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1. Histological Presentation of Eosinophilic Esophagitis: Simply a Magic Number?

Author

William Sterlacci, Michael Vieth, and Markus Neurath

Subjects
histology, esophagus, eosinophilic esophagitis, inflammation, scoring, grading, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background: Eosinophilic esophagitis is an increasing condition in industrialized countries. The etiology is still somewhat unclear. It was thought that it can be part of eosinophilic gastroenteritis but nowadays seen as a separate entity and thus more often the esophagus is the only part of the gastrointestinal tract that is affected. Immunosuppressive and immunomodulatory treatment is available and can lead to symptom relief and remission. Summary and Key Messages: In this article, the value and practicability of the histological criteria used for this disease are discussed. Also, the situation regarding the requirements for grading in clinical studies and routine settings is discussed.

Published
2024
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2. World Congress Integrative Medicine & Health 2017: part two

Author

Carolyn Ee, Sharmala Thuraisingam, Marie Pirotta, Simon French, Charlie Xue, Helena Teede, Agnete E. Kristoffersen, Fuschia Sirois, Trine Stub, Jennifer Engler, Stefanie Joos, Corina Güthlin, Jennifer Felenda, Christiane Beckmann, Florian Stintzing, Roni Evans, Gert Bronfort, Daniel Keefe, Anna Taberko, Linda Hanson, Alex Haley, Haiwei Ma, Joseph Jolton, Lana Yarosh, Francis Keefe, Jung Nam, Liwanag Ojala, Mary J. Kreitzer, Careen Fink, Karin Kraft, Andrew Flower, George Lewith, Kim Harman, Beth Stuart, Felicity L. Bishop, Jane Frawley, Lilla Füleki, Eva Kiss, Tamas Vancsik, Tibor Krenacs, Martha Funabashi, Katherine A. Pohlman, Silvano Mior, Haymo Thiel, Michael D. Hill, David J. Cassidy, Michael Westaway, Jerome Yager, Eric Hurwitz, Gregory N. Kawchuk, Maeve O’Beirne, Sunita Vohra, Isabelle Gaboury, Chantal Morin, Katharina Gaertner, Loredana Torchetti, Martin Frei-Erb, Michael Kundi, Michael Frass, Eugenia Gallo, Valentina Maggini, Mattia Comite, Francesco Sofi, Sonia Baccetti, Alfredo Vannacci, Mariella Di Stefano, Maria V. Monechi, Luigi Gori, Elio Rossi, Fabio Firenzuoli, Rocco D. Mediati, Giovanna Ballerini, Paula Gardiner, Anna S. Lestoquoy, Lily Negash, Sarah Stillman, Prachi Shah, Jane Liebschutz, Pamela Adelstein, Christine Farrell-Riley, Ivy Brackup, Brian Penti, Robert Saper, Isabel Giralt Sampedro, Gilda Carvajal, Andreas Gleiss, Marie M. Gross, Dorothea Brendlin, Jonas Röttger, Wiebke Stritter, Georg Seifert, Noelle Grzanna, Rainer Stange, Peter W. Guendling, Wen Gu, Yan Lu, Jie Wang, Chengcheng Zhang, Hua Bai, Yuxi He, Xiaoxu Zhang, Zhengju Zhang, Dali Wang, Fengxian Meng, Alexander Hagel, Heinz Albrecht, Claudia Vollbracht, Wolfgang Dauth, Wolfgang Hagel, Francesco Vitali, Ingo Ganzleben, Hans Schultis, Peter Konturek, Jürgen Stein, Markus Neurath, Martin Raithel, Bianka Krick, Heidemarie Haller, Petra Klose, Gustav Dobos, Sherko Kümmel, Holger Cramer, Felix J. Saha, Anna Kowoll, Barbara Ebner, Bettina Berger, Kyung-Eun Choi, Lisha He, Han Wang, X. He, C. Gu, Y. Zhang, Linhua Zhao, Xiaolin