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1. Diet prevents the expansion of segmented filamentous bacteria and ileo-colonic inflammation in a model of Crohn’s disease

Author

Amira Metwaly, Jelena Jovic, Nadine Waldschmitt, Sevana Khaloian, Helena Heimes, Deborah Häcker, Mohamed Ahmed, Nassim Hammoudi, Lionel Le Bourhis, Aida Mayorgas, Kolja Siebert, Marijana Basic, Tobias Schwerd, Matthieu Allez, Julian Panes, Azucena Salas, André Bleich, Sebastian Zeissig, Pamela Schnupf, Fabio Cominelli, and Dirk Haller

Subjects
Crohn’s disease, Segmented filamentous bacteria, Purified diet, Tnf ΔARE mice, Inflammation, Pathobiont, Microbial ecology, QR100-130
Abstract

Abstract Background Crohn’s disease (CD) is associated with changes in the microbiota, and murine models of CD-like ileo-colonic inflammation depend on the presence of microbial triggers. Increased abundance of unknown Clostridiales and the microscopic detection of filamentous structures close to the epithelium of Tnf ΔARE mice, a mouse model of CD-like ileitis pointed towards segmented filamentous bacteria (SFB), a commensal mucosal adherent bacterium involved in ileal inflammation. Results We show that the abundance of SFB strongly correlates with the severity of CD-like ileal inflammation in two mouse models of ileal inflammation, including Tnf ΔARE and SAMP/Yit mice. SFB mono-colonization of germ-free Tnf ΔARE mice confirmed the causal link and resulted in severe ileo-colonic inflammation, characterized by elevated tissue levels of Tnf and Il-17A, neutrophil infiltration and loss of Paneth and goblet cell function. Co-colonization of SFB in human-microbiota associated Tnf ΔARE mice confirmed that SFB presence is indispensable for disease development. Screening of 468 ileal and colonic mucosal biopsies from adult and pediatric IBD patients, using previously published and newly designed human SFB-specific primer sets, showed no presence of SFB in human tissue samples, suggesting a species-specific functionality of the pathobiont. Simulating the human relevant therapeutic effect of exclusive enteral nutrition (EEN), EEN-like purified diet antagonized SFB colonization and prevented disease development in Tnf ΔARE mice, providing functional evidence for the protective mechanism of diet in modulating microbiota-dependent inflammation in IBD. Conclusions We identified a novel pathogenic role of SFB in driving severe CD-like ileo-colonic inflammation characterized by loss of Paneth and goblet cell functions in Tnf ΔARE mice. A purified diet antagonized SFB colonization and prevented disease development in Tnf ΔARE mice in contrast to a fiber-containing chow diet, clearly demonstrating the important role of diet in modulating a novel IBD-relevant pathobiont and supporting a direct link between diet and microbial communities in mediating protective functions. Video Abstract

Published
2023
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2. The risk of COVID-19 in IBD patients is increased by urban living and is not influenced by disease activity or intravenous biologics

Author

Margaux Lelong, Régis Josien, Marianne Coste-Burel, Marie Rimbert, Céline Bressollette-Bodin, Stéphane Nancey, Guillaume Bouguen, Matthieu Allez, Mélanie Serrero, Ludovic Caillo, Cléa Rouillon, Pierre Blanc, David Laharie, Raphaël Olivier, Laurent Peyrin-Biroulet, Nina Dib, Astrid De Maissin, Céline Montuclard, Caroline Trang-Poisson, Fabienne Vavasseur, Géraldine Gallot, Mathilde Berthome, Cécile Braudeau, Justine Chevreuil, Arnaud Bourreille, and Catherine Le Berre

Subjects
Crohn’s disease, ulcerative colitis, infliximab, vedolizumab, SARS-CoV-2, trough levels, Immunologic diseases. Allergy, RC581-607
Abstract

BackgroundPatients with inflammatory bowel disease (IBD) may have a modified immune response to SARS-CoV-2. The objectives were to evaluate the prevalence of COVID-19 in patients treated with infliximab or vedolizumab, to analyze the factors associated with the infection, the impact of treatments and trough levels.MethodsPatients with IBD treated with intravenous biologics in 14 French centers were included between March and June 2020 and followed-up for 6 months. Blood samples were collected for serologies and trough levels. The analysis of factors associated with COVID-19 was conducted in a matched 1:1 case-control sub-study with positive patients.ResultsIn total, 1026 patients were included (74.9% infliximab). Over the follow-up period, 420 patients reported the occurrence of COVID-19 symptoms; 342 had been tested of whom 18 were positive. At the end of follow-up, 38 patients had a positive serology. Considering both nasal tests and serologies together, 46 patients (4.5%) had been infected. The risk of COVID-19 was related neither to the use of treatments (whatever the trough levels) nor to disease activity. Infections were more frequent when using public transport or living in flats in urban areas.ConclusionsThe prevalence rate of COVID-19 in this IBD population treated with intravenous infliximab or vedolizumab was the same as the one in the French population before the start of the vaccination campaign. The risk was increased by urban living and was not influenced by disease activity or biologics. Sanitary barrier measures remain the best way to protect against SARS-CoV-2 in patients with IBD in biological therapy.

Published
2023
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3. Fecal microbiota and bile acids in IBD patients undergoing screening for colorectal cancer

Author

Aonghus Lavelle, Stéphane Nancey, Jean-Marie Reimund, David Laharie, Philippe Marteau, Xavier Treton, Matthieu Allez, Xavier Roblin, Georgia Malamut, Cyriane Oeuvray, Nathalie Rolhion, Xavier Dray, Dominique Rainteau, Antonin Lamaziere, Emilie Gauliard, Julien Kirchgesner, Laurent Beaugerie, Philippe Seksik, Laurent Peyrin-Biroulet, and Harry Sokol

Subjects
Gut microbiota, inflammatory bowel disease, dysplasia, colitis-associated colorectal cancer, crohn’s disease, ulcerative colitis, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Due to the potential role of the gut microbiota and bile acids in the pathogenesis of both inflammatory bowel disease (IBD) and sporadic colorectal cancer, we aimed to determine whether these factors were associated with colorectal cancer in IBD patients. 215 IBD patients and 51 non-IBD control subjects were enrolled from 10 French IBD centers between September 2011 and July 2018. Fecal samples were processed for bacterial 16S rRNA gene sequencing and bile acid profiling. Demographic, clinical, endoscopic, and histological outcomes were recorded. Characteristics of IBD patients included: median age: 41.6 (IQR 22); disease duration 13.2 (13.1); 47% female; 21.9% primary sclerosing cholangitis; 109 patients with Crohn’s disease (CD); 106 patients with ulcerative colitis (UC). The prevalence of cancer was 2.8% (6/215: 1 CD; 5 UC), high-grade dysplasia 3.7% (8/215) and low-grade dysplasia 7.9% (17/215). Lachnospira was decreased in IBD patients with cancer, while Agathobacter was decreased and Escherichia-Shigella increased in UC patients with any neoplasia. Bile acids were not associated with cancer or neoplasia. Unsupervised clustering identified three gut microbiota clusters in IBD patients associated with bile acid composition and clinical features, including a higher risk of neoplasia in UC in two clusters when compared to the third (relative risk (RR) 4.07 (95% CI 1.6–10.3, P

Published
2022
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4. Epigenetic master regulators HDAC1 and HDAC5 control pathobiont Enterobacteria colonization in ileal mucosa of Crohn’s disease patients

Author

Mélissa Chervy, Adeline Sivignon, Flavie Dambrine, Anthony Buisson, Pierre Sauvanet, Catherine Godfraind, Matthieu Allez, Lionel Le Bourhis, The Remind Group, Nicolas Barnich, and Jérémy Denizot

Subjects
Histone deacetylases, Adherent-InvasiveE. coli, Crohn’s disease, histone acetylation, High-fat diet, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Adherent-invasive Escherichia coli (AIEC), which abnormally colonize the ileal mucosa of Crohn’s disease (CD) patients, are known to contribute to the etiopathogenesis of CD. Molecular mechanisms favoring AIEC ileal colonization have not been completely characterized yet. The aim of this study was to investigate whether epigenetic regulators histone deacetylases (HDAC) expression in intestinal epithelial cells of CD patients regulate Enterobacteria and AIEC encroachment to intestinal mucosa. HDAC were inhibited in vitro and in CEABAC10 mice to decipher their involvement in the entry of AIEC within host cells. CD ileal samples from the REMIND cohort were used to study the relationship between HDAC expression level and Enterobacteria/AIEC colonization in patients. Mice were fed a westernized diet and orally challenged with AIEC to determine the impact of diet on HDAC expression. Global level of acetylated histone H3 is higher in patients colonized by AIEC bacteria compared to patients non-colonized by Enterobacteria and HDAC inhibition-mediated H3 hyperacetylation promotes the entry of AIEC bacteria within intestinal epithelial cells. HDAC1 and HDAC5 are central and antagonistic in the regulation of AIEC entry within host cells in vitro, in mouse models and in ileal mucosa of CD patients. In mice fed a western-type diet, AIEC infection decreases HDAC1 expression, inducing H3 hyperacetylation to favor their own colonization. CD patients under a western diet are more prone to be colonized by AIEC bacteria as such a diet affects intestinal homeostasis, enables AIEC access to intestinal mucosa where they then manipulate host-epigenome to their advantage.Abbreviations AIEC Adherent-Invasive Escherichia coli; BSA Bovine serum albumin; CD Crohn’s disease; CEABAC10 Carcinoembryonic antigen bacterial artificial chromosome 10; CEACAM Carcinoembryonic antigen-related cell adhesion molecule; FBS Fetal bovine serum; IBD Inflammatory Bowel Disease; HAT Histone acetyltransferase; HDAC Histone deacetylase; kDa KiloDalton; SAHA Suberoylanilide Hydroxamic Acid; Scr Scramble

Published
2022
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5. Autologous organoid co-culture model reveals T cell-driven epithelial cell death in Crohn’s Disease

Author

Nassim Hammoudi, Sarah Hamoudi, Julie Bonnereau, Hugo Bottois, Kevin Pérez, Madeleine Bezault, Déborah Hassid, Victor Chardiny, Céline Grand, Brice Gergaud, Joëlle Bonnet, Leila Chedouba, My-Linh Tran Minh, Jean-Marc Gornet, Clotilde Baudry, Hélène Corte, Léon Maggiori, Antoine Toubert, Jacqueline McBride, Camille Brochier, Margaret Neighbors, Lionel Le Bourhis, and Matthieu Allez

Subjects
lymphoepithelial interactions, crohn’s disease, inflammatory bowel diseases, organoids, CD103, NKG2D, Immunologic diseases. Allergy, RC581-607
Abstract

Lympho-epithelial interactions between intestinal T resident memory cells (Trm) and the epithelium have been associated with inflammatory bowel disease (IBD) activity. We developed ex vivo autologous organoid-mucosal T cell cocultures to functionally assess lymphoepithelial interactions in Crohn’s Disease (CD) patients compared to controls. We demonstrate the direct epithelial cell death induced by autologous mucosal T cells in CD patients but not in controls. These findings were positively correlated with T cell infiltration of the organoids. This potential was inhibited by limiting lympho-epithelial interactions through CD103 and NKG2D blocking antibodies. These data directly demonstrate for the first time the direct deleterious effect of mucosal T cells on the epithelium of CD patients. Such ex-vivo models are promising techniques to unravel the pathophysiology of these diseases and the potential mode of action of current and future therapies.

Published
2022
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6. A Genetic Association Test Accounting for Skewed X-Inactivation With Application to Biotherapy Immunogenicity in Patients With Autoimmune Diseases

Author

Signe Hässler, Sophie Camilleri-Broët, Matthieu Allez, Florian Deisenhammer, Anna Fogdell-Hahn, Xavier Mariette, Marc Pallardy, and Philippe Broët

Subjects
immunogenicity, anti-drug antibodies, biotherapy, autoimmune disease, X-chromosome, skewed X-Chromosome inactivation, Medicine (General), R5-920
Abstract

Despite being assayed on commercialized DNA chips, the X chromosome is commonly excluded from genome-wide association studies (GWAS). One of the reasons is the complexity to analyze the data taking into account the X-chromosome inactivation (XCI) process in women and in particular the XCI process with a potentially skewed pattern. This is the case when investigating the role of X-linked genetic variants in the occurrence of anti-drug antibodies (ADAs) in patients with autoimmune diseases treated by biotherapies. In this context, we propose a novel test statistic for selecting loci of interest harbored by the X chromosome that are associated with time-to-event data taking into account skewed X-inactivation (XCI-S). The proposed statistic relies on a semi-parametric additive hazard model and is straightforward to implement. Results from the simulation study show that the test provides higher power gains than the score tests from the Cox model (under XCI process or its escape) and the Xu et al.'s XCI-S likelihood ratio test. We applied the test to the data from the real-world observational multicohort study set-up by the IMI-funded ABIRISK consortium for identifying X chromosome susceptibility loci for drug immunogenicity in patients with autoimmune diseases treated by biotherapies. The test allowed us to select two single nucleotide polymorphisms (SNPs) with high linkage disequilibrium (rs5991366 and rs5991394) located in the cytoband Xp22.2 that would have been overlooked by the Cox score tests and the Xu et al.'s XCI-S likelihood ratio test. Both SNPs showed a similar protective effect for drug immunogenicity without any occurrence of ADA positivity for the homozygous females and hemizygous males for the alternative allele. To our knowledge, this is the first study to investigate the association between X chromosome loci and the occurrence of anti-drug antibodies. We think that more X-Chromosome GWAS should be performed and that the test is well-suited for identifying X-Chromosome SNPs, while taking into account all patterns of the skewed X-Chromosome inactivation process.

Published
2022
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7. Integrated microbiota and metabolite profiles link Crohn’s disease to sulfur metabolism

Author

Amira Metwaly, Andreas Dunkel, Nadine Waldschmitt, Abilash Chakravarthy Durai Raj, Ilias Lagkouvardos, Ana Maria Corraliza, Aida Mayorgas, Margarita Martinez-Medina, Sinah Reiter, Michael Schloter, Thomas Hofmann, Matthieu Allez, Julian Panes, Azucena Salas, and Dirk Haller

Subjects
Science
Abstract

Gut microbial and metabolite alterations are linked to inflammatory bowel diseases pathogenesis. Here the authors identify functional microbiota signatures that correlate with disease activity by comparing patients with Crohn’s disease undergoing autologous hematopoietic stem cell transplantation who either did not respond to therapy, experienced relapse after remission or maintained remission, and show that these microbial signatures recapitulate disease activity when transferred to mice.

Published
2020
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8. Assessing the effect of genetic markers on drug immunogenicity from a mechanistic model-based approach

Author

Julianne Duhazé, Miguel Caubet, Signe Hässler, Delphine Bachelet, Matthieu Allez, Florian Deisenhammer, Anna Fogdell-Hahn, Aude Gleizes, Salima Hacein-Bey-Abina, Xavier Mariette, Marc Pallardy, Philippe Broët, and on behalf of the ABIRISK Consortium

Subjects
Genetic, Drug immunogenicity, Semi-continuous data, Two-part improper survival model, Semi-parametric, Medicine (General), R5-920
Abstract

Abstract Background With the growth in use of biotherapic drugs in various medical fields, the occurrence of anti-drug antibodies represents nowadays a serious issue. This immune response against a drug can be due either to pre-existing antibodies or to the novel production of antibodies from B-cell clones by a fraction of the exposed subjects. Identifying genetic markers associated with the immunogenicity of biotherapeutic drugs may provide new opportunities for risk stratification before the introduction of the drug. However, real-world investigations should take into account that the population under study is a mixture of pre-immune, immune-reactive and immune-tolerant subjects. Method In this work, we propose a novel test for assessing the effect of genetic markers on drug immunogenicity taking into account that the population under study is a mixed one. This test statistic is derived from a novel two-part semiparametric improper survival model which relies on immunological mechanistic considerations. Results Simulation results show the good behavior of the proposed statistic as compared to a two-part logrank test. In a study on drug immunogenicity, our results highlighted findings that would have been discarded when considering classical tests. Conclusion We propose a novel test that can be used for analyzing drug immunogenicity and is easy to implement with standard softwares. This test is also applicable for situations where one wants to test the equality of improper survival distributions of semi-continuous outcomes between two or more independent groups.

Published
2020
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9. Cocultures of human colorectal tumor spheroids with immune cells reveal the therapeutic potential of MICA/B and NKG2A targeting for cancer treatment

Author

Tristan Courau, Julie Bonnereau, Justine Chicoteau, Hugo Bottois, Romain Remark, Laura Assante Miranda, Antoine Toubert, Mathieu Blery, Thomas Aparicio, Matthieu Allez, and Lionel Le Bourhis

Subjects
Immunotherapy, Colorectal cancer, Spheroids, NKG2A, MICA/B, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Immunotherapies still fail to benefit colorectal cancer (CRC) patients. Relevant functional assays aimed at studying these failures and the efficacy of cancer immunotherapy in human are scarce. 3D tumor cultures, called tumor organoids or spheroids, represent interesting models to study cancer treatments and could help to challenge these issues. Methods We analyzed heterotypic cocultures of human colon tumor-derived spheroids with immune cells to assess the infiltration, activation and function of T and NK cells toward human colorectal tumors in vitro. Results We showed that allogeneic T and NK cells rapidly infiltrated cell line-derived spheroids, inducing immune-mediated tumor cell apoptosis and spheroid destruction. NKG2D, a key activator of cytotoxic responses, was engaged on infiltrating cells. We thus assessed the therapeutic potential of an antibody targeting the specific ligands of NKG2D, MICA and MICB, in this system. Anti-MICA/B enhanced immune-dependent destruction of tumor spheroid by driving an increased NK cells infiltration and activation. Interestingly, tumor cells reacted to immune infiltration by upregulating HLA-E, ligand of the inhibitory receptor NKG2A expressed by CD8 and NK cells. NKG2A was increased after anti-MICA/B treatment and, accordingly, combination of anti-MICA/B and anti-NKG2A was synergistic. These observations were ultimately confirmed in a clinical relevant model of coculture between CRC patients-derived spheroids and autologous tumor-infiltrating lymphocytes. Conclusions Altogether, we show that tumor spheroids represent a relevant tool to study tumor-lymphocyte interactions on human tissues and revealed the antitumor potential of immunomodulatory antibodies targeting MICA/B and NKG2A.

Published
2019
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10. Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium.

Author

Signe Hässler, Delphine Bachelet, Julianne Duhaze, Natacha Szely, Aude Gleizes, Salima Hacein-Bey Abina, Orhan Aktas, Michael Auer, Jerôme Avouac, Mary Birchler, Yoram Bouhnik, Olivier Brocq, Dorothea Buck-Martin, Guillaume Cadiot, Franck Carbonnel, Yehuda Chowers, Manuel Comabella, Tobias Derfuss, Niek De Vries, Naoimh Donnellan, Abiba Doukani, Michael Guger, Hans-Peter Hartung, Eva Kubala Havrdova, Bernhard Hemmer, Tom Huizinga, Kathleen Ingenhoven, Poul Erik Hyldgaard-Jensen, Elizabeth C Jury, Michael Khalil, Bernd Kieseier, Anna Laurén, Raija Lindberg, Amy Loercher, Enrico Maggi, Jessica Manson, Claudia Mauri, Badreddine Mohand Oumoussa, Xavier Montalban, Maria Nachury, Petra Nytrova, Christophe Richez, Malin Ryner, Finn Sellebjerg, Claudia Sievers, Dan Sikkema, Martin Soubrier, Sophie Tourdot, Caroline Trang, Alessandra Vultaggio, Clemens Warnke, Sebastian Spindeldreher, Pierre Dönnes, Timothy P Hickling, Agnès Hincelin Mery, Matthieu Allez, Florian Deisenhammer, Anna Fogdell-Hahn, Xavier Mariette, Marc Pallardy, Philippe Broët, and ABIRISK consortium

Subjects
Medicine
Abstract

BackgroundBiopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited.Methods and findingsThe European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings.ConclusionIn our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.

