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1. Age-stratification reveals age-specific intestinal microbiota signatures in juvenile idiopathic arthritis

Author

Lisa Budzinski, Toni Sempert, Leonie Lietz, René Maier, Gi-Ung Kang, Anne Sae Lim von Stuckrad, Carl Christoph Goetzke, Maria Roth, Aayushi Shah, Amro Abbas, Katrin Lehman, Kathleen Necke, Stefanie Bartsch, Ute Hoffmann, Mir-Farzin Mashreghi, Robert Biesen, Tilmann Kallinich, and Hyun-Dong Chang

Subjects
JIA, Microbiome, Microbiota phenotyping, Flow cytometry, 16S rRNA sequencing, Age, Pediatrics, RJ1-570
Abstract

Abstract Objective Juvenile Idiopathic Arthritis (JIA) comprises diverse chronic inflammatory conditions driven by malfunction of the immune system. The intestinal microbiota is considered a crucial environmental factor correlating with chronic inflammatory diseases, and for JIA certain alterations in the microbiota have already been described. Methods Here, we have characterized intestinal microbiota samples from 54 JIA patients and 38 pediatric healthy controls by conventional 16S rRNA sequencing and by single-cell analysis for phenotypic features by multi-parameter microbiota flow cytometry (mMFC), which complements the population-based taxonomic profiling with the characterization of individual bacterial cells. Results We found age to be a crucial confounder in microbiota analyses of JIA patients. Age stratification revealed specific microbiota alterations neglected by the general comparison of JIA patients and pediatric controls. Conclusion Age groups presented distinct taxonomic profiles and microbiota phenotypic signatures which transitioned with age, highlighting changes in the microbiota-immune system interaction with age.

Published
2024
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2. Treat-to-target strategies for the management of familial Mediterranean Fever in children

Author

Lisa Ehlers, Elisabeth Rolfes, Mareike Lieber, Dominik Müller, Elke Lainka, Faekah Gohar, Günter Klaus, Hermann Girschick, Jana Hörstermann, Jasmin Kümmerle-Deschner, Jürgen Brunner, Katharina Palm-Beden, Klaus Tenbrock, Lusine von Wrangel, Maria Faßhauer, Norbert Blank, Ralf Trauzeddel, Anne Sae Lim von Stuckrad, Sonja Higgins, Tatjana Welzel, Thomas Lutz, Véronique Hentgen, Dirk Foell, Helmut Wittkowski, and Tilmann Kallinich

Subjects
Children, Colchicine, Colchicine resistance, Disease activity, Familial Mediterranean Fever, interleukin-1 antagonists, Pediatrics, RJ1-570, Diseases of the musculoskeletal system, RC925-935
Abstract

Abstract Background The objective of this initiative was to develop a treat-to-target (T2T) approach for the management of patients with Familial Mediterranean Fever (FMF), including the definition of a complex treatment target, and establish strategies that improve patient care and long-term outcome. Methods An initial set of statements as well as a flow chart visualising the proposed concept was developed. To adapt the preliminary statements to the current state of knowledge, a systematic literature search was performed and the modified statements were subject to a Delphi approach. To ensure the applicability of the statements in daily practice, an online survey was conducted among paediatric rheumatologists in Germany. In addition, data from the national AID-NET registry were analysed with respect to therapeutic response. Results This T2T initiative yielded a total of 26 statements guiding FMF management with respect to diagnosis, treatment targets, treatment strategies and monitoring. The online survey identified cut-off values for inflammatory markers indicating treatment intensification and appropriate measures in case of colchicine intolerance or non-adherence. The analysis of data derived from the national AID-NET showed that colchicine therapy was successfully terminated in 61% of patients (27 out of 44) with heterozygous MEFV mutations. Multidimensional treatment targets incorporating objective and subjective reported outcome measures were developed. These provide the basis for stratifying patients into the following treatment paths: continue colchicine, persisting attacks / inflammation, colchicine intolerance, persisting arthritis, colchicine reduction and adjustment/reduction of biologics. Conclusions The proposed consensus treatment plan for the management of FMF incorporates multidimensional targets allowing transparent treatment decisions, which will promote personalised disease management and increase adherence to therapy.

Published
2023
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4. Proceedings of the 23rd Paediatric Rheumatology European Society Congress: part one