Tong, Xinhui He, Chengjuan Gu, Ying Zhang, Robin S. T. Ho, Vincent C. H. Chung, Xinyin Wu, Charlene H. L. Wong, Justin C. Y. Wu, Samuel Y. S. Wong, Alexander Y. L. Lau, Regina W. S. Sit, Wendy Wong, Michelle Holmes, Felicity Bishop, Lynn Calman, Dave Newell, Jonathan Field, Win L. Htut, Dongwoon Han, Da I. Choi, Soo J. Choi, Ha Y. Kim, Jung H. Hwang, Ching W. Huang, Bo H. Jang, Fang P. Chen, Seong G. Ko, Wenjing Huang, De Jin, Fengmei Lian, Soobin Jang, Kyeong H. Kim, Eun K. Lee, Seung H. Sun, Ho Y. Go, Youme Ko, Sunju Park, Yong C. Shin, Hubert Janik, Natalie Greiffenhagen, Jürgen Bolte, Mariusz Jaworski, Miroslawa Adamus, Aleksandra Dobrzynska, Michael Jeitler, Jessica Jaspers, Christel von Scheidt, Barbara Koch, Andreas Michalsen, Nico Steckhan, Christian Kessler, Wen-jing Huang, Bing Pang, Feng-Mei Lian, Miek Jong, Erik Baars, Anja Glockmann, Harald Hamre, Mosaburo Kainuma, Aya Murakami, Toshio Kubota, Daisuke Kobayashi, Yasuhiro Sumoto, Norihiro Furusyo, Shin-Ichi Ando, Takao Shimazoe, Olaf Kelber, S. Verjee, Eva Gorgus, Dieter Schrenk, Kathi Kemper, Ellie Hill, Nisha Rao, Gregg Gascon, John Mahan, Gunver Kienle, Jörg Dietrich, Claudia Schmoor, Roman Huber, Weon H. Kim, Mansoor Ahmed, Luzhu He, Jung Hye Hwang, Nora Meggyeshazi, Csaba Kovago, Anne K. Klaus, Roland Zerm, Danilo Pranga, Thomas Ostermann, Marcus Reif, Hans Broder von Laue, Benno Brinkhaus, Matthias Kröz, Daniela Rodrigues Recchia, Hans B. von Laue, Christien T. Klein-Laansma, Mats Jong, Cornelia von Hagens, Jean P. Jansen, Herman van Wietmarschen, Miek C. Jong, Seung-Ho Sun, Ho-Yeon Go, Chan-Yong Jeon, Yun-Kyung Song, Seong-Gyu Ko, Anna K. Koch, Sybille Rabsilber, Romy Lauche, Jost Langhorst, Milena Trifunovic-Koenig, Evi Koster, Diana Delnoij, Lena Kroll, Kathrin Weiss, Ai Kubo, Sarah Hendlish, Andrea Altschuler, Nancy Connolly, Andy Avins, Jon Wardle, David Lee, David Sibbritt, Jon Adams, Crystal Park, Gita Mishra, Johann Lechner, Inseon Lee, Younbyoung Chae, Jisu Lee, Seung H. Cho, Yujin Choi, Jee Y. Lee, Han S. Ryu, Sung S. Yoon, Hye K. Oh, Lyun K. Hyun, Jin O. Kim, Seong W. Yoon, Ju-Yeon Lee, Sang-Hoon Shin, Min Jang, Indra Müller, So-Hyun Janson Park, Lance Laird, Suzanne Mitchell, Xiaofei Li, Yunhui Wang, Jianhua Zhen, He Yu, Tiegang Liu, Xiaohong Gu, Hui Liu, Weiguo Ma, Xuezheng Shang, Yu Bai, Wei Liu, Collin Rooney, Amos Smith, Shirlene Lopes, Marcelo Demarzo, Maria do Patrocínio Nunes, Peter Lorenz, Carsten Gründemann, Miriam Heinrich, Manuel Garcia-Käufer, Franziska Grunewald, Silke Messerschmidt, Anja Herrick, Kim Gruber, Matthias Knödler, Carmen Steinborn, Taoying Lu, Lixin Wang, Darong Wu, Christina M Luberto, Daniel L. Hall, Emma Chad-Friedman, Suzanne Lechner, Elyse R. Park, Christina M. Luberto, Elyse Park, Janice Goodman, Sonja Luer, Matthias Heri, Klaus von Ammon, Ida Landini, Andrea Lapucci, Stefania Nobili, Enrico Mini, Clare McDermott, Selwyn Richards, Diane Cox, Sarah Frossell, Geraldine Leydon, Caroline Eyles, Hilly Raphael, Rachael Rogers, Michelle Selby, Charlotte Adler, Jo Allam, Xiangwei Bu, Honghong Zhang, Jianpeng Zhang, Michael Mikolasek, Jonas Berg, Claudia Witt, Jürgen Barth, Ivan Miskulin, Zdenka Lalic, Maja Miskulin, Albina Dumic, Damir Sebo, Aleksandar Vcev, Nasr A. A. Mohammed, Soo Jeung Choi, Hyea Bin Im, Anwesha Mukherjee, Amit Kandhare, Subhash Bodhankar, Prasad Thakurdesai, Niki Munk, Erica Evans, Amanda Froman, Matthew Kline, Matthew J. Bair, Frauke Musial, Terje Alræk, Harald J. Hamre, Lars Björkman, Vinjar M. Fønnebø, Feng-mei Lian, Qing Ni, Xiao-lin Tong, Xin-long Li, Wen-ke Liu, Shuo Feng, Xi-yan Zhao, Yu-jiao Zheng, Xue-min Zhao, Yi-qun Lin, Tian-yu Zhao, Xi-Yan Zhao, Hui Che Phd, Chen Zhang, Feng Liu, Lin-hua Zhao, Ru Ye, Cheng-juan Gu, Wenbo Peng, Diana De Carvalho, Mohamed El-Bayoumi, Bob Haig, Kimbalin Kelly, Darrell J. Wade, Emanuela Portalupi, Giampietro Gobo, Luigi Bellavita, Chiara Guglielmetti, Christa Raak, Myriam Teuber, Friedrich Molsberger, Ulrich von Rath, Ulrike Reichelt, Uta Schwanebeck, Sabine Zeil, Christian Vogelberg, Dolores Rodríguez Veintimilla, Guerrero Tapia Mery, Marisol Maldonado Villavicencio, Sandra Herrera Moran, Christian Sachse, Peter W Gündlin, Monirsadat Sahebkarkhorasani, Hoda Azizi, Dania Schumann, Tobias Sundberg, Matthew J. Leach, Susana Seca, Henry Greten, Sugir Selliah, Anu Shakya, Ha Yun Kim, Hyea B. Im, Anna Sherbakova, Gudrun Ulrich-Merzenich, Heba Abdel-Aziz, Erica Sibinga, Lindsey Webb, Jonathan Ellen, Kari Skrautvol, Dagfinn Nåden, Rhayun Song, Weronika Grabowska, Kamila Osypiuk, Gloria V. Diaz, Paolo Bonato, Moonkyoung Park, Jeffrey Hausdorff, Michael Fox, Lewis R. Sudarsky, Daniel Tarsy, James Novakowski, Eric A. Macklin, Peter M. Wayne, Inok Hwang, Sukhee Ahn, Myung-Ah Lee, Min K. Sohn, Oleg Sorokin, Dagmar Heydeck, Astrid Borchert, Christoph-Daniel Hohmann, Harmut Kühn, Clemens Kirschbaum, Tobias Stalder, Barbara Stöckigt, Michael Teut, Ralf Suhr, Daniela Sulmann, Chris Streeter, Patrica Gerbarg, Marisa Silveri, Richard Brown, John Jensen, Britta Rutert, Angelika Eggert, Alfred Längler, Christine Holmberg, Jin Sun, Xin Deng, Wen-Yuan Li, Bin Wen, Nicola Robinson, Jian-Ping Liu, Hyun K. Sung, Narae Yang, Seon M. Shin, Hee Jung, Young J. Kim, Woo S. Jung, Tae Y. Park, Kiyoshi Suzuki, Toshinori Ito, Seiya Uchida, Seika Kamohara, Naoya Ono, Mitsuyuki Takamura, Ayumu Yokochi, Kazuo Maruyama, Patricio Tapia, Katarzyna Thabaut, Anja Thronicke, Megan Steele, Harald Matthes, Cornelia Herbstreit, Friedemann Schad, Jiaxing Tian, Libo Yang, Tian Tian, Hewei Zhang, Xia Tian, CongCong Wang, Qian Yun Chai, Lijuan Zhang, Ruyu Xia, Na Huang, Yutong Fei, Jianpin Liu, Natalie Trent, Mindy Miraglia, Jeffrey Dusek, Edi Pasalis, Sat B. Khalsa, Milena Trifunovic-König, Anna Koch, Lisa Uebelacker, Geoffrey Tremont, Lee Gillette, Gary Epstein-Lubow, David Strong, Ana Abrantes, Audrey Tyrka, Tanya Tran, Brandon Gaudiano, Ivan Miller, Gerhild Ullmann, Yuhua Li, Sujata Vaidya, Vinod Marathe, Ana C. Vale, Jacquelyne Motta, Fabíola Donadão, Angela C. Valente, Luana C. Carvalho Valente, Ricardo Ghelman, Dusan Vesovic, Dragan Jevdic, Aleksandar Jevdic, Katarina Jevdic, Mihael Djacic, Dragica Letic, Drago Bozic, Marija Markovic, Slobodan Dunjic, Gordana Ruscuklic, Dezire Baksa, Kenan Vrca, Ann Vincent, Dietlind Wahner-Roedler, Mary Whipple, Maria M. Vogelius, Iris Friesecke, Peter W. Gündling, Saswati Mahapatra, Rebecca Hynes, Kimberly Van Rooy, Sherry Looker, Aditya Ghosh, Brent Bauer, Susanne Cutshall, Harald Walach, Ana Borges Flores, Michael Ofner, Andreas Kastner, Gerhard Schwarzl, Hermann Schwameder, Nathalie Alexander, Gerda Strutzenberger, Xianwei Bu, Jianping Zhang, Shang Wang, Jinfeng Shi, Yu Hao, Jun Wu, Zeji Qiu, Yuh-Hai Wang, Chi-Jung Lou, Sam Watts, Peter Wayne, Gloria Vergara-Diaz, Brian Gow, Jose Miranda, Lewis Sudarsky, Eric Macklin, Kathrin Wode, Jenny Bergqvist, Britt-Marie Bernhardsson, Johanna Hök Nordberg, Lena Sharp, Roger Henriksson, Yeonju Woo, Min K. Hyun, Hao Wu, Tian-Fang Wang, Yan Zhao, Yu Wei, Lei Tian, Lei He, Xue Wang, Ruohan Wu, Mei Han, Patrina H. Y. Caldwell, Shigang Liu, Jing Zhang, Jianping Liu, Qianyun Chai, Zhongning Guo, Congcong Wang, Zhijun Liu, Xun Li, I. J. Yang, V. Ruberio Lincha, S. H. Ahn, D. U. Lee, H. M. Shin, Lu Yang, N. Yang, H. Sung, S. M. Shin, H. Y. Go, H. Jung, Y. Kim, T. Y. Park, Angela Yap, Yu H. Kwan, Chuen S. Tan, Syed Ibrahim, Seng B. Ang, Alfred Yayi, Jeong E. Yoo, Ho R. Yoo, Sae B. Jang, Hye L. Lee, Ala’a Youssef, Shahira Ezzat, Amira Abdel Motaal, Hesham El-Askary, Xiaotong Yu, Yashan Cui, Younghee Yun, Jin-Hyang Ahn, Bo-Hyung Jang, Kyu-Seok Kim, Inhwa Choi, Augustina Glinz, Fadime ten Brink, Arnd Büssing, Christoph Gutenbrunner, Bert Helbrecht, Tiesheng Fang, Fengxion Meng, Zhiming Shen, Ruixin Zhang, Fan Wu, Ming Li, Xinyun Xuan, Xueyong Shen, Ke Ren, Brian Berman, Zian Zheng, Yuxiang Wan, Xueyan Ma, Fei Dong, Suzie Zick, Richard Harris, Go E. Bae, Jung N. Kwon, Hye Y. Lee, Jong K. Nam, Sang D. Lee, Dong H. Lee, Ji Y. Han, Young J. Yun, Ji H. Lee, Hye L. Park, Seong H. Park, Chiara Bocci, Giovanni B. Ivaldi, Ilaria Vietti, Ilaria Meaglia, Marta Guffi, Rubina Ruggiero, Marita Gualea, Emanuela Longa, Massimo Bonucci, Sarah Croke, Lourdes Diaz Rodriguez, Juan C. Caracuel-Martínez, Manuel F. Fajardo-Rodríguez, Angélica Ariza-García, Francisca García-De la Fuente, Manuel Arroyo-Morales, Maria S. Estrems, Vicente G. Gómez, Mónica Valero Sabater, Rosaria Ferreri, Simonetta Bernardini, Roberto Pulcri, Franco Cracolici, Massimo Rinaldi, Claudio Porciani, Peter Fisher, John Hughes, Ariadna Mendoza, Hugh MacPherson, Jacqueline Filshie, Antonia Di Francesco, Alberto Bernardini, Monica Messe, Vincenzo Primitivo, Piera A. Iasella, Monica Taminato, Jaqueline Do Carmo Alcantara, Katia R. De Oliveira, Debora C. De Azevedo Rodrigues, Juliana R. Campana Mumme, Olga K. Matsumoto Sunakozawa, Vicente Odone Filho, Joshua Goldenberg, Andrew Day, Masa Sasagawa, Lesley Ward, Kieran Cooley, Thora Gunnarsdottir, Ingibjorg Hjaltadottir, Mahdie Hajimonfarednejad, Nicole Hannan, Rut Hellsing, Susanne Andermo, Maria Arman, Iris von Hörsten, Patricia Vásquez Torrielo, Carmen L. Andrade Vilaró, Francisco Cerda Cabrera, Henny Hui, Eric Ziea, Dora Tsui, Joyce Hsieh, Christine Lam, Edith Chan, Mark P. Jensen, Samuel L. Battalio, Joy Chan, Karlyn A. Edwards, Kevin J. Gertz, Melissa A. Day, Leslie H. Sherlin, Dawn M. Ehde, Bo-Hyoung Jang, Anja Börner, Jihong Lee, Boram Lee, Gyu T. Chang, Alejandra Menassa, Yoshiharu Motoo, Jürgen Müller, Sabine Rabini, Bettina Vinson, Martin Storr, Martin Niemeijer, Joop Hoekman, Wied Ruijssenaaars, Faith C. Njoku, Arne J. Norheim, Filiz Okumus, and Halime Oncu-Celik

Subjects
Other systems of medicine, RZ201-999
Published
2017
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3. Gp96 Peptide Antagonist gp96-II Confers Therapeutic Effects in Murine Intestinal Inflammation

Author

Claudia A. Nold-Petry, Marcel F. Nold, Ofer Levy, Yossef Kliger, Anat Oren, Itamar Borukhov, Christoph Becker, Stefan Wirtz, Manjeet K. Sandhu, Markus Neurath, and Charles A. Dinarello

Subjects
Gp96, cytokines and inflammation, biologics, therapeutics, immunemodulatory, anti-inflammatory agent, Immunologic diseases. Allergy, RC581-607
Abstract

BackgroundThe expression of heat shock protein gp96 is strongly correlated with the degree of tissue inflammation in ulcerative colitis and Crohn’s disease, thereby leading us to the hypothesis that inhibition of expression via gp96-II peptide prevents intestinal inflammation.MethodsWe employed daily injections of gp96-II peptide in two murine models of intestinal inflammation, the first resulting from five daily injections of IL-12/IL-18, the second via a single intrarectal application of TNBS (2,4,6-trinitrobenzenesulfonic acid). We also assessed the effectiveness of gp96-II peptide in murine and human primary cell culture.ResultsIn the IL-12/IL-18 model, all gp96-II peptide-treated animals survived until day 5, whereas 80% of placebo-injected animals died. gp96-II peptide reduced IL-12/IL-18-induced plasma IFNγ by 89%, IL-1β by 63%, IL-6 by 43% and tumor necrosis factor (TNF) by 70% compared to controls. The clinical assessment Disease Activity Index of intestinal inflammation severity was found to be significantly lower in the gp96-II-treated animals when compared to vehicle-injected mice. gp96-II peptide treatment in the TNBS model limited weight loss to 5% on day 7 compared with prednisolone treatment, whereas placebo-treated animals suffered a 20% weight loss. Histological disease severity was reduced equally by prednisolone (by 40%) and gp96-II peptide (35%). Mice treated with either gp96-II peptide or prednisolone exhibited improved endoscopic scores compared with vehicle-treated control mice: vascularity, fibrin, granularity, and translucency scores were reduced by up to 49% by prednisolone and by up to 30% by gp96-II peptide. In vitro, gp96-II peptide reduced TLR2-, TLR4- and IL-12/IL-18-induced cytokine expression in murine splenocytes, with declines in constitutive IL-6 (54%), lipopolysaccharide-induced TNF (48%), IL-6 (81%) and in Staphylococcus epidermidis-induced TNF (67%) and IL-6 (81%), as well as IL-12/IL-18-induced IFNγ (75%). gp96-II peptide reduced IL–1β, IL-6, TNF and GM-CSF in human peripheral blood mononuclear cells to a similar degree without affecting cell viability, whereas RANTES, IL-25 and MIF were twofold to threefold increased.Conclusiongp96-II peptide protects against murine intestinal inflammation by regulating inflammation in vivo and in vitro, pointing to its promise as a novel treatment for inflammatory bowel disease.

Published
2017
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8. Contrast-enhanced Multispectral Optoacoustic Tomography for Functional Assessment of the Gastrointestinal Tract

Author

Ferdinand Knieling, Lars-Philip Paulus, Adrian Buehler, Alexandra Wagner, Roman Raming, Jörg Jüngert, David Simon, Koray Tascilar, Alexander Schnell, Ulrich Rother, Werner Lang, André Hörning, Georg Schett, Markus Neurath, Maximilian Waldner, Regina Trollmann, Joachim Wölfle, Sarah Bohndiek, Adrian Regensburger, Markus Eckstein, Regensburger, Adrian P [0000-0001-8244-1261], Knieling, Ferdinand [0000-0002-3535-2626], and Apollo - University of Cambridge Repository

Subjects
indocyanine green, multispectral optoacoustic tomography, photoacoustics, optoacoustics, intestine
Abstract

Real-time imaging and functional assessment of the intestinal tract and its transit poses a significant challenge to traditional clinical diagnostic methods. Multispectral optoacoustic tomography (MSOT), a molecular-sensitive imaging technology, offers the potential to visualize endogenous and exogenous chromophores in tissue. Herein we present a novel approach using the orally administered clinical-approved fluorescent dye indocyanine green (ICG) for bed-side, non-ionizing evaluation of gastrointestinal passage. We were able to show the detectability and stability of ICG in phantom experiments. Furthermore, ten healthy subjects underwent MSOT imaging at multiple timepoints over eight hours after ingestion of a standardized meal with and without ICG. ICG signals could be visualized and quantified in different intestinal segments, while its excretion was confirmed by fluorescent imaging of stool samples. These findings indicate that contrast-enhanced MSOT (CE-MSOT) provides a translatable real-time imaging approach for functional assessment of the gastrointestinal tract.

Published
2022
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9. Efficient and Easy Conversion of Human iPSCs into Functional Induced Microglia-like Cells

Author

Jonas Lanfer, Johanna Kaindl, Laura Krumm, Miguel Gonzalez Acera, Markus Neurath, Martin Regensburger, Florian Krach, and Beate Winner

Subjects
Organic Chemistry, Induced Pluripotent Stem Cells, Cell Differentiation, microglia, pluripotent stem cells, cell differentiation, neurology, immunology, General Medicine, Hematopoietic Stem Cells, Catalysis, Computer Science Applications, Inorganic Chemistry, Humans, Microglia, ddc:610, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, Biological Specimen Banks
Abstract

Current protocols converting human induced pluripotent stem cells (iPSCs) into induced microglia-like cells (iMGL) are either dependent on overexpression of transcription factors or require substantial experience in stem-cell technologies. Here, we developed an easy-to-use two-step protocol to convert iPSCs into functional iMGL via: (1) highly efficient differentiation of hematopoietic progenitor cells (HPCs) from iPSCs, and (2) optimized maturation of HPCs to iMGL. A sequential harvesting approach led to an increased HPC yield. The protocol implemented a freezing step, thus allowing HPC biobanking and flexible timing of differentiation into iMGL. Our iMGL responded adequately to the inflammatory stimuli LPS, and iMGL RNAseq analysis matched those of other frequently used protocols. Comparing three different coating modalities, we increased the iMGL yield by culturing on uncoated glass surfaces, thereby retaining differentiation efficiency and functional hallmarks of iMGL. In summary, we provide a high-quality, easy-to-use protocol, rendering generation and functional studies on iMGL an accessible lab resource.

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

11. Etrolizumab for maintenance therapy in patients with moderately to severely active ulcerative colitis (LAUREL): a randomised, placebo-controlled, double-blind, phase 3 study

Author

Severine Vermeire, Peter L Lakatos, Timothy Ritter, Stephen Hanauer, Brian Bressler, Reena Khanna, Kim Isaacs, Saumin Shah, Alysha Kadva, Helen Tyrrell, Young S Oh, Swati Tole, Akiko Chai, Jennifer Pulley, Christopher Eden, Wenhui Zhang, Brian G Feagan, Philip Abraham, Mauro Acir Crippa Júnior, Humberto Aguilar, Tasneem Ahmed, Istvan Altorjay, Vibeke Andersen, Ronen Arai, Hays Arnold, Karlee Ausk, Jeffrey Axler, Kamran Ayub, Avinash Balekuduru, Guerino Barbalaco Neto, Isaac Bassan, Brian Behm, Pradeep Bekal, Shobna Bhatia, Barnabas Bod, Carlos Eduardo Brandão Mello, Julia Brandeburova, Johannes Breedt, Ivan Chopey, Michael Connor, Richard Corlin, Carlos Alejandro Cortez Hernandez, Arijit De, Alexander de Sá Rolim, Sandra Di Felice Boratto, Tyler Dixon, Debora Dourado Poli, David Dresner, George Aaron Du Vall, Matthias Ebert, Robert Ehehalt, Atilla Ertan, Ruben Escarcega Valencia, Jason Etzel, Jan Fallingborg, Brian Feagan, Miroslav Fedurco, Enrique Fernandez Castro, Valéria Ferreira de Almeida Borges, Mark Finklestein, Andreas Fischer, Mark Fleisher, Angel Ricardo Flores Rendon, Ronald Fogel, Osvaldo Franceschi Junior, Curtis Freedland, David Gatof, Kanwar Gill, Henning Glerup, Vardaraj Gokak, Eran Goldin, Hector Alejandro Gomez Jaramillo, Nitin Gupta, Zoltan Gurzo, Olga Gyrina, Mohammed Aejaz Habeeb, Robert Hardi, William Harlan, Ammar Hemaidan, Melvin Heyman, Peter Hoffmann, William Holderman, Frank Holtkamp-Endemann, Gyula Horvat, Eran Israeli, Sender Jankiel Miszputen, Søren Jensen, Kenneth Johnson, Jennifer Jones, Osvaldo Junior, Barbora Kadleckova, Mukesh Kalla, Zsuzsanna Kallo, Nicholas Karyotakis, Lior Katz, Leo Katz, Nirmal Kaur, Pavel Kohout, Peter Lakatos, Emmanuel Larriva de los Reyes, Robert Lee, Bernard Leman, Olena Levchenko, Henry Levine, Lúcia Libanez Bessa Campelo Braga, Edward Loftus, Tetiana Lohdanidi, Randy Longman, Josefina Lozano, Christian Maaser, Laszlo Madi-Szabo, Everson Fernando Malluta, John Marshall, Francisca Martinez Silva, Kenneth Maynard, Agnieszka Meder, Chetan Mehta, Peter Minarik, Joachim Mueller, Shrikant Mukewar, Bela Nagy, Vasyl Neiko, Markus Neurath, Brian Nichol, James Novick, Nitin Pai, William Pandak, Sarat Panigrahi, Ulrich-Frank Pape, Raymundo Paraná, Nimisha Parekh, Bhaktasharan Patel, Gyula Pecsi, Sergio Peralta, Martin Pesta, Eva Peterfai, Carlo Petruzzellis, Robert Petryka, Roberta Pica, Carlos Piniella, Vijayalakshmi Pratha, Vlastimil Prochazka, Sergey Prokopchuk, Ludmyla Prystupa, Amarender Puri, Tova Rainis, Bhashyakarla Ramesh Kumar, Odery Ramos Júnior, Iaroslava Rishko, Bryan Robbins, Elizabeth Rock, Marcelo Rodrigues Borba, Miguel Rodriguez, Jerzy Rozciecha, Azalia Yuriria Ruiz Flores, Grazyna Rydzewska, Rifaat Safadi, Simone Saibeni, Anja Schirbel, Wolff Schmiegel, Róbert Schnabel, Herbert Schneider, Armando Segui, Jakob Seidelin, Ursula Seidler, Joseph Sellin, Ira Shafran, Aasim Sheikh, Alex Sherman, Haim Shirin, Akash Shukla, Firdous Siddiqui, Robert Sike, Ajit Sood, Andreas Stallmach, Mykola Stanislavchuk, Michael Staun, Daniel Stein, Alon Steinberg, Hillary Steinhart, Jonathas Stifft, Rakesh Tandon, Vishwanath Tantry, Syed Thiwan, Matthias Treiber, Jan Ulbrych, John Valentine, Rajeev Vasudeva, Byron Vaughn, Brenda Velasco, Aron Vincze, Miroslava Volfova, Mattitiahu Waterman, L. Michael Weiss, Elise Wiesner, Alonzo Williams, Thomas Witthoeft, Robert Wohlman, John Wright, Jesus Kazuo Yamamoto Furusho, Ziad Younes, Khurshid Yousuf, Yaroslav Zborivskyy, Stefan Zeuzem, and Vyacheslav Zhdan

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Population, Phases of clinical research, Placebo, Antibodies, Monoclonal, Humanized, Severity of Illness Index, Maintenance Chemotherapy, Young Adult, Maintenance therapy, Double-Blind Method, Gastrointestinal Agents, Internal medicine, Clinical endpoint, Medicine, Humans, education, Adverse effect, Aged, education.field_of_study, Science & Technology, Hepatology, Gastroenterology & Hepatology, business.industry, Remission Induction, Gastroenterology, Colonoscopy, Middle Aged, medicine.disease, Symptom Flare Up, Ulcerative colitis, Etrolizumab, Colitis, Ulcerative, Female, business, Life Sciences & Biomedicine
Abstract

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 evaluate the efficacy and safety of etrolizumab for maintenance of remission in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, placebo-controlled, double-blind, phase 3 study (LAUREL) across 111 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. During open-label induction, participants received subcutaneous etrolizumab 105 mg once every 4 weeks. Participants who had clinical response at week 10 (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) proceeded into the double-blind maintenance phase and were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or matched placebo until week 62. Randomisation was stratified by baseline concomitant treatment with corticosteroids, treatment with immunosuppressants, baseline disease activity, and week 10 remission status. All participants and study site personnel were masked to treatment assignment. The primary endpoint was remission at week 62 (MCS ≤2, with individual subscores ≤1, and rectal bleeding subscore of 0) among patients with a clinical response at week 10, measured in the modified intention-to-treat population (all randomised patients who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, NCT02165215, and is now closed to recruitment. FINDINGS: Between Aug 12, 2014, and June 4, 2020, 658 patients were screened for eligibility and 359 were enrolled into the induction phase. 214 (60%) patients had a clinical response at week 10 and were randomly assigned to receive etrolizumab (n=108) or placebo (n=106) in the maintenance phase. 80 (74%) patients in the etrolizumab group and 42 (40%) in the placebo group completed the study through week 62. Four patients in the placebo group did not receive study treatment and were excluded from the analyses. At week 62, 32 (29·6%) of 108 patients in the etrolizumab group and 21 (20·6%) of 102 in the placebo group were in remission (adjusted treatment difference 7·7% [95% CI -4·2 to 19·2]; p=0·19). A greater proportion of patients reported one or more adverse events in the placebo group (82 [80%] of 102) than in the etrolizumab group (70 [65%] of 108); the most common adverse event in both groups was ulcerative colitis (16 [15%] patients in the etrolizumab group and 37 [36%] in the placebo group). Ten (9%) patients in the etrolizumab group and eight (8%) in the placebo group reported one or more serious adverse events. No deaths were reported in either treatment group. INTERPRETATION: No significant differences were observed between maintenance etrolizumab and placebo in the primary endpoint of remission at week 62 among patients who had a clinical response at week 10. Etrolizumab was well tolerated in this population and no new safety signals were identified. FUNDING: F Hoffmann-La Roche. ispartof: LANCET GASTROENTEROLOGY & HEPATOLOGY vol:7 issue:1 pages:28-37 ispartof: location:Netherlands status: published

Published
2021

15. Cytokines in Colitis-Associated Cancer: Potential Drug Targets?

Author

Maximilian Waldner, Markus Neurath, and Markus Markus

Subjects
Colorectal cancer, Immunology, Inflammation, Inflammatory bowel disease, Pathogenesis, Immune system, T-Lymphocyte Subsets, Animals, Humans, Immunology and Allergy, Medicine, Colitis, Pharmacology, Interleukin-6, Tumor Necrosis Factor-alpha, business.industry, Cancer, General Medicine, Inflammatory Bowel Diseases, medicine.disease, Interleukin-12, Interleukin-10, Cytokines, Tumor necrosis factor alpha, medicine.symptom, Colorectal Neoplasms, business
Abstract

In inflammatory bowel disease (IBD), such as UC and CD, the development of colorectal carcinoma can be initiated through chronic inflammation, depending on the duration and severity of the disease. Growing evidence supports a role for various cytokines, released by epithelial and immune cells, in the pathogenesis of colitis associated cancer (CAC). For instance, TNF-alpha has been recently shown to promote tumor development in experimental colitis. Due to its role in the pathogenesis of IBD, TNF-alpha blockade has become one of the cornerstones of IBD therapy. Thus, anti-TNF-alpha strategies could also provide effective anti-tumor therapies. TGF-beta has been shown to attenuate an anti-tumor immune-response through the induction of regulatory T cells in spontaneous and inflammation associated cancer. However, IL-6 signaling promotes tumor growth in experimental CAC, and this signaling is inhibited by TGF-beta. Members of the IL-12 family, such as IL-12, IL-23, and IL-27, have been implicated in pathogenesis of colitis and IL-23 seems to be involved in inflammation associated carcinogenesis. However, a role for those cytokines in CAC remains to be shown. Whereas the above-mentioned cytokines promote tumor growth, others provide an anti tumor effect. IL-10 deficient mice develop colitis and CAC a few weeks after birth. Besides its immunosuppressive properties, IL-10 also has anti angiogenic and both tumor promoting and -inhibiting properties, which could be responsible for these observations. Since most of the above mentioned cytokines are involved in both, inflammation and carcinogenesis, it is difficult to account their contribution to the individual steps during pathogenesis of CAC. However, as already shown in IBD, cytokines may also provide promising therapeutic targets in CAC.

Published
2008
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