Published
2020
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11. KLRG1 and CD103 Expressions Define Distinct Intestinal Tissue-Resident Memory CD8 T Cell Subsets Modulated in Crohn's Disease

Author

Hugo Bottois, Marjolaine Ngollo, Nassim Hammoudi, Tristan Courau, Julie Bonnereau, Victor Chardiny, Céline Grand, Brice Gergaud, Matthieu Allez, and Lionel Le Bourhis

Subjects
T cells, IBD – inflammatory bowel diseases, Crohn's disease, TRM cells, CD103, KLRG1, Immunologic diseases. Allergy, RC581-607
Abstract

Intestinal tissue-resident memory CD8 T cells (Trm) are non-recirculating effector cells ideally positioned to detect and react to microbial infections in the gut mucosa. There is an emerging understanding of Trm cell differentiation and functions, but their implication in inflammatory bowel diseases, such as Crohn's disease (CD), is still unknown. Here, we describe CD8 cells in the human intestine expressing KLRG1 or CD103, two receptors of E-cadherin. While CD103 CD8 T cells are present in high numbers in the mucosa of CD patients and controls, KLRG1 CD8 T cells are increased in inflammatory conditions. Mucosal CD103 CD8 T cells are more responsive to TCR restimulation, but KLRG1 CD8 T cells show increased cytotoxic and proliferative potential. CD103 CD8 T cells originate mostly from KLRG1 negative cells after TCR triggering and TGFβ stimulation. Interestingly, mucosal CD103 CD8 T cells from CD patients display major changes in their transcriptomic landscape compared to controls. They express Th17 related genes including CCL20, IL22, and IL26, which could contribute to the pathogenesis of CD. Overall, these findings suggest that CD103 CD8 T cells in CD induce a tissue-wide alert increasing innate immune responses and recruitment of effector cells such as KLRG1 CD8 T cells.

Published
2020
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12. A Machine Learning Approach for High-Dimensional Time-to-Event Prediction With Application to Immunogenicity of Biotherapies in the ABIRISK Cohort

Author

Julianne Duhazé, Signe Hässler, Delphine Bachelet, Aude Gleizes, Salima Hacein-Bey-Abina, Matthieu Allez, Florian Deisenhammer, Anna Fogdell-Hahn, Xavier Mariette, Marc Pallardy, and Philippe Broët

Subjects
immunogenicity, biotherapy, machine learning, survival random forest, prediction, Immunologic diseases. Allergy, RC581-607
Abstract

Predicting immunogenicity for biotherapies using patient and drug-related factors represents nowadays a challenging issue. With the growing ability to collect massive amount of data, machine learning algorithms can provide efficient predictive tools. From the bio-clinical data collected in the multi-cohort of autoimmune diseases treated with biotherapies from the ABIRISK consortium, we evaluated the predictive power of a custom-built random survival forest for predicting the occurrence of anti-drug antibodies. This procedure takes into account the existence of a population composed of immune-reactive and immune-tolerant subjects as well as the existence of a tiny expected proportion of relevant predictive variables. The practical application to the ABIRISK cohort shows that this approach provides a good predictive accuracy that outperforms the classical survival random forest procedure. Moreover, the individual predicted probabilities allow to separate high and low risk group of patients. To our best knowledge, this is the first study to evaluate the use of machine learning procedures to predict biotherapy immunogenicity based on bioclinical information. It seems that such approach may have potential to provide useful information for the clinical practice of stratifying patients before receiving a biotherapy.

Published
2020
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13. Distinct blood protein profiles associated with the risk of short-term and mid/long-term clinical relapse in patients with Crohn’s disease stopping infliximab: when the remission state hides different types of residual disease activity

Author

Nicolas Pierre, Vân Anh Huynh-Thu, Thomas Marichal, Matthieu Allez, Yoram Bouhnik, David Laharie, Arnaud Bourreille, Jean-Frédéric Colombel, Marie-Alice Meuwis, and Edouard Louis

Subjects
Gastroenterology
Abstract

ObjectiveDespite being in sustained and stable remission, patients with Crohn’s disease (CD) stopping anti-tumour necrosis factor α (TNFα) show a high rate of relapse (~50% within 2 years). Characterising non-invasively the biological profiles of those patients is needed to better guide the decision of anti-TNFα withdrawal.DesignNinety-two immune-related proteins were measured by proximity extension assay in serum of patients with CD (n=102) in sustained steroid-free remission and stopping anti-TNFα (infliximab). As previously shown, a stratification based on time to clinical relapse was used to characterise the distinct biological profiles of relapsers (short-term relapsers: 6 months). Associations between protein levels and time to clinical relapse were determined by univariable Cox model.ResultsThe risk (HR) of mid/long-term clinical relapse was specifically associated with a high serum level of proteins mainly expressed in lymphocytes (LAG3, SH2B3, SIT1; HR: 2.2–4.5; pConclusionWe identified distinct blood protein profiles associated with the risk of short-term and mid/long-term clinical relapse in patients with CD stopping infliximab. These findings constitute an advance for the development of non-invasive biomarkers guiding the decision of anti-TNFα withdrawal.

Published
2022
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14. Autologous T cell responses to primary human colorectal cancer spheroids are enhanced by ectonucleotidase inhibition

Author

Julie Bonnereau, Tristan Courau, Nicolas Asesio, Delphine Salfati, Fatiha Bouhidel, Hélène Corte, Sarah Hamoudi, Nassim Hammoudi, Julie Lavolé, Justine Vivier-Chicoteau, Victor Chardiny, Leon Maggiori, Mathieu Blery, Romain Remark, Cécile Bonnafous, Pierre Cattan, Antoine Toubert, Purnima Bhat, Matthieu Allez, Thomas Aparicio, and Lionel Le Bourhis

Subjects
Gastroenterology
Abstract

ObjectiveT cells are major effectors of the antitumoural immune response. Their activation by tumour-associated antigens can unleash their proliferation and cytotoxic functions, leading to tumour cell elimination. However, tumour-related immunosuppressive mechanisms including the overexpression of immune checkpoints like programmed cell death protein-1 (PD-1), are also engaged, promoting immune escape. Current immunotherapies targeting these pathways have demonstrated weak efficacy in colorectal cancer (CRC). It is thus crucial to find new targets for immunotherapy in this cancer type.DesignIn a prospective cohort of patients with CRC, we investigated the phenotype of tumour-related and non-tumour related intestinal T cells (n=44), particularly the adenosinergic pathway, correlating with clinical phenotype. An autologous coculture model was developed between patient-derived primary tumour spheroids and their autologous tumour-associated lymphocytes. We used this relevant model to assess the effects of CD39 blockade on the antitumour T cell response.ResultsWe show the increased expression of CD39, and its co-expression with PD-1, on tumour infiltrating T cells compared with mucosal lymphocytes. CD39 expression was higher in the right colon and early-stage tumours, thus defining a subset of patients potentially responsive to CD39 blockade. Finally, we demonstrate in autologous conditions that CD39 blockade triggers T cell infiltration and tumour spheroid destruction in cocultures.ConclusionIn CRC, CD39 is strongly expressed on tumour infiltrating lymphocytes and its inhibition represents a promising therapeutic strategy for treating patients.

Published
2022
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15. Endpoints for extraintestinal manifestations in inflammatory bowel disease trials: the EXTRA consensus from the International Organization for the Study of Inflammatory Bowel Diseases

Author

Lucas Guillo, Maria Abreu, Remo Panaccione, William J Sandborn, Valderilio F Azevedo, Lianne Gensler, Bahar Moghaddam, Vineet Ahuja, Sabrina A Ali, Matthieu Allez, Ashwin N Ananthakrishnan, Abhik Bhattacharya, Marla Dubinsky, Anne Griffiths, Ailsa Hart, Burton Korelitz, Paulo G Kotze, Ioannis E Koutroubakis, Peter L Lakatos, James O Lindsay, Fernando Magro, Gerassimos J Mantzaris, Siew C Ng, Colm O'Morain, Julian Panés, Tommaso Parigi, Zhihua Ran, Gerhard Rogler, David T Rubin, David B Sachar, Britta Siegmund, Flavio Steinwurz, Curt Tysk, Stephan Vavricka, Sofia G Verstraete, Antoine P Brezin, Anna K Haemel, Axel Dignass, Bruce E Sands, Silvio Danese, and Laurent Peyrin-Biroulet

Subjects
Clinical Trials as Topic, Eye Diseases, Hepatology, Rheumatic Diseases, Gastroenterology, Humans, Inflammatory Bowel Diseases, Skin Diseases
Abstract

Extraintestinal manifestations occur frequently in patients with inflammatory bowel disease (IBD) and remain a diagnostic and therapeutic challenge. The aim of the Endpoints for Extraintestinal Manifestations in Inflammatory Bowel Disease Trials (EXTRA) initiative was to achieve international expert consensus on how to assess these manifestations in IBD trials. A systematic literature review was done to identify methods to diagnose extraintestinal manifestations in patients with IBD and measure treatment outcomes. A consensus meeting involving a panel of 41 attendees, including gastroenterologists and referral specialists, was held on March 31, 2021, as part of an International Organization for the Study of Inflammatory Bowel Diseases initiative. The panel agreed that a specialist's expertise is needed to confirm the diagnosis of extraintestinal manifestations before the inclusion of a patient in IBD trials, except for axial spondyloarthritis, for which typical symptoms and MRI can be sufficient. Easy-to-measure endpoints were identified to assess the response of extraintestinal manifestations to treatment without needing specialist involvement. For uveitis, peripheral spondyloarthritis, and arthralgia, endpoint measurements need specialist expertise. The timing of endpoint measurements was discussed for individual extraintestinal manifestations. The EXTRA consensus proposes guidelines on how to thoroughly evaluate extraintestinal manifestations within IBD trials, and recommends that these guidelines are implemented in future trials to enable prospective assessment of these manifestations and comparison between studies.

Published
2022
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17. Obesity in adult patients with inflammatory bowel disease: Clinical features and impact on disability. A cross-sectional survey from the GETAID

Author

Rose Al Bacha, Yoram Bouhnik, Melanie Serrero, Jerome Filippi, Xavier Roblin, Anne Bourrier, Guillaume Bouguen, Denis Franchimont, Guillaume Savoye, Anthony Buisson, Edouard Louis, Stephane Nancey, Vered Abitbol, Jean-Marie Reimund, Olivier DeWit, Lucine Vuitton, Nicolas Mathieu, Laurent Peyrin-Biroulet, Cyrielle Gilletta, Matthieu Allez, Stephanie Viennot, Catherine Le Berre, David Laharie, Maria Nachury, Aurelien Amiot, Sara Tadbiri, Charlotte Gagniere, Jenny Tannoury, Benjamin Pariente, Pauline Wils, Carmen Stefanescu, Xavier Treton, Carole Martins, Mathieu Uzzan, Xavier Hébuterne, Nadia Arab, Virginie Cluzeau, Emilie Del Tedesco, Laurent Beaugerie, Philippe Seksik, Cecilia Landmann, Julien Kirchgesner, Harry Sokol, Laurent Siproudhis, Marie DeWitte, Catherine Reenaers, Gilles Boschetti, Claire Gay, Pauline Danion, Bernard Flourié, Georgia Malamut, Benedicte Caron, Olivier DeWitt, Sandie Pestour, Thomas Chateau, Camille Zallot, Jean-Marc Gornet, Clotilde Baudry, Arnaud Bourreille, Caroline Trang-Poisson, Nina Dib, Hedi Brixi, Guillaume Cadiot, Medina Boualit, Claire Painchart, Laurianne Plastaras, Romain Altwegg, Lucile Boivineau, Mathurin Fumery, Ludovic Caillo, Pauline Riviere, Florian Poullenot, Benoit Coffin, Henri Duboc, Stephane Nahon, Noemie Tavernier, Marion Simon, Baya Coulibaly, Morgane Amil, Duveau Nicolas, Sherine Khater, Mehdi Kaassis, Felix Goutorbe, Driffa Moussata, Laurence Picon, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Nord [CHU - APHM], Immunité muqueuse et vaccination, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Service de Gastro-entérologie et Hépatologie [CHU Saint-Etienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pontchaillou [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), CHU Rouen, Normandie Université (NU), CHU Clermont-Ferrand, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Centre Hospitalier Universitaire de Liège (CHU-Liège), Hospices Civils de Lyon (HCL), Hôpital Cochin [AP-HP], Voies de Signalisation du Développement et du Stress Cellulaire dans les Cancers Digestifs et Urologiques, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Service de Gastro-Entérologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Grenoble, Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hopital Saint-Louis [AP-HP] (AP-HP), CHU Amiens-Picardie, Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Groupe d’Étude Thérapeutique des Affections Inflammatoires du Tube Digestif (GETAID), and This study was supported by Abbvie.

Subjects
Crohn's disease, Disability, Ulcerative colitis, Hepatology, Gastroenterology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Fatigue, Inflammatory bowel disease, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Background: In recent years, an increasing prevalence of obesity in inflammatory bowel disease (IBD) has been observed. However, only a few studies have focused on the impact of overweight and obesity on IBD-related disability.Aims: To identify the factors associated with obese and overweight patients with IBD, including IBD-related disability.Patients and methods: In this cross-sectional study, we included 1704 consecutive patients with IBD in 42 centres affiliated with the Groupe d'Etude Therapeutique des Affections Inflammatoires du tube Digestif (GETAID) using a 4-page questionnaire. Factors associated with obesity and overweight were assessed using univariate and multivariate analyses (odds ratios (ORs) are provided with 95% confidence intervals).Results: The prevalence rates of overweight and obesity were 24.1% and 12.2%, respectively. Multivariable analyses were stratified by age, sex, type of IBD, clinical remission and age at diagnosis of IBD. Overweight was significantly associated with male sex (OR = 0.52, 95% CI [0.39-0.68], p < 0.001), age (OR = 1.02, 95% CI [1.01-1.03], p < 0.001) and body image subscore (OR = 1.15, 95% CI [1.10-1.20], p < 0.001) (Table 2). Obesity was significantly associated with age (OR = 1.03, 95% CI [1.02-1.04], p < 0.001), joint pain subscore (OR = 1.08, 95% CI [1.02-1.14], p < 0.001) and body image subscore (OR = 1.25, 95% CI [1.19-1.32], p < 0.001) (Table 3).Conclusion: The increasing prevalence of overweight and obesity in patients with IBD is associated with age and poorer body image. A holistic approach to IBD patient care should be encouraged to improve IBD-related disability and to prevent rheumatological and cardiovascular complications.

Published
2023
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18. A Phase 2b, Randomised, Double-blind, Placebo-controlled, Parallel-arm, Multicenter Study Evaluating the Safety and Efficacy of Tesnatilimab in Patients with Moderately to Severely Active Crohn’s Disease

Author

Matthieu Allez, Bruce E Sands, Brian G Feagan, Geert D’Haens, Gert De Hertogh, Charles W Randall, Bin Zou, Jewel Johanns, Christopher O’Brien, Mark Curran, Rory Rebuck, Mei-Lun Wang, Nina Sabins, Thomas Baker, and Taku Kobayashi

Subjects
Gastroenterology, General Medicine
Abstract

Background and Aims Tesnatilimab, a monoclonal antibody targeting NKG2D, was evaluated in Crohn’s disease [CD] patients who had failed or were intolerant to biologic or conventional therapy. Methods TRIDENT was a phase 2b, two-part, randomised, double-blind, placebo-controlled, parallel-arm, multicenter study. In Part 1 [proof of concept], 145 patients who were biologic intolerant or refractory [Bio-IR] or had not failed biologic therapy [Bio-NF] were randomised in a 1:1 ratio to placebo subcutaneously [SC] or tesnatilimab 400 mg SC. In Part 2 [dose ranging], 243 Bio-IR and Bio-NF patients were randomised in a 1:1:1:1:1 ratio to placebo, tesnatilimab [50 mg, 150 mg, 400 mg], or intravenous infusion of ustekinumab ~6 mg/kg at Week 0 and 90 mg SC at Weeks 8 and 16. The primary endpoint was mean change from baseline in Crohn’s Disease Activity Index [CDAI] at Week 8 [Part 1] and Week 12 [Part 2]. Clinical and endoscopic remission/response were evaluated. Efficacy analyses were also assessed by NKG2D and MICB single nucleotide polymorphism [SNP] status [SNP-positive means positive in at least one of two SNPs]. Safety events were summarised. Results In Part 1, mean change from baseline in CDAI score was significantly greater with tesnatilimab vs placebo at Week 8 [-103.6 vs -60.0; p Conclusions Tesnatilimab was well tolerated. The efficacy of tesnatilimab in patients with CD was significant for the primary endpoint in Part 1; however, no dose-response signal was detected for the primary endpoint in Part 2. Based on these inconsistent findings, tesnatilimab was not considered an effective treatment for patients with CD and no further development is planned. ClinicalTrials.gov Identifier NCT02877134

Published
2023
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20. Prevalence of Yersinia Species in the Ileum of Crohn's Disease Patients and Controls

Author

Guillaume Le Baut, Claire O'Brien, Paul Pavli, Maryline Roy, Philippe Seksik, Xavier Tréton, Stéphane Nancey, Nicolas Barnich, Madeleine Bezault, Claire Auzolle, Dominique Cazals-Hatem, Jérome Viala, Matthieu Allez, The REMIND GROUP, Jean-Pierre Hugot, and Anne Dumay

Subjects
yersinia, Crohn's disease, gut microbiota, ileal mucosa, innate immunity, mucosal immune system, Microbiology, QR1-502
Abstract

Yersinia are common contaminants of food products, but their prevalence in the human gut is poorly documented. Yersinia have been implicated in Crohn's Disease (CD, an inflammatory bowel disease) however their role in CD is controversial. We performed highly sensitive PCR assays of specific sequences for the gyrB gene of Y. aldovae, Y. bercovieri, Y. enterocolitica, Y. intermedia, Y. mollaretii and the inv gene of Y. pseudotuberculosis. We analyzed a total of 470 ileal samples taken from 338 participants (262 CD patients and 76 controls) belonging to three independent cohorts. All patients and controls were phenotyped and genotyped for the main CD susceptibility variants: NOD2, ATG16L1, and IRGM. Yersinia were found in 7.7% of ileal samples (respectively 7.9 and 7.6% in controls and CD patients) corresponding to 10% of participants (respectively 11.8 and 9.5% in controls and CD patients). Y. enterocolitica, Y. pseudotuberculosis and Y. intermedia were the most frequently identified species. The bacteria were more frequent in resected specimens, lymph nodes and Peyer's patches. Yersinia were no more likely to be detected in CD tissues than tissues from inflammatory and non-inflammatory controls. CD patients treated with immunosuppressants were less likely to be Yersinia carriers. In conclusion, this work shows that Yersinia species are frequently found at low levels in the human ileum in health and disease. The role of Yersinia species in this ecosystem should now be explored.