Author

F. De Benedetti, J. Anton, M. Gattorno, H. Lachmann, I. Kone-Paut, S. Ozen, J. Frenkel, A. Simon, A. Zeft, E. Ben-Chetrit, H. M. Hoffman, Y. Joubert, K. Lheritier, A. Speziale, J. Guido, Roberta Caorsi, Federica Penco, Alice Grossi, Antonella Insalaco, Maria Alessio, Giovanni Conti, Federico Marchetti, Alberto Tommasini, Silvana Martino, Romina Gallizzi, Annalisa Salis, Francesca Schena, Francesco Caroli, Alberto Martini, Gianluca Damonte, Isabella Ceccherini, Marco Gattorno, Marie-Louise Frémond, Carolina Uggenti, Lien Van Eyck, Isabelle Melki, Darragh Duffy, Vincent Bondet, Yoann Rose, Bénédicte Neven, Yanick Crow, Mathieu P. Rodero, Yvonne Kusche, Johannes Roth, Katarzyna Barczyk-Kahlert, Giovanna Ferrara, Annalisa Chiocchetti, Silvio Polizzi, Josef Vuch, Diego Vozzi, Anna Mondino, Erica Valencic, Serena Pastore, Andrea Taddio, Flavio Faletra, Umberto Dianzani, Ugo Ramenghi, Qing Zhou, Xiaomin Yu, Erkan Demirkaya, Natalie Deuitch, Deborah Stone, Wanxia Tsai, Amanda Ombrello, Tina Romeo, Elaine F. Remmers, JaeJin Chae, Massimo Gadina, Steven Welch, Seza Ozen, Rezan Topaloglu, Mario Abinun, Daniel L. Kastner, Ivona Aksentijevich, Donatella Vairo, Rosalba Monica Ferraro, Giulia Zani, Jessica Galli, Micaela De Simone, Marco Cattalini, Elisa Fazzi, Silvia Giliani, Ebun Omoyinmi, Ariane Standing, Dorota Rowczenio, Annette Keylock, Sonia Melo Gomes, Fiona Price-Kuehne, Sira Nanthapisal, Claire Murphy, Thomas Cullup, Lucy Jenkins, Kimberly Gilmour, Despina Eleftheriou, Helen Lachmann, Philip Hawkins, Nigel Klein, Paul Brogan, Anita Dhanrajani, Mercedes Chan, Stephanie Pau, Janet Ellsworth, Jaime Guzman, Florence A. Aeschlimann, Marinka Twilt, Simon W. Eng, Shehla Sheikh, Ronald M. Laxer, Diane Hebert, Damien Noone, Christian Pagnoux, Susanne M. Benseler, Rae S. Yeung, Christoph Kessel, Katrin Lippitz, Toni Weinhage, Claas Hinze, Helmut Wittkowski, Dirk Holzinger, Niklas Grün, Dirk Föll, Pieter Van Dijkhuizen, Federica Del Chierico, Clara Malattia, Alessandra Russo, Denise Pires Marafon, Nienke M. ter Haar, Silvia Magni-Manzoni, Sebastiaan J. Vastert, Bruno Dallapiccola, Berent Prakken, Fabrizio De Benedetti, Lorenza Putignani, Berna Eren Fidanci, Kenan Barut, Serap Arıcı, Dogan Simsek, Mustafa Cakan, Ezgi D. Batu, Sezgin Şahin, Ayşenur Kısaarslan, Ebru Yilmaz, Özge Basaran, Ferhat Demir, Kubra Ozturk, Zübeyde Gunduz, Betül Sozeri, Balahan Makay, Nuray Ayaz, Onder Yavascan, Ozlem Aydog, Yelda Bilginer, Zelal Ekinci, Dilek Yıldız, Faysal Gök, Muferret Erguven, Erbil Unsal, Ozgur Kasapcopur, For the FMF Arthritis Vasculitis and Orphan Disease Research in Paediatric Rheumatology (FAVOR), Hafize E. Sönmez, Betül Sözeri, Yonatan Butbul, Seza Özen, Claudia Bracaglia, Giusi Prencipe, Manuela Pardeo, Geneviève Lapeyre, Emiliano Marasco, Walter Ferlin, Robert Nelson, Cristina de Min, N. Ruperto, H. I. Brunner, P. Quartier, T. Constantin, E. Alexeeva, K. Marzan, N. Wulffraat, R. Schneider, S. Padeh, V. Chasnyk, C. Wouters, J. B. Kuemmerle-Deschner, T. Kallinich, B. Lauwerys, E. Haddad, E. Nasonov, M. Trachana, O. Vougiouka, K. Leon, E. Vritzali, A. Martini, D. Lovell, PRINTO/PRCSG, Stefano Volpi, Claudia Pastorino, Francesca Kalli, Alessia Omenetti, Sabrina Chiesa, Arinna Bertoni, Paolo Picco, Gilberto Filaci, Elisabetta Traggiai, Marie-Louise Fremond, Naoki Kitabayashi, Olivero Sacco, Isabelle Meyts, Marie-Anne Morren, Carine Wouters, Eric Legius, Isabelle Callebaut, Christine Bodemer, Frederic Rieux-Laucat, Mathieu Rodero, Nadia Jeremiah, Alexandre Belot, Eric Jeziorski, Didier Bessis, Guilhem Cros, Gillian I. Rice, Bruno Charbit, Anne Hulin, Nihel Khoudour, Consuelo Modesto Caballero, Monique Fabre, Laureline Berteloot, Muriel Le Bourgeois, Philippe Reix, Thierry Walzer, Despina Moshous, Stéphane Blanche, Alain Fischer, Brigitte Bader-Meunier, Frédéric Rieux-Laucat, K. Annink, N. ter Haar, S. Al-Mayouf, G. Amaryan, K. Barron, S. Benseler, P. Brogan, L. Cantarini, M. Cattalini, A. Cochino, F. Dedeoglu, A. De Jesus, O. Dellacasa, E. Demirkaya, P. Dolezalova, K. Durrant, G. Fabio, R. Gallizzi, R. Goldbach-Mansky, E. Hachulla, V. Hentgen, T. Herlin, M. Hofer, H. Hoffman, A. Insalaco, A. Jansson, I. Koné-Paut, A. Kozlova, J. Kuemmerle-Deschner, R. Laxer, S. Nielsen, I. Nikishina, A. Ombrello, E. Papadopoulou-Alataki, A. Ravelli, D. Rigante, R. Russo, Y. Uziel, Nienke ter Haar, Jerold Jeyaratnam, Anna Simon, Matteo Doglio, Jordi Anton, Consuelo Modesto, Pierre Quartier, Esther Hoppenreijs, Luca Cantarini, Loredana Lepore, Inmaculada Calvo Penades, Christina Boros, Rita Consolini, Donato Rigante, Ricardo Russo, Jana Pachlopnik Schmid, Thirusha Lane, Nicolino Ruperto, Joost Frenkel, Chiara Passarelli, Elisa Pisaneschi, Virginia Messia, Antonio Novelli, Fabrizio Debenedetti, P. A. Brogan, X. Wei, Martina Finetti, Francesca Orlando, Elisabetta Cortis, Angela Miniaci, Nicola Ruperto, Charlotte Eijkelboom, Pavla Dolezalova, Isabelle Koné-Paut, Marija Jelusic-Drazic, Liliana Bezrodnik, Mari Carmen Pinedo, Valda Stanevicha, Marielle van Gijn, Silvia Federici, Hermann Girschick, Gerd Ganser, Susan Nielsen, Troels Herlin, Sulaiman Mohammed Al-Mayouf, Michael Hofer, Jasmin Kuemmerle-Deschner, Susanne Schalm, Annette Jansson, on behalf of PRINTO and Eurofever registry, Marta Marchi, Chiara Marini, Angelo Ravelli, Alberto Garaventa, Sonia Carta, Enrica Balza, Patrizia Castellani, Caterina Pellecchia, Silvia Borghini, Maria Libera Trotta, Anna Rubartelli, Andrew Henrey, Thomas Loughin, Roberta Berard, Natalie Shiff, Roman Jurencak, Susanne Benseler, Lori Tucker, on behalf of ReACCh-Out Investigators, Charalampia Papadopoulou, Ying Hong, Petra Krol, Yiannis Ioannou, Clarissa Pilkington, Hema Chaplin, Stephania Simou, Marietta Charakida, Lucy Wedderburn, Lynn R. Spiegel, Sara Ahola Kohut, Jennifer Stinson, Paula Forgeron, Miriam Kaufman, Nadia Luca, Khush Amaria, Mary Bell, J Swart, F. Boris, E. Castagnola, A. Groll, G. Giancane, G. Horneff, H. I. Huppertz, T. Wolfs, E. Alekseeva, V. Panaviene, F. Uettwiller, V. Stanevicha, L. M. Ailioaie, E. Tsitami, S. Kamphuis, G. Susic, F. Sztajnbok, B. Flato, A. Pistorio, Stephanie J. W. Shoop, Suzanne M. M. Verstappen, Janet E. McDonagh, Wendy Thomson, Kimme L. Hyrich, CAPS, Maarit Tarkiainen, Pirjo Tynjala, Pekka Lahdenne, Janne Martikainen, Acute-JIA Study Group, Meredyth Wilkinson, Christopher Piper, Georg Otto, Claire T. Deakin, Stefanie Dowle, Stefania Simou, Daniel Kelberman, Claudia Mauri, Elizabeth Jury, David Isenberg, Lucy R. Wedderburn, Kiran Nistala, I. Foeldvari, D. J. Lovell, G. Simonini, M. Bereswill, J. Kalabic, Kiem Oen, Brian M. Feldman, Brenden Dufault, Jennifer Lee, Karen Watanabe Duffy, Ciaran Duffy, ReACCh-Out Investigators, N. Tzaribachev, G. Vega-Cornejo, I. Louw, A. Berman, I. Calvo, R. Cuttica, F. Avila-Zapata, R. Cimaz, E. Solau-Gervais, R. Joos, G. Espada, X. Li, M. Nys, R. Wong, S. Banerjee, For Pediatric Rheumatology International Trials Organization (PRINTO)/Pediatric Rheumatology Collaborative Study Group (PRCSG), Rebecca Nicolai, Margherita Verardo, Adele D’Amico, Luisa Bracci-Laudiero, Gian Marco Moneta, Gillian Rice, Anne-Laure Mathieu, Sulliman O. Omarjee, Tracy A. Briggs, James O’Sullivan, Simon Williams, Rolando Cimaz, Eve Smith, Michael W. Beresford, Yanick J. Crow, GENIAL Investigators, UK JSLE Study Group, Madeleine Rooney, Nick Bishop, joyce davidson, Clarissa pilkington, Michael Beresford, Jacqui Clinch, Rangaraj Satyapal, Helen Foster, Janet Gardner Medwin, Janet McDonagh, Sue Wyatt, On Behalf of the British Society for Paediatric and Adolescent Rheumatology, Valentina Litta Modignani, Francesco Baldo, Stefano Lanni, Alessandro Consolaro, Giovanni Filocamo, Helen J. Lachmann, on behalf of Eurofever Registry, Gianmarco Moneta, Camilla