties that might have a role in the chemoprevention of CRC via the inhibition or modulation of carcinogenic gut microbiota and potentially biofilm formation. Whether biologics and other IBD-targeted therapies can decrease the progression towards dysplasia and CRC via mechanisms independent of inflammation is still unknown. Further research is warranted to identify potential new microbial targets of therapy for chemoprevention of dysplasia and CRC in IBD.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140832116","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 : 2024-05-02DOI: 10.1093/ecco-jcc/jjae060
Miguel Regueiro, Britta Siegmund, Andres J Yarur, Flavio Steinwurz, Krisztina B Gecse, Martina Goetsch, Abhishek Bhattacharjee, Joseph Wu, Jesse Green, Aoibhinn McDonnell, Catherine Crosby, Krisztina Lazin, Diogo Branquinho, Irene Modesto, Maria T Abreu
Background and Aims Infections are a safety concern in patients with ulcerative colitis (UC). Etrasimod is an oral, once-daily (QD), selective sphingosine 1phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active UC. It leads to selective and reversible lymphocyte sequestration, and partial peripheral lymphocyte count decrease. We report infection events from the phase 3 ELEVATE program. Methods Proportions, incidence rates (IRs; per 100 patient-years) and descriptive analyses of all, serious, severe, herpes zoster, and opportunistic infections are reported in the Pivotal UC cohort (ELEVATE UC 52 and ELEVATE UC 12). Cox regression models evaluated potential baseline risk factors. Results In this analysis (n=787), proportions (IRs) of all infection events were similar for patients receiving etrasimod 2 mg QD (18.8% [41.1]) or placebo (17.7% [49.0]). Serious infections occurred in three (0.6%) and five (1.9%) patients receiving etrasimod and placebo, respectively. Two herpes zoster events were reported in each group (etrasimod: 0.4%; placebo: 0.8%); all localized and non-serious. One opportunistic infection event was reported in each group. No patient with an absolute lymphocyte count (ALC) <0.2 × 109/L reported serious/severe or opportunistic infections; no baseline risk factors were identified for such events. No deaths occurred. Conclusions Patients receiving etrasimod demonstrated no increased risk of infection. The incidence of serious infections and herpes zoster was similar in each group. Among patients receiving etrasimod, no association between ALC <0.5 × 109/L and infection events was observed. Longer-term follow-up will further characterize the etrasimod safety profile.
{"title":"Etrasimod for the Treatment of Ulcerative Colitis: Analysis of Infection Events From the ELEVATE UC Clinical Program","authors":"Miguel Regueiro, Britta Siegmund, Andres J Yarur, Flavio Steinwurz, Krisztina B Gecse, Martina Goetsch, Abhishek Bhattacharjee, Joseph Wu, Jesse Green, Aoibhinn McDonnell, Catherine Crosby, Krisztina Lazin, Diogo Branquinho, Irene Modesto, Maria T Abreu","doi":"10.1093/ecco-jcc/jjae060","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae060","url":null,"abstract":"Background and Aims Infections are a safety concern in patients with ulcerative colitis (UC). Etrasimod is an oral, once-daily (QD), selective sphingosine 1phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active UC. It leads to selective and reversible lymphocyte sequestration, and partial peripheral lymphocyte count decrease. We report infection events from the phase 3 ELEVATE program. Methods Proportions, incidence rates (IRs; per 100 patient-years) and descriptive analyses of all, serious, severe, herpes zoster, and opportunistic infections are reported in the Pivotal UC cohort (ELEVATE UC 52 and ELEVATE UC 12). Cox regression models evaluated potential baseline risk factors. Results In this analysis (n=787), proportions (IRs) of all infection events were similar for patients receiving etrasimod 2 mg QD (18.8% [41.1]) or placebo (17.7% [49.0]). Serious infections occurred in three (0.6%) and five (1.9%) patients receiving etrasimod and placebo, respectively. Two herpes zoster events were reported in each group (etrasimod: 0.4%; placebo: 0.8%); all localized and non-serious. One opportunistic infection event was reported in each group. No patient with an absolute lymphocyte count (ALC) &lt;0.2 × 109/L reported serious/severe or opportunistic infections; no baseline risk factors were identified for such events. No deaths occurred. Conclusions Patients receiving etrasimod demonstrated no increased risk of infection. The incidence of serious infections and herpes zoster was similar in each group. Among patients receiving etrasimod, no association between ALC &lt;0.5 × 109/L and infection events was observed. Longer-term follow-up will further characterize the etrasimod safety profile.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140831720","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 : 2024-05-01DOI: 10.1093/ecco-jcc/jjae064
Helena Tavares de Sousa, Marta Ferreira, Irene Gullo, Ana Mafalda Rocha, Ana Pedro, Dina Leitão, Carla Oliveira, Fátima Carneiro, Fernando Magro
Background and aims Stricturing (B2) and penetrating (B3) ileal Crohn’s disease have been reported to present similar levels of histopathological transmural fibrosis. This study aimed to compare the fibrosis-related transcriptomic profiles of penetrating and stricturing ileal Crohn’s disease. Methods Using Nanostring technology and comparative bioinformatics, we analyzed the expression of 787 fibrosis-related genes in 36 ileal surgical specimens, 12 B2 and 24 B3, the latter including 12 cases with associated stricture(s) (B3s) and 12 without (B3o). Quality control of extracted RNA was performed according to Nanostring parameters and principal component analysis for the distribution analysis. For the selection of the differentially expressed genes a p-adjusted <0.05 and Fold Change ≤-1.5 or ≥ 1.5 was adopted. qPCR and immunohistochemistry analyses were used to validate selected differentially expressed genes. Results We included 34 patients with B2 and B3 phenotypes, balanced for age at diagnosis, age at surgery, gender, Crohn’s disease localization, perianal disease and therapy. Inflammation and fibrosis histopathological scoring were similar in all cases. B2 and B3 groups showed a very good clustering regarding 30 significantly differentially expressed genes, all being remarkably upregulated in B3. More than half of these genes were involved in Crohn’s disease fibrogenesis, while eight differentially expressed genes were so in other organs. The most significantly active biologic processes and pathways in penetrating disease were response to TGFβand matrix organization and degradation, as validated by immunohistochemistry. Conclusions Despite the histopathological similarities in fibrosis between stricturing and penetrating ileal Crohn’s disease, their fibrosis-related transcriptomic profiles are distinct. Penetrating disease exhibits a distinctive transcriptomic landscape related to enhanced matrix remodeling.
{"title":"Fibrosis-related transcriptome unveils a distinctive remodeling matrix pattern in penetrating ileal Crohn's disease","authors":"Helena Tavares de Sousa, Marta Ferreira, Irene Gullo, Ana Mafalda Rocha, Ana Pedro, Dina Leitão, Carla Oliveira, Fátima Carneiro, Fernando Magro","doi":"10.1093/ecco-jcc/jjae064","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae064","url":null,"abstract":"Background and aims Stricturing (B2) and penetrating (B3) ileal Crohn’s disease have been reported to present similar levels of histopathological transmural fibrosis. This study aimed to compare the fibrosis-related transcriptomic profiles of penetrating and stricturing ileal Crohn’s disease. Methods Using Nanostring technology and comparative bioinformatics, we analyzed the expression of 787 fibrosis-related genes in 36 ileal surgical specimens, 12 B2 and 24 B3, the latter including 12 cases with associated stricture(s) (B3s) and 12 without (B3o). Quality control of extracted RNA was performed according to Nanostring parameters and principal component analysis for the distribution analysis. For the selection of the differentially expressed genes a p-adjusted &lt;0.05 and Fold Change ≤-1.5 or ≥ 1.5 was adopted. qPCR and immunohistochemistry analyses were used to validate selected differentially expressed genes. Results We included 34 patients with B2 and B3 phenotypes, balanced for age at diagnosis, age at surgery, gender, Crohn’s disease localization, perianal disease and therapy. Inflammation and fibrosis histopathological scoring were similar in all cases. B2 and B3 groups showed a very good clustering regarding 30 significantly differentially expressed genes, all being remarkably upregulated in B3. More than half of these genes were involved in Crohn’s disease fibrogenesis, while eight differentially expressed genes were so in other organs. The most significantly active biologic processes and pathways in penetrating disease were response to TGFβand matrix organization and degradation, as validated by immunohistochemistry. Conclusions Despite the histopathological similarities in fibrosis between stricturing and penetrating ileal Crohn’s disease, their fibrosis-related transcriptomic profiles are distinct. Penetrating disease exhibits a distinctive transcriptomic landscape related to enhanced matrix remodeling.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140831793","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 : 2024-04-20DOI: 10.1093/ecco-jcc/jjae056
Matthew K Schroeder, Suha Abushamma, Alvin T George, Balakrishna Ravella, John Hickman, Anusha Elumalai, Paul Wise, Maria Zulfiqar, Daniel R Ludwig, Anup Shetty, Satish E Viswanath, Chongliang Luo, Shaji Sebastian, David H Ballard, Parakkal Deepak
Background and Aims Perianal fistulizing Crohn’s disease (PFCD) is an aggressive phenotype of Crohn’s disease defined by frequent relapses and disabling symptoms. A novel consensus classification system was recently outlined by the TOpCLASS consortium that seeks to unify disease severity with patient-centered goals but has not yet been validated. We aimed to apply this to a real-world cohort and identify factors that predict transition between classes over time. Methods We identified all patients with PFCD and at least one baseline and one follow-up pelvic (pMRI). TOpCLASS classification, disease characteristics, and imaging indices were collected retrospectively at time periods corresponding with respective MRIs. Results We identified 100 patients with PFCD of which 96 were assigned TOpCLASS Classes 1 – 2c at baseline. Most patients (78.1%) started in Class 2b, but changes in classification were observed in 52.1% of all patients. Male sex (72.0%, 46.6%, 40.0%, p = 0.03) and prior perianal surgery (52.0% vs 44.6% vs 40.0%, p = 0.02) were more frequently observed in those with improved class. Baseline pMRI indices were not associated with changes in classification, however, greater improvements in mVAI, MODIFI-CD, and PEMPAC were seen among those who improved. Linear mixed effect modeling identified only male sex (-0.31, 95% CI -0.60 to -0.02) with improvement in class. Conclusion The TOpCLASS classification highlights the dynamic nature of PFCD over time, however, our ability to predict transitions between classes remains limited and requires prospective assessment. Improvement in MRI index scores over time was associated with a transition to lower TOpCLASS classification.
{"title":"TOpCLASS Expert Consensus Classification of Perianal Fistulizing Crohn’s Disease: A Real-World Application in a Serial Fistula MRI Cohort","authors":"Matthew K Schroeder, Suha Abushamma, Alvin T George, Balakrishna Ravella, John Hickman, Anusha Elumalai, Paul Wise, Maria Zulfiqar, Daniel R Ludwig, Anup Shetty, Satish E Viswanath, Chongliang Luo, Shaji Sebastian, David H Ballard, Parakkal Deepak","doi":"10.1093/ecco-jcc/jjae056","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae056","url":null,"abstract":"Background and Aims Perianal fistulizing Crohn’s disease (PFCD) is an aggressive phenotype of Crohn’s disease defined by frequent relapses and disabling symptoms. A novel consensus classification system was recently outlined by the TOpCLASS consortium that seeks to unify disease severity with patient-centered goals but has not yet been validated. We aimed to apply this to a real-world cohort and identify factors that predict transition between classes over time. Methods We identified all patients with PFCD and at least one baseline and one follow-up pelvic (pMRI). TOpCLASS classification, disease characteristics, and imaging indices were collected retrospectively at time periods corresponding with respective MRIs. Results We identified 100 patients with PFCD of which 96 were assigned TOpCLASS Classes 1 – 2c at baseline. Most patients (78.1%) started in Class 2b, but changes in classification were observed in 52.1% of all patients. Male sex (72.0%, 46.6%, 40.0%, p = 0.03) and prior perianal surgery (52.0% vs 44.6% vs 40.0%, p = 0.02) were more frequently observed in those with improved class. Baseline pMRI indices were not associated with changes in classification, however, greater improvements in mVAI, MODIFI-CD, and PEMPAC were seen among those who improved. Linear mixed effect modeling identified only male sex (-0.31, 95% CI -0.60 to -0.02) with improvement in class. Conclusion The TOpCLASS classification highlights the dynamic nature of PFCD over time, however, our ability to predict transitions between classes remains limited and requires prospective assessment. Improvement in MRI index scores over time was associated with a transition to lower TOpCLASS classification.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140629821","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 : 2024-04-18DOI: 10.1093/ecco-jcc/jjae052
Helen Burton-Murray, Katheryn Kiser, Jenny Gurung, Katherine Williams, Jennifer J Thomas, Hamed Khalili
Background and Aim Recent studies have shown that up to 53% of patients with inflammatory bowel disease (IBD) screen positive for avoidant/restrictive food intake disorder (ARFID). There is however concern that ARFID screening rates are over-inflated in patients with active disease. We aimed to evaluate the frequency and characteristics of ARFID symptoms using the Nine Item ARFID Screen (NIAS), and to use another eating disorder measure, the Eating Disorder Examination-Questionnaire 8 (EDE-Q8), to rule-out/characterize other eating disorder cognitive and behavioral symptoms. Methods Participants included adults with UC who are enrolled in an in an ongoing cohort study with quiescent UC (SCCAI ≤2 or fecal calprotectin <150 µg/g with corticosteroid-free clinical remission for ≥ 3 months) at baseline. We used self-reported data on demographics, gastrointestinal medications, medical comorbidities, NIAS scores, and other eating disorder symptom scores (8-item Eating Disorder Examination-Questionnaire; EDE-Q-8). Results We included 101 participants who completed the NIAS at their baseline cohort assessment (age 49.9±16.5 years; 55% female). Eleven participants (11%) screened positively for ARFID on at least one NIAS subscale (n=8 male). Up to thirty participants (30%) screened positive for other eating disorder symptoms (EDE-Q-8 Global ≥2.3). Overall score distributions on the EDE-Q-8 showed that participants scored highest on the Weight Concern and Shape Concern subscales. Conclusions Among adults with UC in remission, we found a low rate of ARFID symptoms by the NIAS but a high rate of positive screens for other eating disorder symptoms.
{"title":"Avoidant/restrictive food intake disorder symptoms are not as frequent as other eating disorder symptoms when ulcerative colitis is in remission","authors":"Helen Burton-Murray, Katheryn Kiser, Jenny Gurung, Katherine Williams, Jennifer J Thomas, Hamed Khalili","doi":"10.1093/ecco-jcc/jjae052","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae052","url":null,"abstract":"Background and Aim Recent studies have shown that up to 53% of patients with inflammatory bowel disease (IBD) screen positive for avoidant/restrictive food intake disorder (ARFID). There is however concern that ARFID screening rates are over-inflated in patients with active disease. We aimed to evaluate the frequency and characteristics of ARFID symptoms using the Nine Item ARFID Screen (NIAS), and to use another eating disorder measure, the Eating Disorder Examination-Questionnaire 8 (EDE-Q8), to rule-out/characterize other eating disorder cognitive and behavioral symptoms. Methods Participants included adults with UC who are enrolled in an in an ongoing cohort study with quiescent UC (SCCAI ≤2 or fecal calprotectin &lt;150 µg/g with corticosteroid-free clinical remission for ≥ 3 months) at baseline. We used self-reported data on demographics, gastrointestinal medications, medical comorbidities, NIAS scores, and other eating disorder symptom scores (8-item Eating Disorder Examination-Questionnaire; EDE-Q-8). Results We included 101 participants who completed the NIAS at their baseline cohort assessment (age 49.9±16.5 years; 55% female). Eleven participants (11%) screened positively for ARFID on at least one NIAS subscale (n=8 male). Up to thirty participants (30%) screened positive for other eating disorder symptoms (EDE-Q-8 Global ≥2.3). Overall score distributions on the EDE-Q-8 showed that participants scored highest on the Weight Concern and Shape Concern subscales. Conclusions Among adults with UC in remission, we found a low rate of ARFID symptoms by the NIAS but a high rate of positive screens for other eating disorder symptoms.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140624258","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 : 2024-04-13DOI: 10.1093/ecco-jcc/jjae055
Margaret Brown, Anne Dodd, Fang Shi, Emily Greenwood, Sini Nagpal, Vasantha L Kolachala, Subra Kugathasan, Greg Gibson
Background and Aims Crohn’s disease is characterized by inflammation in the gastrointestinal tract due to a combination of genetic, immune, and environmental factors. Transcriptomic and epigenomic profiling of intestinal tissue of Crohn’s disease patients have revealed valuable insights into pathology, however have not been conducted jointly on less invasive peripheral blood mononuclear cells (PBMCs). Furthermore, the heterogeneous responses to treatments among individuals with Crohn’s disease imply hidden diversity of pathological mechanisms. Methods We employed single nucleus multiomic analysis, integrating both snRNA-seq and snATAC-seq of PBMCs with a variety of open source bioinformatics applications. Results Our findings reveal a diverse range of transcriptional signatures among individuals, highlighting the heterogeneity in PBMC profiles. Nevertheless, striking concordance between three heterogeneous groups was observed across B cells and T cells. Differential gene regulatory mechanisms partially explain these profiles, notably including a signature involving TGFß signaling in two individuals with Crohn’s disease. A mutation mapped to a transcription factor binding site within a differentially accessible peak associated with the expression of this pathway, with implications for a personalized approach to understanding disease pathology. Conclusions This study highlights how multiomic analysis can reveal common regulatory mechanisms that underlie heterogeneity of PBMC profiles, one of which may be specific to inflammatory disease.
背景和目的 克罗恩病的特征是由遗传、免疫和环境因素共同导致的胃肠道炎症。克罗恩病患者肠道组织的转录组学和表观基因组学分析揭示了有价值的病理学观点，但尚未对侵入性较小的外周血单核细胞（PBMCs）进行联合分析。此外，克罗恩病患者对治疗的不同反应意味着病理机制隐藏的多样性。方法 我们采用了单核多组学分析方法，将外周血单核细胞的 snRNA-seq 和 snATAC-seq 与多种开源生物信息学应用结合起来。结果 我们的研究结果揭示了个体间多种多样的转录特征，突显了 PBMC 特征的异质性。然而，在 B 细胞和 T 细胞中观察到了三个异质性群体之间惊人的一致性。不同的基因调控机制部分解释了这些特征，特别是在两个患有克罗恩病的个体中发现了涉及 TGFß 信号转导的特征。一个突变映射到了一个转录因子结合位点上，该位点位于一个与该通路表达相关的可访问差异峰上，这对以个性化方法了解疾病病理具有重要意义。结论 本研究强调了多组学分析如何揭示导致 PBMC 特征异质性的共同调控机制，其中一种机制可能是炎症性疾病所特有的。
{"title":"Concordant B and T Cell Heterogeneity Inferred from the Multiomic Landscape of Peripheral Blood Mononuclear Cells in a Crohn’s Disease Cohort","authors":"Margaret Brown, Anne Dodd, Fang Shi, Emily Greenwood, Sini Nagpal, Vasantha L Kolachala, Subra Kugathasan, Greg Gibson","doi":"10.1093/ecco-jcc/jjae055","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae055","url":null,"abstract":"Background and Aims Crohn’s disease is characterized by inflammation in the gastrointestinal tract due to a combination of genetic, immune, and environmental factors. Transcriptomic and epigenomic profiling of intestinal tissue of Crohn’s disease patients have revealed valuable insights into pathology, however have not been conducted jointly on less invasive peripheral blood mononuclear cells (PBMCs). Furthermore, the heterogeneous responses to treatments among individuals with Crohn’s disease imply hidden diversity of pathological mechanisms. Methods We employed single nucleus multiomic analysis, integrating both snRNA-seq and snATAC-seq of PBMCs with a variety of open source bioinformatics applications. Results Our findings reveal a diverse range of transcriptional signatures among individuals, highlighting the heterogeneity in PBMC profiles. Nevertheless, striking concordance between three heterogeneous groups was observed across B cells and T cells. Differential gene regulatory mechanisms partially explain these profiles, notably including a signature involving TGFß signaling in two individuals with Crohn’s disease. A mutation mapped to a transcription factor binding site within a differentially accessible peak associated with the expression of this pathway, with implications for a personalized approach to understanding disease pathology. Conclusions This study highlights how multiomic analysis can reveal common regulatory mechanisms that underlie heterogeneity of PBMC profiles, one of which may be specific to inflammatory disease.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140596405","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 : 2024-04-12DOI: 10.1093/ecco-jcc/jjae038
Laurent Peyrin-Biroulet, Marla C Dubinsky, Bruce E Sands, Julian Panés, Stefan Schreiber, Walter Reinisch, Brian G Feagan, Silvio Danese, Andres J Yarur, Geert R D’Haens, Martina Goetsch, Karolina Wosik, Michael Keating, Krisztina Lazin, Joseph Wu, Irene Modesto, Aoibhinn McDonnell, Lauren Bartolome, Séverine Vermeire
Background and Aims Pivotal trials in ulcerative colitis have historically excluded patients with isolated proctitis. Etrasimod is an oral, oncedaily, selective sphingosine 1phosphate1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis. This post hoc analysis assessed efficacy and safety of etrasimod 2 mg once daily in patients with isolated proctitis (centrally read) from the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials. Methods Patients, including those with isolated proctitis (<10 cm rectal involvement) who met all other inclusion criteria in ELEVATE UC 52 and ELEVATE UC 12, were randomised 2:1 to receive etrasimod or placebo. Primary, secondary and other identified efficacy endpoints and safety were assessed. Results We analysed data from 64 and 723 patients at Week 12 (both trials pooled), and 36 and 397 patients at Week 52 (ELEVATE UC 52 only) with isolated proctitis and more extensive colitis (≥10 cm rectal involvement), respectively. Patients with isolated proctitis receiving etrasimod demonstrated significant improvements versus placebo, including clinical remission rates at Weeks 12 (42.9% vs 13.6%) and 52 (44.4% vs 11.1%), endoscopic improvement (52.4% vs 22.7%) at Week 12 and bowel urgency numerical rating scale score at Week 12 (all p<0.01). Generally similar trends were observed in patients with more extensive colitis. Safety was consistent across subgroups, with no new findings. Conclusions Etrasimod demonstrated significant improvements versus placebo in patients with isolated proctitis, and those with more extensive disease, in most efficacy endpoints at Week 12 and 52.
{"title":"Efficacy and Safety of Etrasimod in Patients with Moderately to Severely Active Isolated Proctitis: Results From the Phase 3 ELEVATE UC Clinical Programme","authors":"Laurent Peyrin-Biroulet, Marla C Dubinsky, Bruce E Sands, Julian Panés, Stefan Schreiber, Walter Reinisch, Brian G Feagan, Silvio Danese, Andres J Yarur, Geert R D’Haens, Martina Goetsch, Karolina Wosik, Michael Keating, Krisztina Lazin, Joseph Wu, Irene Modesto, Aoibhinn McDonnell, Lauren Bartolome, Séverine Vermeire","doi":"10.1093/ecco-jcc/jjae038","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae038","url":null,"abstract":"Background and Aims Pivotal trials in ulcerative colitis have historically excluded patients with isolated proctitis. Etrasimod is an oral, oncedaily, selective sphingosine 1phosphate1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis. This post hoc analysis assessed efficacy and safety of etrasimod 2 mg once daily in patients with isolated proctitis (centrally read) from the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials. Methods Patients, including those with isolated proctitis (&lt;10 cm rectal involvement) who met all other inclusion criteria in ELEVATE UC 52 and ELEVATE UC 12, were randomised 2:1 to receive etrasimod or placebo. Primary, secondary and other identified efficacy endpoints and safety were assessed. Results We analysed data from 64 and 723 patients at Week 12 (both trials pooled), and 36 and 397 patients at Week 52 (ELEVATE UC 52 only) with isolated proctitis and more extensive colitis (≥10 cm rectal involvement), respectively. Patients with isolated proctitis receiving etrasimod demonstrated significant improvements versus placebo, including clinical remission rates at Weeks 12 (42.9% vs 13.6%) and 52 (44.4% vs 11.1%), endoscopic improvement (52.4% vs 22.7%) at Week 12 and bowel urgency numerical rating scale score at Week 12 (all p&lt;0.01). Generally similar trends were observed in patients with more extensive colitis. Safety was consistent across subgroups, with no new findings. Conclusions Etrasimod demonstrated significant improvements versus placebo in patients with isolated proctitis, and those with more extensive disease, in most efficacy endpoints at Week 12 and 52.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140596528","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 : 2024-04-11DOI: 10.1093/ecco-jcc/jjae050
Pascal Petit, Ariane Leroyer, Sylvain Chamot, Mathurin Fumery, Vincent Bonneterre
Background and Aims Epidemiological data regarding inflammatory bowel disease (IBD) are lacking, in particular for occupationally exposed populations. We investigated whether, among the entire French farm manager (FM) workforce, certain agricultural activities are more strongly associated with IBD than others. Methods Nationwide population-based insurance claims and electronic health records from all FMs that worked at least once over the period 2002-2016 were used (n=1088561, 69% males). The outcome measure was the association between 26 farming activities and the risk of IBD, Crohn’s disease (CD), and ulcerative colitis (UC), measured as hazard ratios (HRs), after adjusting for age, sex, pre-existing medical comorbidities, and farm location. The time to first chronic disease declaration was used as the underlying timescale. A model was generated for every activity and disease, utilizing a reference group comprising all FMs who abstained from the specified activity from 2002 to 2016. Results There were 1752 IBD cases, with 704 CD (40.2%) and 1048 UC (59.8%) cases, respectively. Elevated HRs were observed for fruit arboriculture (HR from 1.17 to 1.52) and dairy farming (HR from 1.22 to 1.46) for all IBD, in crop farming for CD only (HR=1.26 [95CI%: 1.06-1.49]), and in shellfish farming (HR from 2.12 to 2.51) for both CD and IBD. Conclusions Further research regarding specific farming activities and exposures likely to modify the microbiota (e.g., pesticides, pathogens) is required to identify potential occupational risk factors (agricultural exposome) for IBD. Exposure to Mycobacterium avium subspecies paratuberculosis, cryptosporidium, environmental toxins, micro/nanoplastics, and pesticides represents promising research avenues.
{"title":"Farming activities and risk of inflammatory bowel disease: a French nationwide population-based cohort study","authors":"Pascal Petit, Ariane Leroyer, Sylvain Chamot, Mathurin Fumery, Vincent Bonneterre","doi":"10.1093/ecco-jcc/jjae050","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae050","url":null,"abstract":"Background and Aims Epidemiological data regarding inflammatory bowel disease (IBD) are lacking, in particular for occupationally exposed populations. We investigated whether, among the entire French farm manager (FM) workforce, certain agricultural activities are more strongly associated with IBD than others. Methods Nationwide population-based insurance claims and electronic health records from all FMs that worked at least once over the period 2002-2016 were used (n=1088561, 69% males). The outcome measure was the association between 26 farming activities and the risk of IBD, Crohn’s disease (CD), and ulcerative colitis (UC), measured as hazard ratios (HRs), after adjusting for age, sex, pre-existing medical comorbidities, and farm location. The time to first chronic disease declaration was used as the underlying timescale. A model was generated for every activity and disease, utilizing a reference group comprising all FMs who abstained from the specified activity from 2002 to 2016. Results There were 1752 IBD cases, with 704 CD (40.2%) and 1048 UC (59.8%) cases, respectively. Elevated HRs were observed for fruit arboriculture (HR from 1.17 to 1.52) and dairy farming (HR from 1.22 to 1.46) for all IBD, in crop farming for CD only (HR=1.26 [95CI%: 1.06-1.49]), and in shellfish farming (HR from 2.12 to 2.51) for both CD and IBD. Conclusions Further research regarding specific farming activities and exposures likely to modify the microbiota (e.g., pesticides, pathogens) is required to identify potential occupational risk factors (agricultural exposome) for IBD. Exposure to Mycobacterium avium subspecies paratuberculosis, cryptosporidium, environmental toxins, micro/nanoplastics, and pesticides represents promising research avenues.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140596553","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 : 2024-04-09DOI: 10.1093/ecco-jcc/jjae053
Ho Tuan Tiong, Dali Fan, Chris Frampton, Ashwin N Ananthakrishnan, Richard B Gearry
Background and aims Modifiable risk factors in Inflammatory Bowel Disease (IBD), such as physical activity, may be utilised as prevention strategies. However, the findings of previous studies on the association between physical activity and IBD risk have been inconsistent. We aimed to perform a systematic review and meta-analysis to estimate the effect of physical activity on IBD risk. Methods A search was conducted for relevant studies published before April 2023 that assessed the effect of pre-IBD diagnosis levels of physical activity on IBD incidence. Individual summary statistics (relative risks; RR), and confidence intervals (CI) were extracted with forest plots generated. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence. Results 10 observational studies were included. For cohort studies, there were 1,182 Crohn’s disease (CD) and 2,361 ulcerative colitis (UC) patients, with 860,992 participants without IBD. For case-control studies, there were 781 CD to 2,636 controls, and 1,127 UC to 3,752 controls. Compared to individuals with low physical activity levels, the RRs of CD in individuals with high physical activity levels for cohort and case-control studies were 0.78 (95% CI 0.68-0.88, P = 0.0001) and 0.87 (95% CI 0.79-0.95, P = 0.003), respectively. For UC, the RRs were 0.62 (95% CI 0.43-0.88, P = 0.008) and 0.74 (95% CI 0.51-1.07, P = 0.11). Conclusion This meta-analysis suggests that physical activity is inversely associated with the risk of developing IBD, more so in CD than in UC.
{"title":"Physical Activity Is Associated With A Decreased Risk Of Developing Inflammatory Bowel Disease: A Systematic Review And Meta-Analysis","authors":"Ho Tuan Tiong, Dali Fan, Chris Frampton, Ashwin N Ananthakrishnan, Richard B Gearry","doi":"10.1093/ecco-jcc/jjae053","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae053","url":null,"abstract":"Background and aims Modifiable risk factors in Inflammatory Bowel Disease (IBD), such as physical activity, may be utilised as prevention strategies. However, the findings of previous studies on the association between physical activity and IBD risk have been inconsistent. We aimed to perform a systematic review and meta-analysis to estimate the effect of physical activity on IBD risk. Methods A search was conducted for relevant studies published before April 2023 that assessed the effect of pre-IBD diagnosis levels of physical activity on IBD incidence. Individual summary statistics (relative risks; RR), and confidence intervals (CI) were extracted with forest plots generated. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence. Results 10 observational studies were included. For cohort studies, there were 1,182 Crohn’s disease (CD) and 2,361 ulcerative colitis (UC) patients, with 860,992 participants without IBD. For case-control studies, there were 781 CD to 2,636 controls, and 1,127 UC to 3,752 controls. Compared to individuals with low physical activity levels, the RRs of CD in individuals with high physical activity levels for cohort and case-control studies were 0.78 (95% CI 0.68-0.88, P = 0.0001) and 0.87 (95% CI 0.79-0.95, P = 0.003), respectively. For UC, the RRs were 0.62 (95% CI 0.43-0.88, P = 0.008) and 0.74 (95% CI 0.51-1.07, P = 0.11). Conclusion This meta-analysis suggests that physical activity is inversely associated with the risk of developing IBD, more so in CD than in UC.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140596558","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}
Inflammatory bowel disease (IBD) is associated with various immune mediated disorders including spondylarthritis, pyoderma gangrenosum, primary sclerosing cholangitis and uveitis. Chronic kidney disease (CKD) is defined by a reduction in kidney function (eGFR less than 60ml/min/1.73m2) and/ or damage markers that are present for at least three months, regardless of the aetiology. Case reports and cohort studies suggest that IBD is associated with CKD. The extent and magnitude of a potential association is unknown. A comprehensive search was conducted in EMBASE, MEDLINE, Web of Science, the Cochrane database, and SCOPUS. Two separate reviewers were involved in the process of article selection and evaluation. Odds ratios were calculated in those papers with a comparison between an IBD population and a non-IBD control population, the Mantel Haenszel test was employed, utilizing a random effect model. The systematic review was registered in PROSPERO (RD42023381927). Fifty-four articles were included in the systematic review. Of these, eight articles included data on prevalence of CKD in IBD patients (n = 102,230) vs. healthy populations (n = 762,430). Of these, diagnosis of CKD was based on ICD codes in five studies vs. on eGFR in three studies. The overall odds ratio of developing CKD in the IBD population is 1.59 (95%CI 1.31-1.93), without any difference between studies using diagnostic coding (OR 1.70 95%CI 1.33-2.19) vs. diagnosis based on eGFR (OR 1.36 95%CI 1.33-1.64). IBD is associated with a clinically meaningful increased CKD prevalence. We provide recommendations on diagnostic evaluation, as well as suggestions for future research.
{"title":"Chronic kidney disease in inflammatory bowel disease, a systematic review and meta-analysis","authors":"Ward Zadora, Tommaso Innocenti, Bram Verstockt, Bjorn Meijers","doi":"10.1093/ecco-jcc/jjae049","DOIUrl":"https://doi.org/10.1093/ecco-jcc/jjae049","url":null,"abstract":"Inflammatory bowel disease (IBD) is associated with various immune mediated disorders including spondylarthritis, pyoderma gangrenosum, primary sclerosing cholangitis and uveitis. Chronic kidney disease (CKD) is defined by a reduction in kidney function (eGFR less than 60ml/min/1.73m2) and/ or damage markers that are present for at least three months, regardless of the aetiology. Case reports and cohort studies suggest that IBD is associated with CKD. The extent and magnitude of a potential association is unknown. A comprehensive search was conducted in EMBASE, MEDLINE, Web of Science, the Cochrane database, and SCOPUS. Two separate reviewers were involved in the process of article selection and evaluation. Odds ratios were calculated in those papers with a comparison between an IBD population and a non-IBD control population, the Mantel Haenszel test was employed, utilizing a random effect model. The systematic review was registered in PROSPERO (RD42023381927). Fifty-four articles were included in the systematic review. Of these, eight articles included data on prevalence of CKD in IBD patients (n = 102,230) vs. healthy populations (n = 762,430). Of these, diagnosis of CKD was based on ICD codes in five studies vs. on eGFR in three studies. The overall odds ratio of developing CKD in the IBD population is 1.59 (95%CI 1.31-1.93), without any difference between studies using diagnostic coding (OR 1.70 95%CI 1.33-2.19) vs. diagnosis based on eGFR (OR 1.36 95%CI 1.33-1.64). IBD is associated with a clinically meaningful increased CKD prevalence. We provide recommendations on diagnostic evaluation, as well as suggestions for future research.","PeriodicalId":15453,"journal":{"name":"Journal of Crohn's and Colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140596501","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}
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