Pub Date : 2024-08-06DOI: 10.1093/ecco-jcc/jjae025
Anouk Teugels, Ilse van den Eijnden, Bep Keersmaekers, Bram Verstockt, João Sabino, Séverine Vermeire, Livia Guadagnoli, Ilse Van Diest, Marc Ferrante
Background and aims: Disability, an important aspect of disease burden in patients with inflammatory bowel disease [IBD], has been suggested as a valuable clinical endpoint. We aimed to investigate how disease acceptance and perceived control, two psychological predictors of subjective health, are associated with IBD-related disability.
Methods: In this cross-sectional study, adult IBD patients from the University Hospitals Leuven received a survey with questions about clinical and demographic characteristics, disease acceptance and perceived control [Subjective Health Experience model questionnaire], and IBD-related disability [IBD Disk]. Multiple linear regressions assessed predictors of IBD-related disability in the total sample and in the subgroups of patients in clinical remission or with active disease.
Results: In the total sample (N = 1250, 54.2% female, median [interquartile range: IQR] age 51 [39-61] years, 61.3% Crohn's disease, 34.9% active disease), adding the psychological predictors to the model resulted in an increased explained variance in IBD-related disability of 19% compared with a model with only demographic and clinical characteristics [R2adj 38% vs 19%, p <0.001]. The increase in explained variance was higher for patients in clinical remission [ΔR2adj 20%, p <0.001] compared with patients with active disease [ΔR2adj 10%, p <0.001]. Of these predictors, disease acceptance was most strongly associated with disability in the total sample [β = -0.44, p <0.001], as well as in both subgroups [β = -0.47, p <0.001 and β = -0.31, p <0.001 respectively]. Perceived control was not significantly associated with disability when accounting for all other predictors.
Conclusions: Disease acceptance is strongly associated with IBD-related disability, supporting further research into disease acceptance as a treatment target.
{"title":"Disease Acceptance, but not Perceived Control, is Uniquely Associated with Inflammatory Bowel Disease-related Disability.","authors":"Anouk Teugels, Ilse van den Eijnden, Bep Keersmaekers, Bram Verstockt, João Sabino, Séverine Vermeire, Livia Guadagnoli, Ilse Van Diest, Marc Ferrante","doi":"10.1093/ecco-jcc/jjae025","DOIUrl":"10.1093/ecco-jcc/jjae025","url":null,"abstract":"<p><strong>Background and aims: </strong>Disability, an important aspect of disease burden in patients with inflammatory bowel disease [IBD], has been suggested as a valuable clinical endpoint. We aimed to investigate how disease acceptance and perceived control, two psychological predictors of subjective health, are associated with IBD-related disability.</p><p><strong>Methods: </strong>In this cross-sectional study, adult IBD patients from the University Hospitals Leuven received a survey with questions about clinical and demographic characteristics, disease acceptance and perceived control [Subjective Health Experience model questionnaire], and IBD-related disability [IBD Disk]. Multiple linear regressions assessed predictors of IBD-related disability in the total sample and in the subgroups of patients in clinical remission or with active disease.</p><p><strong>Results: </strong>In the total sample (N = 1250, 54.2% female, median [interquartile range: IQR] age 51 [39-61] years, 61.3% Crohn's disease, 34.9% active disease), adding the psychological predictors to the model resulted in an increased explained variance in IBD-related disability of 19% compared with a model with only demographic and clinical characteristics [R2adj 38% vs 19%, p <0.001]. The increase in explained variance was higher for patients in clinical remission [ΔR2adj 20%, p <0.001] compared with patients with active disease [ΔR2adj 10%, p <0.001]. Of these predictors, disease acceptance was most strongly associated with disability in the total sample [β = -0.44, p <0.001], as well as in both subgroups [β = -0.47, p <0.001 and β = -0.31, p <0.001 respectively]. Perceived control was not significantly associated with disability when accounting for all other predictors.</p><p><strong>Conclusions: </strong>Disease acceptance is strongly associated with IBD-related disability, supporting further research into disease acceptance as a treatment target.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140041234","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 : 2024-08-06DOI: 10.1093/ecco-jcc/jjae017
Katharina Foelsch, Penelope Pelczar, Elisabeth Zierz, Stephanie Kondratowicz, Minyue Qi, Christian Mueller, Malik Alawi, Sina Huebener, Till Clauditz, Nicola Gagliani, Samuel Huber, Peter Huebener
Background: High-mobility group box protein 1 [HMGB1] is a ubiquitous nucleoprotein with immune-regulatory properties following cellular secretion or release in sterile and in infectious inflammation. Stool and serum HMGB1 levels correlate with colitis severity and colorectal cancer [CRC] progression, yet recent reports indicate that HMGB1 mainly operates as an intracellular determinant of enterocyte fate during colitis, and investigations into the roles of HMGB1 in CRC are lacking.
Methods: Using mice with conditional HMGB1-knockout in enterocytes [Hmgb1ΔIEC] and myeloid cells [Hmgb1ΔLysM], respectively, we explored functions of HMGB1 in pathogenetically diverse contexts of colitis and colitis-associated CRC.
Results: HMGB1 is overexpressed in human inflammatory bowel disease and gastrointestinal cancers, and HMGB1 protein localises in enterocytes and stromal cells in colitis and CRC specimens from humans and rodents. As previously described, enterocyte HMGB1 deficiency aggravates severe chemical-induced intestinal injury, but not Citrobacter rodentium or T cell transfer colitis in mice. HMGB1-deficient enterocytes and organoids do not exhibit deviant apoptotic or autophagic activity, altered proliferative or migratory capacity, abnormal intestinal permeability, or aberrant DSS-induced organoid inflammation in vitro. Instead, we observed altered in vivo reprogramming of both intestinal epithelia and infiltrating myeloid cells in Hmgb1ΔIEC early during colitis, suggesting HMGB1-mediated paracrine injury signalling. Hmgb1ΔIEC had higher CRC burden than wild types in the Apc+/min model, whereas inflammatory CRC was attenuated in Hmgb1ΔLysM. Cellular and molecular phenotyping of Hmgb1ΔIEC and Hmgb1ΔLysM cancers indicates context-dependent transcriptional modulation of immune signalling and extracellular matrix remodelling via HMGB1.
Conclusion: Enterocytes and myeloid cells context-dependently regulate host responses to severe colitis and maladaptive intestinal wound healing via HMGB1.
{"title":"Intestinal Epithelia and Myeloid Immune Cells Shape Colitis Severity and Colorectal Carcinogenesis via High-mobility Group Box Protein 1.","authors":"Katharina Foelsch, Penelope Pelczar, Elisabeth Zierz, Stephanie Kondratowicz, Minyue Qi, Christian Mueller, Malik Alawi, Sina Huebener, Till Clauditz, Nicola Gagliani, Samuel Huber, Peter Huebener","doi":"10.1093/ecco-jcc/jjae017","DOIUrl":"10.1093/ecco-jcc/jjae017","url":null,"abstract":"<p><strong>Background: </strong>High-mobility group box protein 1 [HMGB1] is a ubiquitous nucleoprotein with immune-regulatory properties following cellular secretion or release in sterile and in infectious inflammation. Stool and serum HMGB1 levels correlate with colitis severity and colorectal cancer [CRC] progression, yet recent reports indicate that HMGB1 mainly operates as an intracellular determinant of enterocyte fate during colitis, and investigations into the roles of HMGB1 in CRC are lacking.</p><p><strong>Methods: </strong>Using mice with conditional HMGB1-knockout in enterocytes [Hmgb1ΔIEC] and myeloid cells [Hmgb1ΔLysM], respectively, we explored functions of HMGB1 in pathogenetically diverse contexts of colitis and colitis-associated CRC.</p><p><strong>Results: </strong>HMGB1 is overexpressed in human inflammatory bowel disease and gastrointestinal cancers, and HMGB1 protein localises in enterocytes and stromal cells in colitis and CRC specimens from humans and rodents. As previously described, enterocyte HMGB1 deficiency aggravates severe chemical-induced intestinal injury, but not Citrobacter rodentium or T cell transfer colitis in mice. HMGB1-deficient enterocytes and organoids do not exhibit deviant apoptotic or autophagic activity, altered proliferative or migratory capacity, abnormal intestinal permeability, or aberrant DSS-induced organoid inflammation in vitro. Instead, we observed altered in vivo reprogramming of both intestinal epithelia and infiltrating myeloid cells in Hmgb1ΔIEC early during colitis, suggesting HMGB1-mediated paracrine injury signalling. Hmgb1ΔIEC had higher CRC burden than wild types in the Apc+/min model, whereas inflammatory CRC was attenuated in Hmgb1ΔLysM. Cellular and molecular phenotyping of Hmgb1ΔIEC and Hmgb1ΔLysM cancers indicates context-dependent transcriptional modulation of immune signalling and extracellular matrix remodelling via HMGB1.</p><p><strong>Conclusion: </strong>Enterocytes and myeloid cells context-dependently regulate host responses to severe colitis and maladaptive intestinal wound healing via HMGB1.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139577332","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 : 2024-08-06DOI: 10.1093/ecco-jcc/jjae021
{"title":"Corrigendum to: Influence of Early Life Factors, including breast milk Composition, on the Microbiome of Infants Born to Mothers with and without Inflammatory Bowel Disease.","authors":"","doi":"10.1093/ecco-jcc/jjae021","DOIUrl":"10.1093/ecco-jcc/jjae021","url":null,"abstract":"","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11302962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140178323","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 : 2024-08-06DOI: 10.1093/ecco-jcc/jjae016
James Kuo, Jasmina Uzunovic, Amanda Jacobson, Michelle Dourado, Sarah Gierke, Manohary Rajendram, Daniela Keilberg, Jordan Mar, Emily Stekol, Joanna Curry, Sofia Verstraete, Jessica Lund, Yuxin Liang, Fiona B Tamburini, Natalie S Omattage, Matthieu Masureel, Steven T Rutherford, David H Hackos, Man-Wah Tan, Allyson L Byrd, Mary E Keir, Elizabeth Skippington, Kelly M Storek
Background and aims: This study aimed to identify microbial drivers of inflammatory bowel disease [IBD], by investigating mucosal-associated bacteria and their detrimental products in IBD patients.
Methods: We directly cultured bacterial communities from mucosal biopsies from paediatric gastrointestinal patients and examined for pathogenicity-associated traits. Upon identifying Clostridium perfringens as toxigenic bacteria present in mucosal biopsies, we isolated strains and further characterized toxicity and prevalence.
Results: Mucosal biopsy microbial composition differed from corresponding stool samples. C. perfringens was present in eight of nine patients' mucosal biopsies, correlating with haemolytic activity, but was not present in all corresponding stool samples. Large IBD datasets showed higher C. perfringens prevalence in stool samples of IBD adults [18.7-27.1%] versus healthy controls [5.1%]. In vitro, C. perfringens supernatants were toxic to cell types beneath the intestinal epithelial barrier, including endothelial cells, neuroblasts, and neutrophils, while the impact on epithelial cells was less pronounced, suggesting C. perfringens may be particularly damaging when barrier integrity is compromised. Further characterization using purified toxins and genetic insertion mutants confirmed perfringolysin O [PFO] toxin was sufficient for toxicity. Toxin RNA signatures were found in the original patient biopsies by PCR, suggesting intestinal production. C. perfringens supernatants also induced activation of neuroblast and dorsal root ganglion neurons in vitro, suggesting C. perfringens in inflamed mucosal tissue may directly contribute to abdominal pain, a frequent IBD symptom.
Conclusions: Gastrointestinal carriage of certain toxigenic C. perfringens may have an important pathogenic impact on IBD patients. These findings support routine monitoring of C. perfringens and PFO toxins and potential treatment in patients.
{"title":"Toxigenic Clostridium perfringens Isolated from At-Risk Paediatric Inflammatory Bowel Disease Patients.","authors":"James Kuo, Jasmina Uzunovic, Amanda Jacobson, Michelle Dourado, Sarah Gierke, Manohary Rajendram, Daniela Keilberg, Jordan Mar, Emily Stekol, Joanna Curry, Sofia Verstraete, Jessica Lund, Yuxin Liang, Fiona B Tamburini, Natalie S Omattage, Matthieu Masureel, Steven T Rutherford, David H Hackos, Man-Wah Tan, Allyson L Byrd, Mary E Keir, Elizabeth Skippington, Kelly M Storek","doi":"10.1093/ecco-jcc/jjae016","DOIUrl":"10.1093/ecco-jcc/jjae016","url":null,"abstract":"<p><strong>Background and aims: </strong>This study aimed to identify microbial drivers of inflammatory bowel disease [IBD], by investigating mucosal-associated bacteria and their detrimental products in IBD patients.</p><p><strong>Methods: </strong>We directly cultured bacterial communities from mucosal biopsies from paediatric gastrointestinal patients and examined for pathogenicity-associated traits. Upon identifying Clostridium perfringens as toxigenic bacteria present in mucosal biopsies, we isolated strains and further characterized toxicity and prevalence.</p><p><strong>Results: </strong>Mucosal biopsy microbial composition differed from corresponding stool samples. C. perfringens was present in eight of nine patients' mucosal biopsies, correlating with haemolytic activity, but was not present in all corresponding stool samples. Large IBD datasets showed higher C. perfringens prevalence in stool samples of IBD adults [18.7-27.1%] versus healthy controls [5.1%]. In vitro, C. perfringens supernatants were toxic to cell types beneath the intestinal epithelial barrier, including endothelial cells, neuroblasts, and neutrophils, while the impact on epithelial cells was less pronounced, suggesting C. perfringens may be particularly damaging when barrier integrity is compromised. Further characterization using purified toxins and genetic insertion mutants confirmed perfringolysin O [PFO] toxin was sufficient for toxicity. Toxin RNA signatures were found in the original patient biopsies by PCR, suggesting intestinal production. C. perfringens supernatants also induced activation of neuroblast and dorsal root ganglion neurons in vitro, suggesting C. perfringens in inflamed mucosal tissue may directly contribute to abdominal pain, a frequent IBD symptom.</p><p><strong>Conclusions: </strong>Gastrointestinal carriage of certain toxigenic C. perfringens may have an important pathogenic impact on IBD patients. These findings support routine monitoring of C. perfringens and PFO toxins and potential treatment in patients.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11302968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139547707","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 : 2024-08-06DOI: 10.1093/ecco-jcc/jjae024
Pim J Koelink, Valentina E Gómez-Mellado, Suzanne Duijst, Manon van Roest, Sander Meisner, Kam S Ho-Mok, Sabrina Frank, Babette S Appelman, Lysbeth Ten Bloemendaal, Georg F Vogel, Stan F J van de Graaf, Piter J Bosma, Ronald P J Oude Elferink, Manon E Wildenberg, Coen C Paulusma
Aims: Patients with mutations in ATP8B1 develop progressive familial intrahepatic cholestasis type 1 [PFIC1], a severe liver disease that requires life-saving liver transplantation. PFIC1 patients also present with gastrointestinal problems, including intestinal inflammation and diarrhoea, which are aggravated after liver transplantation. Here we investigate the intestinal function of ATP8B1 in relation to inflammatory bowel diseases.
Methods: ATP8B1 expression was investigated in intestinal samples of patients with Crohn's disease [CD] or ulcerative colitis [UC] as well as in murine models of intestinal inflammation. Colitis was induced in ATP8B1-deficient mice with dextran sodium sulphate [DSS] and intestinal permeability was investigated. Epithelial barrier function was assessed in ATP8B1 knockdown Caco2-BBE cells. Co-immunoprecipitation experiments were performed in Caco2-BBE cells overexpressing ATP8B1-eGFP. Expression and localization of ATP8B1 and tight junction proteins were investigated in cells and in biopsies of UC and PFIC1 patients.
Results: ATP8B1 expression was decreased in UC and DSS-treated mice, and was associated with a decreased tight junctional pathway transcriptional programme. ATP8B1-deficient mice were extremely sensitive to DSS-induced colitis, as evidenced by increased intestinal barrier leakage. ATP8B1 knockdown cells showed delayed barrier establishment that affected Claudin-4 [CLDN4] levels and localization. CLDN4 immunohistochemistry showed a tight junctional staining in control tissue, whereas in UC and intestinal PFIC1 samples, CLDN4 was not properly localized.
Conclusion: ATP8B1 is important in the establishment of the intestinal barrier. Downregulation of ATP8B1 levels in UC, and subsequent altered localization of tight junctional proteins, including CLDN4, might therefore be an important mechanism in UC pathophysiology.
{"title":"The Phospholipid Flippase ATP8B1 is Involved in the Pathogenesis of Ulcerative Colitis via Establishment of Intestinal Barrier Function.","authors":"Pim J Koelink, Valentina E Gómez-Mellado, Suzanne Duijst, Manon van Roest, Sander Meisner, Kam S Ho-Mok, Sabrina Frank, Babette S Appelman, Lysbeth Ten Bloemendaal, Georg F Vogel, Stan F J van de Graaf, Piter J Bosma, Ronald P J Oude Elferink, Manon E Wildenberg, Coen C Paulusma","doi":"10.1093/ecco-jcc/jjae024","DOIUrl":"10.1093/ecco-jcc/jjae024","url":null,"abstract":"<p><strong>Aims: </strong>Patients with mutations in ATP8B1 develop progressive familial intrahepatic cholestasis type 1 [PFIC1], a severe liver disease that requires life-saving liver transplantation. PFIC1 patients also present with gastrointestinal problems, including intestinal inflammation and diarrhoea, which are aggravated after liver transplantation. Here we investigate the intestinal function of ATP8B1 in relation to inflammatory bowel diseases.</p><p><strong>Methods: </strong>ATP8B1 expression was investigated in intestinal samples of patients with Crohn's disease [CD] or ulcerative colitis [UC] as well as in murine models of intestinal inflammation. Colitis was induced in ATP8B1-deficient mice with dextran sodium sulphate [DSS] and intestinal permeability was investigated. Epithelial barrier function was assessed in ATP8B1 knockdown Caco2-BBE cells. Co-immunoprecipitation experiments were performed in Caco2-BBE cells overexpressing ATP8B1-eGFP. Expression and localization of ATP8B1 and tight junction proteins were investigated in cells and in biopsies of UC and PFIC1 patients.</p><p><strong>Results: </strong>ATP8B1 expression was decreased in UC and DSS-treated mice, and was associated with a decreased tight junctional pathway transcriptional programme. ATP8B1-deficient mice were extremely sensitive to DSS-induced colitis, as evidenced by increased intestinal barrier leakage. ATP8B1 knockdown cells showed delayed barrier establishment that affected Claudin-4 [CLDN4] levels and localization. CLDN4 immunohistochemistry showed a tight junctional staining in control tissue, whereas in UC and intestinal PFIC1 samples, CLDN4 was not properly localized.</p><p><strong>Conclusion: </strong>ATP8B1 is important in the establishment of the intestinal barrier. Downregulation of ATP8B1 levels in UC, and subsequent altered localization of tight junctional proteins, including CLDN4, might therefore be an important mechanism in UC pathophysiology.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11302967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139747890","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 : 2024-08-06DOI: 10.1093/ecco-jcc/jjae022
Nora Vladimirova, Lene Terslev, Mohamed Attauabi, Gorm Madsen, Viktoria Fana, Charlotte Wiell, Uffe Møller Døhn, Flemming Bendtsen, Jakob Seidelin, Johan Burisch, Mikkel Østergaard
Objectives: Musculoskeletal [MSK] manifestations in patients with inflammatory bowel disease [IBD] are common and associated with poorer outcomes. Hence, early detection is important to optimally tailor treatment. We aimed to determine the prevalence and distribution of inflammatory lesions in peripheral joints and entheses in newly diagnosed IBD patients.
Design: Patients with newly diagnosed IBD from a prospective population-based inception cohort were consecutively included. Data on MSK symptoms were collected by questionnaires and by structured rheumatological interview. Peripheral joints and entheses were assessed clinically and by ultrasound [US], using standardized definitions.
Results: Of 110 included patients (mean age: 42 years, 40% male, 70 with ulcerative colitis [UC], 40 with Crohn's disease [CD]), a history of ≥1 peripheral musculoskeletal symptom was reported by 49%. Clinical examination revealed peripheral MSK manifestations in 56 [52.3%] patients; 29 [27.1%] had ≥1 tender and/or swollen joints and 49 [45.8%] ≥1 tender entheses. Small peripheral joints were predominantly affected. US found inflammation in ≥1 joint or enthesis in 52 [49.5 %] patients; 29 [27.4 %] had US synovitis in ≥1 joint, while 36 [34%] had US enthesitis. Fibromyalgia classification criteria were fulfilled in seven [7.9%] patients. There was no difference in clinical or US findings between patients with UC and CD, nor between patients with active and inactive IBD.
Conclusion: Half of the patients with newly diagnosed IBD had inflammation in their peripheral joints and/or entheses, documented by rheumatological clinical and US evaluations. This indicates a need for multidisciplinary collaboration to ensure an optimal therapeutic strategy for suppressing inflammation in all disease domains.
{"title":"Peripheral Joint and Enthesis Involvement in Patients With Newly Diagnosed Inflammatory Bowel Disease: Symptoms, and Clinical and Ultrasound Findings - A Population-Based Cohort Study.","authors":"Nora Vladimirova, Lene Terslev, Mohamed Attauabi, Gorm Madsen, Viktoria Fana, Charlotte Wiell, Uffe Møller Døhn, Flemming Bendtsen, Jakob Seidelin, Johan Burisch, Mikkel Østergaard","doi":"10.1093/ecco-jcc/jjae022","DOIUrl":"10.1093/ecco-jcc/jjae022","url":null,"abstract":"<p><strong>Objectives: </strong>Musculoskeletal [MSK] manifestations in patients with inflammatory bowel disease [IBD] are common and associated with poorer outcomes. Hence, early detection is important to optimally tailor treatment. We aimed to determine the prevalence and distribution of inflammatory lesions in peripheral joints and entheses in newly diagnosed IBD patients.</p><p><strong>Design: </strong>Patients with newly diagnosed IBD from a prospective population-based inception cohort were consecutively included. Data on MSK symptoms were collected by questionnaires and by structured rheumatological interview. Peripheral joints and entheses were assessed clinically and by ultrasound [US], using standardized definitions.</p><p><strong>Results: </strong>Of 110 included patients (mean age: 42 years, 40% male, 70 with ulcerative colitis [UC], 40 with Crohn's disease [CD]), a history of ≥1 peripheral musculoskeletal symptom was reported by 49%. Clinical examination revealed peripheral MSK manifestations in 56 [52.3%] patients; 29 [27.1%] had ≥1 tender and/or swollen joints and 49 [45.8%] ≥1 tender entheses. Small peripheral joints were predominantly affected. US found inflammation in ≥1 joint or enthesis in 52 [49.5 %] patients; 29 [27.4 %] had US synovitis in ≥1 joint, while 36 [34%] had US enthesitis. Fibromyalgia classification criteria were fulfilled in seven [7.9%] patients. There was no difference in clinical or US findings between patients with UC and CD, nor between patients with active and inactive IBD.</p><p><strong>Conclusion: </strong>Half of the patients with newly diagnosed IBD had inflammation in their peripheral joints and/or entheses, documented by rheumatological clinical and US evaluations. This indicates a need for multidisciplinary collaboration to ensure an optimal therapeutic strategy for suppressing inflammation in all disease domains.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139747889","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 : 2024-08-06DOI: 10.1093/ecco-jcc/jjae014
Fernando Magro, Samuel Fernandes, Marta Patita, Bruno Arroja, Paula Lago, Isadora Rosa, Helena Tavares de Sousa, Paula Ministro, Irina Mocanu, Ana Vieira, Joana Castela, Joana Moleiro, Joana Roseira, Eugénia Cancela, Paula Sousa, Francisco Portela, Luís Correia, Paula Moreira, Sandra Dias, Joana Afonso, Silvio Danese, Laurent Peyrin-Biroulet, Katarina M Vucicevic, Mafalda Santiago
Background and aims: Effective management of inflammatory bowel disease (IBD) relies on a comprehensive understanding of infliximab (IFX) pharmacokinetics (PK). This study's primary goal was to develop a robust PK model, identifying key covariates influencing IFX clearance (CL), while concurrently evaluating the risk of disease progression during the maintenance phase of IBD treatment.
Methods: The multicenter, prospective, real-world DIRECT study was conducted in several care centers, which included 369 IBD patients in the maintenance phase of IFX therapy. A two-compartment population PK model was used to determine IFX CL and covariates. Logistic and Cox regressions were applied to elucidate the associations between disease progression and covariates embedded in the PK model.
Results: The PK model included the contributions of weight, albumin, antidrug antibody (ADA), and fecal calprotectin (FC). On average, higher ADA, FC concentration and weight, and lower albumin concentration resulted in higher IFX CL. In the multivariate regression analyses, FC levels influenced the odds of disease progression in the majority of its definitions, when adjusted for several confounding factors. Additionally, alongside FC, both IFX and CL demonstrated a significant impact on the temporal aspect of disease progression.
Conclusion: In this 2-year real-world study, readily available clinical covariates, notably FC, significantly impacted IFX availability in IBD patients. We demonstrated that subclinical active inflammation, as mirrored by FC or CRP, substantially influenced IFX clearance. Importantly, FC emerged as a pivotal determinant, not only of IFX pharmacokinetics but also of disease progression. These findings underscore the need to integrate FC into forthcoming IFX pharmacokinetic models, amplifying its clinical significance.
{"title":"The Influence of Subclinical Active Inflammation on IFX Pharmacokinetic Modeling and Disease Progression Assessment: Findings from a Prospective Real-World Study in Inflammatory Bowel Disease Patients.","authors":"Fernando Magro, Samuel Fernandes, Marta Patita, Bruno Arroja, Paula Lago, Isadora Rosa, Helena Tavares de Sousa, Paula Ministro, Irina Mocanu, Ana Vieira, Joana Castela, Joana Moleiro, Joana Roseira, Eugénia Cancela, Paula Sousa, Francisco Portela, Luís Correia, Paula Moreira, Sandra Dias, Joana Afonso, Silvio Danese, Laurent Peyrin-Biroulet, Katarina M Vucicevic, Mafalda Santiago","doi":"10.1093/ecco-jcc/jjae014","DOIUrl":"10.1093/ecco-jcc/jjae014","url":null,"abstract":"<p><strong>Background and aims: </strong>Effective management of inflammatory bowel disease (IBD) relies on a comprehensive understanding of infliximab (IFX) pharmacokinetics (PK). This study's primary goal was to develop a robust PK model, identifying key covariates influencing IFX clearance (CL), while concurrently evaluating the risk of disease progression during the maintenance phase of IBD treatment.</p><p><strong>Methods: </strong>The multicenter, prospective, real-world DIRECT study was conducted in several care centers, which included 369 IBD patients in the maintenance phase of IFX therapy. A two-compartment population PK model was used to determine IFX CL and covariates. Logistic and Cox regressions were applied to elucidate the associations between disease progression and covariates embedded in the PK model.</p><p><strong>Results: </strong>The PK model included the contributions of weight, albumin, antidrug antibody (ADA), and fecal calprotectin (FC). On average, higher ADA, FC concentration and weight, and lower albumin concentration resulted in higher IFX CL. In the multivariate regression analyses, FC levels influenced the odds of disease progression in the majority of its definitions, when adjusted for several confounding factors. Additionally, alongside FC, both IFX and CL demonstrated a significant impact on the temporal aspect of disease progression.</p><p><strong>Conclusion: </strong>In this 2-year real-world study, readily available clinical covariates, notably FC, significantly impacted IFX availability in IBD patients. We demonstrated that subclinical active inflammation, as mirrored by FC or CRP, substantially influenced IFX clearance. Importantly, FC emerged as a pivotal determinant, not only of IFX pharmacokinetics but also of disease progression. These findings underscore the need to integrate FC into forthcoming IFX pharmacokinetic models, amplifying its clinical significance.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139514394","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 : 2024-08-06DOI: 10.1093/ecco-jcc/jjae018
{"title":"Corrigendum to: P032 Exploring the genetic sequence of action across the natural history of IBD.","authors":"","doi":"10.1093/ecco-jcc/jjae018","DOIUrl":"10.1093/ecco-jcc/jjae018","url":null,"abstract":"","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139747923","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 : 2024-08-06DOI: 10.1093/ecco-jcc/jjae012
Sebastian Schramm, Li-Juan Liu, Marek Saad, Lisa Dietz, Mark Dedden, Tanja M Müller, Imke Atreya, Caroline J Voskens, Raja Atreya, Markus F Neurath, Sebastian Zundler
Background and aims: The G protein coupled receptor GPR15 is expressed on and functionally important for T cells homing to the large intestine. However, the precise mechanisms by which GPR15 controls gut homing have been unclear. Thus, we aimed to elucidate these mechanisms as well as to explore the potential of targeting GPR15 for interfering with T cell recruitment to the colon in inflammatory bowel disease [IBD].
Methods: We used dynamic adhesion and transmigration assays, as well as a humanised in vivo model of intestinal cell trafficking, to study GPR15-dependent effects on gut homing. Moreover, we analysed GPR15 and integrin expression in patients with and without IBD, cross-sectionally and longitudinally.
Results: GPR15 controlled T cell adhesion to MAdCAM-1 and VCAM-1 upstream of α4β7 and α4β1 integrin, respectively. Consistently, high co-expression of these integrins with GPR15 was found on T cells from patients with IBD, and GPR15 also promoted T cell recruitment to the colon in humanised mice. Anti-GPR15 antibodies effectively blocked T cell gut homing in vitro and in vivo. In vitro data, as well as observations in a cohort of patients treated with vedolizumab, suggest that this might be more effective than inhibiting α4β7.
Conclusions: GPR15 seems to have a broad, but organ-selective, impact on T cell trafficking and is therefore a promising target for future therapy of IBD. Further studies are needed.
背景和目的:G 蛋白偶联受体 GPR15 在大肠表达,对 T 细胞归巢具有重要功能。然而,GPR15 控制肠道归巢的确切机制尚不清楚。因此,我们旨在阐明这些机制,并探索靶向 GPR15 干扰 T 细胞招募至 IBD 结肠的可能性:我们使用动态粘附和转运试验以及人源化体内肠道细胞迁移模型来研究 GPR15 对肠道归巢的依赖性影响。此外,我们还横向和纵向分析了IBD患者和非IBD患者体内GPR15和整合素的表达情况:结果:GPR15分别控制T细胞粘附到α4β7整合素和α4β1整合素上游的MAdCAM-1和VCAM-1上。一致的是,这些整合素与 GPR15 在 IBD 患者的 T 细胞中高度共表达,而且 GPR15 还能促进人源化小鼠的 T 细胞招募到结肠。抗 GPR15 抗体能有效阻止 T 细胞在体外和体内的肠道归巢。体外数据以及对使用维多珠单抗治疗的一组患者的观察表明,这可能比抑制α4β7更有效:结论:GPR15似乎对T细胞的迁移具有广泛但有器官选择性的影响,因此是未来治疗IBD的一个有希望的靶点。还需要进一步研究。
{"title":"Blocking GPR15 Counteracts Integrin-dependent T Cell Gut Homing in Vivo.","authors":"Sebastian Schramm, Li-Juan Liu, Marek Saad, Lisa Dietz, Mark Dedden, Tanja M Müller, Imke Atreya, Caroline J Voskens, Raja Atreya, Markus F Neurath, Sebastian Zundler","doi":"10.1093/ecco-jcc/jjae012","DOIUrl":"10.1093/ecco-jcc/jjae012","url":null,"abstract":"<p><strong>Background and aims: </strong>The G protein coupled receptor GPR15 is expressed on and functionally important for T cells homing to the large intestine. However, the precise mechanisms by which GPR15 controls gut homing have been unclear. Thus, we aimed to elucidate these mechanisms as well as to explore the potential of targeting GPR15 for interfering with T cell recruitment to the colon in inflammatory bowel disease [IBD].</p><p><strong>Methods: </strong>We used dynamic adhesion and transmigration assays, as well as a humanised in vivo model of intestinal cell trafficking, to study GPR15-dependent effects on gut homing. Moreover, we analysed GPR15 and integrin expression in patients with and without IBD, cross-sectionally and longitudinally.</p><p><strong>Results: </strong>GPR15 controlled T cell adhesion to MAdCAM-1 and VCAM-1 upstream of α4β7 and α4β1 integrin, respectively. Consistently, high co-expression of these integrins with GPR15 was found on T cells from patients with IBD, and GPR15 also promoted T cell recruitment to the colon in humanised mice. Anti-GPR15 antibodies effectively blocked T cell gut homing in vitro and in vivo. In vitro data, as well as observations in a cohort of patients treated with vedolizumab, suggest that this might be more effective than inhibiting α4β7.</p><p><strong>Conclusions: </strong>GPR15 seems to have a broad, but organ-selective, impact on T cell trafficking and is therefore a promising target for future therapy of IBD. Further studies are needed.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139503243","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 : 2024-08-06DOI: 10.1093/ecco-jcc/jjae023
Ralley Prentice, Emma Flanagan, Emily Wright, Lani Prideaux, William Connell, Miles Sparrow, Peter De Cruz, Mark Lust, Winita Hardikar, Rimma Goldberg, Sara Vogrin, Kirsten Palmer, Alyson Ross, Megan Burns, Tessa Greeve, Sally Bell
Background and aims: The risk of intrahepatic cholestasis of pregnancy [ICP] is increased in thiopurine-exposed pregnancies. Thiopurine 'shunting', with a 6-methylmercaptopurine [MMP] to 6-thioguanine [TGN] ratio of >11, progresses over pregnancy, and may promote ICP development. We aimed to explore the association between thiopurine exposure and ICP, including the hypothesised impact of thiopurine shunting, and identify risk minimisation strategies.
Methods: This prospective multicentre cohort study compared thiopurine and biologic monotherapy-exposed pregnant participants. Disease activity and obstetric outcome data, thiopurine metabolites, bile acids, and transaminases were obtained before conception, in each trimester, at delivery, and postpartum. Thiopurine dose management was at the discretion of the treating physician.
Results: Included were 131 thiopurine and 147 biologic monotherapy-exposed pregnancies. MMP/TGN ratio increased from preconception to third trimester [p <0.01], with approximately 25% of participants shunting in pregnancy. Second trimester split dosing led to a decrease in the median MMP/TGN ratio from 18 (interquartile range [IQR] 6-57) to 3 [IQR 2-3.5] at delivery [p = 0.04]. The risk of ICP was increased in thiopurine-exposed pregnancies (6.7% [7/105] vs 0% [0/112], p <0.001), with all ICP cases occurring in the setting of antenatal thiopurine shunting. Thiopurine dose increases (risk ratio [RR] 8.10, 95% confidence interval [CI] 1.88-34.85, p = 0.005) and shunting in third trimester [6.20, 1.21-30.73, p = 0.028] and at delivery [14.18, 1.62-123.9, p = 0.016] were associated with an increased risk of ICP.
Conclusions: Thiopurine exposure is associated with an increased risk of ICP, particularly following dose increases antenatally and with shunting in late pregnancy. The latter may be effectively managed with split dosing, although further studies are warranted.
{"title":"Thiopurine Metabolite Shunting in Late Pregnancy Increases the Risk of Intrahepatic Cholestasis of Pregnancy in Women With Inflammatory Bowel Disease, and Can be Managed With Split Dosing.","authors":"Ralley Prentice, Emma Flanagan, Emily Wright, Lani Prideaux, William Connell, Miles Sparrow, Peter De Cruz, Mark Lust, Winita Hardikar, Rimma Goldberg, Sara Vogrin, Kirsten Palmer, Alyson Ross, Megan Burns, Tessa Greeve, Sally Bell","doi":"10.1093/ecco-jcc/jjae023","DOIUrl":"10.1093/ecco-jcc/jjae023","url":null,"abstract":"<p><strong>Background and aims: </strong>The risk of intrahepatic cholestasis of pregnancy [ICP] is increased in thiopurine-exposed pregnancies. Thiopurine 'shunting', with a 6-methylmercaptopurine [MMP] to 6-thioguanine [TGN] ratio of >11, progresses over pregnancy, and may promote ICP development. We aimed to explore the association between thiopurine exposure and ICP, including the hypothesised impact of thiopurine shunting, and identify risk minimisation strategies.</p><p><strong>Methods: </strong>This prospective multicentre cohort study compared thiopurine and biologic monotherapy-exposed pregnant participants. Disease activity and obstetric outcome data, thiopurine metabolites, bile acids, and transaminases were obtained before conception, in each trimester, at delivery, and postpartum. Thiopurine dose management was at the discretion of the treating physician.</p><p><strong>Results: </strong>Included were 131 thiopurine and 147 biologic monotherapy-exposed pregnancies. MMP/TGN ratio increased from preconception to third trimester [p <0.01], with approximately 25% of participants shunting in pregnancy. Second trimester split dosing led to a decrease in the median MMP/TGN ratio from 18 (interquartile range [IQR] 6-57) to 3 [IQR 2-3.5] at delivery [p = 0.04]. The risk of ICP was increased in thiopurine-exposed pregnancies (6.7% [7/105] vs 0% [0/112], p <0.001), with all ICP cases occurring in the setting of antenatal thiopurine shunting. Thiopurine dose increases (risk ratio [RR] 8.10, 95% confidence interval [CI] 1.88-34.85, p = 0.005) and shunting in third trimester [6.20, 1.21-30.73, p = 0.028] and at delivery [14.18, 1.62-123.9, p = 0.016] were associated with an increased risk of ICP.</p><p><strong>Conclusions: </strong>Thiopurine exposure is associated with an increased risk of ICP, particularly following dose increases antenatally and with shunting in late pregnancy. The latter may be effectively managed with split dosing, although further studies are warranted.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139747891","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}