Celani, Bilade Cherqaoui, Linda Rossi-Semerano, Perrine Dusser, Véronique Hentgen, Claire Grimwood, Linda Rossi, Isabelle Kone Paut, Veronique Hentgen, Denise Lasigliè, Denise Ferrera, Giulia Amico, Marco Di Duca, Laura Obici, Roberto Ravazzolo, Ryuta Nishikomori, Juan Arostegui, Andrea Petretto, Chiara Lavarello, Elvira Inglese, Federica Vanoni, Michaël Hofer, on behalf of EUROFEVER PROJECT, P. N. Hawkins, T. van der Poll, U. A. Walker, H. H. Tilson, Pascal N. Tyrrell, Raphaela Goldbach-Mansky, Norbert Blank, Hal M. Hoffman, Elisabeth Weissbarth-Riedel, Boris Huegle, Tilmann Kallinich, Ahmet Gul, Marlen Oswald, Fatma Dedeoglu, Aki Hanaya, Takako Miyamae, Manabu Kawamoto, Yumi Tani, Takuma Hara, Yasushi Kawaguchi, Satoru Nagata, Hisashi Yamanaka, Almira Ćosićkić, Fahrija Skokić, Belkisa Čolić, Sanimir Suljendić, Anna Kozlova, Irina Mersiyanova, Mariya Panina, Lily Hachtryan, Vasiliy Burlakov, Elena Raikina, Alexey Maschan, Anna Shcherbina, Banu Acar, Meryem Albayrak, Betul Sozeri, Sezgin Sahin, Amra Adrovic, Nese Inan, Serhan Sevgi, Caroline M. Andreasen, Anne Grethe Jurik, Mia B. Glerup, Christian Høst, Birgitte T. Mahler, Ellen-Margrethe Hauge, Cecilia Lazea, Laura Damian, Calin Lazar, Rodica Manasia, Chloe M. Stephenson, Vimal Prajapati, Paivi M. Miettunen, Dilek Yılmaz, Yavuz Tokgöz, Yasin Bulut, Harun Çakmak, Ferah Sönmez, Elif Comak, Gülşah Kaya Aksoy, Mustafa Koyun, Sema Akman, Yunus Arıkan, Ender Terzioğlu, Osman Nidai Özdeş, İbrahim Keser, Hüseyin Koçak, Ayşen Bingöl, Aygen Yılmaz, Reha Artan, X. Xu, Fatemeh F. Mehregan, Vahid Ziaee, Mohammad H. Moradinejad, Francesco La Torre, Clotilde Alizzi, Pio D’Adamo, G. Junge, J. Gregson, Hasmik Sargsyan, Hulya Zengin, Berna E. Fidanci, Cagla Kaymakamgil, Dilek Konukbay, Dilek Yildiz, Faysal Gok, Iris Stoler, Judith Freytag, Banu Orak, Christine Seib, Lars Esmann, Eva Seipelt, Faekah Gohar, Dirk Foell, Ismail Dursun, Sebahat Tulpar, Sibel Yel, Demet Kartal, Murat Borlu, Funda Bastug, Hakan Poyrazoglu, Zubeyde Gunduz, Kader Kose, Mehmet E. Yuksel, Abdullah Calıskan, Ahmet B. Cekgeloglu, Ruhan Dusunsel, Katerina Bouchalova, Jana Franova, Marcel Schuller, Marie Macku, Katerina Theodoropoulou, Raffaella Carlomagno, Annette von Scheven-Gête, Claudia Poloni, Laura O. Damian, Dan Cosma, Amanda Radulescu, Dan Vasilescu, Liliana Rogojan, Simona Rednic, Mihaela Lupse, Lien De Somer, Pierre Moens, Rocio Galindo Zavala, Laura Martín Pedraz, Esmeralda Núñez Cuadros, Gisela Díaz-Cordovés Rego, Antonio L. Urda Cardona, Ilaria Dal Forno, Sara Pieropan, Ombretta Viapiana, Davide Gatti, Gloria Dallagiacoma, Paola Caramaschi, Domenico Biasi, Daniel Windschall, Ralf Trauzeddel, Hartwig Lehmann, Rainer Berendes, Maria Haller, Manuela Krumrey-Langkammerer, Antje Nimtz-Talaska, Philipp Schoof, Ralf Felix Trauzeddel, Christine Nirschl, Estefania Quesada-Masachs, Carla Aguilar Blancafort, Sara Marsal Barril, Francisca Aguiar, Rita Fonseca, Duarte Alves, Ana Vieira, Alberto Vieira, Jorge A. Dias, Iva Brito, Gordana Susic, Vera Milic, Goran Radunovic, Ivan Boricic, Pauline Marteau, Catherine Adamsbaum, Michel De Bandt, Irène Lemelle, Chantal Deslandre, Tu Anh Tran, Anne Lohse, Elisabeth Solau-Gervais, Pascal Pillet, Julien Wipff, Cécile Gaujoux-Viala, Sylvain Breton, Valérie Devauchelle-Pensec, Sandra Gran, Olesja Fehler, Stefanie Zenker, Michael Schäfers, Thomas Vogl, Severine Guillaume Czitrom, EH Pieter Van Dijkhuizen, Silvia Magni Manzoni, Francesca Magnaguagno, Laura Tanturri de Horatio, Nienke M. Ter Haar, Annemieke S. Littooij, Vitor A. Teixeira, Raquel Campanilho-Marques, Ana F. Mourão, Filipa O. Ramos, Manuela Costa, Wafa A. Madan, Orla G. Killeen, Adriana Rodriguez Vidal, Diana Sueiro Delgado, Maria Isabel Gonzalez Fernandez, Berta Lopez Montesinos, Aleksey Kozhevnikov, Nina Pozdeeva, Mikhail Konev, Evgeniy Melchenko, Vladimir Kenis, Gennadiy Novik, Aysenur Pac Kısaarslan, Butsabong Lerkvaleekul, Suphaneewan Jaovisidha, Witaya Sungkarat, Niyata Chitrapazt, Praman Fuangfa, Thumanoon Ruangchaijatuporn, Soamarat Vilaiyuk, Dan Ø. Pradsgaard, Arne Hørlyck, Anne H. Spannow, Carsten W. Heuck, Talia Diaz, Fernando Garcia, Lorenia De La Cruz, Nadina Rubio, Joanna Świdrowska-Jaros, Elzbieta Smolewska, Mirta Lamot, Lovro Lamot, Mandica Vidovic, Edi Paleka Bosak, Ivana Rados, Miroslav Harjacek, Nikolay Tzaribachev, Polymnia Louka, Romiesa Hagoug, Chiara Trentin, Olga Kubassova, Mark Hinton, Mikael Boesen, Olena A. Oshlianska, Illya A. Chaikovsky, G. Mjasnikov, A. Kazmirchyk, Umberto Garagiola, Irene Borzani, Paolo Cressoni, Fabrizia Corona, Eszter Dzsida, Giampietro Farronato, Antonella Petaccia, Alenka Gagro, Agneza Marija Pasini, Goran Roic, Ozren Vrdoljak, Lucija Lujic, Matija Zutelija-Fattorini, Monika M. Esser, Deepthi R. Abraham, Craig Kinnear, Glenda Durrheim, Mike Urban, Eileen Hoal, Victoria B. Nikolayenko, Kubilay Şahin, Yasar Karaaslan, Adele Civino, Giovanni Alighieri, Sergio Davì, Roberto Rondelli, Andrea Magnolato, Francesca Ricci, Alma Olivieri, Valeria Gerloni, Bianca Lattanzi, Francesca Soscia, Alessandro De Fanti, Stefania Citiso, Lorenzo Quartulli, Maria Cristina Maggio, Manuela Marsili, Maria Antonietta Pelagatti, Valentino Conter, Franca Fagioli, Andrea Pession, Marco Garrone, Mariangela Rinaldi, Jaime De Inocencio, Stella Garay, Daniel J. Lovell, Berit Flato, EPOCA Study Group, Angela Aquilani, Simona Cascioli, Ivan Caiello, Denise Pires-Marafón, Rita Carsetti, Emily Robinson, Salvatore Albani, Wilco de Jager, Sytze de Roock, Trang Duong, Justine Ellis, Kimme Hyrich, Laetitia Jervis, Daniel Lovell, Lucy Marshall, Elizabeth D. Mellins, Kirsten Minden, Jane Munro, Peter A. Nigrovic, Jason Palman, Sunil Sampath, Laura E. Schanberg, Susan D. Thompson, Richard Vesely, Chris Wallace, Chris Williams, Qiong Wu, Nico Wulffraat, Rae S. M. Yeung, M. B. Seyger, D. Arikan, J. K. Anderson, A. Lazar, D. A. Williams, C. Wang, R. Tarzynski-Potempa, J. S. Hymans, Gabriele Simonini, Erika Scoccimarro, Irene Pontikaki, Teresa Giani, Alessandro Ventura, Pier Luigi Meroni, Gaetana Minnone, Marzia Soligo, Luigi Manni, Luisa Bracci Laudiero, Noortje Groot, I. Grein, N. M. Wulffraat, R. Schepp, G. Berbers, C. C. Barbosa Sandoval de Souza, V. Paes Leme Ferriani, G. Pileggi, S. de Roock, Ingrid H. R. Grein, Silvia Scala, Elisa Patrone, Casper Schoemaker, on behalf of Dutch JIA patient organization, Wendy Costello, on behalf of ENCA, Suzanne Parsons, Jean-David Cohen, Damien Bentayou, Marc-Antoine Bernard Brunel, Sonia Trope, Jens Klotsche, Miriam Listing, Martina Niewerth, Gerd Horneff, Angelika Thon, Hans-Iko Huppertz, Kirsten Mönkemöller, Ivan Foeldvari, ICON study group, Achille Marino, Stefano Stagi, Niccolò Carli, Federico Bertini, Adriana S. Díaz-Maldonado, Sally Pino, Pilar Guarnizo, Alfonso Ragnar Torres-Jimenez, Berenice Sanchez-Jara, Eunice Solis-Vallejo, Adriana Ivonne Cespedes-Cruz, Maritza Zeferino-Cruz, Julia Veronica Ramirez-Miramontes, Ankur Kumar, Anju Gupta, Deepti Suri, Amit Rawat, Nandita Kakkar, Surjit Singh, Özge A. Gücenmez, Erbil Ünsal, Bo Magnusson, Karina Mördrup, Anna Vermé, Christina Peterson, Board of the Swedish Pediatric Rheumatology Registry, Caroline Freychet, Jean Louis Stephan, Cathryn E. Harkness, Leanne Foster, Emma Henry, Pauline Taggart, Coskun F. Ozkececi, Esra Kurt, Gokalp Basbozkurt, Daiva Gorczyca, Jacek Postępski, Aleksandra Czajkowska, Bogumiła Szponar, Mariola Paściak, Anna Gruenpeter, Iwona Lachór-Motyka, Daria Augustyniak, Edyta Olesińska, Emediong S. Asuka, Tatyana Golovko, Samuel U. Aliejim, Emilio Inarejos Clemente, Estibaliz Iglesias Jimenez, Joan Calzada Hernandez, Sergi Borlan Fernandez, Clara Gimenez Roca, David Moreno Romo, Natalia Rodriguez Nieva, Juan Manuel Mosquera Angarita, Jordi Anton Lopez, Esmeralda Nuñez-Cuadros, Gisela Diaz-Cordovés, Rocío Galindo-Zavala, Antonio Urda-Cardona, Antonio Fernández-Nebro, Daniel Álvarez de la Sierra, Marina Garcia Prat, Mónica Martínez Gallo, Ricardo Pujol Borrell, Ana M. Marín Sánchez, Etienne Merlin, Sylvie Fraitag, Jean-Louis Stephan, Federico Annoni, Giancarla Di Landro, Sofia Torreggiani, Marta Torcoletti, Georgina Tiller, Jo Buckle, Angela Cox, Peter Gowdie, Roger C. Allen, Jonathan D. Akikusa, Hayde G. Hernández-Huirache, Edel R. Rodea-Montero, William Fahy, Christelle Sordet, Karin B. Berggren, Johanna T. Kembe, Joyce Bos, Wineke Armbrust, Marco van Brussel, Jeanette Cappon, Pieter Dijkstra, Jan Geertzen, Elizabeth Legger, Marion van Rossum, Pieter Sauer, Otto Lelieveld, Levent Buluc, Gur Akansel, Bahar Muezzinoglu, Ljubov Rychkova, Tatyana Knyazeva, Anna Pogodina, Tatyana Belova, Tamara Mandzyak, Ekaterina Kulesh, Alessandro Cafarotti, Cosimo Giannini, Roberta Salvatore, Giuseppe Lapergola, Caterina Di Battista, Maria Loredana Marcovecchio, Raffaella Basilico, Piernicola Pelliccia, Francesco Chiarelli, Luciana Breda, Beverley Almeida, Sarah Tansley, Harsha Gunawardena, Neil McHugh, Juvenile Dermatomyositis Research Group (JDRG), Jessie Aouizerate, Marie De Antonio, Christine Barnerias, Guillaume Bassez, Isabelle Desguerre, Romain Gherardi, Jean-Luc Charuel, François-Jérôme Authier, Cyril Gitiaux, C. H. Spencer, Rabheh Abdul Aziz, Chack-Yung Yu, Brent Adler, Sharon Bout-Tabaku, Katherine Lintner, Melissa Moore-Clingenpeel, Liza McCann, Nicola Ambrose, Mario Cortina-Borja, Juvenile Dermatomyositis Cohort and Biomarker Study (JCDBS), Prasad T. Oommen, Fabian Speth, Johannes-Peter Haas, Working Group “Juvenile Dermatomyositis” of the German Society for Paediatric and Adolescent Rheumatology (GKJR), Claudio Lavarello, Gabriella Giancane, Angela Pistorio, Lisa Rider, Rohit Aggarwal, Sheila K. Oliveira, Ruben Cuttica, Michel Fischbach, Gary Sterba, Karine Brochard, Frank Dressler, Patrizia Barone, Ruben Burgos-Vargas, Elizabeth Candell Chalom, Marine Desjonqueres, Graciela Espada, Anders Fasth, Stella Maris Garay, Rose-Marie Herbigneaux, Claire Hoyoux, Chantal Job Deslandre, Frederick W. Miller, Jiri Vencovsky, Erdal Sag, Gulsev Kale, Haluk Topaloglu, Beril Talim, Francesco Zulian, Tadej Avcin, Roberto Marini, Anne Pagnier, Michel Rodiere, Christine Soler, Rebecca Ten Cate, Yosef Uziel, Jelena Vojinovic, Ana V. Villarreal, Nydia Acevedo, Yuridiana Ramirez, Enrique Faugier, Rocio Maldonado, Bita Arabshahi, John H. Lee, Ian Leibowitz, Lawrence O. Okong’o, Jo Wilmshurst, Monika Esser, Christiaan Scott, Ezgi Deniz Batu, Nagehan Emiroglu, Hafize Emine Sonmez, Gokcen Dilsa Tugcu, Zehra Serap Arici, Ebru Yalcin, Deniz Dogru, Ugur Ozcelik, Mithat Haliloglu, Nural Kiper, Masato Yashiro, Mutsuko Yamada, Toshihiko Yabuuchi, Tomonobu Kikkawa, Nobuyuki Nosaka, Yosuke Fujii, Yukie Saito, Hirokazu Tsukahara, Sulaiman M. Al-Mayouf, Nora AlMutiari, Mohammed Muzaffer, Rawiah shehata, Adel Al-Wahadneh, Reem Abdwani, Safia Al-Abrawi, Mohammed Abu-shukair, Zeyad El-Habahbeh, Abdullah Alsonbul, Aleksandra Szabat, Monika Chęć, Violetta Opoka-Winiarska, Biman Saikia, Ranjana W. Minz, Christine Arango, Clara Malagon, Maria D. P. Gomez, Angela C. Mosquera, Ricardo Yepez, Tatiana Gonzalez, Camilo Vargas, GRIP study group, Marta Balzarin, Biagio Castaldi, Elena Reffo, Francesca Sperotto, Giorgia Martini, Alessandra Meneghel, Ornella Milanesi, Ozgur Kasapçopur, Maria Teresa Terreri, Ekaterina Alexeeva, Maria Katsicas, Mikhail Kostik, Thomas Lehman, W.-Alberto Sifuentes-Giraldo, Vanessa Smith, Flavio Sztajnbok, Tadey Avcin, Maria Jose Santos, Dana Nemcova, Cristina Battagliotti, Liora Harel, Mahesh Janarthanan, Kathryn Torok, Nicola Helmus, Eileen Baildem, Michael Blakley, Kim Fligelstone, Antonia Kienast, Clare Pain, Amanda Saracino, Gabriele Simoni, Lisa Weibel, Maria K. Osminina, Nathalia A. Geppe, Olga V. Niconorova, Olesya V. Karashtina, Oksana V. Abbyasova, Olga V. Shpitonkova, Sinem Durmus, Hafize Uzun, Angela Mauro, Eleonora Fanti, Fabio Voller, Franca Rusconi, Fernando Garcia-Rodriguez, Ana V. Villarreal-Treviño, Angel J. Flores-Pineda, Paola B. Lara-Herrea, Diego R. Salinas-Encinas, Talia Diaz-Prieto, Maria R. Maldonado-Velazquez, Sarbelio Moreno-Espinosa, Enrique Faugier-Fuentes, Mirella Crapanzano, Ilaria Parissenti, Man S. Parihar, Pandiarajan Vignesh, ManojKumar Rohit, Kavitha Gopalan, Savita V. Attri, Alan Salama, David Jayne, Mark Little, Yulia Kostina, Galina Lyskina, Olga Shpitonkova, Alena Torbyak, Olga Shirinsky, Maria Francesca Gicchino, Maria Cristina Smaldone, Mario Diplomatico, Alma Nunzia Olivieri, C H. Spencer, Richard McClead, Hiren Patel, Chung-Yung Yu, Dita Cebecauerová, Tomáš Dallos, Edita Kabíčková, Martin Kynčl, Daniela Chroustová, Jozef Hoza, Dana Němcová, Vladimír Tesař, Pavla Doležalová, Tuncay Hazirolan, Fatih Ozaltin, Fabiola Almeida, Isabela H. Faria de Paula, Maíra M. Sampaio, Fernando N. Arita, Andressa G. Alves, Maria Carolina Santos, Eunice M. Okuda, Silvana B. Sacchetti, Fernanda Falcini, Marini Francesca, Gemma Lepri, Marco Matucci-Cerinic, Maria Luisa Brandi, Hakan Kisaoglu, Sema Misir, Selim Demir, Yuksel Aliyazicioglu, Mukaddes Kalyoncu, Carlos Eduardo Ramalho, Fabiola D. Almeida, Joan Calzada-Hernández, Rosa Bou, Estíbaliz Iglesias, Judith Sánchez-Manubens, Fredy Hermógenes Prada Martínez, Clara Giménez Roca, Sergi Borlan Fernández, Marek Bohm, Kamran Mahmood, Valentina Leone, Mark Wood, Ken-Ichi Yamaguchi, Satoshi Fujikawa, Working Group of Behçet’s Disease, Pediatric Rheumatology Association of Japan (PRAJ), Kyu Yeun Kim, Do Young Kim, Dong Soo Kim, Maka Ioseliani, Ivane Chkhaidze, Maia Lekishvili, Nana Tskhakaia, Shorena Tvalabeishvili, Aleksandre Kajrishvili, Maiko Takakura, Masaki Shimizu, Natsumi Inoue, Mao Mizuta, Akihiro Yachie, Giovanni Corsello, Maryam Piram, Carla Maldini, Sandra Biscardi, Nathalie Desuremain, Catherine Orzechowski, Emilie Georget, Delphine Regnard, Isabelle Kone-Paut, Alfred Mahr, Mihaela Sparchez, Zeno Sparchez, Nydia Acevedo Silva, Ana V. Villarreal Treviño, Yuridiana Ramirez Loyola, Talia Diaz Prieto, Enrique Faugier Fuentes, Maria D. R. Maldonado Velazquez, Pilar Perez, Sagar Bhattad, Ranjana Minz, Jitendra Shandilya, Pediatric Allergy and Immunology Unit, PGIMER, Chandigarh, Ana Villarreal, Yuridiana Ramírez, Zeynep Birsin Özçakar, Suat Fitoz, Fatos Yalcinkaya, Annacarin Horne, Francesca Minoia, Francesca Bovis, Sergio Davi, Priyankar Pal, Kimo Stein, Sandra Enciso, Michael Jeng, Despoina Maritsi, Randy C. Cron, Anne Thorwarth, Sae Lim von Stuckrad, Angela Rösen-Wolff, Hella Luksch, Patrick Hundsdoerfer, Peter Krawitz, Nuray Aktay Ayaz, Doğan Simsek, Şebnem Sara Kılıc, Emine Sonmez, Aysenur Pac Kisaarslan, Ozge Altug Gucenmez, Z. Serap Arıcı, Fatih Kelesoglu, Zelal Ekinci Ekinci, Maria Miranda-Garcia, Carolin Pretzer, Michael Frosch, F. Gohar, Angela McArdle, Niamh Callan, Belinda Hernandez, Miha Lavric, Oliver FitzGerald, Stephen R. Pennington, Joachim Peitz, Joern Kekow, Ariane Klein, Anna C. Schulz, Frank Weller-Heinemann, Anton Hospach, J-Peter Haas, BIKER collaborative group, Karen Put, Jessica Vandenhaute, Anneleen Avau, Annemarie van Nieuwenhuijze, Ellen Brisse, Tim Dierckx, Omer Rutgeerts, Josselyn E. Garcia-Perez, Jaan Toelen, Mark Waer, Georges Leclercq, An Goris, Johan Van Weyenbergh, Adrian Liston, Patrick Matthys, Carine H. Wouters, Yasuo Nakagishi, Michael J. Ombrello, Victoria Arthur, Anne Hinks, Patricia Woo, International Childhood Arthritis Genetics (INCHARGE) Consortium, Barbara Stanimirovic, Biljana Djurdjevic-Banjac, Olivera Ljuboja, Boris Hugle, MArgarita Onoufriou, Olga Vougiouka, Kenza Bouayed, Sanae El Hani, Imane Hafid, Nabiha Mikou, Nunu Shelia, Mari Laan, Jaanika Ilisson, and Chris Pruunsild

Subjects
Pediatrics, RJ1-570, Diseases of the musculoskeletal system, RC925-935
Published
2017
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5. Neue Kriterien zur Klassifikation und Diagnose der juvenilen Arthritis

Author

Sae Lim von Stuckrad and Kirsten Minden

Abstract

ZUSAMMENFASSUNGSeit Mitte der 1990er-Jahre wird die heterogene Gruppe der chronischen Arthritiden des Kindes- und Jugendalters auf Empfehlung eines Expertengremiums der ILAR unter dem Oberbegriff juvenile idiopathische Arthritis zusammengefasst, wobei die Klassifikation der einzelnen Formen der JIA auf der Basis klinischer Parameter erfolgt. Diese international akzeptierte und heutzutage üblicherweise angewandte Klassifikation der JIA definiert sieben verschiedene Erkrankungen bzw. Kategorien der JIA, die sich in ihrer klinischen Präsentation, ihrem Verlauf sowie z. T. genetischen Hintergrund voneinander unterscheiden. Trotz vieler Vorzüge im Vergleich zu früheren Klassifikationen weist die ILAR-Klassifikation auch Schwächen auf. Neue Vorschläge zur Klassifikation der chronischen Arthritiden des Kindes- und Jugendalters, u. a. von der PRINTO, wurden gemacht. Ob sie die ILAR-Klassifikation ablösen werden, bleibt abzuwarten. Evaluationen der neuen Klassifikationskriterien der PRINTO sind unterwegs.

Published
2021
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6. Eine neue Lungenerkrankung bei Kindern mit systemischer JIA/Still-Syndrom

Author

Elisabeth Rolfes, Tilmann Kallinich, and Sae Lim von Stuckrad

Subjects
Gynecology, medicine.medical_specialty, business.industry, medicine, business, Lung involvement
Abstract

ZUSAMMENFASSUNGIm letzten Jahrzehnt hat eine neue Komplikation der systemischen juvenilen Arthritis mehr und mehr Beachtung in Fachkreisen und als „sJIA Lung Disease“ (sJIA-LD) Einzug in die Literatur gefunden. Die Kinder mit sJIA-LD präsentieren sich mit initial oft unspezifischen respiratorischen Symptomen, Hypoxie und Hautausschlag. Ein häufiges eindrückliches erstes Zeichen sind Trommelschlegelfinger mit digitalen Erythemen. Möglicherweise scheint die sJIA-LD gehäuft aufzutreten, wenn Kinder ein junges Alter bei sJIA-Diagnose hatten sowie ein oder mehrere Makrophagen-Aktivierungssyndrome in der Vorgeschichte, hohe Interleukin-18-Spiegel im Serum und eine Unverträglichkeit gegenüber Biologika (IL-1- oder IL-6-Blocker). Die Mortalität variiert stark zwischen den einzelnen Fallsammlungen, in der größten Kohorte ist sie mit 36 % hoch 1.

Published
2021
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7. Antigen‐driven PD‐1 + TOX + BHLHE40 + and PD‐1 + TOX + EOMES + T lymphocytes regulate juvenile idiopathic arthritis in situ

Author

Bas Vastert, Alessio Mazzoni, Lorenz Elias Wirth, Tilmann Kallinich, Francesco Giudici, Francesco Annunziato, Pawel Durek, Philipp Enghard, Patrick Maschmeyer, Mir-Farzin Mashreghi, Katrin Lehmann, Sae Lim von Stuckrad, Femke van Wijk, Cam Loan Tran, Andreas Radbruch, Imme Sakwa, Christopher Mark Skopnik, Marcus A. Mall, René Riedel, Hyun-Dong Chang, Lisanne Lutter, Gitta Anne Heinz, Rolando Cimaz, and Frederik Heinrich

Subjects
0301 basic medicine, education.field_of_study, biology, Immunology, Population, T-cell receptor, Arthritis, Inflammation, medicine.disease, Major histocompatibility complex, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Immune system, Antigen, medicine, biology.protein, Immunology and Allergy, medicine.symptom, education, CD8, 030215 immunology
Abstract

T lymphocytes accumulate in inflamed tissues of patients with chronic inflammatory diseases (CIDs) and express pro-inflammatory cytokines upon re-stimulation in vitro. Further, a significant genetic linkage to MHC genes suggests that T lymphocytes play an important role in the pathogenesis of CIDs including juvenile idiopathic arthritis (JIA). However, the functions of T lymphocytes in established disease remain elusive. Here we dissect the transcriptional and the clonal heterogeneity of synovial T lymphocytes in JIA patients by single-cell RNA sequencing combined with T cell receptor profiling on the same cells. We identify clonally expanded subpopulations of T lymphocytes expressing genes reflecting recent activation by antigen in situ. A PD-1+ TOX+ EOMES+ population of CD4+ T lymphocytes expressed immune regulatory genes and chemoattractant genes for myeloid cells. A PD-1+ TOX+ BHLHE40+ population of CD4+ , and a mirror population of CD8+ T lymphocytes expressed genes driving inflammation, and genes supporting B lymphocyte activation in situ. This analysis points out that multiple types of T lymphocytes have to be targeted for therapeutic regeneration of tolerance in arthritis.

Published
2021
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8. SIGLEC1 (CD169) is a sensitive biomarker for the deterioration of the clinical course in childhood systemic lupus erythematosus

Author

Christian Meisel, Jens Klotsche, Sae Lim von Stuckrad, Mareike Lieber, Nadine Unterwalder, Julia Thumfart, Tilmann Kallinich, and Robert Biesen

Subjects
Pediatric systemic lupus erythematosus, Male, Oncology, medicine.medical_specialty, hydroxychloroquine, Adolescent, Sialic Acid Binding Ig-like Lectin 1, Minimal Clinically Important Difference, Monocytes, Disease activity, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Internal medicine, medicine, Humans, Lupus Erythematosus, Systemic, SIGLEC1, skin and connective tissue diseases, Child, Type 1 interferon, childhood, Retrospective Studies, 030203 arthritis & rheumatology, SLEDAI, business.industry, Clinical course, type 1 interferon, Hydroxychloroquine, Flow Cytometry, Symptom Flare Up, Child, Preschool, Papers, Disease Progression, biomarker, Biomarker (medicine), Female, business, Biomarkers, 030215 immunology, medicine.drug
Abstract

Background To analyse the validity of membrane-bound SIGLEC1 (CD169) as a sensitive biomarker for monitoring disease activity in pediatric systemic lupus erythematosus (SLE). Methods 27 children and adolescents with SLE were followed for a mean of 13.5 months. During consecutive routine visits SLEDAI-2k, C3, C4 and ds-DNA values were determined. Additionally, expression of SIGLEC1 on monocytes was determined by flow cytometry. The amount of PE-labelled CD169 mAb bound per monocyte was analyzed using QuantiBRITE™ PE tubes. Associations between biomarkers and the clinical course were investigated by regression analysis. Results In general, SIGLEC1 expression is high on SLE-derived monocytes (mean 6 359 (SD 6 056) molecules/monocyte, cut-off 2 500 molecules/monocyte), all patients with newly diagnosed SLE exhibit elevated expression (mean 13366 (SD 7 750) molecules/monocyte). Changes (Δ) in SIGLEC1 levels during the clinical course is the only biomarker that significantly correlates with the change in SLEDAI-2k (betaST = 0.28, p = 0.001). At follow-up visit, a clinically important worsening was experienced by 47.6% of patients with a Δ SIGLEC1 > 2 151 molecules/cell (OR 5.31) and 72.4% with a Δ SIGLEC1 > 756 molecules/cell (OR 8.90). Conversely, 36.4% of patients with a Δ SIGLEC1 Conclusions SIGLEC1 expression on monocytes is a sensitive biomarker for adjusting disease activity in childhood SLE and represents a promising and easily applicable tool for disease monitoring.

Published
2020
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9. Evaluation of SIGLEC1 in the diagnosis of suspected systemic lupus erythematosus

Author

Robert Biesen, Anne Sae Lim von Stuckrad, Udo Schneider, Falk Hiepe, Tilmann Kallinich, Marie Burns, Philipp Enghard, Jens Klotsche, Lennard Ostendorf, Thomas Rose, Tobias Alexander, Christian Meisel, Lydia Zorn-Pauly, Gerd Burmester, Nadine Unterwalder, and Thomas Doerner

Subjects
medicine.medical_specialty, Surrogate endpoint, business.industry, Area under the curve, Diagnostic accuracy, Newly diagnosed, Negative Test Result, Gastroenterology, INCEPTION COHORT, Central laboratory, Rheumatology, Antibodies, Antinuclear, Internal medicine, medicine, Biomarker (medicine), Humans, Lupus Erythematosus, Systemic, Pharmacology (medical), In patient, skin and connective tissue diseases, business, Biomarkers, Autoantibodies
Abstract

Objectives To evaluate and compare the diagnostic accuracy of SIGLEC1, a surrogate marker of type I IFN, with established biomarkers in an inception cohort of systemic lupus erythematosus (SLE). Methods SIGLEC1 was analysed by flow cytometry in 232 patients referred to our institution with suspected SLE between October 2015 and September 2020. Results SLE was confirmed in 76 of 232 patients (32.8 %) according to the 2019 EULAR/ACR classification criteria and their SIGLEC1 values were significantly higher compared with patients without SLE (P 99.9 % and 0.1 %, respectively. Using receiver operating characteristic (ROC) analysis and DeLong testing, the area under the curve (AUC) for SIGLEC1 (AUC = 0.95) was significantly higher than for ANA (AUC = 0.88, P = 0.031), C3 (AUC = 0.83, P = 0.001) and C4 (AUC = 0.83, P = 0.002) but not for anti-dsDNA antibodies (AUC = 0.90, P = 0.163). Conclusion IFN-I pathway activation is detectable in almost all newly diagnosed SLE patients. Thus, a negative test result for SIGLEC1 is powerful to exclude SLE in suspected cases.

Published
2021
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10. SIGLEC1 enables straightforward assessment of type I interferon activity in inflammatory myopathies

Author

Falk Hiepe, Lydia Zorn-Pauly, Udo Schneider, Gerd R Burmester, Thomas Buttgereit, Thomas Rose, Nadine Unterwalder, Akinori Uruha, Martin Krusche, Robert Biesen, Christian Meisel, Tilman Kallinich, Werner Stenzel, Manuel Graf, Jens Klotsche, and Sae Lim von Stuckrad

Subjects
medicine.medical_specialty, business.industry, Area under the curve, Context (language use), Antisynthetase syndrome, Dermatomyositis, medicine.disease, Gastroenterology, Adult dermatomyositis, Internal medicine, medicine, Biomarker (medicine), Inclusion body myositis, business, Myositis
Abstract

ObjectiveTo evaluate SIGLEC1 expression on monocytes by flow cytometry as a type I interferon biomarker in idiopathic inflammatory myopathies (IIM).MethodsWe performed a retrospective analysis of adult and pediatric patients with the diagnosis of IIM. SIGLEC1 expression was assessed by flow cytometry and was compared with Physician Global Assessment (PGA) or Childhood Myositis Assessment Scale (CMAS) disease activity scores. Mann Whitney-U test and receiver operating characteristic (ROC) curves were used for cross-sectional data analysis (n=96), two-level mixed-effects linear regression model for longitudinal analyses (n=26, 110 visits). Response to treatment was analyzed in 14 patients within 12 months, using Wilcoxon test. SIGLEC1 was compared to ISG15/MxA status by immunohistochemical staining of muscle biopsies (n=17).Results96 patients with adult (a) and juvenile (j) dermatomyositis (DM, n=38), antisynthetase syndrome (AS, n=19), immune-mediated necrotizing myopathy (IMNM, n=8), inclusion body myositis (IBM, n=9), and overlap myositis (n=22) were included. SIGLEC1 distinguished significantly between active and inactive disease with an area under the curve (AUC) of 0.92 (95% CI: 0.83–1) in DM and correlated with disease activity longitudinally (aDM: standardized beta=0.54, pConclusionSIGLEC1 is a candidate biomarker to assess type I interferon activity in IIM and proved useful for monitoring disease activity and response to treatment in juvenile and adult DM.Key messagesWhat is already known about this subject?There is an unmet need for routine clinical biomarkers to assess type I interferon activity in rheumatic musculoskeletal diseasesSIGLEC1 is part of the type I interferon signature and transcripts were found to be upregulated in various autoimmune diseases such as systemic lupus erythematosus (SLE), Sjoegren syndrome and dermatomyositis.SIGLEC1 is expressed on the surface of monocytes and thus is easily assessable by flow cytometry, which enables straightforward monitoring of type I interferon activityWhat does this study add?An activation of the type I interferon system in IIM can be identified by flow cytometry analysing SIGLEC1 expression. SIGLEC1 correlated to disease activity and improvement under therapy in juvenile and adult dermatomyositis.How might this impact on clinical practice or future developments?SIGLEC1 expression is a suitable biomarker for monitoring type I interferon activation in rheumatic musculoskeletal diseases, which has clinical implications for patient stratification and treatment decision making especially in the context of interferon inhibitory therapies.

Published
2021
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11. SIGLEC1 enables straightforward assessment of type I interferon activity in idiopathic inflammatory myopathies

Author

Manuel Graf, Sae Lim von Stuckrad, Akinori Uruha, Jens Klotsche, Lydia Zorn-Pauly, Nadine Unterwalder, Thomas Buttgereit, Martin Krusche, Christian Meisel, Gerd R Burmester, Falk Hiepe, Robert Biesen, Tilmann Kallinich, Werner Stenzel, Udo Schneider, and Thomas Rose

Subjects
Adult, Cross-Sectional Studies, Rheumatology, Myositis, Sialic Acid Binding Ig-like Lectin 1, Immunology, Interferon Type I, Immunology and Allergy, Humans, Child, Dermatomyositis, Retrospective Studies
Abstract

ObjectiveTo evaluate sialic acid binding Ig-like lectin 1 (SIGLEC1) expression on monocytes by flow cytometry as a type I interferon biomarker in idiopathic inflammatory myopathies (IIM).MethodsWe performed a retrospective analysis of adult and paediatric patients with the diagnosis of IIM. SIGLEC1 expression was assessed by flow cytometry and was compared with Physician Global Assessment or Childhood Myositis Assessment Scale disease activity scores. Mann Whitney U test and receiver operating characteristic curves were used for cross-sectional data analysis (n=96), two-level mixed-effects linear regression model for longitudinal analyses (n=26, 110 visits). Response to treatment was analysed in 14 patients within 12 months, using Wilcoxon test. SIGLEC1 was compared with interferon-stimulated gene 15/MxA status by immunohistochemical staining of muscle biopsies (n=17).Results96 patients with adult (a) and juvenile (j) dermatomyositis (DM, n=38), antisynthetase syndrome (AS, n=19), immune-mediated necrotising myopathy (IMNM, n=8), inclusion body myositis (IBM, n=9) and overlap myositis (n=22) were included. SIGLEC1 distinguished significantly between active and inactive disease with an area under the curve of 0.92 (95% CI 0.83 to 1) in DM and correlated with disease activity longitudinally (aDM: standardised beta=0.54, pConclusionSIGLEC1 is a candidate biomarker to assess type I interferon activity in IIM and proved useful for monitoring disease activity and response to treatment in juvenile and adult DM.

Published
2021

13. Tapering Canakinumab Monotherapy in Patients with Systemic Juvenile Idiopathic Arthritis in Clinical Remission: Results from an Open‐label, Randomized Phase IIIb/IV Study

Author

Pierre, Quartier, Ekaterina, Alexeeva, Constantin, Tamàs, Vyacheslav, Chasnyk, Nico, Wulffraat, Karin, Palmblad, Carine, Wouters, Hermine, Brunner, Katherine, Marzan, Rayfel, Schneider, Gerd, Horneff, Martini, Alberto, Jordi, Anton, Xiaoling, Wei, Alan, Slade, Ruperto, Nicolino, Ken, Abrams, Wolfgang, Emminger, Andrea, Ulbrich, Sugarka, Fodor, Lien, Desomer, Bernard, Lauwerys, Bénédicte, Brichard, Cécile, Boulanger, Gabriel, Levy, Laurence, Goffin, Phu Quoc Le, Marcia, Bandeira, Christina Feitosa Pelajo, Sheila Knupp Feitosa, Christianne, Costa, Marta Cristine Felix Rodrigues, Clovis Artur Almeida da Silva, Lucia Maria Mattei de, Katia, Kozu, Ronald, Laxer, Kristin, Houghton, Lori, Tucker, Kimberly, Morishita, Agnes, Mogenet, Richard, Mouy, Brigitte Bader Meunier, Candice, Meyzer, Michaela, Semeraro, Ouafa, Ben‐brahim, Isabelle, Kone‐paut, Caroline, Galeotti, Linda, Rossi, Perrine, Dusser, Bilade, Cherquaoui, Alexandre, Belot, Agnes, Duquesne, Freychet, Caroline, Laurent, Audrey, Marine, Desjonqueres, Ivan, Foeldvari, Antonia, Kienast, Barbara, Willig, Deborah, Barthel, Joachim, Peitz, Stefanie, Wintrich, Tilman Felix Geikowski, Anna Carina Schulz, Markus, Hufnagel, Marc, Hirdes, Rouven, Kubicki, Janbernd, Kirschner, Ales, Janda, Andre, Jacob, Cornelia, Emerich, Anna, Raab, Gonza, Ngoumou, Kirsten, Minden, Mareike, Lieber, Sae‐Lim von Stuckrad, Jasmin Kuemmerle Deschner, Sandra, Hansmann, Tom, Schleich, Ines Maria Magunia, Joachim, Riethmuller, Nicole, Anders, Hartwig, Lehmann, Jan de Laffolie, Thomas, Lutz, Juergen, Grulich‐henn, Johannes, Pfeil, Astrid, Helling‐bakki, Ralf, Trauzeddel, Daniel, Haselbusch, Henryk, Kolbeck, Elisabeth, Weissbarth‐riedel, Anja, Froehlich, Andrea, Ponyi, Diana, Garan, Ilonka, Orban, Krisztina, Sevcic, Yonatan, Butbul, Riva, Brik, Philip, Hashkes, Ori, Toker, Ruby, Haviv, Yosef, Uziel, Rubi, Haviv, Veronica, Moshe, Michal, Rothschild, Liora, Harel, Gil, Amarilyo, Rotem, Tal, Mohamad Hamad Said, Irit, Tirosh, Shiri, Spielman, Maya, Gerstein, Ravelli, Angelo, Schiappapietra, Benedetta, Varnier, GIULIA CAMILLA, Finetti, Martina, Marasini, Maurizio, Caorsi, Roberta, Rosina, Silvia, Federici, Silvia, Irene, Pontikaki, Pier Luigi Meroni, Valeri, Gerloni, Nicola, Ughi, Tania, Ubiali, Maria, Alessio, Roberto Della Casa, Sebastiaan Jozef Vastert, Joost Frans Swart, van Royen‐Kerhof, A., Ellen, Schatorje, Van Iperen‐Schutte, G., Lidia, Rutkowska‐sak, Izabela, Szczygielska, Malgorzata, Kwiatkowska, Maria, Marusak‐banacka, Piotr, Gietka, Kseniya, Isaeva, Rina, Denisova, Ludmila, Snegireva, Margarita, Dubko, Mikhail, Kostik, Natalia, Buchinskaia, Olga, Kalashnikova, Sergey, Avrusin, Vera, Masalova, Esmeralda Nunez Cuadros, Gisela, Diez, Rocio Galindo Zavala, Rosa Bou Torrent, Estibaliz, Iglesias, Joan, Calzada, Violeta, Bittermann, Alina Lucica Boteanu, Maria Luz Gamir, Inmaculada, Calvo, Berta, Lopez, Isabel, Gonzalez, Laura, Fernandez, Daniel Clemente Garulo, Juan Carlos Lopez Robledillo, Rosa, Merino, Rosa, Alcobendas, Agustin, Remesal, Sara, Murias, Magnusson, Bo, Ozgur, Kasapcopur, Kenan, Barut, Amra, Adrovic, Sezgin, Sahin, Muferet, Erguven, Refia Gozdenur Savci, Seza, Ozen, Selcan, Demir, Yelda, Bilginer, Zehra Serap Avci, Ezgi Deriz Batu, Andreas, Reiff, Anusha, Ramanatham, Diana, Brown, Bracha, Shaham, Shirley, Parks, Michal, Cidon, Gloria, Higgins, Charles, Spencer, Jenny, Rossette, Karla, Jones, Sharon Bout Tabaku, Shelli, Farley, Shoghik, Akoghlanian, Quartier, Pierre, Alexeeva, Ekaterina, Tamàs, Constantin, Chasnyk, Vyacheslav, Wulffraat, Nico, Palmblad, Karin, Wouters, Carine, Brunner, Hermine, Marzan, Katherine, Schneider, Rayfel, Horneff, Gerd, Martini, Alberto, Anton, Jordi, Wei, Xiaoling, Slade, Alan, Ruperto, Nicolino, Abrams, Ken, Emminger, Wolfgang, Ulbrich, Andrea, Fodor, Sugarka, Desomer, Lien, Lauwerys, Bernard, Brichard, Bénédicte, Boulanger, Cécile, Levy, Gabriel, Goffin, Laurence, Quoc Le, Phu, Bandeira, Marcia, Feitosa Pelajo, Christina, Knupp Feitosa, Sheila, Costa, Christianne, Cristine Felix Rodrigues, Marta, Artur Almeida da Silva, Clovi, Maria Mattei de, Lucia, Kozu, Katia, Laxer, Ronald, Houghton, Kristin, Tucker, Lori, Morishita, Kimberly, Mogenet, Agne, Mouy, Richard, Bader Meunier, Brigitte, Meyzer, Candice, Semeraro, Michaela, Ben‐brahim, Ouafa, Kone‐paut, Isabelle, Galeotti, Caroline, Rossi, Linda, Dusser, Perrine, Cherquaoui, Bilade, Belot, Alexandre, Duquesne, Agne, Caroline, Freychet, Audrey, Laurent, Desjonqueres, Marine, Foeldvari, Ivan, Kienast, Antonia, Willig, Barbara, Barthel, Deborah, Peitz, Joachim, Wintrich, Stefanie, Felix Geikowski, Tilman, Carina Schulz, Anna, Hufnagel, Marku, Hirdes, Marc, Kubicki, Rouven, Kirschner, Janbernd, Janda, Ale, Jacob, Andre, Emerich, Cornelia, Raab, Anna, Ngoumou, Gonza, Minden, Kirsten, Lieber, Mareike, von Stuckrad, Sae‐lim, Kuemmerle Deschner, Jasmin, Hansmann, Sandra, Schleich, Tom, Maria Magunia, Ine, Riethmuller, Joachim, Anders, Nicole, Lehmann, Hartwig, de Laffolie, Jan, Lutz, Thoma, Grulich‐henn, Juergen, Pfeil, Johanne, Helling‐bakki, Astrid, Trauzeddel, Ralf, Haselbusch, Daniel, Kolbeck, Henryk, Weissbarth‐riedel, Elisabeth, Froehlich, Anja, Ponyi, Andrea, Garan, Diana, Orban, Ilonka, Sevcic, Krisztina, Butbul, Yonatan, Brik, Riva, Hashkes, Philip, Toker, Ori, Haviv, Ruby, Uziel, Yosef, Haviv, Rubi, Moshe, Veronica, Rothschild, Michal, Harel, Liora, Amarilyo, Gil, Tal, Rotem, Hamad Said, Mohamad, Tirosh, Irit, Spielman, Shiri, Gerstein, Maya, Ravelli, Angelo, Schiappapietra, Benedetta, Camilla Varnier, Giulia, Finetti, Martina, Marasini, Maurizio, Caorsi, Roberta, Rosina, Silvia, Federici, Silvia, Pontikaki, Irene, Luigi Meroni, Pier, Gerloni, Valeri, Ughi, Nicola, Ubiali, Tania, Alessio, Maria, DELLA CASA, Roberto, Jozef Vastert, Sebastiaan, Frans Swart, Joost, van Royen‐Kerhof, A., Schatorje, Ellen, Van Iperen‐Schutte, G., Rutkowska‐sak, Lidia, Szczygielska, Izabela, Kwiatkowska, Malgorzata, Marusak‐banacka, Maria, Gietka, Piotr, Isaeva, Kseniya, Denisova, Rina, Snegireva, Ludmila, Dubko, Margarita, Kostik, Mikhail, Buchinskaia, Natalia, Kalashnikova, Olga, Avrusin, Sergey, Masalova, Vera, Nunez Cuadros, Esmeralda, Diez, Gisela, Galindo Zavala, Rocio, Bou Torrent, Rosa, Iglesias, Estibaliz, Calzada, Joan, Bittermann, Violeta, Lucica Boteanu, Alina, Luz Gamir, Maria, Calvo, Inmaculada, Lopez, Berta, Gonzalez, Isabel, Fernandez, Laura, Clemente Garulo, Daniel, Carlos Lopez Robledillo, Juan, Merino, Rosa, Alcobendas, Rosa, Remesal, Agustin, Murias, Sara, Magnusson, Bo, Kasapcopur, Ozgur, Barut, Kenan, Adrovic, Amra, Sahin, Sezgin, Erguven, Muferet, Gozdenur Savci, Refia, Ozen, Seza, Demir, Selcan, Bilginer, Yelda, Serap Avci, Zehra, Deriz Batu, Ezgi, Reiff, Andrea, Ramanatham, Anusha, Brown, Diana, Shaham, Bracha, Parks, Shirley, Cidon, Michal, Higgins, Gloria, Spencer, Charle, Rossette, Jenny, Jones, Karla, Bout Tabaku, Sharon, Farley, Shelli, and Akoghlanian, Shoghik

Published
2021

14. Author response for 'Antigen‐driven PD‐1 + TOX + BHLHE40 + and PD‐1 + TOX + EOMES + T lymphocytes regulate juvenile idiopathic arthritis in situ'

Author

Gitta Anne Heinz, Katrin Lehmann, Frederik Heinrich, Lisanne Lutter, Imme Sakwa, Patrick Maschmeyer, Christopher Mark Skopnik, Philipp Enghard, Sae Lim von Stuckrad, Rolando Cimaz, Femke van Wijk, Tilmann Kallinich, Cam Loan Tran, Pawel Durek, Bas Vastert, René Riedel, Alessio Mazzoni, Francesco Annunziato, Hyun-Dong Chang, Lorenz Elias Wirth, Marcus A. Mall, Mir-Farzin Mashreghi, Francesco Giudici, and Andreas Radbruch

Subjects
In situ, Antigen, Immunology, medicine, Juvenile, