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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. 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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3. Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE)

Author

William J Sandborn, Séverine Vermeire, Laurent Peyrin-Biroulet, Marla C Dubinsky, Julian Panes, Andres Yarur, Timothy Ritter, Filip Baert, Stefan Schreiber, Sheldon Sloan, Fabio Cataldi, Kevin Shan, Christopher J Rabbat, Michael Chiorean, Douglas C Wolf, Bruce E Sands, Geert D'Haens, Silvio Danese, Martina Goetsch, Brian G Feagan, Gastroenterology and Hepatology, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism

Subjects
General Medicine
Abstract

BACKGROUND: Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis. METHODS: In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (modified Mayo score [MMS]; 4-6 vs 7-9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively. FINDINGS: Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients vs ten [7%] of 135 patients; p

Published
2023

5. An Expert Consensus to Standardize Assessment of Bowel Cleansing for Clinical Trials of Bowel Preparations for Crohn’s Disease

Author

Jennifer K. Maratt, Corey A. Siegel, Alan N. Barkun, Yoram Bouhnik, Brian Bressler, Audrey H. Calderwood, James E. East, Monika Fischer, Johannes Grossmann, Joshua R. Korzenik, Stacy B. Menees, Julian Panes, Douglas K. Rex, Michael S. L. Sey, Michael K. Allio, K. Adam Baker, Leonardo Guizzetti, Julie Remillard, Rocio Sedano, Brian G. Feagan, Christopher Ma, and Vipul Jairath

Subjects
Physiology, Gastroenterology
Abstract

Despite regular need for colonoscopy in patients with Crohn's disease (CD), the efficacy and tolerability of bowel preparation (BP) agents is rarely assessed in this population. Assessing BP quality with existing scales may be challenging in CD due to presence of inflammation, bowel resection, and strictures.To provide recommendations for assessing BP quality in clinical trials for CD using a modified Research and Development/University of California, Los Angeles appropriateness process.Based on systematic reviews and a literature search, 110 statements relating to BP quality assessment in CD were developed. A panel of 15 gastroenterologists rated the statements as appropriate, uncertain, or inappropriate using a 9-point Likert scale.Panelists considered it appropriate that central readers, either alone or with local assessment, score BP quality in clinical trials. Central readers should be trained on scoring BP quality and local endoscopists on performing high-quality video recording. Both endoscope insertion and withdrawal phases should be reviewed to score BP quality in each colonic segment and segments should align with endoscopic disease activity indices. The Harefield Cleansing Scale and the Boston Bowel Preparation Scale were considered appropriate. The final score should be calculated as the average of all visualized segments. Both total and worst segment scores should also be assessed.We developed a framework for assessing BP quality in patients with CD based on expert feedback. This framework could support the development or refinement of BP quality scales and the integration of BP quality assessment in future CD studies.

Published
2022

6. Effect of risankizumab on health‐related quality of life in patients with Crohn's disease: results from phase 3 <scp>MOTIVATE</scp> , <scp>ADVANCE</scp> and <scp>FORTIFY</scp> clinical trials

Author

Laurent Peyrin‐Biroulet, Subrata Ghosh, Scott D. Lee, Wan‐Ju Lee, Jenny Griffith, Kori Wallace, Sofie Berg, Xiaomei Liao, Julian Panes, Edward V. Loftus, and Edouard Louis

Subjects
Hepatology, Gastroenterology, Pharmacology (medical)
Abstract

Crohn's disease has a substantial negative impact on health-related quality of life (HRQoL).To examine the effects of risankizumab on HRQoL in Crohn's disease METHODS: We analysed data from patients with Crohn's disease from 12-week induction trials ADVANCE (N = 850) and MOTIVATE (N = 569) with risankizumab 600 mg or 1200 mg intravenous (IV) versus placebo IV and a 52-week maintenance trial FORTIFY (N = 462) with risankizumab 180 or 360 mg subcutaneous (SC) versus placebo SC. Outcomes included Inflammatory Bowel Disease Questionnaire (IBDQ), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), 36-item Short Form Health Survey (SF-36), EuroQol 5-Dimension-5-Level (EQ-5D-5L) and work productivity. The mean change and percentages of patients achieving clinically meaningful improvement in all outcomes were determined at weeks 12 and 52.At week 12, more patients in the risankizumab 600 or 1200 mg groups achieved IBDQ response than with placebo (ADVANCE: 70.2%, 75.5% vs. 47.8%, p ≤ 0.001; MOTIVATE: 61.7%, 68.5% vs. 48.2%, p ≤ 0.01) and FACIT-F response (ADVANCE: 51.3%, 48.0% vs. 35.7%, p ≤ 0.01; MOTIVATE: 44.2%, 49.1% vs. 33.7%, p 0.05). These improvements persisted at week 52 with risankizumab maintenance treatment. Similar trends were observed for SF-36 physical and mental component summary scores, EQ-5D-5L and activity impairment within work productivity measures.Risankizumab induction therapy (600 or 1200 mg IV) led to clinically meaningful improvements in disease-specific and general patient-reported outcomes, including fatigue, in patients with moderate to severe Crohn's disease. These improvements were sustained after 52 weeks of risankizumab (180 or 360 mg SC) maintenance therapy.

Published
2022

7. 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

8. 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

9. Real-world multicentre observational study including population pharmacokinetic modelling to evaluate the exposure-response relationship of vedolizumab in inflammatory bowel disease: ERELATE Study

Author

Niels Vande Casteele, William J. Sandborn, Brian G. Feagan, Séverine Vermeire, Parambir S. Dulai, Andres Yarur, Xavier Roblin, Shomron Ben‐Horin, Iris Dotan, Mark T. Osterman, Maria Rosario, Teresa McRorie Osborn, Julian Panes, Dirk Lindner, and Christian Agboton

Subjects
Adult, Male, MAINTENANCE THERAPY, Antibodies, Monoclonal, Humanized, FREQUENCY, Crohn Disease, Gastrointestinal Agents, TROUGH LEVELS, Humans, Pharmacology (medical), Pharmacology & Pharmacy, Retrospective Studies, OUTCOMES, Science & Technology, Hepatology, Gastroenterology & Hepatology, Remission Induction, Gastroenterology, Bayes Theorem, ASSOCIATION, REMISSION, Inflammatory Bowel Diseases, INDUCTION THERAPY, CROHNS-DISEASE, Treatment Outcome, ULCERATIVE-COLITIS, Colitis, Ulcerative, Female, Life Sciences & Biomedicine
Abstract

BACKGROUND: ERELATE was a phase 4, multinational, retrospective, observational study. AIM: To evaluate the relationship between intravenous vedolizumab exposure and treatment outcomes over 52 weeks in adults with ulcerative colitis (UC) or Crohn's disease (CD). METHODS: Real-world data from patients with UC or CD treated with intravenous vedolizumab in nine centres in six countries were collected retrospectively. Treatment outcomes were collected at Weeks 14, 26 and 52. An established population pharmacokinetic model (incorporating observed vedolizumab concentrations based on a Bayesian approach) was used to predict individual vedolizumab exposure. Vedolizumab exposure-response relationship was evaluated overall, by indication and based on baseline characteristics. RESULTS: The study population (n = 695; UC, n = 304; CD, n = 391) had a median age of 39 years; 47.9% were male and 86.9% had prior tumour necrosis factor antagonist exposure. By Week 14, clinical, endoscopic, deep (clinical plus endoscopic) and biologic remission was achieved by 47.3%, 59.6%, 30.7% and 19.0% of patients respectively. Higher vedolizumab trough concentration early in treatment was consistently associated with clinical remission at later time points. Clinical remission at Week 14 and Week 52 was associated with Week 6 trough concentrations of ≥31.0 and ≥32.0 μg/ml respectively. Importantly, multivariable analysis identified baseline clearance as the only exposure measure predictive of clinical and deep remission at Week 52. CONCLUSIONS: In this real-world study, a positive exposure-response relationship was observed for vedolizumab. Vedolizumab concentration during induction may be an important predictor of short- and long-term outcomes, and similarly, vedolizumab baseline clearance may be an important predictor of remission. ispartof: ALIMENTARY PHARMACOLOGY & THERAPEUTICS vol:56 issue:3 pages:463-476 ispartof: location:England status: published

Published
2022

10. 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

12. 867f: EFFICACY AND SAFETY OF UPADACITINIB INDUCTION THERAPY IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE CROHN'S DISEASE WHO FAILED PRIOR BIOLOGICS: RESULTS FROM A RANDOMIZED PHASE 3 U-EXCEED STUDY

Author

Jean-Frederic Colombel, Julian Panes, Ana P. Lacerda, Laurent Peyrin-Biroulet, Geert R. D'Haens, Remo Panaccione, Walter Reinisch, Edouard Louis, Minhu Chen, Hiroshi Nakase, Susan Greenbloom, George DuVall, Yuri Sanchez Gonzalez, Mohamed-Eslam F. Mohamed, Susan Rhee, Qian Zhou, and Edward V. Loftus

Subjects
Hepatology, Gastroenterology
Published
2022

13. 884a: THE IDEAL STUDY: A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, MULTI-CENTER STUDY TO EVALUATE THE SAFETY AND EFFICACY OF THE ORAL α4β7 INTEGRIN PEPTIDE ANTAGONIST PN-943 IN PATIENTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS

Author

Scott E. Plevy, Julian Panes, Geert R. D'Haens, Vipul Jairath, Brian G. Feagan, Suneel K. Gupta, CC Hwang, Bruce E. Sands, Alessandro Armuzzi, Walter Reinisch, Stefan Schreiber, and William J. Sandborn

Subjects
Hepatology, Gastroenterology
Published
2022

14. 968a: ETRASIMOD 2MG ONCE DAILY AS TREATMENT FOR MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS: RESULTS FROM THE PHASE 3 ELEVATE UC 52 AND ELEVATE UC 12 TRIALS

Author

William J. Sandborn, Severine Vermeire, Laurent Peyrin-Biroulet, Marla C. Dubinsky, Julian Panes, Andres J. Yarur, Timothy E. Ritter, Filip J. Baert, Sheldon Sloan, Fabio Cataldi, Kevin Shan, Christopher J. Rabbat, Michael V. Chiorean, Douglas C. Wolf, Bruce E. Sands, Geert D'Haens, Silvio Danese, Martina Goetsch, and Brian G. Feagan

Subjects
Hepatology, Gastroenterology
Published
2022

15. A phase II study of laquinimod in Crohnʼs disease

Author

DʼHaens, Geert, Sandborn, William J, Colombel, Jean Frederic, Rutgeerts, Paul, Brown, Kurt, Barkay, Hadas, Sakov, Anat, Haviv, Asi, Feagan, Brian G, Baert, Filip, Dupas, Jean-Louis, Bouhnik, Yoram, Bonaz, Bruno, Hebuterne, Xavier, Allez, Matthieu, Israeli, Eran, Fraser, Gerald, Segol, Ori, Fishman, Sigal, Lahat, Adi, Melzer, Ehud, Pallone, Francesco, Campieri, Massimo, Gasbarrini, Antonio, Kohn, Anna, Vecchi, Maurizo, Ponsioen, Cyriel, Van der Woude, Janneke, Rydzewska, Grazyna, Mach, Tomasz, Paradowski, Leszek, Wright, John Philip, Watermeyer, Gillian Ann, Pettengell, Keith Edward, Mahomed, Adam Dawood, Prins, Maarten Jeroen, Aboo, Nazimuddin, Diaz, Julian Panes, Taxonera, Carlos, Gisbert, Javier, Hinojosa, Joaquin, Garcia, Fernand Gomollon, Sanchez, Valle Garcia, Parkes, Miles, Probert, Chris, Leiper, Keith, Nwokolo, Chuka, Mayberry, John, and Bloom, Stuart

Published
2015
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16. Challenges and Opportunities in IBD Clinical Trial Design

Author

Marla C. Dubinsky, Rory Collins, Maria T. Abreu, Vipul Jairath, James D. Lewis, James Lindsay, Miriam Merad, Siew Ng, Remo Panaccione, Julian Panes, Bruce Sands, Corey A. Siegal, Siddarth Singh, Severine Vermeire, Vineet Ahuja, Matthieu Allez, Ashwin Ananthakrishnan, Willem Bemelman, Jonathan Braun, Jean-Frederic Colombel, Silvio Danese, Geert D’Haens, André D’Hoore, Axel Dignass, Iris Dotan, Miguel Angel Gassul, Anne Griffiths, Jonas Halfvarson, Stephen Hanauer, Paulo Kotze, Ioannis Koutroubakis, Edward Loftus, Edouard Louis, Fernando Magro, Gerassimos Mantzaris, Jean-Yves Mary, Dermot McGovern, Pia Munkholm, Colm O’Morain, Yves Panis, Laurent Peyrin-Biroulet, Cosimo Prantera, Zhihua Ran, Britta Siegmund, Mark Silverberg, Eduard Stange, Stephan Targan, Curt Tysk, Simon Travis, Morton Vatn, Yesus Yamamoto-Furusho, Janske Aarts, Brihad Abhyankar, Harris Ahmad, Richard Aranda, Vipin Arora, Jalil Benjacoub, Sofie Berg, Robin Besuyen, Daniela Bojic, Valerio Carriero, Fabio Cataldi, Laurence D’Agay, Silvia Delgado-Aros, Paul Giannasca, Kavitha Goyal, Roland Greinwald, Savion Gropper, Shunsuke Kageyama, Raphaël Laoun, Barrett Levesque, Trevor Lissoos, Irene Modesto, Ralf Mohrbacher, Ralph Mueller, April Naegeli, Snehal Naik, Deanne Nguyen, Wojciech Niezychowski, Caitriona O’Brien, Irina Odnoletkova, Alessandra Oortwijn, Kun K.T. Park, Waldemar Radziszewski, Leonardo Salese, Johannes Spleiss, Andrea Stancati, Amanda Tatro, Jennifer Thompson, Robert Hofmann, Javier Zambrano, Wen Zhou, Ellen Zigmont, Surgery, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Gastroenterology and Hepatology

Subjects
medicine.medical_specialty, Ibd clinical, Crohn's disease, Hepatology, business.industry, Inflammatory Bowel Disease, Gastroenterology, Crohn's Disease, medicine.disease, Ulcerative colitis, Crohn's Disease Activity Index, Inflammatory bowel disease, law.invention, Food and drug administration, Clinical trial, Randomized controlled trial, law, Internal medicine, medicine, Ulcerative Colitis, Clinical Trials, business
Published
2021

17. Defining Endpoints and Biomarkers in Inflammatory Bowel Disease: Moving the Needle Through Clinical Trial Design

Author

Maria T. Abreu, William J. Sandborn, Fabio Cataldi, Geert D'Haens, Brian G. Feagan, Stephen Hanauer, Vipul Jairath, Peter Lakatos, Christopher Leptak, Dermot McGovern, Andrew Mulberg, Julian Panes, Asit Parikh, Laurent Peyrin-Biroulet, Walter Reinisch, Robert Riddell, David Rubin, Bruce Sands, Johannes Spleiss, Richard Strauss, Swati Tole, Juli Tomaino, Gastroenterology and Hepatology, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism

Subjects
medicine.medical_specialty, Colon, MEDLINE, Anti-Inflammatory Agents, Inflammatory bowel disease, Severity of Illness Index, Text mining, Crohn Disease, Ileum, Internal medicine, Drug Discovery, medicine, Humans, Cecum, Crohn's disease, Clinical Trials as Topic, Hepatology, business.industry, Clinical study design, Gastroenterology, Colonoscopy, medicine.disease, Ulcerative colitis, Crohn's Disease Activity Index, Treatment Outcome, Research Design, Patient-reported outcome, Colitis, Ulcerative, business, Biomarkers
Published
2020

18. Macrophage and neutrophil heterogeneity at single-cell spatial resolution in human inflammatory bowel disease

Author

Alba Garrido-Trigo, Ana M. Corraliza, Marisol Veny, Isabella Dotti, Elisa Melón-Ardanaz, Aina Rill, Helena L. Crowell, Ángel Corbí, Victoria Gudiño, Miriam Esteller, Iris Álvarez-Teubel, Daniel Aguilar, M. Carme Masamunt, Emily Killingbeck, Youngmi Kim, Michael Leon, Sudha Visvanathan, Domenica Marchese, Ginevra Caratù, Albert Martin-Cardona, Maria Esteve, Ingrid Ordás, Julian Panés, Elena Ricart, Elisabetta Mereu, Holger Heyn, and Azucena Salas

Subjects
Science
Abstract

Abstract Ulcerative colitis and Crohn’s disease are chronic inflammatory intestinal diseases with perplexing heterogeneity in disease manifestation and response to treatment. While the molecular basis for this heterogeneity remains uncharacterized, single-cell technologies allow us to explore the transcriptional states within tissues at an unprecedented resolution which could further understanding of these complex diseases. Here, we apply single-cell RNA-sequencing to human inflamed intestine and show that the largest differences among patients are present within the myeloid compartment including macrophages and neutrophils. Using spatial transcriptomics in human tissue at single-cell resolution (CosMx Spatial Molecular Imaging) we spatially localize each of the macrophage and neutrophil subsets identified by single-cell RNA-sequencing and unravel further macrophage diversity based on their tissue localization. Finally, single-cell RNA-sequencing combined with single-cell spatial analysis reveals a strong communication network involving macrophages and inflammatory fibroblasts. Our data sheds light on the cellular complexity of these diseases and points towards the myeloid and stromal compartments as important cellular subsets for understanding patient-to-patient heterogeneity.

Published
2023
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20. Author Correction: Macrophage and neutrophil heterogeneity at single-cell spatial resolution in human inflammatory bowel disease

Author

Alba Garrido-Trigo, Ana M. Corraliza, Marisol Veny, Isabella Dotti, Elisa Melón-Ardanaz, Aina Rill, Helena L. Crowell, Ángel Corbí, Victoria Gudiño, Miriam Esteller, Iris Álvarez-Teubel, Daniel Aguilar, M. Carme Masamunt, Emily Killingbeck, Youngmi Kim, Michael Leon, Sudha Visvanathan, Domenica Marchese, Ginevra Caratù, Albert Martin-Cardona, Maria Esteve, Ingrid Ordás, Julian Panés, Elena Ricart, Elisabetta Mereu, Holger Heyn, and Azucena Salas

Subjects
Science
Published
2024
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22. Influenza Adverse Events in Patients with Rheumatoid Arthritis, Ulcerative Colitis, or Psoriatic Arthritis in the Tofacitinib Clinical Development Programs

Author

Kevin L. Winthrop, Arne Yndestad, Dan Henrohn, Silvio Danese, Sara Marsal, Maria Galindo, John C. Woolcott, Hyejin Jo, Kenneth Kwok, Andrea B. Shapiro, Thomas V. Jones, Annette Diehl, Chinyu Su, Julian Panés, and Stanley B. Cohen

Subjects
Ulcerative colitis, Rheumatoid arthritis, Psoriatic arthritis, JAK inhibitor, Safety, Tofacitinib, Diseases of the musculoskeletal system, RC925-935
Abstract

Abstract Introduction This post hoc analysis evaluated influenza adverse events (AEs) across rheumatoid arthritis (RA), ulcerative colitis (UC), and psoriatic arthritis (PsA) tofacitinib clinical programs. Methods Available data from phase 1, randomized phase 2/3/3b/4 clinical trials (completed by 2018), and long-term extension (LTE) studies (up to May 2019) in patients with RA, UC, and PsA were included [randomized or Overall (phase 1–3b/4 and LTE studies) tofacitinib cohorts]. Incidence rates (IRs; events per 100 patient-years) of combined influenza AEs (seasons 2004/2005 to 2018/2019) were analyzed, including by tofacitinib dose [5 or 10 mg twice daily (BID)] and age (

Published
2022
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28. Modified Mayo score Mayo score for evaluation of treatment efficacy in patients with ulcerative colitis: data from the tofacitinib OCTAVE program

Author

William J. Sandborn, Bruce E. Sands, Séverine Vermeire, Yvette Leung, Xiang Guo, Irene Modesto, Chinyu Su, Wenjin Wang, and Julian Panés

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Objectives: The subjectivity of the Physician Global Assessment (PGA) is a limitation of the Mayo score in assessing severity of ulcerative colitis (UC). We compared treatment efficacy using endpoint definitions based on modified Mayo (mMayo) score, versus those based on Mayo score, using data from the tofacitinib OCTAVE program. Design: This post hoc analysis included data from two 8-week induction studies (OCTAVE Induction 1 and 2) and a 52-week maintenance study (OCTAVE Sustain). Methods: Remission and clinical response [with nonresponder imputation (NRI)] were assessed using mMayo (without PGA) and Mayo scores, and further stratified by prior tumor necrosis factor inhibitor (TNFi) failure status. Results: At week 8 of OCTAVE Induction 1 and 2, remission rates with placebo and tofacitinib 10 mg twice daily (BID), respectively, were 7.7% and 24.8% (mMayo) and 6.0% and 17.6% (Mayo). At week 52 of OCTAVE Sustain, remission rates with placebo, tofacitinib 5 and 10 mg BID, respectively, were 12.1%, 35.9%, and 42.1% (mMayo) and 11.1%, 34.3%, and 40.6% (Mayo). A statistically significant ( p

Published
2022
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29. Experimental and genetic evidence for the impact of CD5 and CD6 expression and variation in inflammatory bowel disease

Author

Sergi Casadó-Llombart, María Velasco-de Andrés, Cristina Català, Alejandra Leyton-Pereira, Rebeca Gutiérrez-Cózar, Belén Suárez, Noelia Armiger, Esther Carreras, Miriam Esteller, Elena Ricart, Ingrid Ordás, Javier P. Gisbert, María Chaparro, María Esteve, Lucía Márquez, David Busquets, Eva Iglesias, Esther García-Planella, María Dolores Martín-Arranz, Juliane Lohmann, C. Korcan Ayata, Jan Hendrik Niess, Pablo Engel, Julián Panés, Azucena Salas, Eugeni Domènech, Francisco Lozano, ENEIDA Project of GETECCU, Alfredo J. Lucendo, Jordi Guardiola, Xavier Calvet, Lorenzo Olivá́n, and Marta Piqueras

Subjects
Crohn’s disease, inflammatory bowel disease, ulcerative colitis, CD5, CD6, Immunologic diseases. Allergy, RC581-607
Abstract

Crohn’s disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) resulting from the interaction of multiple environmental, genetic and immunological factors. CD5 and CD6 are paralogs encoding lymphocyte co-receptors involved in fine-tuning intracellular signals delivered upon antigen-specific recognition, microbial pattern recognition and cell adhesion. While CD5 and CD6 expression and variation is known to influence some immune-mediated inflammatory disorders, their role in IBD remains unclear. To this end, Cd5- and Cd6-deficient mice were subjected to dextran sulfate sodium (DSS)-induced colitis, the most widely used experimental animal model of IBD. The two mouse lines showed opposite results regarding body weight loss and disease activity index (DAI) changes following DSS-induced colitis, thus supporting Cd5 and Cd6 expression involvement in the pathophysiology of this experimental IBD model. Furthermore, DNA samples from IBD patients of the ENEIDA registry were used to test association of CD5 (rs2241002 and rs2229177) and CD6 (rs17824933, rs11230563, and rs12360861) single nucleotide polymorphisms with susceptibility and clinical parameters of CD (n=1352) and UC (n=1013). Generalized linear regression analyses showed association of CD5 variation with CD ileal location (rs2241002CC) and requirement of biological therapies (rs2241002C-rs2229177T haplotype), and with poor UC prognosis (rs2241002T-rs2229177T haplotype). Regarding CD6, association was observed with CD ileal location (rs17824933G) and poor prognosis (rs12360861G), and with left-sided or extensive UC, and absence of ankylosing spondylitis in IBD (rs17824933G). The present experimental and genetic evidence support a role for CD5 and CD6 expression and variation in IBD’s clinical manifestations and therapeutic requirements, providing insight into its pathophysiology and broadening the relevance of both immunomodulatory receptors in immune-mediated disorders.

Published
2022
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30. A phase 2 study of tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn's disease

Author

William J. Sandborn, Subrata Ghosh, Julian Panes, Ivana Vranic, Wenjin Wang, Wojciech Niezychowski, Severine A.R.A. Vermeire, Olivier Dewit, Harald Peeters, Jiri Stehlik, Tomas Vanasek, David Laharie, Jean Frederic Colombel, Marc-André Bigard, Marta Varga, Margit Zeher, Janos Novak, Bela Hunyady, Agnes Salamon, Istvan Racz, Paolo Gionchetti, Anna Kohn, Cosimo Prantera, P.C.F. Stokkers, Maria Slomka, Leszek Paradowski, Tomasz Arlukowicz, Ladislav Kuzela, Boris Baricky, Tibor Hlavaty, Maria Isabel Vera, Jordi Guardiola, Christopher Probert, Jonathan Lionel Shaffer, Mark Fleisher, Ronald Edward Pruitt, John Sawyer Goff, John Weber, Raymond Lloyd Bell, Andrew Harrison Zwick, Alexandra Gutierrez, Robert H. Levine, Stephen Brett Hanauer, Lori Ann Lavelle, Ravindranath K. Kottoor, Gerald Wayne Dryden, Robert Hardi, David Vaughn Glorioso, Prabhakar Swaroop, Scott D. Lee, Teressa Joan Patrick, Sheldon Scheinert, Charles A. Sninsky, Seymour Katz, Mark D. Noar, Michael Marion Gaspari, Glenn L. Gordon, Thomas A. Dalton, Douglas Edward Homoky, William Ransom Kilgore, Joel A. Levien, Herbert R. Schneider, Suleman Abdul Moola, Frederik Cornelius Kruger, John P. Wright, Nazimuddin Aboo, Sandborn WJ, Ghosh S, Panes J, Vranic I, Wang W, Niezychowski W, Study A3921043 Investigators [.., Gionchetti P, and ]

Subjects
Adult, Male, medicine.medical_specialty, Placebo, Gastroenterology, Placebos, Feces, Crohn Disease, Piperidines, Internal medicine, Clinical endpoint, medicine, Animals, Humans, Pyrroles, Adverse effect, Protein Kinase Inhibitors, Janus kinase inhibitor, Janus Kinases, therapy, Tofacitinib, Hepatology, biology, business.industry, C-reactive protein, Middle Aged, Crohn's Disease Activity Index, C-Reactive Protein, Pyrimidines, Treatment Outcome, Immunology, biology.protein, Female, Calprotectin, business, Leukocyte L1 Antigen Complex, Blood Chemical Analysis, CROHN’S DISEASE
Abstract

BACKGROUND & AIMS: Tofacitinib, an orally administered Janus kinase inhibitor, blocks signaling through γ-chain-containing cytokines (interleukins 2, 4, 7, 9, 15, and 21). We performed a phase 2 trial to measure its efficacy in patients with moderate-to-severe active Crohn's disease. METHODS: Patients (N = 139; age, ≥18 y) with moderate-to-severe active Crohn's disease were assigned randomly to groups given 1 mg (n = 36), 5 mg (n = 34), or 15 mg (n = 35) tofacitinib or placebo (n = 34), twice daily for 4 weeks, at 48 centers in 12 countries. The primary end point was the proportion of clinical responders at week 4 (decrease from baseline in the Crohn's Disease Activity Index score of ≥70 points [Response-70]). Secondary end points included clinical remission (Crohn's Disease Activity Index score of

Published
2013

34. Clinically reversible ustekinumab-induced encephalopathy: case report and review of the literature

Author

Jordi Sarto, Berta Caballol, Joan Berenguer, Iban Aldecoa, Álvaro Carbayo, Daniel Santana, Ivan Archilla, Carles Gaig, Francesc Graus, Julián Panés, and Albert Saiz

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Ustekinumab, a monoclonal antibody against interleukin (IL)-12 and IL-23 approved for the treatment of Crohn’s disease, has shown to be an effective therapy with a favourable safety profile. Clinical trials and real-world studies have reported very few neurological adverse events, including posterior reversible encephalopathy syndrome, idiopathic intracranial hypertension and headache. We describe the case of a 48-year-old man with Crohn’s disease who initiated treatment with ustekinumab on top of ongoing treatment with methotrexate 25 mg/week who presented with an acute-onset encephalopathy that rapidly evolved to severe tetraparesis and akinetic mutism, associated with extensive leukoencephalopathy and restricted diffusion on brain magnetic resonance imaging (MRI), 1 month after the second dose of ustekinumab. Comprehensive in-patient diagnostic testing ruled out vascular, demyelinating, metabolic, tumoral and infectious etiologies. Brain biopsy showed patchy infiltrates of foamy histiocytes with perivascular distribution, associated with edema, diffuse astrocytic gliosis and focal perivascular axonal destruction without demyelination, and ustekinumab-induced neurotoxicity was suspected. After drug discontinuation, the patient presented a complete clinical recovery despite the persistence of leukoencephalopathy. In conclusion, in an era in which biological therapies are continually evolving and expanding, knowledge about the potential neurotoxicity of these new therapies and their management becomes crucial. Although ustekinumab-induced encephalopathy is uncommon, the recognition of this potentially serious side effect is important because prompt withdrawal is associated with a favourable outcome. Whether methotrexate played an additional contributing role is currently unknown, but it is a factor that should be considered.

Published
2022
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36. Multi-omic modelling of inflammatory bowel disease with regularized canonical correlation analysis.

Author

Lluís Revilla, Aida Mayorgas, Ana M Corraliza, Maria C Masamunt, Amira Metwaly, Dirk Haller, Eva Tristán, Anna Carrasco, Maria Esteve, Julian Panés, Elena Ricart, Juan J Lozano, and Azucena Salas

Subjects
Medicine, Science
Abstract

BackgroundPersonalized medicine requires finding relationships between variables that influence a patient's phenotype and predicting an outcome. Sparse generalized canonical correlation analysis identifies relationships between different groups of variables. This method requires establishing a model of the expected interaction between those variables. Describing these interactions is challenging when the relationship is unknown or when there is no pre-established hypothesis. Thus, our aim was to develop a method to find the relationships between microbiome and host transcriptome data and the relevant clinical variables in a complex disease, such as Crohn's disease.ResultsWe present here a method to identify interactions based on canonical correlation analysis. We show that the model is the most important factor to identify relationships between blocks using a dataset of Crohn's disease patients with longitudinal sampling. First the analysis was tested in two previously published datasets: a glioma and a Crohn's disease and ulcerative colitis dataset where we describe how to select the optimum parameters. Using such parameters, we analyzed our Crohn's disease data set. We selected the model with the highest inner average variance explained to identify relationships between transcriptome, gut microbiome and clinically relevant variables. Adding the clinically relevant variables improved the average variance explained by the model compared to multiple co-inertia analysis.ConclusionsThe methodology described herein provides a general framework for identifying interactions between sets of omic data and clinically relevant variables. Following this method, we found genes and microorganisms that were related to each other independently of the model, while others were specific to the model used. Thus, model selection proved crucial to finding the existing relationships in multi-omics datasets.

Published
2021
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37. Treatment of angiodysplasia and arterial malformations of the gastrointestinal tract

Author

Julian Panes

Subjects
medicine.medical_specialty, Pathology, Gastrointestinal tract, medicine.diagnostic_test, Vascular disease, business.industry, medicine.medical_treatment, Arteriovenous malformation, Interventional radiology, medicine.disease, Gastroenterology, Endoscopy, Internal medicine, medicine, Sclerotherapy, Radiology, Nuclear Medicine and imaging, Angiodysplasia, Complication, business
Published
1998

38. Anti-tumour necrosis factor discontinuation in inflammatory bowel disease patients in remission: study protocol of a prospective, multicentre, randomized clinical trial

Author

María Chaparro, María G. Donday, Manuel Barreiro-de Acosta, Eugeni Domènech, María Esteve, Valle García-Sánchez, Pilar Nos, Julián Panés, Concepción Martínez, and Javier P. Gisbert

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background: Patients with inflammatory bowel disease who achieve remission with anti-tumour necrosis factor (anti-TNF) drugs may have treatment withdrawn due to safety concerns and cost considerations, but there is a lack of prospective, controlled data investigating this strategy. The primary study aim is to compare the rates of clinical remission at 1 year in patients who discontinue anti-TNF treatment versus those who continue treatment. Methods: This is an ongoing, prospective, double-blind, multicentre, randomized, placebo-controlled study in patients with Crohn’s disease or ulcerative colitis who have achieved clinical remission for ⩾6 months with an anti-TNF treatment and an immunosuppressant. Patients are being randomized 1:1 to discontinue anti-TNF therapy or continue therapy. Randomization stratifies patients by the type of inflammatory bowel disease and drug (infliximab versus adalimumab) at study inclusion. The primary endpoint of the study is sustained clinical remission at 1 year. Other endpoints include endoscopic and radiological activity, patient-reported outcomes (quality of life, work productivity), safety and predictive factors for relapse. The required sample size is 194 patients. In addition to the main analysis (discontinuation versus continuation), subanalyses will include stratification by type of inflammatory bowel disease, phenotype and previous treatment. Biological samples will be obtained to identify factors predictive of relapse after treatment withdrawal. Results: Enrolment began in 2016, and the study is expected to end in 2020. Conclusions: This study will contribute prospective, controlled data on outcomes and predictors of relapse in patients with inflammatory bowel disease after withdrawal of anti-TNF agents following achievement of clinical remission. Clinical trial reference number: EudraCT 2015-001410-10

Published
2019
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39. Dissecting Allo-Sensitization After Local Administration of Human Allogeneic Adipose Mesenchymal Stem Cells in Perianal Fistulas of Crohn's Disease Patients

Author

Alvaro Avivar-Valderas, Cristina Martín-Martín, Cristina Ramírez, Borja Del Río, Ramón Menta, Pablo Mancheño-Corvo, Maitane Ortiz-Virumbrales, Ángel Herrero-Méndez, Julián Panés, Damián García-Olmo, José Luís Castañer, Itziar Palacios, Eleuterio Lombardo, Wilfried Dalemans, and Olga DelaRosa

Subjects
ASC, cell therapy and immunotherapy, allogeneic, allo-sensitization, CD46, crispr gene editing, Immunologic diseases. Allergy, RC581-607
Abstract

Adipose mesenchymal stem cells (ASC) are considered minimally immunogenic. This is due to the low expression of human leukocyte antigens I (HLA-I), lack of HLA-II expression and low expression of co-stimulatory molecules such as CD40 and CD80. The low rate of observed immunological rejection as well as the immunomodulatory qualities, position ASC as a promising cell-based therapy for the treatment of a variety of inflammatory indications. Yet, few studies have addressed relevant aspects of immunogenicity such as ASC donor-to-patient HLA histocompatibility or assessment of immune response triggered by ASC administration, particularly in the cases of presensitization. The present study aims to assess allo-immune responses in a cohort of Crohn's disease patients administered with allogeneic ASC (darvadstrocel formerly Cx601) for the treatment of complex perianal fistulas. We identified donor-specific antibodies (DSA) generation in a proportion of patients and observed that patients showing preexisting immunity were prone to generating DSA after allogeneic therapy. Noteworthy, naïve patients generating DSA at week 12 (W12) showed a significant reduction in DSA titer at week 52 (W52), whereas DSA titer was reduced in pre-sensitized patients only with no specificities against the donor administered. Remarkably, we did not observe any correlation of DSA generation with ASC therapeutic efficacy. In vitro complement-dependent cytotoxicity (CDC) studies have revealed limited cytotoxic levels based upon HLA-I expression and binding capacity even in pro-inflammatory conditions. We sought to identify CDC coping mechanisms contributing to the limited cytotoxic killing observed in ASC in vitro. We found that ASC express membrane-bound complement regulatory proteins (mCRPs) CD55, CD46, and CD59 at basal levels, with CD46 more actively expressed in pro-inflammatory conditions. We demonstrated that CD46 is a main driver of CDC signaling; its depletion significantly enhances sensitivity of ASC to CDC. In summary, despite relatively high clearance, DSA generation may represent a major challenge for allogeneic cell therapy management. Sensitization may be a significant concern when evaluating re-treatment or multi-donor trials. It is still unknown whether DSA generation could potentially be the consequence of donor-to-patient interaction and, therefore, subsequently link to efficacy or biological activity. Lastly, we propose that CDC modulators such as CD46 could be used to ultimately link CDC specificity with allogeneic cell therapy efficacy.

Published
2019
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40. The Full Picture of Ulcerative Colitis: The Burden, the Patient, the Treatment

Author

Julián Panés, Edouard Louis, and Paul Rutgeerts

Subjects
UEG Week, United European Gastroenterology Week, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Ulcerative colitis (UC) carries a significant, progressive disease burden that is often underestimated or misinterpreted by healthcare providers. Adverse outcomes have a major impact on patient quality of life, with a significant burden of symptoms both during and between inflammation flares. Chronic, uncontrolled disease leads to epithelial fibrosis and ‘lead pipe’ colon, dysplasia, and potential colonic cancer. Healthcare providers and patients share similar treatment goals, even if these are not verbalised in the same way, and clinicians need to fully understand the issues most important to patients. Understanding and collaboration can improve identification of meaningful treatment goals and overall disease management. In real-world practice, patients should be categorised according to disease characteristics and prognosis, and managed with appropriate, optimised therapies. Early, top-down management should be implemented in high-risk patients and all patient-centric therapeutic decisions made within the context of a full benefit/risk assessment.

Published
2015

42. Endoscopic sclerosis in the treatment of bleeding peptic ulcers with a visible vessel

Author

Julian Panes, Forne, M., Bagena, F., and Viver, J.

Subjects
Male, Hemostatic Techniques, Middle Aged, Peptic Ulcer Hemorrhage, Recurrence, Duodenal Ulcer, Gastroscopy, Sclerotherapy, Humans, Female, Prospective Studies, Stomach Ulcer, Duodenoscopy, Aged
Abstract

We have assessed the efficacy of endoscopic sclerosis in the routine clinical management of patients with bleeding ulcers, in whom a visible vessel was identified at endoscopy. Over a period of 14 months, a visible vessel at the base of an ulcer was identified in 53 patients. Three patients could not undergo sclerosis, one because of torrential bleeding and two because of ulcer location. Fifty patients, 18 with a bleeding vessel and 32 with a nonbleeding vessel, were subjected to endoscopic sclerosis with adrenaline plus polidocanol. Permanent hemostasis was achieved in 45 patients (90%), 31 (62%) cases with one session and 14 (28%) cases with two sessions of sclerosis. Four patients had persistent rebleeding in spite of two sessions of sclerosis, and one patient had a massive rebleeding after the first session; all underwent emergency surgery. We believe that endoscopic sclerosis has a primary role in the treatment of ulcer bleeding, particularly in those patients in whom a visible vessel is identified at endoscopy.

43. Pancreatitis-associated protein does not predict disease relapse in inflammatory bowel disease patients.

Author

Tiago Nunes, Maria Josefina Etchevers, Maria Jose Sandi, Susana Pinó Donnay, Teddy Grandjean, Maria Pellisé, Julián Panés, Elena Ricart, Juan Lucio Iovanna, Jean-Charles Dagorn, Mathias Chamaillard, and Miquel Sans

Subjects
Medicine, Science
Abstract

BackgroundThe pancreatitis-associated protein (PAP) is increased in the serum of active inflammatory bowel disease (IBD) patients and its levels seem to be correlated with disease activity. Our aim was to evaluate the usefulness of serum and fecal PAP measurements to predict relapse in patients with inactive IBD.Materials and methodsWe undertook a 12-month prospective study that included 66 Crohn's disease (CD) and 74 ulcerative colitis (UC) patients. At inclusion, patients were in clinical remission, defined by a Harvey-Bradshaw (HB) Index≤4 (CD) or a partial Mayo Score (MS)ResultsActive CD patients had an increased mean serum PAP at the diagnosis of the flare (104.1 ng/ml) and 3 months prior to activity (22.68 ng/ml) compared with patients in remission (13.26 ng/ml), pConclusionSerum PAP is increased only in active CD patients, but this marker does not predict disease activity. Inactive UC patients have marked low levels of PAP in fecal samples compared with CD patients.

Published
2014
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44. Gram-negative enterobacteria induce tolerogenic maturation in dexamethasone conditioned dendritic cells.

Author

Raquel Cabezón, Elena Ricart, Carolina España, Julián Panés, and Daniel Benitez-Ribas

Subjects
Medicine, Science
Abstract

Dendritic cells have been investigated in clinical trials, predominantly with the aim of stimulating immune responses against tumours or infectious diseases. Thus far, however, no clinical studies have taken advantage of their specific immunosuppressive potential. Tolerogenic DCs may represent a new therapeutic strategy for human immune-based diseases, such as Crohn's disease, where the perturbations of the finely tuned balance between the immune system and the microflora result in disease. In the present report, we describe the generation of tolerogenic DCs from healthy donors and Crohn's disease patients using clinical-grade reagents in combination with dexamethasone as immunosuppressive agent and characterize their response to maturation stimuli. Interestingly, we found out that dexamethasone-conditioned DCs keep their tolerogenic properties to Gram-negative bacteria. Other findings included in this study demonstrate that the combination of dexamethasone with a specific cytokine cocktail yielded clinical-grade DCs with the following characteristics: a semi-mature phenotype, a pronounced shift towards anti-inflammatory versus inflammatory cytokine production and low T-cell stimulatory properties. Importantly, in regard to their clinical application, the tolerogenic phenotype of DCs remained stable after the elimination of dexamethasone and after a second stimulation with LPS or bacteria. All these properties make this cell product suitable to be tested in clinical trials of inflammatory conditions including Crohn's disease.

Published
2012
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45. Probiotic sonicates selectively induce mucosal immune cells apoptosis through ceramide generation via neutral sphingomyelinase.

Author

Sandra Angulo, Albert Morales, Silvio Danese, Laura Llacuna, Maria Carme Masamunt, Nicole Pultz, Maria Grazia Cifone, Claudio De Simone, Salvadora Delgado, Jordi Vila, Julián Panés, Curtis Donskey, Jose C Fernández-Checa, Claudio Fiocchi, and Miquel Sans

Subjects
Medicine, Science
Abstract

Probiotics appear to be beneficial in inflammatory bowel disease, but their mechanism of action is incompletely understood. We investigated whether probiotic-derived sphingomyelinase mediates this beneficial effect.Neutral sphingomyelinase (NSMase) activity was measured in sonicates of the probiotic L. brevis (LB) and S. thermophilus (ST) and the non-probiotic E. coli (EC) and E. faecalis (EF). Lamina propria mononuclear cells (LPMC) were obtained from patients with Crohn's disease (CD) and Ulcerative Colitis (UC), and peripheral blood mononuclear cells (PBMC) from healthy volunteers, analysing LPMC and PBMC apoptosis susceptibility, reactive oxygen species (ROS) generation and JNK activation. In some experiments, sonicates were preincubated with GSH or GW4869, a specific NSMase inhibitor. NSMase activity of LB and ST was 10-fold that of EC and EF sonicates. LB and ST sonicates induced significantly more apoptosis of CD and UC than control LPMC, whereas EC and EF sonicates failed to induce apoptosis. Pre-stimulation with anti-CD3/CD28 induced a significant and time-dependent increase in LB-induced apoptosis of LPMC and PBMC. Exposure to LB sonicates resulted in JNK activation and ROS production by LPMC. NSMase activity of LB sonicates was completely abrogated by GW4869, causing a dose-dependent reduction of LB-induced apoptosis. LB and ST selectively induced immune cell apoptosis, an effect dependent on the degree of cell activation and mediated by bacterial NSMase.These results suggest that induction of immune cell apoptosis is a mechanism of action of some probiotics, and that NSMase-mediated ceramide generation contributes to the therapeutic effects of probiotics.

Published
2011
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46. Selecting End Points for Disease-Modification Trials in Inflammatory Bowel Disease: the SPIRIT Consensus From the IOIBD

Author

Ioannis E. Koutroubakis, Simon Travis, Edward V. Loftus, Bruce E. Sands, Yehuda Chowers, Arthur Kaser, Antonino Spinelli, Maria T. Abreu, Gerassimos J. Mantzaris, Gerhard Rogler, Parambir S. Dulai, Milan Lukas, Dan Turner, Ailsa Hart, Colm O'Morain, Jonas Halfvarson, Matthieu Allez, Severine Vermeire, Silvio Danese, Geert R. D'Haens, William J. Sandborn, Walter Reinisch, Siew C. Ng, Subrata Ghosh, Flavio Steinwurz, Pia Munkholm, Jean-Frederic Colombel, Remo Panaccione, Stefan Schreiber, David B. Sachar, Laurent Peyrin-Biroulet, Julián Panés, Vipul Jairath, Aswhin N. Ananthakrishnan, Peter R. Gibson, Wolfgang Kruis, Catherine Le Berre, Iris Dotan, David T. Rubin, Institut des Maladies de l'Appareil Digestif, Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), 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 Régional Universitaire de Nancy (CHRU Nancy), SPIRIT-IOIBD study group: William J Sandborn, Jean-Frédéric Colombel, David Rubin, Yehuda Chowers, Walter Reinisch, Stefan Schreiber, Matthieu Allez, Geert D'Haens, Subrata Ghosh, Ioannis E Koutroubakis, Peter Gibson, Jonas Halfvarson, Ailsa Hart, Arthur Kaser, Pia Munkholm, Wolfgang Kruis, Severine Vermeire, Edward V Loftus Jr, Milan Lukas, Gerassimos J Mantzaris, Colm O'Morain, Julian Panes, Gerhard Rogler, Antonino Spinelli, Bruce E Sands, Aswhin N Ananthakrishnan, Siew C Ng, David Sachar, Simon Travis, Flavio Steinwurz, Dan Turner, Parambir S Dulai, Vipul Jairath, Iris Dotan, Maria Abreu, Remo Panaccione, Silvio Danese, Gastroenterology and Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Arnone, Djésia

Subjects
0301 basic medicine, medicine.medical_specialty, Consensus, Time Factors, SF-36, Endpoint Determination, [SDV]Life Sciences [q-bio], education, Crohn's Disease, Disease, Severity of Illness Index, Inflammatory bowel disease, Disability Evaluation, 03 medical and health sciences, 0302 clinical medicine, Cost of Illness, Crohn Disease, Quality of life, medicine, Humans, Ulcerative Colitis, Fecal incontinence, Disease Severity, Intensive care medicine, Clinical Trials as Topic, Crohn's disease, Hepatology, business.industry, Gastroenterology, Short bowel syndrome, medicine.disease, Ulcerative colitis, digestive system diseases, 3. Good health, [SDV] Life Sciences [q-bio], Functional Status, Treatment Outcome, 030104 developmental biology, Research Design, Quality of Life, Disease Progression, Colitis, Ulcerative, 030211 gastroenterology & hepatology, medicine.symptom, business, Fecal Incontinence, Crohn’s Disease
Abstract

International audience; Background and aims: Inflammatory bowel diseases (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), are chronic and disabling disorders. Prospective disease-modification trials to prevent disease progression are eagerly awaited. However, disease progression is not clearly defined. The objective of the Selecting End PoInts foR Disease-ModIfication Trials (SPIRIT) initiative was to achieve international expert consensus on the endpoints to be used in future IBD-disease modification trials.Methods: This initiative under the auspices of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) began with a systematic literature search to evaluate the current evidence on the definition of disease progression in IBD. On October 22, 2019, a consensus meeting took place during the United European Gastroenterology Week (UEGW) Congress in Barcelona, during which predefined proposed statements were discussed in a plenary session and voted on anonymously. Agreement was defined as at least 75% of participants voting for any one statement.Results: The group agreed that the ultimate therapeutic goal in both CD and UC is to prevent disease impact on patient's life (health-related quality of life, disability, fecal incontinence), midterm complications (encompass bowel damage in CD, IBD-related surgery and hospitalizations, disease extension in UC, extraintestinal manifestations, permanent stoma, short bowel syndrome), and long-term complications (gastrointestinal and extraintestinal dysplasia or cancer, mortality).Conclusions: Recommendations on which goals to achieve in disease-modification trials for preventing disease progression in patients with IBD are proposed by the SPIRIT consensus. However, these recommendations will require validation in actual clinical studies before implementation in disease-modification trials.

Published
2021

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