Published
2018
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21. Critical Contribution of NK Group 2 Member D Expressed on Invariant Natural Killer T Cells in Concanavalin A-Induced Liver Hepatitis in Mice

Author

Dina Al Dulaimi, Jihene Klibi, Veronica Olivo Pimentel, Veronique Parietti, Matthieu Allez, Antoine Toubert, and Kamel Benlagha

Subjects
cytokines, FAS-L, RAE-1, NK-receptors, iNKT, Immunologic diseases. Allergy, RC581-607
Abstract

Natural killer group 2D (NKG2D) is a well-characterized activating receptor expressed on many immune cells, including invariant natural killer T (iNKT) cells. These cells were shown to be responsible of liver injury in the model of concanavalin A (Con A)-induced hepatitis, considered to be an experimental model of human autoimmune hepatitis. In this study, we investigated whether NKG2D plays a role in the hepatitis induced by iNKT cell-mediated immune response to Con A. By using killer cell lectin-like receptor subfamily K, member 1 deficient (Klrk1−/−) mice, we found that the absence of NKG2D reduced the hepatic injury upon Con A administration. This was not due to an intrinsic functional defect of NKG2D-deficient iNKT cells as mice missing NKG2D have normal distribution and function of iNKT cells. Furthermore, increased resistance to Con A-induced hepatitis was confirmed using neutralizing anti-NKG2D antibodies. The reduced pathogenic effect of Con A in the absence of NKG2D correlates with a reduction in pathogenic cytokine production and FAS-Ligand (FAS-L) expression by iNKT cells. We also found that Con A administration led to an increase in the retinoic acid early inducible (RAE-1) surface expression on wild-type hepatocytes. Finally, we found that Con A has no direct action on FAS-L expression or cytokine production by iNKT cells and thus propose that NKG2D-L expression on stressed hepatocytes promote cytotoxic activity of iNKT cells via its interaction with NKG2D contributing to hepatic injury. In conclusion, our results highlight NKG2D as an essential receptor required for the activation of iNKT cells in Con A-induced hepatitis and indicate that it represents a potential drug target for prevention of autoimmune hepatitis.

Published
2018
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22. Etrolizumab versus infliximab for the treatment of moderately to severely active ulcerative colitis (GARDENIA): a randomised, double-blind, double-dummy, phase 3 study

Author

Silvio Danese, Jean-Frederic Colombel, Milan Lukas, Javier P Gisbert, Geert D'Haens, Bu'hussain Hayee, Remo Panaccione, Hyun-Soo Kim, Walter Reinisch, Helen Tyrrell, Young S Oh, Swati Tole, Akiko Chai, Kirsten Chamberlain-James, Meina Tao Tang, Stefan Schreiber, Nazimuddin Aboo, Tariq Ahmad, Xavier Aldeguer Mante, Matthieu Allez, Sven Almer, Romain Altwegg, Montserrat Andreu Garcia, Ramesh Arasaradnam, Sandro Ardizzone, Alessandro Armuzzi, Ian Arnott, Guy Aumais, Irit Avni-Biron, Peter Barrow, Ian Beales, Fernando Bermejo San Jose, Abraham Bezuidenhout, Livia Biancone, Michael Blaeker, Stuart Bloom, Bernd Bokemeyer, Fabrizio Bossa, Peter Bossuyt, Guillaume Bouguen, Yoram Bouhnik, Gerd Bouma, Raymond Bourdages, Arnaud Bourreille, Christian Boustiere, Tomas Brabec, Stephan Brand, Carsten Buening, Anthony Buisson, Guillaume Cadiot, Xavier Calvet Calvo, Franck Carbonnel, Daniel Carpio, Jae Hee Cheon, Naoki Chiba, Camelia Chioncel, Nicoleta-Claudia Cimpoeru, Martin Clodi, Gino Roberto Corazza, Rocco Cosintino, Jose Cotter, Thomas Creed, Fraser Cummings, Gian Luigi de' Angelis, Marc De Maeyer, Milind Desai, Etienne Desilets, Pierre Desreumaux, Olivier Dewit, Johanna Dinter, Ecaterina Daniela Dobru, Tomas Douda, Dan Lucian Dumitrascu, Matthias Ebert, Ana Echarri Piudo, Magdy Elkhashab, Chang Soo Eun, Brian Feagan, Roland Fejes, Catarina Fidalgo, Sigal Fishman, Bernard Flourié, Sharyle Fowler, Walter Fries, Csaba Fulop, Mathurin Fumery, Gyula G Kiss, Sonja Gassner, Daniel Gaya, Bastianello Germanà, Liliana Simona Gheorghe, Cyrielle Gilletta de Saint Joseph, Paolo Gionchetti, Adrian-Eugen Goldis, Raquel Gonçalves, Jean-Charles Grimaud, Tibor Gyökeres, Herve Hagege, Andrei Haidar, Heinz Hartmann, Peter Hasselblatt, Buhussain Hayee, Xavier Hebuterne, Per Hellström, Pieter Hindryckx, Helena Hlavova, Frank Hoentjen, Stefanie Howaldt, Ludek Hrdlicka, Kyu Chan Huh, Maria Isabel Iborra Colomino, Florentina Ionita-Radu, Peter Irving, Jørgen Jahnsen, ByungIk Jang, Jeroen Jansen, Seong Woo Jeon, Rodrigo Jover Martinez, Pascal Juillerat, Per Karlén, Arthur Kaser, Radan Keil, Deepak Kejariwal, Dan Keret, Reena Khanna, Dongwoo Kim, Duk Hwan Kim, Hyo-Jong Kim, Joo Sung Kim, Kueongok Kim, Kyung-Jo Kim, Sung Kook Kim, Young-Ho Kim, Jochen Klaus, Anna Kohn, Vladimir Kojecky, Ja Seol Koo, Robert Kozak, Milan Kremer, Tunde Kristof, Frederik Kruger, David Laharie, Adi Lahat-zok, Evgeny Landa, Jonghun Lee, Kang-Moon Lee, Kook Lae Lee, YooJin Lee, Frank Lenze, Wee Chian Lim, Jimmy Limdi, James Lindsay, Pilar Lopez Serrano, Edouard Louis, Stefan Lueth, Giovanni Maconi, Fazia Mana, Steven Mann, John Mansfield, Santino Marchi, Marco Marino, John Marshall, Maria Dolores Martin Arranz, Radu-Bogdan Mateescu, John McLaughlin, Simon McLaughlin, Ehud Melzer, Jessica Mertens, Paul Mitrut, Tamas Molnar, Vinciane Muls, Pushpakaran Munuswamy, Charles Murray, Timna Naftali, Visvakuren Naidoo, Yusuf Nanabhay, Lucian Negreanu, Augustin Nguyen, Thomas Ochsenkuehn, Ambrogio Orlando, Julian Panes Diaz, Maya Paritsky, Dong Il Park, Jihye Park, Luca Pastorelli, Markus Peck-Radosavljevic, Farhad Peerani, Javier Perez Gisbert, Laurent Peyrin-Biroulet, Laurence Picon, Marieke Pierik, Terry Ponich, Francisco Portela, Maartens Jeroen Prins, Istvan Racz, Khan Fareed Rahman, Jean-Marie Reimund, Max Reinshagen, Xavier Roblin, Rodolfo Rocca, Francesca Rogai, Gerhard Rogler, Agnes Salamon, Ennaliza Salazar, Zoltan Sallo, Sunil Samuel, Miquel de los Santos Sans Cuffi, Edoardo Vincenzo Savarino, Vincenzo Savarino, Guillaume Savoye, Andrada Seicean, Christian Selinger, David Martins Serra, Hang Hock Shim, SungJae Shin, Britta Siegmund, Jesse Siffledeen, Wayne Simmonds, Jan Smid, Jose Sollano, Geun Am Song, Alexander Speight, Ioan Sporea, Dirk Staessen, George Stancu, Alan Steel, David Stepek, Victor Stoica, Andreas Sturm, Gyorgy Szekely, Teck Kiang Tan, Carlos Taxonera Samso, John Thomson, Michal Tichy, Gabor Tamas Toth, Zsolt Tulassay, Marcello Vangeli, Marta Varga, Ana Vieira, Stephanie Viennot, Erica Villa, Petr Vitek, Harald Vogelsang, Petr Vyhnalek, Peter Wahab, Jens Walldorf, Byong Duk Ye, Christopher Ziady, Danese S., Colombel J.-F., Lukas M., Gisbert J.P., D'Haens G., Hayee B., Panaccione R., Kim H.-S., Reinisch W., Tyrrell H., Oh Y.S., Tole S., Chai A., Chamberlain-James K., Tang M.T., Schreiber S., Aboo N., Ahmad T., Aldeguer Mante X., Allez M., Almer S., Altwegg R., Andreu Garcia M., Arasaradnam R., Ardizzone S., Armuzzi A., Arnott I., Aumais G., Avni-Biron I., Barrow P., Beales I., Bermejo San Jose F., Bezuidenhout A., Biancone L., Blaeker M., Bloom S., Bokemeyer B., Bossa F., Bossuyt P., Bouguen G., Bouhnik Y., Bouma G., Bourdages R., Bourreille A., Boustiere C., Brabec T., Brand S., Buening C., Buisson A., Cadiot G., Calvet Calvo X., Carbonnel F., Carpio D., Cheon J.H., Chiba N., Chioncel C., Cimpoeru N.-C., Clodi M., Corazza G.R., Cosintino R., Cotter J., Creed T., Cummings F., de' Angelis G.L., De Maeyer M., Desai M., Desilets E., Desreumaux P., Dewit O., Dinter J., Dobru E.D., Douda T., Dumitrascu D.L., Ebert M., Echarri Piudo A., Elkhashab M., Eun C.S., Feagan B., Fejes R., Fidalgo C., Fishman S., Flourie B., Fowler S., Fries W., Fulop C., Fumery M., G Kiss G., Gassner S., Gaya D., Germana B., Gheorghe L.S., Gilletta de Saint Joseph C., Gionchetti P., Goldis A.-E., Goncalves R., Grimaud J.-C., Gyokeres T., Hagege H., Haidar A., Hartmann H., Hasselblatt P., Hebuterne X., Hellstrom P., Hindryckx P., Hlavova H., Hoentjen F., Howaldt S., Hrdlicka L., Huh K.C., Iborra Colomino M.I., Ionita-Radu F., Irving P., Jahnsen J., Jang B., Jansen J., Jeon S.W., Jover Martinez R., Juillerat P., Karlen P., Kaser A., Keil R., Kejariwal D., Keret D., Khanna R., Kim D., Kim D.H., Kim H.-J., Kim J.S., Kim K., Kim K.-J., Kim S.K., Kim Y.-H., Klaus J., Kohn A., Kojecky V., Koo J.S., Kozak R., Kremer M., Kristof T., Kruger F., Laharie D., Lahat-zok A., Landa E., Lee J., Lee K.-M., Lee K.L., Lee Y., Lenze F., Lim W.C., Limdi J., Lindsay J., Lopez Serrano P., Louis E., Lueth S., Maconi G., Mana F., Mann S., Mansfield J., Marchi S., Marino M., Marshall J., Martin Arranz M.D., Mateescu R.-B., McLaughlin J., McLaughlin S., Melzer E., Mertens J., Mitrut P., Molnar T., Muls V., Munuswamy P., Murray C., Naftali T., Naidoo V., Nanabhay Y., Negreanu L., Nguyen A., Ochsenkuehn T., Orlando A., Panes Diaz J., Paritsky M., Park D.I., Park J., Pastorelli L., Peck-Radosavljevic M., Peerani F., Perez Gisbert J., Peyrin-Biroulet L., Picon L., Pierik M., Ponich T., Portela F., Prins M.J., Racz I., Rahman K.F., Reimund J.-M., Reinshagen M., Roblin X., Rocca R., Rogai F., Rogler G., Salamon A., Salazar E., Sallo Z., Samuel S., Sans Cuffi M.D.L.S., Savarino E.V., Savarino V., Savoye G., Seicean A., Selinger C., Serra D.M., Shim H.H., Shin S., Siegmund B., Siffledeen J., Simmonds W., Smid J., Sollano J., Song G.A., Speight A., Sporea I., Staessen D., Stancu G., Steel A., Stepek D., Stoica V., Sturm A., Szekely G., Tan T.K., Taxonera Samso C., Thomson J., Tichy M., Toth G.T., Tulassay Z., Vangeli M., Varga M., Vieira A., Viennot S., Villa E., Vitek P., Vogelsang H., Vyhnalek P., Wahab P., Walldorf J., Ye B.D., and Ziady C.

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Population, Antibodies, Monoclonal, Humanized, Injections, Subcutaneou, Placebo, Severity of Illness Index, Gastroenterology, Young Adult, Double-Blind Method, Internal medicine, Gastrointestinal Agent, Clinical endpoint, medicine, education, Adverse effect, Aged, Aged, 80 and over, education.field_of_study, Hepatology, business.industry, Middle Aged, medicine.disease, Ulcerative colitis, Infliximab, Treatment Outcome, Etrolizumab, Concomitant, Colitis, Ulcerative, Female, business, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5], Human, medicine.drug
Abstract

Item does not contain fulltext BACKGROUND: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment. FINDINGS: Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference -0·9% [95% CI -8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment. INTERPRETATION: To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint. FUNDING: F Hoffmann-La Roche.

Published
2022
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23. Real-world observational cohort study of treatment patterns and safety outcomes of infliximab biosimilar CT-P13 for the treatment of inflammatory bowel disease (CONNECT-IBD)

Author

Bernd Bokemeyer, Tibor Hlavaty, Matthieu Allez, Pamela Selema, Shahrzad Moosavi, Mary Jane Cadatal, Heather Fowler, Markus Mueller, Katherine F Liau, and Javier P Gisbert

Subjects
Pharmacology, Clinical Biochemistry, Drug Discovery
Abstract

The objective of this non-interventional, observational prospective cohort study (CONNECT-IBD) was to assess the use of CT-P13 (Inflectra®) in the treatment of patients with Crohn’s disease (CD) and ulcerative colitis (UC) in the context of treatment with reference infliximab (IFX; Remicade®). Patients (recruited April 2015 to October 2018) at 150 sites across 13 European countries were followed for up to 2 years. Primary outcomes were safety, population characteristics, and drug utilization patterns. Secondary outcomes included clinical assessment of disease activity. Data were analyzed descriptively. Overall, 2543 patients (CD, n = 1676; UC, n = 867) were included. In the CT-P13 cohort (n = 1522), median disease duration was 63 (0–579) months and 30% of patients were IFX naïve; median duration of prior IFX treatment was 5 months. During the observation period, median duration of drug exposure was 14 (0–28) months. 41% of patients reported 912 all-causality treatment-emergent adverse events (TEAEs); 24% experienced treatment-related TEAEs. Most TEAEs were of mild-to-moderate severity. Treatment-emergent serious adverse events were reported by 17% of patients. Safety information for CT-P13 in this large study was consistent with the known safety profile for IFX and did not alter the established benefit-risk profile of CT-P13.

Published
2023
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25. Faster and less invasive tools to identify patients with ileal colonization by adherent‐invasive E. coli in Crohn's disease

Author

Clara Yzet, Anthony Buisson, Elisabeth Billard, Benjamin Pariente, Caroline Chevarin, Jérôme Filippi, Philippe Seksik, Nicolas Barnich, Laurent Peyrin-Biroulet, Gilles Bommelaer, Emilie Vazeille, Marion Goutte, Gilles Boschetti, Mathurin Fumery, Stéphane Nancey, Maria Nachury, Anaëlle Dubois, Bruno Pereira, Nathalie Ballet, Matthieu Allez, Stéphanie Rodriguez, Xavier Hébuterne, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), CHU Amiens-Picardie, CHU Lille, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Lesaffre, Centre Hospitalier Universitaire de Nice (CHU Nice), Service d'Hépato Gastroenterologie [CHU Amiens-Picardie], Hôpital Claude Huriez [Lille], INRAeUSC-2018Clermont Auvergne UniversityLesaffre InternationalMinistere de la Recherche et de la TechnologieI-SITE projectCAP 2025, Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Gestionnaire, HAL Sorbonne Université 5, Unité de Nutrition Humaine (UNH), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
Male, Saliva, anti-E, Biopsy, adherent‐invasive E. coli, Gastroenterology, Inflammatory bowel disease, Feces, 0302 clinical medicine, Crohn Disease, Prospective Studies, Intestinal Mucosa, 0303 health sciences, Crohn's disease, biology, medicine.diagnostic_test, Colonoscopy, Antibodies, Bacterial, CEACAM6. IBD, medicine.anatomical_structure, Oncology, Biomarker (medicine), Female, Original Article, 030211 gastroenterology & hepatology, Antibody, adherent-invasive E, medicine.medical_specialty, IBD, Ileum, 03 medical and health sciences, inflammatory bowel disease, Internal medicine, Escherichia coli, medicine, anti‐E. coli antibodies, Humans, CEACAM6, 030304 developmental biology, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, coli, coli antibodies, biology.protein, business, Biomarkers
Abstract

International audience; Background and AimsThe identification of Crohn's disease (CD)-associated adherent and invasive Escherichia coli (AIEC) is time-consuming and requires ileal biopsies. We aimed to identify a faster and less invasive methods to detect ileal colonization by AIEC in CD patients.MethodsCD patients requiring ileo-colonoscopy were consecutively enrolled in this prospective multicenter study. Samples from saliva, serum, stools, and ileal biopsies of CD patients were collected.ResultsAmong 102 CD patients, the prevalence of AIEC on ileal biopsies was 24.5%. The abundance and global invasive ability of ileal-associated total E. coli were respectively ten-fold (p = 0.0065) and two-fold (p = 0.0007) higher in AIEC-positive (vs. AIEC-negative), while abundance of total E. coli in the feces was not correlated with AIEC status in the ileum. The best threshold of ileal total E. coli was 60 cfu/biopsy to detect AIEC-positive patients, with high negative predictive value (NPV) (94.1%[80.3–99.3]), while the global invasive ability (>9000 internalized bacteria) was able to detect the presence of AIEC with high positive predictive value (80.0% [55.2–100.0]). Overall, 78.1% of the AIEC + patients were colonized by two or less different AIEC strains. The level of serum anti-total E. coli antibodies (AEcAb) was higher in AIEC-positive patients (p = 0.038) with a very high negative predictive value (96.6% [89.9–100.0]) (p = 0.038) for a cut-off value > 1.9 × 10−3.ConclusionsMore than two thirds of AIEC-positive CD patients were colonized by two or less AIEC strains. While stools samples are not accurate to screen AIEC status, the AEcAb level appears to be an attractive, rapid and easier biomarker to identify patients with Crohn's disease harboring AIEC.

Published
2021
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27. Steroid-Free Deep Remission at One Year Does Not Prevent Crohn's Disease Progression: Long-Term Data From the TAILORIX Trial

Author

Filip Baert, David Laharie, Severine Vermeire, Christien J. van der Woude, Laurent Peyrin-Biroulet, Nicolas Duveau, Philippe Van Hootegem, Geert R. D'Haens, Edouard Louis, Laurence Picon, Cyrielle Gilletta, Guy Lambrecht, Matthieu Allez, Anthony Buisson, Jérôme Filippi, Maria Nachury, Peter Bossuyt, Yoram Bouhnik, Hedia Brixi, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, and Gastroenterology & Hepatology

Subjects
medicine.medical_specialty, Crohn's Disease, Disease, Deep Remission, Endoscopic Remission, Crohn Disease, Internal medicine, Clinical endpoint, Humans, Steroid free, Medicine, Prospective Studies, Crohn's disease, Hepatology, business.industry, Remission Induction, Gastroenterology, medicine.disease, Infliximab, Natural history, Treatment Outcome, Cohort, Disease Progression, Steroids, business, Follow-Up Studies, Abdominal surgery, medicine.drug
Abstract

Background & Aims: Crohn's disease (CD) patients included in the Tailored Treatment With Infliximab for Active Crohn's Disease (TAILORIX) trial started infliximab in combination with an immunosuppressant for 1 year. The aim of the present study was to determine the long-term disease course beyond the study period. Methods: We compared the outcomes of patients who did or did not reach the primary end point of the TAILORIX trial, defined as sustained corticosteroid-free clinical remission from weeks 22 through 54, with no ulcers on ileocolonoscopy at week 54. The primary outcome of this follow-up study was the progression-free survival of CD defined by anal or major abdominal surgery, CD-related hospitalization, or the need for a new systemic CD treatment. Results: The 95 patients (median disease duration, 4.5 mo; interquartile range, 1.0–56.6 mo) analyzed, including 45 (47%) who achieved the primary end point, were followed up for a median duration of 64.2 months (interquartile range, 57.6–69.9 mo) after the end of the study period. There was no significant difference in CD progression-free survival at 1, 3, and 5 years between patients who achieved the TAILORIX primary end point and patients who did not (P =.64). No difference was observed between both groups for each component of CD progression: anal surgery, major abdominal surgery, CD-related hospitalization, or the need for a new systemic CD treatment. Conclusions: Achieving a sustained clinical remission off steroids with complete endoscopic remission in this cohort of 95 patients with early CD was not associated with less disease progression. Prospective trials to define the therapeutic goals that change the natural history of CD and prevent complications are needed.

Published
2022

28. Cephalic Duodenopancreatectomy for Hyperalgic Duodenal Crohn's Disease Fistulized in the Pancreatic Gland

Author

Sabra Guellouz, Benjamin Pariente, Claire Benet, Clotilde Baudry, Nelson Lourenco, Aurore Kraemer, Matthieu Allez, and Jean-Marc Gornet

Subjects
Cephalic duodenopancreatectomy, Crohn’s disease, Fistula, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Upper gastrointestinal (GI) tract involvement in adult Crohn's disease (CD) is rare and severe complications unusual. Stenosis has been reported, but gastroduodenal fistulae are seldom detected during surgery and most of the fistulae are cologastric or ileogastric. In complicated gastroduodenal CD, medical treatments are often effective and surgery is only considered in exceptional cases. We here report the unusual case of a 23-year-old patient with upper GI CD presenting a hyperalgic giant ulcer of the bulb fistulized in the pancreatic gland. The failure of steroids and two lines of combined treatment led us to a salvage surgical option. Abdominal exploration showed a plate stomach with an inflammatory bulboduodenal block. Cephalic duodenopancreatectomy and cholecystectomy were performed; histological analysis reported large fissuring pylorus ulceration with micro abscesses reaching the pancreas and the presence of non-caseating granulomas. Six months after the surgery, the patient had stopped antalgic treatment and did not have residual abdominal pain. He had gained 11 kg in weight and had no diarrhea with pancreatic enzymes. To our knowledge, we report the first case of an upper GI and fistulizing CD patient heavily treated with steroids and combined immunosuppressant agents requiring salvage cephalic duodenopancreatectomy.

Published
2014
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29. Effectiveness and safety of ustekinumab maintenance therapy in 103 patients with ulcerative colitis: a GETAID cohort study

Author

Mathurin Fumery, Jérôme Filippi, Vered Abitbol, Amélie Biron, David Laharie, Melanie Serrero, Romain Altwegg, Yoram Bouhnik, Laurent Peyrin‐Biroulet, Cyrielle Gilletta, Xavier Roblin, Guillaume Pineton de Chambrun, Lucine Vuitton, Anne Bourrier, Stephane Nancey, Jean‐Marc Gornet, Stephane Nahon, Guillaume Bouguen, Stephanie Viennot, Maria Nachury, Aurelien Amiot, Franck Brazier, Clara Yzet, Xavier Hebuterne, Guillaume Cadiot, Hedia Brixi, Pauline Rivière, Florian Poullenot, Xavier Treton, Carmen Stefanescu, Camille Zallot, Laurent Beaugerie, Philippe Seksik, Harry Sokol, Julien Kirchgesner, Gilles Boschetti, Bernard Flourié, Claire Gay, Pauline Danion, Chloe Venturin, Matthieu Allez, Clotilde Baudry, Benjamin Pariente, Pauline Wils, Charlotte Gagnière, Jenny Tannoury, CHU Amiens-Picardie, Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Bordeaux [Bordeaux], CHU Marseille, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire de Nancy (CHU Nancy), CHU Toulouse [Toulouse], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Groupe Hospitalier Intercommunal Le Raincy-Montfermeil, CHU Pontchaillou [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Lille, CHI Créteil, GETAID, Université de Montpellier (UM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Adult, Male, medicine.medical_specialty, Pancolitis, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Vedolizumab, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Maintenance therapy, Internal medicine, Ustekinumab, Humans, Medicine, Pharmacology (medical), Adverse effect, Colectomy, Hepatology, business.industry, Remission Induction, Gastroenterology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Middle Aged, medicine.disease, Ulcerative colitis, 3. Good health, Treatment Outcome, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Colitis, Ulcerative, 030211 gastroenterology & hepatology, medicine.symptom, business, medicine.drug, Cohort study
Abstract

International audience; Background Phase III trials have demonstrated the efficacy and safety of ustekinumab in ulcerative colitis (UC), but few real-life long-term data are currently available. Aims To assess the real-world effectiveness and safety of ustekinumab in patients with UC. Methods From January to September 2019, all consecutive patients with active UC treated with ustekinumab in a GETAID centre were included. Patients were evaluated at week 52. Remission was defined as a partial Mayo Clinic score

Published
2021
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30. Diet prevents the expansion of segmented filamentous bacteria and ileo-colonic inflammation in a model of Crohn’s disease

Author

Amira Metwaly, Jelena Jovic, Nadine Waldschmitt, Sevana Khaloian, Helena Heimes, Deborah Häcker, Nassim Hammoudi, Lionel Le Bourhis, Aida Mayorgas, Kolja Siebert, Marijana Basic, Tobias Schwerd, Matthieu Allez, Julian Panes, Azucena Salas, André Bleich, Sebastian Zeissig, Pamela Schnupf, Fabio Cominelli, and Dirk Haller

Abstract

Crohn’s disease (CD) is associated with changes in the microbiota, and murine models of CD-like ileo-colonic inflammation depend on the presence of microbial triggers. Increased abundance of unknown Clostridiales and the microscopic detection of filamentous structures close to the epithelium of TnfΔARE mice pointed towards segmented filamentous bacteria (SFB), a commensal well-known to induce the maturation of Th17 cell-derived immune responses that is highly implicated in the pathogenesis of IBD. We show that the abundance of SFB strongly correlates with the severity of CD-like ileal inflammation in TnfΔARE and SAMP/Yit mice. SFB mono-colonization of germ-free TnfΔARE mice confirmed the causal link and resulted in severe ileo-colonic inflammation, characterized by elevated tissue levels of Tnf and Il-17, neutrophil infiltration and loss of Paneth and goblet cell function. Co-colonization of SFB in human-microbiota associated TnfΔARE mice confirmed that SFB presence is indispensable for disease development. Screening of 412 ileal and colonic mucosal biopsies from IBD patients using previously published and newly designed human SFB-specific primer sets showed no presence of SFB in human tissue samples. Simulating the protective effect of exclusive enteral nutrition (EEN) by feeding SFB mono-colonized TnfΔARE mice EEN-like purified diet antagonized SFB colonization and prevented disease development in TnfΔARE mice, clearly demonstrating the important role of diet in modulating this IBD-related but murine pathobiont.

Published
2022
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32. S770 Health-Related Quality of Life With Ustekinumab vs Adalimumab for Induction and Maintenance Therapy in Biologic-Naïve Patients With Moderate-To-Severe Crohn’s Disease: IBDQ in the SEAVUE Study

Author

Matthieu Allez, Christopher Gasink, Silvio Danese, Bruce E. Sands, Peter M. Irving, Zhijie Ding, Erik Muser, Remo Panaccione, Tony Ma, Edward V. Loftus, James L. Izanec, Timothy Hoops, and James D. Lewis

Subjects
Moderate to severe, Health related quality of life, medicine.medical_specialty, Crohn's disease, Hepatology, business.industry, Gastroenterology, medicine.disease, Therapy naive, Maintenance therapy, Internal medicine, Ustekinumab, Adalimumab, medicine, business, medicine.drug
Published
2021
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33. Long‐term efficacy of fibrin glue injection for perianal fistulas in patients with Crohn's disease

Author

Xavier Treton, Helene Corte, Jean-Marc Gornet, Jérôme Lambert, Nicolas Munoz-Bongrand, Mathias Vidon, Yves Panis, Jean-David Zeitoun, Philippe Seksik, Laurent Abramowitz, Matthieu Allez, and Léon Maggiori

Subjects
Adult, Anal fistula, medicine.medical_specialty, Combination therapy, Fistula, Population, Fibrin Tissue Adhesive, law.invention, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, Randomized controlled trial, law, Humans, Rectal Fistula, Medicine, Cumulative incidence, education, Fibrin glue, Retrospective Studies, education.field_of_study, Crohn's disease, business.industry, Gastroenterology, medicine.disease, Surgery, Treatment Outcome, 030220 oncology & carcinogenesis, Tissue Adhesives, 030211 gastroenterology & hepatology, business
Abstract

Aim The treatment of perianal fistulas in Crohn's disease remains challenging. Fibrin glue injection has previously shown short-term efficacy in a randomized controlled trial. No long-term data are available to assess the benefit of this treatment. Methods This retrospective multicentre study included all patients with drained fistulas treated by at least one fibrin glue injection between January 2004 and June 2015 in three tertiary French centres. The primary end-point was the rate of complete clinical remission at 1 year after injection defined by the closure of all fistula tracts with no need for iterative anal surgery or for optimization of immunosuppressants and/or biologics. Results In all, 119 patients (median age 33 years, complex fistulas 65%, median previous anal surgery two, median Harvey Bradshaw score 3, immunosuppressants exposure 50%, anti-tumor necrosis factor exposure 60% with median time of administration of 1.1 year) were analysed with a median follow-up of 18.3 months. The complete clinical remission rate at 1 year was 45.4%. The primary end-point was achieved in 63% of the cases in the combination therapy group and 37% in other patients. The only predictor of complete clinical remission at 1 year was combination therapy at the time of injection (P = 0.01). The rate of early reintervention after glue injection was 2.5%. The cumulative incidence of iterative anal surgery and ostomy in the whole population was 54% and 5.6% respectively at 5 years. Conclusion An adjunct of fibrin glue to conventional medical therapy may be an effective and safe treatment for perianal fistulas in patients with Crohn's disease.

Published
2020
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34. Long-term outcome of patients with acute severe ulcerative colitis responding to intravenous steroids

Author

Julien Kirchgesner, Antoine Meyer, Jean-Marc Gornet, Aurelien Amiot, Laurent Beaugerie, Matthieu Allez, Franck Carbonnel, and Robert Salameh

Subjects
medicine.medical_specialty, Multivariate analysis, Hepatology, business.industry, medicine.medical_treatment, Hazard ratio, Gastroenterology, Retrospective cohort study, medicine.disease, Ulcerative colitis, Vedolizumab, 03 medical and health sciences, 0302 clinical medicine, Maintenance therapy, Internal medicine, Medicine, 030211 gastroenterology & hepatology, Pharmacology (medical), 030212 general & internal medicine, business, Intravenous steroids, medicine.drug, Colectomy
Abstract

BACKGROUND The long-term outcome of patients with acute severe ulcerative colitis (ASUC) responding to intravenous steroids (IVS) has been poorly reported. AIMS To assess relapse-free survival in patients with ASUC responding to IVS. METHODS Between January 2006 and December 2017, 142 consecutive patients with ASUC (according to modified Truelove-and-Witts criteria) responding to IVS were included in this multicentre retrospective study. Relapse was defined by a partial Mayo Clinic score >4 and/or the need for another maintenance therapy. RESULTS Among the 142 included patients (100 naive of immunomodulator and/or biological agent) hospitalised for ASUC, 59 (41.5%) were treated at discharge with 5-aminosalicylic acid, 60 (42%) with immunomodulators, 18 (13%) with anti-tumour necrosis factor (TNF) agents and 5 (3.5%) with vedolizumab. After a median follow-up of 4.8 (2.6-7.3) years, 90 (63.4%) had relapsed and 12 (8.5%) had required colectomy. The probabilities of relapse-free survival were 58%, 48% and 40% at 1, 2 and 5 years respectively. The multivariate analysis demonstrated that patients with

Published
2020
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35. Prognosis of Lymphoma in Patients With Known Inflammatory Bowel Disease: A French Multicentre Cohort Study

Author

Vered Abitbol, Aurelien Amiot, Caroline Besson, Xavier Treton, Laurent Beaugerie, Catherine Thieblemont, Paul Coppo, Anouk Walter-Petrich, Thomas Aparicio, Georgia Malamut, Julien Kirchgesner, Lionel Galicier, Dominique Cazals-Hatem, Bénédicte Deau-Fischer, Matthieu Allez, Jean Marc Gornet, T. Severyns, Jérôme Lambert, Service d'hépato-gastro-entérologie [Hôpital Saint-Louis, APHP], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA) (SBIM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national du cancer [Boulogne] (INCA)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Institut Universitaire d'Hématologie [Hôpital Saint-Louis - APHP], Hopital Saint-Louis [AP-HP] (AP-HP), CHU Henri Mondor AP-HP/UPEC, AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Gastroentérologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Hôpital Beaujon, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Unité de neurophysiologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)

Subjects
Male, medicine.medical_specialty, Lymphoma, [SDV]Life Sciences [q-bio], medicine.medical_treatment, IBD, Population, Antineoplastic Agents, Lymphoma, T-Cell, Inflammatory bowel disease, Gastroenterology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, Interquartile range, hemic and lymphatic diseases, Internal medicine, medicine, Humans, B-cell lymphoma, education, Digestive System Surgical Procedures, Neoplasm Staging, Biological Products, education.field_of_study, Chemotherapy, business.industry, Retrospective cohort study, General Medicine, Middle Aged, Prognosis, medicine.disease, Hodgkin Disease, Chemotherapy regimen, 3. Good health, Intestines, 030220 oncology & carcinogenesis, Colitis, Ulcerative, Female, 030211 gastroenterology & hepatology, France, Lymphoma, Large B-Cell, Diffuse, business, Immunosuppressive Agents
Abstract

Background and Aims The prognosis of lymphoma that occurs in patients with inflammatory bowel disease [IBD] is poorly known. Methods A multicentre retrospective cohort analysis was done in seven French tertiary centres from 1999 to 2019. Only lymphoma occurring in patients with previous established diagnosis of IBD were analysed. The primary outcome was progression-free survival at 3 years. Results A total of 52 patients [male 65%, Crohn’s disease 79%, median age 48.3 years, median duration of IBD 10.1 years] were included, of whom 37 had been previously exposed to immunosuppressants and/or biologics for at least 3 months and 20 had primary intestinal lymphomas. The lymphoma histological types were: diffuse large B cell lymphomas [N = 17], Hodgkin lymphomas [N = 17], indolent B cell lymphomas [N = 12], and others including T cell lymphomas, mantle cell lymphomas, and unclassifiable B cell lymphoma [N = 6]. The median follow-up after lymphoma was 5.1 years (interquartile range [IQR] 4–7.8). Progression-free survival at 3 years was 85% in the overall population (95% confidence interval [CI] 75%–96%) with no significant difference between the exposed and unexposed group, 79% for patients exposed to immunosuppressants and/or biologics [95% CI 67%–94%], and 83% for patients diagnosed with primary intestinal lymphoma [95% CI 67%–100%]. No relapse of IBD has been observed during chemotherapy. The IBD relapse rate at the end of the last chemotherapy cycle was 23% at 3 years [95% CI 11%-39%] in the overall population. Conclusions In this large cohort, the prognosis for lymphomas occurring in IBD appears to be good and similar to what is expected, irrespective of the exposure to biologics and/or immunosuppressants.

Published
2020
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36. Prevalence of anti-TNF contraindications in Crohn’s disease: A cross-sectional survey from the GETAID

Author

Aurelien Amiot, Philippe Seksik, Jean-Marie Reimund, Maria Nachury, Romain Altwegg, Arnaud Bourreille, Stephanie Viennot, Mathurin Fumery, Xavier Roblin, Melanie Serrero, Matthieu Allez, Claire Painchart, Elise Chanteloup, Lucine Vuitton, Ginette Fotsing, Anthony Buisson, Baya Coulibaly, Stephane Nancey, Cyrielle Gilletta, Laurianne Plastaras, Vered Abitbol, Lucas Guillo, Marion Simon, Stephane Nahon, David Laharie, Laurent Peyrin-Biroulet, Guillaume Bouguen, Charlotte Gagniere, Pauline Wils, Yoram Bouhnik, Carmen Stefanescu, Xavier Treton, Carole Martins, Mathieu Uzzan, Emilie Del Tedesco, Laurent Beaugerie, Anne Bourrier, Cecilia Landmann, Julien Kirchgesner, Harry Sokol, Gilles Boschetti, Claire Gay, Pauline Danion, Bernard Flourié, Georgia Malamut, Benedicte Caron, Camille Zallot, Jean-Marc Gornet, Clotilde Baudry, Caroline Trang-Poisson, Medina Boualit, Lucile Boivineau, Pauline Riviere, Florian Poullenot, Benoit Coffin, Henri Duboc, Early detection of Colon Cancer using Molecular Markers and Microbiota (EA 7375) (EC2M3), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Voies de Signalisation du Développement et du Stress Cellulaire dans les Cancers Digestifs et Urologiques, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University Hospital of Montpellier, Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, CHU Amiens-Picardie, Groupe d’Étude Thérapeutique des Affections Inflammatoires du Tube Digestif (GETAID), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Aix Marseille Université (AMU), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier [Valenciennes, Nord], Hôpital Saint-Joseph [Marseille], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Clermont-Ferrand, Centre Hospitalier Henri Duffaut (Avignon), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CH Colmar, Hôpital Cochin [AP-HP], Institut Mutualiste de Montsouris (IMM), Groupe Hospitalier Intercommunal Le Raincy-Montfermeil, CHU Bordeaux [Bordeaux], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Pontchaillou [Rennes], This study was supported by an institutional grant by Takeda, CRHU Nancy, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Saint-Etienne, and CHU Toulouse [Toulouse]

Subjects
Crohn’s disease, Hepatology, Contraindications, [SDV]Life Sciences [q-bio], Gastroenterology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Inflammatory bowel disease, Anti-TNF, Cross-Sectional Studies, Treatment Outcome, Crohn Disease, Prevalence, Humans, Tumor Necrosis Factor Inhibitors, Ustekinumab, Contraindication
Abstract

International audience; BACKGROUND: The exact rate of contraindications to anti-TNF therapy and physician perspectives on treatment choices facing to anti-TNF contraindication, are poorly reported. METHODS: A two-week cross-sectional study was conducted in 31 centres. Physicians completed a questionnaire for a total of 1,314 consecutive outpatients with Crohn’s disease, assessing each patient’s potential contraindications to anti-TNF therapy, the choice of alternative therapy to anti-TNFs, and their preference in an unrestricted reimbursement setting. RESULTS: Among the 1,293 responses to the first item, 148 (11.5%) reported 32 absolute contraindications (2.5%) and 116 relative contraindications (9.0%) to anti-TNF therapy. When asked about their preference of alternative therapies in those cases with contraindications to anti-TNF, physicians chose ustekinumab and vedolizumab, 75.6% and 23.9%, respectively. In multivariable analysis, the choice of vedolizumab was the preferred choice for patients aged > 60 years with the L2 phenotype and the absence of perianal lesions. In a hypothetical setting of unrestricted reimbursement, anti-TNFs remained physicians’ preferred first-line biological therapy choice for 78.2%. CONCLUSION: Anti-TNF contraindications occurred in up to 11.5% of patients with Crohn’s disease. Physicians’ choices for alternative therapy to anti-TNF relied on ustekinumab in 75.6% and vedolizumab in 23.9% of these cases. This choice was driven mainly by phenotypical criteria and age.

Published
2022
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37. CORE-IBD: A Multidisciplinary International Consensus Initiative to Develop a Core Outcome Set for Randomized Controlled Trials in Inflammatory Bowel Disease

Author

Christopher Ma, Jurij Hanzel, Remo Panaccione, William J. Sandborn, Geert R. D’Haens, Vineet Ahuja, Raja Atreya, Charles N. Bernstein, Peter Bossuyt, Brian Bressler, Robert V. Bryant, Benjamin Cohen, Jean-Frederic Colombel, Silvio Danese, Axel Dignass, Marla C. Dubinsky, Phillip R. Fleshner, Richard B. Gearry, Stephen B. Hanauer, Ailsa Hart, Paulo Gustavo Kotze, Torsten Kucharzik, Peter L. Lakatos, Rupert W. Leong, Fernando Magro, Julian Panés, Laurent Peyrin-Biroulet, Zhihua Ran, Miguel Regueiro, Siddharth Singh, Antonino Spinelli, A. Hillary Steinhart, Simon P. Travis, C. Janneke van der Woude, Bruce Yacyshyn, Takayuki Yamamoto, Matthieu Allez, Willem A. Bemelman, Amy L. Lightner, Edouard Louis, David T. Rubin, Ellen J. Scherl, Corey A. Siegel, Mark S. Silverberg, Severine Vermeire, Claire E. Parker, Stefanie C. McFarlane, Leonardo Guizzetti, Michelle I. Smith, Niels Vande Casteele, Brian G. Feagan, Vipul Jairath, Collaborators, CORE-IBD, Gastroenterology & Hepatology, Gastroenterology and Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Surgery

Subjects
Crohn’s disease, Consensus, Hepatology, endpoint, Gastroenterology, Crohn's Disease, Outcomes, outcomes, Inflammatory Bowel Diseases, End Point, C-Reactive Protein, Crohn Disease, Chronic Disease, Outcome Assessment, Health Care, Quality of Life, Ulcerative Colitis, Humans, Colitis, Ulcerative, Leukocyte L1 Antigen Complex, Biomarkers, ulcerative colitis, Randomized Controlled Trials as Topic
Abstract

BACKGROUND & AIMS: End points to determine the efficacy and safety of medical therapies for Crohn's disease (CD) and ulcerative colitis (UC) are evolving. Given the heterogeneity in current outcome measures, harmonizing end points in a core outcome set for randomized controlled trials is a priority for drug development in inflammatory bowel disease. METHODS: Candidate outcome domains and outcome measures were generated from systematic literature reviews and patient engagement surveys and interviews. An iterative Delphi process was conducted to establish consensus: panelists anonymously voted on items using a 9-point Likert scale, and feedback was incorporated between rounds to refine statements. Consensus meetings were held to ratify the outcome domains and core outcome measures. Stakeholders were recruited internationally, and included gastroenterologists, colorectal surgeons, methodologists, and clinical trialists. RESULTS: A total of 235 patients and 53 experts participated. Patient-reported outcomes, quality of life, endoscopy, biomarkers, and safety were considered core domains; histopathology was an additional domain for UC. In CD, there was consensus to use the 2-item patient-reported outcome (ie, abdominal pain and stool frequency), Crohn's Disease Activity Index, Simple Endoscopic Score for Crohn's Disease, C-reactive protein, fecal calprotectin, and co-primary end points of symptomatic remission and endoscopic response. In UC, there was consensus to use the 9-point Mayo Clinic Score, fecal urgency, Robarts Histopathology Index or Geboes Score, fecal calprotectin, and a composite primary end point including both symptomatic and endoscopic remission. Safety outcomes should be reported using the Medical Dictionary for Regulatory Activities. CONCLUSIONS: This multidisciplinary collaboration involving patients and clinical experts has produced the first core outcome set that can be applied to randomized controlled trials of CD and UC. ispartof: GASTROENTEROLOGY vol:163 issue:4 pages:950-964 ispartof: location:United States status: published

Published
2022

38. Treat to target versus standard of care for patients with Crohn's disease treated with ustekinumab (STARDUST):an open-label, multicentre, randomised phase 3b trial

Author

Silvio Danese, Severine Vermeire, Geert D'Haens, Julian Panés, Axel Dignass, Fernando Magro, Maciej Nazar, Manuela Le Bars, Marjolein Lahaye, Lioudmila Ni, Ivana Bravata, Frederic Lavie, Marco Daperno, Milan Lukáš, Alessandro Armuzzi, Mark Löwenberg, Daniel R Gaya, Laurent Peyrin-Biroulet, Rodolfo Rocca, Susana Lopes, Flavio Caprioli, Sandro Ardizzone, Ana Echarri Piudo, Paolo Gionchetti, Xavier Roblin, Ursula Seidler, David Andersson, Kamal Patel, Pierre Desreumaux, Simone Saibeni, Gustav From, Miroslav Fedurco, Milos Gregus, Yoram Bouhnik, Andreas Luegering, Rocco Cosintino, Ivan Bunganic, Jaime Ramos, Mariam Aguas Peris, Olivier Dewit, Mariabeatrice Principi, Emma Wesley, Paula Lago, Stephane Nancey, María Dolores Martín Arranz, Pieter Hindryckx, Ambrogio Orlando, Andrea Geccherle, Maria Laura Annunziata, Bu'hussain Hayee, Jozef Balaz, Francisco Portela, Cyrielle Gilletta, Torsten Kucharzik, Miguel Mínguez, Javier Pérez Gisbert, Ana Gutiérrez Casbas, Edouard Louis, Marco Marino, Gareth Parkes, Fraser Cummings, Bindia Jharap, Jens Kjeldsen, Luís Correia, Paula Ministro, Matthias Ebert, Erik Hertervig, Dirk Staessen, Joris Dutré, Arnaud Colard, Graham Morrison, Henning Glerup, Jens Frederik Dahlerup, Frank Wolfhagen, Marian Batovsky, Martin Molnar, Barbora Kadleckova, Paulo Caldeira, David Laharie, Xavier Hebuterne, Bruno Bonaz, Matthieu Allez, Andreas Fischer, Joaquín Ernesto Hinojosa Del Val, Miriam Mañosa Ciria, Jose Manuel Herrera Justiniano, Charlotte Soderman, Rajiv Chandy, Craig Mowat, Peter Irving, Jan Fallingborg, Jan Matous, Tomas Douda, Romain Altwegg, Jose Manuel Benitez, María Teresa Arroyo Villarino, Jordi Guardiola Capón, Daniel Ginard Vicenc, Pieter Dewint, Sven Almer, Sebastien Kindt, Gastroenterology and Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and hepatology, Clinical sciences, and Gastroenterology

Subjects
Adult, STARDUST, BLOOD, Hepatology, Remission Induction, Gastroenterology, Standard of Care, GUIDELINES, C-REACTIVE PROTEIN, Crohn's disease, Crohn Disease, MARKER, randomised phase 3b trial, MANAGEMENT, Humans, Administration, Intravenous, Ustekinumab
Abstract

Background: A treat-to-target strategy, in which strictly defined treatment targets facilitate decision making in clinical practice, is advocated as an optimised management approach for some chronic disorders. The aim of the STARDUST trial was to assess whether a treat-to-target strategy with early endoscopy, regular biomarker and clinical symptom monitoring, and dose intensification for persistent inflammatory activity, was more successful in achieving endoscopic improvement at week 48 than a clinically driven maintenance strategy in patients with moderate-to-severe active Crohn's disease receiving ustekinumab. Methods: This open-label, multicentre, randomised phase 3b trial included adults with active, moderate-to-severe Crohn's disease (Crohn's Disease Activity Index [CDAI] 220–450 and Simple Endoscopic Score in Crohn's Disease [SES-CD] ≥3) for whom conventional therapy or one biologic therapy, or both, had failed. Patients received intravenous ustekinumab approximating 6 mg/kg at baseline and subcutaneous ustekinumab 90 mg at week 8. At week 16, patients with a CDAI improvement of 70 or more points from baseline were randomly assigned (1:1) to receive standard-of-care or treat-to-target maintenance treatment through week 48. Randomisation was balanced by using randomly permuted blocks and was stratified by biologic history status and baseline SES-CD score. All patients who signed informed consent, who were not screening failures, and who received at least one dose of study treatment were included in week 16 analyses. All patients included in week 16 analyses and randomly assigned to one of the maintenance treatment regimens were included in the week 48 efficacy and safety analyses (ie, on an intention-to-treat basis). Patients assigned to the treat-to-target arm received ustekinumab every 12 weeks or every 8 weeks based on SES-CD improvement from baseline and could escalate to every 4 weeks through week 48 if prespecified targets were missed. Patients assigned to the standard-of-care arm received ustekinumab every 12 weeks or every 8 weeks; those receiving treatment every 12 weeks could escalate per European labelling. The primary efficacy endpoint was endoscopic response at week 48 (SES-CD score ≥50% decrease from baseline), analysed by non-responder imputation. This trial is registered at ClinicalTrials.gov, NCT03107793, and is active but not recruiting. Findings: 498 patients received standard induction treatment, of whom 440 were randomly assigned to the treat-to-target group (n=219) or the standard-of-care group (n=221). At week 48, there was no significant difference in endoscopic response (83 [38%] of 219 patients vs 66 [30%] of 221 patients; p=0·087), endoscopic remission (25 [11%] vs 32 [15%]; p=0·334), mucosal healing (31 [14%] vs 37 [17%]; p=0·449), and clinical remission (135 [62%] vs 154 [70%]; p=0·072) between the two groups; clinical response was significantly lower in the treat-to-target group than in the standard-of-care group (149 [68%] vs 172 [78%]; p=0·020). Other endoscopic, clinical, and biomarker outcomes were generally not significantly different between groups. The most commonly reported treatment-emergent adverse events were nasopharyngitis (29 [13%] of 219 patients in the treat-to-target group vs 29 [13%] of 221 patients in the standard-of-care group), abdominal pain (23 [11%] vs 19 [9%]), arthralgia (24 [11%] vs 19 [9%]), and headache (24 [11%] vs 21 [10%]). Interpretation: Timely escalation of ustekinumab therapy for patients with Crohn's disease, based on early endoscopic response, clinical symptoms, and biomarkers, did not result in significantly better endoscopic outcomes at week 48 than symptom-driven decisions alone. Future studies need to confirm if some subgroups of patient might benefit from a treat-to-target strategy with ustekinumab. Funding: Janssen-Cilag.

Published
2022
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39. Patients’ real-world experience with inflammatory bowel disease: A cross-sectional survey in tertiary care centres from the GETAID group

Author

Maria Nachury, Yoram Bouhnik, Melanie Serrero, Jerome Filippi, Xavier Roblin, Julien Kirchgesner, Guillaume Bouguen, Denis Franchimont, Guillaume Savoye, Anthony Buisson, Edouard Louis, Stephane Nancey, Vered Abitbol, Jean-Marie Reimund, Olivier DeWit, Lucine Vuitton, Nicolas Matthieu, Laurent Peyrin-Biroulet, Cyrielle Gilletta, Sara Tadbiri, Matthieu Allez, Stephanie Viennot, Arnaud Bourreille, David Laharie, Aurelien Amiot, Charlotte Gagniere, Jenny Tannoury, Benjamin Pariente, Pauline Wils, Carmen Stefanescu, Xavier Treton, Xavier Hébuterne, Nadia Arab, Virginie Cluzeau, Emilie Del Tedesco, Laurent Beaugerie, Philippe Seksik, Anne Bourrier, Cecilia Landmann, Harry Sokol, Laurent Siproudhis, Marie DeWitte, Catherine Reenaers, Gilles Boschetti, Claire Gay, Pauline Danion, Bernard Flourié, Georgia Malamut, Benedicte Caron, Olivier DeWitt, Nicolas Mathieu, Sandie Pestour, Camille Zallot, Jean-Marc Gornet, Clotilde Baudry, Caroline Trang-Poisson, Nina Dib, Hedi Brixi, Guillaume Cadiot, Medina Boualit, Claire Painchart, Laurianne Plastaras, Romain Altwegg, Lucile Boivineau, Mathurin Fumery, Ludovic Caillo, Pauline Riviere, Florian Poullenot, Benoit Coffin, Henri Duboc, Stephane Nahon, Noemie Tavernier, Marion Simon, Baya Coulibaly, Morgane Amil, Duveau Nicolas, Sherine Khater, Mehdi Kaassis, Felix Goutorbe, Driffa Moussata, Laurence Picon, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Gastroentérologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Nord [CHU - APHM], CIC - Biotherapie - Marseille, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Pasteur [Nice] (CHU), Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire des biomolécules (LBM UMR 7203), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Pontchaillou [Rennes], Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), CHU Rouen, Normandie Université (NU), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Université Clermont Auvergne (UCA), Centre Hospitalier Universitaire de Liège (CHU-Liège), Service d'Hépatologie et de Gastroentérologie [Lyon], Hospices Civils de Lyon (HCL), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de Hautepierre [Strasbourg], Interface de Recherche Fondamentale et Appliquée en Cancérologie (IRFAC - Inserm U1113), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS), Cliniques Universitaires Saint-Luc [Bruxelles], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Universitaire [Grenoble] (CHU), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Early detection of Colon Cancer using Molecular Markers and Microbiota (EA 7375) (EC2M3), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'hépato-gastro-entérologie [APHP Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hopital Saint-Louis [AP-HP] (AP-HP), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre hospitalier universitaire de Nantes (CHU Nantes), CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Haut-Lévêque - CHU de Bordeaux (Centre médico chirurgical Magellan), AbbVie, GETAID-patient experience study group: Aurelien Amiot , Sara Tadbiri , Charlotte Gagniere , Jenny Tannoury , Maria Nachury , Benjamin Pariente , Pauline Wils , Yoram Bouhnik , Carmen Stefanescu , Xavier Treton , Melanie Serrero , Jerome Filippi , Xavier Hébuterne , Nadia Arab , Virginie Cluzeau , Xavier Roblin , Emilie Del Tedesco , Laurent Beaugerie , Philippe Seksik , Anne Bourrier , Cecilia Landmann , Julien Kirchgesner , Harry Sokol , Guillaume Bouguen , Laurent Siproudhis , Marie DeWitte , Denis Franchimont , Guillaume Savoye , Anthony Buisson , Edouard Louis , Catherine Reenaers , Stephane Nancey , Gilles Boschetti , Claire Gay , Pauline Danion , Bernard Flourié , Vered Abitbol , Georgia Malamut , Jean-Marie Reimund , Benedicte Caron , Olivier DeWitt , Lucine Vuitton , Nicolas Mathieu , Sandie Pestour , Laurent Peyrin-Biroulet , Camille Zallot , Cyrielle Gilletta , Matthieu Allez , Jean-Marc Gornet , Clotilde Baudry , Stephanie Viennot , Arnaud Bourreille , Caroline Trang-Poisson , Nina Dib , Hedi Brixi , Guillaume Cadiot , Medina Boualit , Claire Painchart , Laurianne Plastaras , Romain Altwegg , Lucile Boivineau , Mathurin Fumery , Ludovic Caillo , David Laharie , Pauline Riviere , Florian Poullenot , Benoit Coffin , Henri Duboc , Stephane Nahon , Noemie Tavernier , Marion Simon , Baya Coulibaly , Morgane Amil , Duveau Nicolas , Sherine Khater , Mehdi Kaassis , Felix Goutorbe , Driffa Moussata , Laurence Picon, CHU Saint-Etienne, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen]-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Autophagie infection et immunité - Autophagy Infection Immunity (APY), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Voies de Signalisation du Développement et du Stress Cellulaire dans les Cancers Digestifs et Urologiques, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Catholique de Louvain = Catholic University of Louvain (UCL), CHU Toulouse [Toulouse], CIC - Biotherapie - CHU Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (SLuc) Service de gastro-entérologie, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, Crohn’s disease, medicine.medical_specialty, Health Knowledge, Attitudes, Practice, Cross-sectional study, [SDV]Life Sciences [q-bio], Disease, Patients experience, Inflammatory bowel disease, Tertiary care, digestive system, Tertiary Care Centers, 03 medical and health sciences, 0302 clinical medicine, Belgium, Physicians, Outpatients, medicine, Quantitative assessment, Humans, Adverse effect, Crohn's disease, Physician-Patient Relations, Hepatology, business.industry, Gastroenterology, Middle Aged, Patient Acceptance of Health Care, medicine.disease, Inflammatory Bowel Diseases, Ulcerative colitis, digestive system diseases, 3. Good health, Cross-Sectional Studies, 030220 oncology & carcinogenesis, Family medicine, 030211 gastroenterology & hepatology, Female, France, Self Report, business
Abstract

International audience; BACKGROUND: Patients’ experience with healthcare professionals could influence their clinical outcomes. AIMS: To assess inflammatory bowel disease (IBD) patients’ experience with their disease, their treatment and their relationship with their physician. METHODS: A one-week cross-sectional study was conducted in 42 IBD centres. 2011 consecutive outpatients with IBD completed an anonymous self-report questionnaire assessing their experience with and knowledge of IBD. RESULTS: A quantitative assessment of the doctor-patient relationship revealed that patients’ knowledge of IBD and IBD treatment ranged from 7.4 to 8.3 out of 10. In addition to IBD physicians, other sources of information about IBD and current treatment mainly included the internet (80% and 63%, respectively) and general practitioners (61% and 54%). Knowledge about education programmes (28%) was poor, resulting in a lack of willingness to further use these resources (25%). Concerns about IBD treatment were raised in 76% of patients, mostly related to the fear of adverse events (47%) and a lack of efficacy (33%). The need of alternative healthcare professionals was reported by 89% of the sample. CONCLUSION: In a large cohort of patients, we highlighted gaps in the management of patients with IBD regarding the need for higher-quality information and the implementation of alternative healthcare professionals.

Published
2021
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40. IOIBD Recommendations for Clinical Trials in Ulcerative Proctitis: The PROCTRIAL Consensus

Author

Bénédicte Caron, Maria T. Abreu, Corey A. Siegel, Remo Panaccione, Bruce E. Sands, Axel Dignass, Dan Turner, Iris Dotan, Ailsa L. Hart, Vineet Ahuja, Matthieu Allez, Ashwin N. Ananthakrishnan, Subrata Ghosh, Anne M. Griffiths, Jonas Halfvarson, Arthur Kaser, Paulo G. Kotze, Ioannis E. Koutroubakis, Peter L. Lakatos, Arie Levine, James D. Lewis, Fernando Magro, Gerassimos J. Mantzaris, Colm O’Morain, Zhihua Ran, Walter Reinisch, Gerhard Rogler, David B. Sachar, Britta Siegmund, Mark S. Silverberg, Ajit Sood, Antonino Spinelli, Flavio Steinwurz, Curt Tysk, Jesus K. Yamamoto-Furusho, Stefan Schreiber, David T. Rubin, William J. Sandborn, Silvio Danese, and Laurent Peyrin-Biroulet

Subjects
Adult, Hepatology, Crohn Disease, Gastroenterology, Quality of Life, Humans, Colitis, Ulcerative, Endoscopy, Proctitis
Abstract

Clinical trials evaluating biologics and small molecules in patients with ulcerative colitis are predominantly excluding ulcerative proctitis. The objective of the Definition and endpoints for ulcerative PROCtitis in clinical TRIALs initiative was to develop consensus statements for definitions, inclusion criteria, and endpoints for the evaluation of ulcerative proctitis in adults.Thirty-five international experts held a consensus meeting to define ulcerative proctitis, and the endpoints to use in clinical trials. Based on a systematic review of the literature, statements were generated, discussed, and approved by the working group participants using a modified Delphi method. Consensus was defined as at least 75% agreement among voters.The group agreed that the diagnosis of ulcerative proctitis should be made by ileocolonoscopy and confirmed by histopathology, with the exclusion of infections, drug-induced causes, radiation, trauma, and Crohn's disease. Ulcerative proctitis was defined as macroscopic extent of lesions limited to 15 cm distance from the anal verge in adults. Primary and secondary endpoints were identified to capture response of ulcerative proctitis to therapy. A combined clinical and endoscopic primary endpoint for the evaluation of ulcerative proctitis disease activity was proposed. Secondary endpoints that should be evaluated include endoscopic remission, histologic remission, mucosal healing, histologic endoscopic mucosal improvement, disability, fecal incontinence, urgency, constipation, and health-related quality of life.In response to the need for guidance on the design of clinical trials in patients with ulcerative proctitis, the Definition and end points for ulcerative PROCtitis in clinical TRIALs consensus provides recommendations on the definition and endpoints for ulcerative proctitis clinical trials.

Published
2022

41. Etrolizumab as induction and maintenance therapy for ulcerative colitis in patients previously treated with tumour necrosis factor inhibitors (HICKORY): a phase 3, randomised, controlled trial

Author

Laurent Peyrin-Biroulet, Ailsa Hart, Peter Bossuyt, Millie Long, Matthieu Allez, Pascal Juillerat, Alessandro Armuzzi, Edward V Loftus, Elham Ostad-Saffari, Astrid Scalori, Young S Oh, Swati Tole, Akiko Chai, Jennifer Pulley, Stuart Lacey, William J Sandborn, Humberto Aguilar, Tariq Ahmad, Evangelos Akriviadis, Xavier Aldeguer Mante, Istvan Altorjay, Ashwin Ananthakrishnan, Vibeke Andersen, Montserrat Andreu Garcia, Guy Aumais, Irit Avni-Biron, Jeffrey Axler, Kamran Ayub, Filip Baert, Mauro Bafutto, George Bamias, Isaac Bassan, Curtis Baum, Laurent Beaugerie, Brian Behm, Pradeep Bekal, Michael Bennett, Fernando Bermejo San Jose, Charles Bernstein, Dominik Bettenworth, Sudhir Bhaskar, Livia Biancone, Bahri Bilir, Michael Blaeker, Stuart Bloom, Verle Bohman, Francisco Javier Bosques Padilla, Yoram Bouhnik, Gerd Bouma, Raymond Bourdages, Stephan Brand, Brian Bressler, Markus Brückner, Carsten Buening, Franck Carbonnel, Thomas Caves, Jonathon Chapman, Jae Hee Cheon, Naoki Chiba, Camelia Chioncel, Dimitrios Christodoulou, Martin Clodi, Albert Cohen, Gino Roberto Corazza, Richard Corlin, Rocco Cosintino, Fraser Cummings, Robin Dalal, Silvio Danese, Marc De Maeyer, Carlos Fernando De Magalhães Francesconi, Aminda De Silva, Henry Debinski, Pierre Desreumaux, Olivier Dewit, Geert D'Haens, Sandra Di Felice Boratto, John Nik Ding, Tyler Dixon, Gerald Dryden, George Aaron Du Vall, Matthias Ebert, Ana Echarri Piudo, Robert Ehehalt, Magdy Elkhashab, Craig Ennis, Jason Etzel, Jan Fallingborg, Brian Feagan, Roland Fejes, Daniel Ferraz de Campos Mazo, Valéria Ferreira de Almeida Borges, Andreas Fischer, Alan Fixelle, Mark Fleisher, Sharyle Fowler, Bradley Freilich, Keith Friedenberg, Walter Fries, Csaba Fulop, Mathurin Fumery, Sergio Fuster, Gyula G Kiss, Santiago Garcia Lopez, Sonja Gassner, Kanwar Gill, Cyrielle Gilletta de Saint Joseph, Philip Ginsburg, Paolo Gionchetti, Eran Goldin, Adrian-Eugen Goldis, Hector Alejandro Gomez Jaramillo, Maciej Gonciarz, Glenn Gordon, Daniel Green, Jean-Charles Grimaud, Rogelio Guajardo Rodriguez, Zoltan Gurzo, Alexandra Gutierrez, Tibor Gyökeres, Ki Baik Hahm, Stephen Hanauer, John Hanson, William Harlan III, Peter Hasselblatt, Buhussain Hayee, Xavier Hebuterne, Peter Hendy, Melvin Heyman, Peter Higgins, Raouf Hilal, Pieter Hindryckx, Frank Hoentjen, Peter Hoffmann, Frank Holtkamp-Endemann, Gerald Holtmann, Gyula Horvat, Stefanie Howaldt, Samuel Huber, Ikechukwu Ibegbu, Maria Isabel Iborra Colomino, Peter Irving, Kim Isaacs, Kiran Jagarlamudi, Rajesh Jain, Sender Jankiel Miszputen, Jeroen Jansen, Jennifer Jones, John Karagiannis, Nicholas Karyotakis, Arthur Kaser, Lior Katz, Seymour Katz, Leo Katz, Nirmal Kaur, Edita Kazenaite, Reena Khanna, Sunil Khurana, Joo Sung Kim, Young-Ho Kim, Sung Kook Kim, Dongwoo Kim, Jochen Klaus, Dariusz Kleczkowski, Pavel Kohout, Bartosz Korczowski, Georgios Kouklakis, Ioannis Koutroubakis, Richard Krause, Tunde Kristof, Ian Kronborg, Annette Krummenerl, Limas Kupcinskas, Jorge Laborda Molteni, David Laharie, Adi Lahat-zok, Jonghun Lee, Kang-Moon Lee, Rupert Leong, Henry Levine, Jimmy Limdi, James Lindsay, Nilesh Lodhia, Edward Loftus, Randy Longman, Pilar Lopez Serrano, Edouard Louis, Maria Helena Louzada Pereira, John Lowe, Stefan Lueth, Milan Lukas, Giovanni Maconi, Finlay Macrae, Laszlo Madi-Szabo, Uma Mahadevan-Velayos, Everson Fernando Malluta, Fazia Mana, Peter Mannon, Gerasimos Mantzaris, Ignacio Marin Jimenez, Maria Dolores Martin Arranz, Radu-Bogdan Mateescu, Felipe Mazzoleni, Agnieszka Meder, Ehud Melzer, Jessica Mertens, Konstantinos Mimidis, Brent Mitchell, Tamas Molnar, Gregory Moore, Luis Alonso Morales Garza, Reme Mountifield, Vinciane Muls, Charles Murray, Bela Nagy, Markus Neurath, Augustin Nguyen, Remo Panaccione, William Pandak, Julian Panes Diaz, Jihye Park, Luca Pastorelli, Bhaktasharan Patel, Markus Peck-Radosavljevic, Gyula Pecsi, Farhad Peerani, Javier Perez Gisbert, Martin Pesta, Robert Petryka, Raymond Phillips, Marieke Pierik, Vijayalakshmi Pratha, Vlastimil Prochazka, Istvan Racz, Graham Radford-Smith, Daniel Ramos Castañeda, Odery Ramos Júnior, Jaroslaw Regula, Jean-Marie Reimund, Bryan Robbins, Xavier Roblin, Francesca Rogai, Gerhard Rogler, Jerzy Rozciecha, David Rubin, Azalia Yuriria Ruiz Flores, Maciej Rupinski, Grazyna Rydzewska, Sumona Saha, Simone Saibeni, Agnes Salamon, Zoltan Sallo, Bruce Salzberg, Douglas Samuel, Sunil Samuel, William Sandborn, Edoardo Vincenzo Savarino, Anja Schirbel, Robert Schnabel, Stefan Schreiber, John Scott, Shahriar Sedghi, Frank Seibold, Jakob Seidelin, Ursula Seidler, Ahmad Shaban, Ira Shafran, Aasim Sheikh, Alex Sherman, Haim Shirin, Patryk Smolinski, Geun Am Song, Konstantinos Soufleris, Alexander Speight, Dirk Staessen, Andreas Stallmach, Michael Staun, Daniel Stein, Hillary Steinhart, Jonathas Stifft, David Stokesberry, Andreas Sturm, Keith Sultan, Gyorgy Szekely, Kuldeep Tagore, Hugo Tanno, Lena Thin, Syed Thiwan, Carlton Thomas, Michal Tichy, Gabor Tamas Toth, Zsolt Tulassay, Jan Ulbrych, John Valentine, Marta Varga, Eduardo Vasconcellos, Byron Vaughn, Brenda Velasco, Francisco Velazquez, Severine Vermeire, Erica Villa, Aron Vincze, Harald Vogelsang, Miroslava Volfova, Lucine Vuitton, Petr Vyhnalek, Peter Wahab, Jens Walldorf, Mattitiahu Waterman, John Weber, L. Michael Weiss, Anna Wiechowska-Kozlowska, Elise Wiesner, Thomas Witthoeft, Robert Wohlman, Barbara Wozniak-Stolarska, Bruce Yacyshyn, Byong-Duk Ye, Ziad Younes, Lígia Yukie Sassaki, Cyrla Zaltman, Stefan Zeuzem, Neurosurgery, ANS - Neurovascular Disorders, Gastroenterology and Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Peyrin-Biroulet L., Hart A., Bossuyt P., Long M., Allez M., Juillerat P., Armuzzi A., Loftus E.V., Ostad-Saffari E., Scalori A., Oh Y.S., Tole S., Chai A., Pulley J., Lacey S., Sandborn W.J., Aguilar H., Ahmad T., Akriviadis E., Aldeguer Mante X., Altorjay I., Ananthakrishnan A., Andersen V., Andreu Garcia M., Aumais G., Avni-Biron I., Axler J., Ayub K., Baert F., Bafutto M., Bamias G., Bassan I., Baum C., Beaugerie L., Behm B., Bekal P., Bennett M., Bermejo San Jose F., Bernstein C., Bettenworth D., Bhaskar S., Biancone L., Bilir B., Blaeker M., Bloom S., Bohman V., Bosques Padilla F.J., Bouhnik Y., Bouma G., Bourdages R., Brand S., Bressler B., Bruckner M., Buening C., Carbonnel F., Caves T., Chapman J., Cheon J.H., Chiba N., Chioncel C., Christodoulou D., Clodi M., Cohen A., Corazza G.R., Corlin R., Cosintino R., Cummings F., Dalal R., Danese S., De Maeyer M., De Magalhaes Francesconi C.F., De Silva A., Debinski H., Desreumaux P., Dewit O., D'Haens G., Di Felice Boratto S., Ding J.N., Dixon T., Dryden G., Du Vall G.A., Ebert M., Echarri Piudo A., Ehehalt R., Elkhashab M., Ennis C., Etzel J., Fallingborg J., Feagan B., Fejes R., Ferraz de Campos Mazo D., Ferreira de Almeida Borges V., Fischer A., Fixelle A., Fleisher M., Fowler S., Freilich B., Friedenberg K., Fries W., Fulop C., Fumery M., Fuster S., G Kiss G., Garcia Lopez S., Gassner S., Gill K., Gilletta de Saint Joseph C., Ginsburg P., Gionchetti P., Goldin E., Goldis A.-E., Gomez Jaramillo H.A., Gonciarz M., Gordon G., Green D., Grimaud J.-C., Guajardo Rodriguez R., Gurzo Z., Gutierrez A., Gyokeres T., Hahm K.B., Hanauer S., Hanson J., Harlan III W., Hasselblatt P., Hayee B., Hebuterne X., Hendy P., Heyman M., Higgins P., Hilal R., Hindryckx P., Hoentjen F., Hoffmann P., Holtkamp-Endemann F., Holtmann G., Horvat G., Howaldt S., Huber S., Ibegbu I., Iborra Colomino M.I., Irving P., Isaacs K., Jagarlamudi K., Jain R., Jankiel Miszputen S., Jansen J., Jones J., Karagiannis J., Karyotakis N., Kaser A., Katz L., Katz S., Kaur N., Kazenaite E., Khanna R., Khurana S., Kim J.S., Kim Y.-H., Kim S.K., Kim D., Klaus J., Kleczkowski D., Kohout P., Korczowski B., Kouklakis G., Koutroubakis I., Krause R., Kristof T., Kronborg I., Krummenerl A., Kupcinskas L., Laborda Molteni J., Laharie D., Lahat-zok A., Lee J., Lee K.-M., Leong R., Levine H., Limdi J., Lindsay J., Lodhia N., Loftus E., Longman R., Lopez Serrano P., Louis E., Louzada Pereira M.H., Lowe J., Lueth S., Lukas M., Maconi G., Macrae F., Madi-Szabo L., Mahadevan-Velayos U., Malluta E.F., Mana F., Mannon P., Mantzaris G., Marin Jimenez I., Martin Arranz M.D., Mateescu R.-B., Mazzoleni F., Meder A., Melzer E., Mertens J., Mimidis K., Mitchell B., Molnar T., Moore G., Morales Garza L.A., Mountifield R., Muls V., Murray C., Nagy B., Neurath M., Nguyen A., Panaccione R., Pandak W., Panes Diaz J., Park J., Pastorelli L., Patel B., Peck-Radosavljevic M., Pecsi G., Peerani F., Perez Gisbert J., Pesta M., Petryka R., Phillips R., Pierik M., Pratha V., Prochazka V., Racz I., Radford-Smith G., Ramos Castaneda D., Ramos Junior O., Regula J., Reimund J.-M., Robbins B., Roblin X., Rogai F., Rogler G., Rozciecha J., Rubin D., Ruiz Flores A.Y., Rupinski M., Rydzewska G., Saha S., Saibeni S., Salamon A., Sallo Z., Salzberg B., Samuel D., Samuel S., Sandborn W., Savarino E.V., Schirbel A., Schnabel R., Schreiber S., Scott J., Sedghi S., Seibold F., Seidelin J., Seidler U., Shaban A., Shafran I., Sheikh A., Sherman A., Shirin H., Smolinski P., Song G.A., Soufleris K., Speight A., Staessen D., Stallmach A., Staun M., Stein D., Steinhart H., Stifft J., Stokesberry D., Sturm A., Sultan K., Szekely G., Tagore K., Tanno H., Thin L., Thiwan S., Thomas C., Tichy M., Toth G.T., Tulassay Z., Ulbrych J., Valentine J., Varga M., Vasconcellos E., Vaughn B., Velasco B., Velazquez F., Vermeire S., Villa E., Vincze A., Vogelsang H., Volfova M., Vuitton L., Vyhnalek P., Wahab P., Walldorf J., Waterman M., Weber J., Weiss L.M., Wiechowska-Kozlowska A., Wiesner E., Witthoeft T., Wohlman R., Wozniak-Stolarska B., Yacyshyn B., Ye B.-D., Younes Z., Yukie Sassaki L., Zaltman C., and Zeuzem S.

Subjects
Adult, Male, Ulcerative Colitis Flare, medicine.medical_specialty, Asia, Adolescent, Oceania, Population, Antibodies, Monoclonal, Humanized, Injections, Subcutaneou, Placebo, Severity of Illness Index, law.invention, Middle East, Young Adult, Maintenance therapy, Randomized controlled trial, law, Internal medicine, Gastrointestinal Agent, medicine, Adverse effect, education, Aged, Aged, 80 and over, Tumor Necrosis Factor Inhibitor, education.field_of_study, Hepatology, business.industry, Remission Induction, Gastroenterology, Middle Aged, South America, medicine.disease, Ulcerative colitis, Europe, Treatment Outcome, Etrolizumab, North America, Colitis, Ulcerative, Female, business, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5], Human
Abstract

Summary Background Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab in patients with moderately to severely active ulcerative colitis who had been previously treated with anti-tumour necrosis factor (TNF) agents. Methods HICKORY was a multicentre, phase 3, double-blind, placebo-controlled study in adult (18–80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6–12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) previously treated with TNF inhibitors. Patients were recruited from 184 treatment centres across 24 countries in North America, South America, Europe, Asia, Oceania, and the Middle East. Patients needed to have an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In cohort 1, patients received open-label etrolizumab 105 mg every 4 weeks for a 14-week induction period. In cohort 2, patients were randomly assigned (4:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks for the 14-week induction phase. Patients in either cohort achieving clinical response to etrolizumab induction were eligible for the maintenance phase, in which they were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks through to week 66. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants (induction randomisation only), baseline disease activity, week 14 MCS remission status (maintenance randomisation only), and induction cohort (maintenance randomisation only). All patients and study site personnel were masked to treatment assignment. Primary endpoints were remission (Mayo Clinic total score [MCS] ≤2, with individual subscores of ≤1 and a rectal bleeding subscore of 0) at week 14, and remission at week 66 among patients with a clinical response (MCS with ≥3-point decrease and ≥30% reduction from baseline, plus ≥1 point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) at week 14. Efficacy was analysed using a modified intent-to-treat population. Safety analyses included all patients who received at least one dose of study drug during the induction phase. This study is registered at ClinicalTrials.gov , NCT02100696 . Findings HICKORY was conducted from May 21, 2014, to April 16, 2020, during which time 1081 patients were screened, and 609 deemed eligible for inclusion. 130 patients were included in cohort 1. In cohort 2,479 patients were randomly assigned to the induction phase (etrolizumab n=384, placebo n=95). 232 patients were randomly assigned to the maintenance phase (etrolizumab to etrolizumab n=117, etrolizumab to placebo n=115). At week 14, 71 (18·5%) of 384 patients in the etrolizumab group and six (6·3%) of 95 patients in the placebo group achieved the primary induction endpoint of remission (p=0·0033). No significant difference between etrolizumab and placebo was observed for the primary maintenance endpoint of remission at week 66 among patients with a clinical response at week 14 (27 [24·1%] of 112 vs 23 [20·2%] of 114; p=0·50). Four patients in the etrolizumab group reported treatment-related adverse events leading to treatment discontinuation. The proportion of patients reporting at least adverse event was similar between treatment groups for induction (etrolizumab 253 [66%] of 384; placebo 63 [66%] of 95) and maintenance (etrolizumab to etrolizumab 98 [88%] of 112; etrolizumab to placebo 97 [85%] of 114). The most common adverse event in both groups was ulcerative colitis flare. Most adverse events were mild or moderate. During induction, the most common serious adverse event was ulcerative colitis flare (etrolizumab ten [3%] of 384; placebo: two [2%] of 95). During maintenance, the most common serious adverse event in the etrolizumab to etrolizumab group was appendicitis (two [2%] of 112) and the most common serious adverse events in the etrolizumab to placebo group were ulcerative colitis flare (two [2%] of 114) and anaemia (two [2%] of 114). Interpretation HICKORY demonstrated that a significantly higher proportion of patients with moderately to severely active ulcerative colitis who had been previously treated with anti-TNF agent were able to achieve remission at week 14 when treated with etrolizumab compared with placebo; however, there was no significant difference between groups in remission at week 66 among patients with a clinical response at week 14. Funding F Hoffmann-La Roche.

Published
2022

42. Role of adherent and invasive Escherichia coli in Crohn’s disease: lessons from the postoperative recurrence model

Author

Anthony Buisson, Harry Sokol, Nassim Hammoudi, Stéphane nancey, Xavier Treton, Maria Nachury, Mathurin Fumery, Xavier Hébuterne, Michael Rodrigues, Jean-Pierre Hugot, Gilles Boschetti, Carmen Stefanescu, Pauline Wils, Philippe Seksik, Lionel Le Bourhis, Madeleine Bezault, Pierre Sauvanet, Bruno Pereira, Matthieu Allez, Nicolas Barnich, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Service d'Hépatologie Gastro-entérologie [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Infection Inflammation et Interaction Hôtes Pathogènes [CHU Clermont-Ferrand] (3IHP ), Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Paris Center for Microbiome Medicine (FHU PaCeMM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service de Gastroentérologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Hépato Gastroenterologie [CHU Amiens-Picardie], CHU Amiens-Picardie, Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Servcie Hépato-gastroentérolgie et Nutrition clinique [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Remind Study Group, Service de Chirurgie Digestive et Hépatobiliaire [CHU Clermont-Ferrand], Unité de Biostatistiques [CHU Clermont-Ferrand], MSD France, Association François Aupetit, Helmsley Charitable Trust, Ministère de la Recherche et de la Technologie, Inserm (UMR 1071), University of Clermont Auvergne, Inserm {National Programme 'Microbiote'], INRAE (USC-2018), and ANR-16-IDEX-0001,CAP 20-25,CAP 20-25(2016)

Subjects
Gastroenterology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
Abstract

ObjectiveWe used the postoperative recurrence model to better understand the role of adherent and invasiveEscherichia coli(AIEC) bacteria in Crohn’s disease (CD), taking advantage of a well-characterised postoperative cohort.DesignFrom a prospective, multicentre cohort of operated patients with CD, AIEC identification was performed within the surgical specimen (M0) (N=181 patients) and the neoterminal ileum (n=119 patients/181) during colonoscopy performed 6 months after surgery (M6). Endoscopic postoperative recurrence was graded using Rutgeerts’ index. The mucosa-associated microbiota was analysed by 16S sequencing at M0 and M6. Relative risks or ORs were adjusted on potential confounders.ResultsAIEC prevalence was twofold higher within the neoterminal ileum at M6 (30.3%) than within the surgical specimen (14.9%) (pRuminococcus gnavus.ConclusionBased on the postoperative recurrence model, our data support the idea that AIEC are involved in the early steps of ileal CD.Trial registration numberNCT03458195.

Published
2022
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43. Comparison of the risk of Crohn's disease postoperative recurrence between modified Rutgeerts score i2a and i2b categories: an individual patient data meta-analysis

Author

Pauline Rivière, Joel Pekow, Nassim Hammoudi, Pauline Wils, Peter De Cruz, Christina Pu Wang, Míriam Mañosa, Jacob Ollech, Matthieu Allez, Maria Nachury, Michael A Kamm, Maya Ahanori, Marc Ferrante, Anthony Buisson, Siddarth Singh, David Laharie, Momar Diouf, Mathurin Fumery, Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], The University of Chicago Medicine [Chicago], Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Austin Health, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Hospital Universitari Germans Trias I Pujol, University of Chicago, St. Vincent's Hospital, Melbourne, University of Melbourne, University Hospitals Leuven [Leuven], Service d'Hépatologie Gastro-entérologie [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Infection Inflammation et Interaction Hôtes Pathogènes [CHU Clermont-Ferrand] (3IHP ), Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), University of California [San Diego] (UC San Diego), University of California (UC), CHU Amiens-Picardie, Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, and University of California

Subjects
Crohn’s disease, Crohn's disease, Gastroenterology, postoperative recurrence, General Medicine, Original Articles, endoscopy, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background The modified Rutgeerts’ score [RS] differentiates i2a—lesions confined to the anastomosis—and i2b—more than five aphthous ulcers in the neoterminal ileum with normal intervening mucosa, with or without anastomotic lesions—categories. Its relevance for the therapeutic management of Crohn’s disease [CD] patients after ileocolic resection is still debated. Our objective was to compare the postoperative recurrence risk in patients with an i2a or i2b score, using an individual patient data meta-analysis. Methods We conducted a systematic literature search until July 2020, to identify all relevant studies reporting the i2a/i2b status in the year following ileocolic resection and clinical and/or surgical postoperative CD recurrence in their follow-up. Individual patient-level data were obtained from the corresponding authors. The association between the modified RS and time-to-event was evaluated using a mixed Cox model with the centre as the random effect. Results Seven studies published between 2008 and 2019 were included, corresponding to 400 patients: 189 [47%] i2a and 211 [53%] i2b. Median [interquartile range, IQR] time from ileocolic resection to ileocolonoscopy was 6.2 [5.5, 7.9] months and median [IQR] follow-up time after ileocolonoscopy was 4.5 [2.9, 7.3] years. The risk of clinical postoperative recurrence at 1 and 3 years was 11% [6–15%], and 25% [18–32%] in the i2a group versus 9% [5–13%] and 33% [26–41%] in the i2b group [p = 0.63 and p = 0.12, respectively]. No significant difference was observed in terms of time to clinical postoperative recurrence [p = 0.16] or surgical postoperative recurrence [p = 0.87]. Results did not change after excluding patients having initiated an immunosuppressant or a biologic in the 3 months after endoscopy [remaining cohort, n = 361]. Conclusions In this individual patient data meta-analysis, no difference was observed between i2a and i2b subcategories with regards to clinical or surgical postoperative recurrence. As we wait for prospective trials, the same treatment strategy could be applied to all patients classified as i2 on the Rutgeerts score.

Published
2022
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44. Comparative Real-World Effectiveness of Vedolizumab and Ustekinumab for Patients with Ulcerative Colitis: A GETAID Multicentre Cohort Study

Author

Antoine Meyer, Mathurin Fumery, Laurent Peyrin-Biroulet, Jérôme Filippi, Romain Altwegg, Yoram Bouhnik, Melanie Serrero, David Laharie, Xavier Roblin, Maria Nachury, Vered Abitbol, Guillaume Cadiot, Stephane Nancey, Matthieu Allez, Cyrielle Gilletta, Lucine Vuitton, Guillaume Savoye, Stephane Nahon, Anne Bourrier, Anthony Buisson, Guillaume Bouguen, Arnaud Bourreille, Stephanie Viennot, Franck Carbonnel, Aurelien Amiot, Service d'Hépato-gastro-entérologie [APHP Kremlin-Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, CHU Amiens-Picardie, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Nice (CHU Nice), University Hospital of Montpellier, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service de Gastroentérologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Nord [CHU - APHM], CHU Saint-Etienne, Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Robert Debré, Hospices Civils de Lyon (HCL), Hopital Saint-Louis [AP-HP] (AP-HP), CHU Toulouse [Toulouse], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Nutrition, Inflammation et axe Microbiote-Intestin-Cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Groupe Hospitalier Intercommunal Le Raincy-Montfermeil, Service de Gastroentérologie et nutrition [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Clermont-Ferrand, Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Pontchaillou [Rennes], Centre hospitalier universitaire de Nantes (CHU Nantes), Institut des Maladies de l'Appareil Digestif, Université de Nantes (UN), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Early detection of Colon Cancer using Molecular Markers and Microbiota (EA 7375) (EC2M3), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Aix Marseille Université (AMU), CRHU Nancy, and CHU Bordeaux [Bordeaux]

Subjects
Cohort Studies, Treatment Outcome, Gastrointestinal Agents, Remission Induction, Gastroenterology, Humans, Ustekinumab, Colitis, Ulcerative, Tumor Necrosis Factor Inhibitors, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Retrospective Studies
Abstract

International audience; INTRODUCTION: There are currently no comparative data on the efficacy and safety of vedolizumab and ustekinumab in ulcerative colitis (UC) after anti-TNF therapy fails. METHODS: We retrieved the full datasets of two observational, multicentre, retrospective studies of patients with UC for whom anti-TNF therapy failed and the patients were then treated with either vedolizumab or ustekinumab. The outcomes included steroid-free clinical remission, clinical remission, treatment persistence, colectomy, hospitalization, and serious and infectious adverse events. Propensity scores weighted comparison was applied. RESULTS: In total, 121 patients were included in the vedolizumab group and 97 were included in the ustekinumab group. At week 14 and week 52, in the weighted cohort, no difference was found between vedolizumab and ustekinumab for steroid-free clinical remission (OR = 0.55 [0.21-1.41], p\,=\,.21 and 0.94 [0.40-2.22], p\,=\,.89, respectively). There was no difference between vedolizumab and ustekinumab for secondary outcomes such as clinical remission, hospitalization, UC-related surgery, treatment persistence and serious and infectious adverse events. CONCLUSION: In patients with UC for whom anti-TNF therapy failed, no difference was found between vedolizumab and ustekinumab after propensity scores weighted comparison. Further studies are required to determine predictive factors of the efficacy of both biological agents.

Published
2022
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45. I-CARE, a European Prospective Cohort Study Assessing Safety and Effectiveness of Biologics in Inflammatory Bowel Disease

Author

Laurent Peyrin-Biroulet, Jean-François Rahier, Julien Kirchgesner, Vered Abitbol, Sebastian Shaji, Alessandro Armuzzi, Konstantinos Karmiris, Javier P. Gisbert, Peter Bossuyt, Ulf Helwig, Johan Burisch, Henit Yanai, Glen A. Doherty, Fernando Magro, Tamás Molnar, Mark Löwenberg, Jonas Halfvarson, Edyta Zagorowicz, Hélène Rousseau, Cédric Baumann, Filip Baert, Laurent Beaugerie, Jean-Marc Gornet, Jean-Marie Reimund, Xavier Hebuterne, Aurélien Amiot, Franco Armelao, Pierre Blanc, Claudio Papi, Guillaume Pineton De Chambrun, Xavier Roblin, null Chu, Sohail Shariq, Nikolaos Viazis, Jimmy Limdi, Piotr Eder H, Georgios Michalopoulos, Andrew Bell, Livia Biancone, Marie Dewitte, Zia Mazhar, Denis Franchimont, Stephane Nancey, Gilles Macaigne, Maria Beatrice Principi, Mathurin Fumery, Gareth Parkes, Jean-Christophe Valats, Glen Doherty, Guillaume Bouguen, Hersin Tsai, Mohsin Gangi, Natalia Pedersen, Frédéric Heluwaert, Richard Shenderey, Sebastian Zeissig, Jeffrey Butterworth, Fabiana Castiglione, Lynsey Corless, Camille Zallot, Salil Singh, Sunil Sonwalkar, Elizabeth Clayton, Deven Vani, Guy Bellaiche, Martine De Vos, Uri Kopylov, Triana Lobaton, Christophe Locher, Gerassimos Mantzaris, George Abouda, Katie Smith, Michael Sprakes, Angeliki Theodoropoulou, Emma Wesley, Joëlle Bonnet, David Elphick, Cyrielle Gilletta, John Gordon, David Laharie, Antoine Nakad, Ambrogio Orlando, Patrick Dubois, Peter Hasselblatt, Christophe Michiels, Cathryn Preston, Anca Staicu, Lucine Vuitton, Mehdi Kaassis, Ally Speight, Deb Ghosh, Nicolas Mathieu, Anne-Laure Pelletier, Anne Phillips, Romain Altwegg, Irit Avni, null biron, Jonathon Landy, Maria Nachury, Achuth Shenoy, Caroline Trang, Georgios Bamias, Klaudia Farkas, Christian Maaser, Ariella Shitrit, Britta Siegmund, Jérôme Filippi, Colm O'morain, Laurent Costes, David Hobday, Zoltán Szepes, Emma Calabrese, Helen Dallal, Michael Fung, Arvind Ramadas, Bijay Baburajan, Konrad Koss, Christophe Barberis, Anthony Buisson, Morgane Amil, Paola Balestrieri, Matthew Johnson, Maria Tzouvala, Stéphanie Viennot, Ferenc Nagy, Nick Thompson, Laurent Alric, Sunil Samuel, Anne Bourrier, Elise Chanteloup, Emilie Del Tedesco, Marcus Harbord, Alan Lobo, Sally Myers, Richard Pollok, Tariq Ahmad, Rakesh Chaudhary, Christos Karakoidas, Ashraf Soliman, Carmen Stefanescu, Georgios Theocharis, Stijn Vanden Branden, Belén Beltran, Yoram Bouhnik, Arnaud Bourreille, Joana Branco, Ben Colleypriest, Rami Eliakim, Paul Knight, Aoibhlinn O'toole, Virgina Robles, Konstantinos Triantafyllou, Marta Maia Bosca, Guy Lambrecht, Lucia Marquez Mosquera, Simon Panter, Aikaterini Pappa, Marion Simon, Ganesh Sivaji, Christophe Bellanger, Arthur Belle, Natalia Borruel, Laurence Egan, Harald Peeters, Daniel Sharpstone, Ramesh Arasaradnam, José Manuel Benitez, Jens Frederik Dahlerup, Olga Giouleme, Miguel Minguez, Eftychia Tsironi, Angela Variola, Patrick Allen, Lucille Boivineau, Andy Cole, Nina Dib, Fernando Gomollon, Richard Johnston, Konstantinos Katsanos, Nick Kennedy, Marianne Kiszka-Kanowitz, Ignacio Marin-Jimenez, Pál Miheller, Pilar Nos, Othman Saraj, Lars Vinter-Jensen, Eran Zittan, Clotilde Baudry, Xavier Calvet, Marie-Christine Cazelles-Boudier, Jean-Louis Coenegrachts, Garret Cullen, Marco Daperno, Anjan Dhar, Romain Gerard, Nanna Jensen, Nitsan Maharshak, Mark Mcalindon, Simon Mcloughlin, Miles Parkes, Kamal Patel, Armando Peixoto, Dimitrios Polymeros, Francisco Portela, Rodolfo Rocca, Philippe Seksik, Sreedhar Subramanian, Ruth Tennenbaum, Raja Atreya, Oliver Bachmann, Arthur Berger, Renáta Bor, Maire Buckley, Daniel Carpio, María Chaparro, Francesco Costa, Eugeni Domenech, Maria Esteve, Stephen Foley, Jordi Guardiola, Ioannis Koutroubakis, Tanja Kuehbacher, Cécilia Landman, Alessandro Lavagna, Noemí Manceñido, Míriam Mañosa, Maria Dolores Martín-Arranz, Laurianne Plastaras, Maria Lia Scribano, Subhasish Sengupta, Nils Teich, My-Linh Tran-Minh, Evanthia Zampeli, Leila Amininejad, Teresa Arroyo, Alain Attar, Ann-Sofie Backman, Anita Bálint, John Beckly, Shomron Ben Horin, Sónia Bernardo, Ludovic Caillo, Bénédicte Caron, María Shanika de Silva, Anna FábiáN, Gionata Fiorino, Ana Gutierrez, Adi Lahat, Mohamed Masmoudi, Marco Mendolaro, Vinciane Muls, Florian Poullenot, Christopher Probert, Catherine Reenaers, Mariann Rutka, Zaman Sarwari, Joanne Sayer, Beatriz Sicilia, Helena Sousa, Catherine van Kemseke, Yamile Zabana, Marco Astegiano, Paul Banim, Dominik Bettenworth, Médina Boualit, Jacob Broder Brodersen, Angeliki Christidou, Rachel Cooney, João Cortez Pinto, Portugal Marília Cravo, Anneline Cremer, Silvio Danese, Antonio di Sabatino, Jan Fallingborg, Antonio Ferronato, Esther Garcia Planella, Sanjay Gupta, Eran Israeli, Samantha Kestenbaum, Lone Larsen, Elisabeth Macken, Nicoletta Mathou, Ágnes Milassin, Joanna Pofelski, Chiara Ricci, Francisco Rodriguez-Moranta, Martin Schmidt-Lauber, Ian Shaw, Marta Soares, Heithem Soliman, Christos Triantos, Konstantinos Zografos, Anurag Agrawal, Alexandre Aubourg, Manuel Barreiro-de Acosta, Jesús Barrio, Daniel Bergemalm, Fernando Bermejo, Giorgia Bodini, Johan Bohr, Dimitrios Christodoulou, Christophe Claessens, Paul Collins, Ruth de Francisco, Santiago Garcia, Sotirios Georgopoulos, Felix Goutorbe, Chrisostomos Kalantzis, Anastasia Kourikou, Vincent Mace, Georgia Malamut, Paula Ministro, Isabelle Nion Larmurier, Elena Ricart, Mélanie Serrero, Juliette Sheridan, Petra Weimers, Vibeke Andersen, Bruno Arroja, Bernd Bokemeyer, Luis Bujanda, Thibault Degand, Carl Eriksson, Cécile Garceau, Henning Glerup, Idan Goren, Lucina Jackson, Stéphane Koch, Francisco Mesonero, Ingrid Ordas, Pauline Riviere, Simone Saibeni, João Soares, Noémie Tavernier, Klaus Theede, Bella Ungar, Elke Bästlein, Antonio Gasbarrini, Andreas Protopapas, Wolfgang Reindl, Fabrizio Bossa, Ailsa Hart, Franz-Josef Heil, Anthony O'Connor, Bas Oldenburg, Luca Pastorelli, null Stephen patchett, Subramaniam Ramakrishnan, John de Caestecker, Ana Echarri, David Kevans, Jürgen Büning, Rosa Coelho, Jeroen Jansen, Benjamin Koslowski, Christopher Wells, Daniel Ceballos, Ingrid König, Hari Padmanabhan, Timi Patani, Raheel Qureshi, Matthieu Allez, Emmanouil Archavlis, Delphine Bonnet, Luisa Guidi, Deirdre Mcnamara, Piero Vernia, Michael Weidenhiller, Lang Alon, Trine Boysen, Charlotte Delattre, Richard Farrell, Rolf-Achim Krüger, Thierry Paupard, Ida Vind, Flavio Caprioli, Vladimir Gancho, Vincent Quentin, Benjamin Avidan, Geert D’Haens, Jane Mccarthy, Jonathon Snook, Konstantinos Soufleris, Frank Zerbib, Dan Carter, Annekatrien Depla, Thomas Eisenbach, Walter Fries, Nikolaos Grammatikos, Saskia Ilegems, Antonio Lopez-Sanroman, Jacques Moreau, Gabriele Riegler, Svend Rietdijk, Marta Rocha, Isabelle Rosa, Barbara Ryan, Yelena Yeremenko, Arnaud Boruchowicz, Filipe Damião, Foteini Laoudi, Andreas Lügering, Giampiero Macarri, Konstantinos Thomopoulos, Luísa Barros, Thomas Blixt, Aurélien Garros, Sam Khorrami, Harry Sokol, Andreas Sturm, Dan Livovsky, Jochen Maul, Heinrich Miks, Vasileios Papadopoulos, Carsten Schmidt, Yifat Snir, Lise Svenningsen, Wafaa Ahmed, Yelena Broitman, Emmanuel Cuillerier, Prashant Kant, Jan Leyden, Lev Lichtenstein, Susana Lopes, Chloé Martineau, Hugh Mulcahy, Axel Schweitzer, Fiona Van Schaik, Hagar Banai, Pauline Danion, Charlotte Dulery, Herma Fidder, Claire Gay, Hervé Hagege, Florence Harnois, Søren Peter Jørgensen, Jens Müller-Ziehm, Michail Oikonomou, Carolina Palmela, Jörg Schulze/Röske, Mark Smith, Tamar Thurm, Francesca Bresso, Hedia Brixi, John Jones, Padraig Macmathuna, Claire Painchart, Yulia Ron, Marianne Vester-Andersen, Gonçalo Alexandrino, Norbert Börner, Mariana Cardoso, Cristina Chagas, Axel Dignaß, Iris Dotan, Charlotte Hedin, Pantelis Karatzas, Panagiotis Kasapidis, Károly Palatka, Georgios Sakizlis, Ana Wilson, Nick Bosanko, Paulo Caldeira, Charlotte Gagniere, Louise Libier, Camille Meunier, Gero Moog, Audrey Pasquion, Roberta Pica, Ayesha Akbar, Nadia Arab, Guillaume Cadiot, João Carvalho, Claire Charpignon, Laus Fellermann, Sigal Fishman, Gerald Fraser, Nathan Gluck, Mark Hoesl, Jarosław Kierkus, Maria Klopocka, Eduardo Martin Arranz, Luis Menchen, Susanna Nikolaus, Anca Petrache, Cyriel Ponsioen, Sabino Riestra, Pilar Robledo, Cristina Rodriguez, Misheal Samer, Matthias Tischer, Joanna Wypych, Julien Baudon, Cristina Bezzio, Gilles Boschetti, Tom Creed, Maria Giulia Demarzo, Stefano Festa, Andrés Figueroa, Mette Julsgaard, Pablo Navarro, Pablo Perez-Galindo, Cléa Rouillon, Emanuele Sablich, Joan Tosca, Mathias Vidon, Marine Vidon, René-Louis Vitte, Anne Wampach, Isabelle Clerc Urmes, Marc Borie, Mathieu Uzzan, Kelly Chatten, Rimmer Peter, Iqbal Tariq, Marta Cossignani, Fiorella Cañete, Tom Holvoet, Susanne Krasz, Sandra Dias, Hadas Abalia, Aziza Abaza, Gal Abramovich, Ingrid Ackzell, Carol Adams, Catherine Addleton, Erika Alfambra, Alicia Algaba, Clare Allcock, Joanna Allison, Karine Amouriaux, Julie Anderson, Emma Anderson, Saskia Appelmans, Lisa Armstrong, Stacey Atkins, Masoumeh Attaran-Bandarabadi, Yvonne Bailey, Stephanie Bardot, Natasha Beck, Lillie Bennett, Jonathan Phil Bergfeld, Ramdane Berkane, Hanne Boey, Louise Bowlas, Joanne Bradley-Potts, Tracy Brear, Nicole Bretlander-Peters, Ellen Brown, Johanna Brown, Elizabeth Buckingham, Katrien Buellens, Rhian Bull, Maura Burke, Leighanne Burns, Julie Burton, Agness Bwalya, Karine Cabanas, Muriel Callaghan, Océane Camou, Debbie Campbell, Elvira Capoferro, Mandy Carnahan, Cornelia Carnio, Anne Carter, Concetta Casali Clack, Leïla Chedouba, Bessie Cipriano, Sophie Claeys, Manon Closset, Dilek Coban, Sara Cococcia, Carolann Coe, Helen Cole, Emilie Collet, Kayleigh Collins, Isabelle Combes, Emma Connor, Kathryn Constantin, Susan Cooke, Nathanaëlle Cornet, Estelle Corrihons, Pilar Corsino, Rosie Cortaville, Donna Cotterill, Amanda Cowton, Harriet Cox, Viktoria Cripps, Amanda Crowder, Tzufit Cukier, Amelia Daniel, Chris Dawe, Jose de Haan, Rosanna de la Croix, Evva Dejonckheere, Juan Delare Villanegro, Guillaume Delaval, Mariangela Delliponti, Aude Delommez, Emilie Detry, Melanie Dhanaratne, Laura Diez Galan, Marie Dodel, Emma Dooks, Joseph Du Cheyron, Linda Duane, Jennifer Dulling Vulgo Cochran, Simona Dyer, Harvey Dymond, Charlotte Ekblad, Kerry Elliott, Ingrid Emmerson, Irène Eugene-Jolchine, Lorna Fleming, Eve Fletcher, Sarah Ford, Greg Forshaw, Angela Foulds, Caroline Francois, Nicole Fuge, Gal Gafni, Miri Ganon, Olga Garcia Nuñez, Laura Garcia Ramirez, Sophie Gelder, Raimonda Gettkowski, Daniela Gilardi, Paolo Giuffrida, Vincent Gobert, Jo Godden, Nuala Godwin, Kay Goulden, Sharon Graham, Charlotte Green, Marie Green, Aboubakar Gueye, Tuba Guler, Ida Gustavsson, Helena Hadjisavvas, Fiona Hammonds, Christina Hantzi, Marion Hauke, Julie Haydock, Orla Hayes, Lizette Helbo Nislev, Jessica Hochstodter, Ashleigh Hogg, Manuela Hölbing, Maureen Holland, Maartje Holsbergen, Linda Howard, Aviya Hoyda, Robert Hull, Jane Irish, Wendy Jackson, Wendy Janssen, Lesley Jeffrey, Sofia Jourdan, Izabela Jutrowska, Chava Kaniel, Theofilos Karezos, Niamh Kelly, Jessica Kelly, Mary Kennedy, Una Kennedy, Joyce Kibaru, Gemma Kirkman, Janine Klaproth, Corinna Kneese, Andrea Koch, Kathleen Kokke, Martha Koppelow, Sabine Krause, Sabine Krauspe, Petra Kwakkenbos, Nunzia Labarile, Hannah Lang, Marianne Lassailly, Martine Leconte, Linda Lepczynski, Emma Levell, Nina Levhar, Kerstin Lindhort, Jessica Lisle, Beatriz Lopez Cauce, Gabriele Lorenz, Ambra Lovati, Tracey Lowry, Margareta Lund, Anne Lutz Vorderbrügge, Suzanne Maansson, Videsheka Madapathage, Maelys Cheviakoff, Alison Magness, Orla Manley, Catherine Manyoni, Ingke Marg, Antonella Marra, Carole Martins, Arianna Massella, Aurore Mathias, Danielle Mervyn, Charlotte Minsart, Sally Mitchell, Kathleen Monks, Mélanie Montero, Alson Moore, Maren Moser, Alison Moss, Angela Mullen, M. Francisca Murciano, Deanna Naylor, Ansgar Nehus, Anne Nicholson, Sarah Nöding, Sinead Nolan, Janet Nörenberg, Clare Northcott, Jim O'Connell, Alison O’Kelly, Noam Orbach-Zingboim, Judit Orobitg, Charlene Otieno, Charlotte Owen, Sarah Patch, Maor Pauker, Renate Pauli, Harriet Pearson, Falgon Peggy, Séverine Petit, Christine Petrissans, Simona Piergallini, Lucy Pippard, Laura Pitt, Gabriella Pócsik, Yoann Poher, Chloé Pomes, Lucy Pritchard, Laura Puchades, Sheena Quaid, Aleem Rana, Dana Raynard, Mykla Reilly, Sonja Reinert, Manuela Reinknecht, Baerbel Renner, Rob Reynolds, Giulia Rizzuto, Matthew Robinson, Joke Robrechts, Eva M. Rodriguez, Efrat Rosenblum, Tamlyn Russel, Ibiyemi Sadare, Noa Salama, Toos Schakel, Anja Schauer, Elisa Schiavoni, Caroline Shaw, Sarah Shelton, Virginie Sicart, Elodie Siouville, Orla Smith, Théo Soude, Sophie Stephenson, Elaine Stephenson, Marjan Steppe, An Sterkx, Jo Stickley, Kathleen Sugrue, Natalia Swietec, Charlotte Tasiaux, Bhavneet Thamu, Susane Thomas, Ogwa Tobi, Kahina Touabi, Shifra Tovi, Julie Tregonning, Laura Turchini, Julia Unkhoff, Olesya Unruh, Nurcan Uzun, Frauke Van Aert, Sandrine Vanden Bergh, Louise Vandenbroucke, Laura Vansteenkiste, Shay Vardit, Valentin Vergriete, Elaine Walker, Eleanor Warner, Olivia Watchorn, Ekaterina Watson, Marie-Claire Wauthier, Belgium Maria Weetman, Margaret Weston, Wiebke West-Petroschka, Susann Wienecke, Kerstin Wierling, Miriam Wiestler, Rebecca Wilcox, Elva Wilhelmsen, Angharad Williams, Georgina Williamson, Deborah Wilson, Kate Wistance, Nicolas Wortmann, Subie Wurie, Karin Yadgar, Gail Young, Megan Young, Julien Aucouturier, Marie- Jo Bertin, Hasnae Bougrine, Marie Coisnon, Antoine Defrance, Kati Gutierrez, Amel Harouz, Laure Jerber, Aida Khlifi, Amina Kirati, Nasaladjine Liworo, Maude Logoltat, Charlotte Mailhat, Chancely M'Bayi, Yasmina Medane, Dalal Merkhoufa, Saouda Mohamed Elhad, Bertille Monthe, Fanny Moyon, Pascaline Rabiega, Jennifer Sekela, Charlotte Thilloy, Naima Hamamouche, Frederic Partisotti, Patrick Blandin, Hocine Mokhtari, Laure Coutard, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de gastro-entérologie, Gastroenterology and hepatology, Gastroenterology and Hepatology, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism

Subjects
Biological Products, Hepatology, Efficacy, Lymphoma, Tumor Necrosis Factor-alpha, Inflammatory Bowel Disease, Gastroenterology, Biologics, Crohn Disease/diagnosis, Inflammatory Bowel Diseases/chemically induced, Colitis, Ulcerative/diagnosis, Cohort Studies, Necrosis, Immunologic Factors/adverse effects, Humans, Female, 03.02. Klinikai orvostan, Prospective Studies, Safety, I-CARE, Cancer, Immunosuppressive Agents
Abstract

BACKGROUND AND AIMS: There is a need to evaluate the benefit-risk ratio of current therapies in inflammatory bowel disease (IBD) patients to provide the best quality of care. The primary objective of I-CARE (IBD Cancer and serious infections in Europe) was to assess prospectively safety concerns in IBD, with specific focus on the risk of cancer/lymphoma and serious infections in patients treated with anti-tumor necrosis factor and other biologic monotherapy as well as in combination with immunomodulators.METHODS: I-CARE was designed as a European prospective longitudinal observational multicenter cohort study to include patients with a diagnosis of Crohn's disease, ulcerative colitis, or IBD unclassified established at least 3 months prior to enrollment.RESULTS: A total of 10,206 patients were enrolled between March 2016 and April 2019, including 6169 (60.4%) patients with Crohn's disease, 3853 (37.8%) with ulcerative colitis, and 184 (1.8%) with a diagnosis of IBD unclassified. Thirty-two percent of patients were receiving azathioprine/thiopurines, 4.6% 6-mercaptopurine, and 3.2% methotrexate at study entry. At inclusion, 47.3% of patients were treated with an anti-tumor necrosis factor agent, 8.8% with vedolizumab, and 3.4% with ustekinumab. Roughly one-quarter of patients (26.8%) underwent prior IBD-related surgery. Sixty-six percent of patients had been previously treated with systemic steroids. Three percent of patients had a medical history of cancer prior to inclusion and 1.1% had a history of colonic, esophageal, or uterine cervix high-grade dysplasia.CONCLUSIONS: I-CARE is an ongoing investigator-initiated observational European prospective cohort study that will provide unique information on the long-term benefits and risks of biological therapies in IBD patients. (EudraCT, Number: 2014-004728-23; ClinicalTrials.gov, Number: NCT02377258).

Published
2022
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46. Efficacy and Safety of Infliximab Retreatment in Crohn's Disease: A Multicentre, Prospective, Observational Cohort (REGAIN) Study from the GETAID

Author

Gilles Boschetti, Maria Nachury, David Laharie, Xavier Roblin, Cyrielle Gilletta, Alexandre Aubourg, Arnaud Bourreille, Camille Zallot, Xavier Hebuterne, Anthony Buisson, Jean-Charles Grimaud, Yoram Bouhnik, Matthieu Allez, Romain Altwegg, Stéphanie Viennot, Lucine Vuitton, Franck Carbonnel, Stéphane Paul, Kristell Desseaux, Jérome Lambert, and Laurent Peyrin-Biroulet

Subjects
Adult, Treatment Outcome, Hepatology, Crohn Disease, Gastrointestinal Agents, Retreatment, Gastroenterology, Humans, Prospective Studies, Antibodies, Infliximab
Abstract

The objective of this study was to describe the efficacy and safety of infliximab (IFX) reintroduction in Crohn's disease (CD) after stopping for loss of response or intolerance.We conducted a prospective multicenter observational cohort study including adult patients with clinically (CD Activity Indexgt;150) and objectively active luminal CD in whom IFX was reintroduced after at least 6 months of discontinuation. The reasons for the initial discontinuation could be a secondary loss of response or IFX intolerance. The reintroduction schedule included 3 IFX infusions at weeks 0, 4, and 8, after a systematic premedication. The primary end point was the efficacy of IFX retreatment at week 26 defined by a CD Activity Index oflt;150 in the absence of IFX discontinuation or use of corticosteroids, surgery, or other biologic.At week 26, 24 patients (35%) among the 69 analyzed reached the primary end point. No significant difference was observed between rates of clinical remission at week 26 in patients with prior LOR (n = 48) and those with IFX intolerance (n = 21) (35% and 33%, P = 0.87, respectively). Thirty-two acute infusion reactions were recorded in 27 patients, leading to withdrawal of IFX in 20 patients. No pharmacokinetic characteristic at baseline but detection of positive anti-drug antibodies at week 4 was predictive of IFX failure or infusion reaction at week 26.In this first prospective cohort study, IFX retreatment was safe and effective in one-third of the patients with CD, regardless the reason of prior discontinuation. Early detection of anti-drug antibodies can predict subsequent IFX reintroduction failure and infusion reactions.

Published
2021

47. Mitochondrial impairment drives intestinal stem cell transition into dysfunctional Paneth cells predicting Crohn’s disease recurrence

Author

Matthieu Allez, Elisabeth Gleisinger, Nadine Waldschmitt, Andreas Blutke, Nassim Hammoudi, Dirk Haller, Sevana Khaloian, Emanuel Berger, Eva Rath, Amira Metwaly, and Pieter Giesbertz

Subjects
Inflammatory Bowel Disease, intestinal stem cell, Gastroenterology, LGR5, Inflammation, Mitochondrion, Biology, medicine.disease, digestive system, Intestinal epithelium, Inflammatory bowel disease, ddc, Crohn's disease, medicine.anatomical_structure, energy metabolism, Paneth cell, medicine, Cancer research, intestinal epithelium, Ileitis, Stem cell, medicine.symptom
Abstract

ObjectiveReduced Paneth cell (PC) numbers are observed in inflammatory bowel diseases and impaired PC function contributes to the ileal pathogenesis of Crohn’s disease (CD). PCs reside in proximity to Lgr5+ intestinal stem cells (ISC) and mitochondria are critical for ISC-renewal and differentiation. Here, we characterise ISC and PC appearance under inflammatory conditions and describe the role of mitochondrial function for ISC niche-maintenance.DesignIleal tissue samples from patients with CD, mouse models for mitochondrial dysfunction (Hsp60Δ/ΔISC) and CD-like ileitis (TNFΔARE), and intestinal organoids were used to characterise PCs and ISCs in relation to mitochondrial function.ResultsIn patients with CD and TNFΔARE mice, inflammation correlated with reduced numbers of Lysozyme-positive granules in PCs and decreased Lgr5 expression in crypt regions. Disease-associated changes in PC and ISC appearance persisted in non-inflamed tissue regions of patients with CD and predicted the risk of disease recurrence after surgical resection. ISC-specific deletion of Hsp60 and inhibition of mitochondrial respiration linked mitochondrial function to the aberrant PC phenotype. Consistent with reduced stemness in vivo, crypts from inflamed TNFΔARE mice fail to grow into organoids ex vivo. Dichloroacetate-mediated inhibition of glycolysis, forcing cells to shift to mitochondrial respiration, improved ISC niche function and rescued the ability of TNFΔARE mice-derived crypts to form organoids.ConclusionWe provide evidence that inflammation-associated mitochondrial dysfunction in the intestinal epithelium triggers a metabolic imbalance, causing reduced stemness and acquisition of a dysfunctional PC phenotype. Blocking glycolysis might be a novel drug target to antagonise PC dysfunction in the pathogenesis of CD.

Published
2020
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48. Impact de la COVID-19 sur l’initiation des prescriptions des biothérapies dans les maladies inflammatoires chroniques

Author

Milka Maravic, Lucas Perray, Matthieu Allez, Augustin Latourte, Simon Pilet, Pascal Richette, and Vincent Descamps

Subjects
2019-20 coronavirus outbreak, biologie, Rheumatology, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19, Medicine, business, Virology, Article, traitement
Published
2022
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49. Role of adherent and invasive

Author

Anthony, Buisson, Harry, Sokol, Nassim, Hammoudi, Stéphane, Nancey, Xavier, Treton, Maria, Nachury, Mathurin, Fumery, Xavier, Hébuterne, Michael, Rodrigues, Jean-Pierre, Hugot, Gilles, Boschetti, Carmen, Stefanescu, Pauline, Wils, Philippe, Seksik, Lionel, Le Bourhis, Madeleine, Bezault, Pierre, Sauvanet, Bruno, Pereira, Matthieu, Allez, Nicolas, Barnich, and Patricia, Detre

Abstract

We used the postoperative recurrence model to better understand the role of adherent and invasiveFrom a prospective, multicentre cohort of operated patients with CD, AIEC identification was performed within the surgical specimen (M0) (N=181 patients) and the neoterminal ileum (n=119 patients/181) during colonoscopy performed 6 months after surgery (M6). Endoscopic postoperative recurrence was graded using Rutgeerts' index. The mucosa-associated microbiota was analysed by 16S sequencing at M0 and M6. Relative risks or ORs were adjusted on potential confounders.AIEC prevalence was twofold higher within the neoterminal ileum at M6 (30.3%) than within the surgical specimen (14.9%) (p0.001). AIEC within the neoterminal ileum at M6 was associated with higher rate of early ileal lesions (i1) (41.6% vs 17.1%; aRR 3.49 (95% CI 1.01 to 12.04), p=0.048) or ileal lesions (i2b+i3) (38.2% vs 17.1%; aRR 3.45 (95% CI 1.06 to 11.30), p=0.040) compared with no lesion (i0). AIEC within the surgical specimen was predictive of higher risk of i2b-endoscopic postoperative recurrence (POR) (aOR 2.54 (95% CI 1.01 to 6.44), p=0.049) and severe endoscopic POR (aOR 3.36 (95% CI 1.25 to 9.06), p=0.017). While only 5.0% (6/119) of the patients were AIEC-positive at both M0 and M6, 43.7% (52/119), patients with history of positive test for AIEC (M0 or M6) had higher risk of ileal endoscopic POR (aOR 2.32 (95% CI 1.01 to 5.39), p=0.048)), i2b-endoscopic postoperative recurrence (aOR 2.41 (95% CI 1.01 to 5.74); p=0.048) and severe endoscopic postoperative (aOR=3.84 (95% CI 1.32 to 11.18), p=0.013). AIEC colonisation was associated with a specific microbiota signature including increased abundance ofBased on the postoperative recurrence model, our data support the idea that AIEC are involved in the early steps of ileal CD.NCT03458195.

Published
2021

50. Meta-Analysis of IBD Gut Samples Gene Expression Identifies Specific Markers of Ileal and Colonic Diseases

Author

Kevin Perez, Marjolaine Ngollo, Keren Rabinowitz, Nassim Hammoudi, Philippe Seksik, Ramnik J Xavier, Mark J Daly, Iris Dotan, Lionel Le Bourhis, and Matthieu Allez

Subjects
Inflammation, Crohn Disease, Ileum, Gastroenterology, Immunology and Allergy, Humans, Colitis, Ulcerative, Pouchitis, Inflammatory Bowel Diseases, Transcriptome, digestive system, digestive system diseases, Biomarkers
Abstract

Background Inflammatory bowel diseases (IBDs) are characterized by chronic inflammation and tissue damages in limited segments of the digestive tract. Pathogenesis in the tissue and mucosal inflammation probably differs according to disease location. Our aim was to further analyze transcriptomic profiles in different locations of IBD, differentiating ulcerative colitis (UC), colonic Crohn’s disease (CD), ileal CD, and pouchitis, with respect to normal colonic and ileal mucosa. We thus performed a meta-analysis focusing on specific transcriptomic signatures of ileal and colonic diseases. Methods We identified 5 cohorts with available transcriptomic data in ileal or colonic samples from active IBD and non-IBD control samples. The meta-analysis was performed on 1047 samples. In each cohort separately, we compared gene expression in CD ileitis and normal ileum; in CD colitis, UC, and normal colon; and finally in pouchitis and normal ileum. Results We identified specific markers of ileal (FOLH1, CA2) and colonic (REG3A) inflammation and showed that, with disease, some cells from the ileum start to express colonic markers. We confirmed by immunohistochemistry that these markers were specifically present in ileal or colonic diseases. We highlighted that, overall, colonic CD resembles UC and is distinct from ileal CD, which is in turn closer to pouchitis. Conclusions We demonstrated that ileal and colonic diseases exhibit specific signatures, independent of their initial clinical classification. This supports molecular, rather than clinical, disease stratification, and may be used to design drugs specifically targeting ileal or colonic diseases.

Published
2021

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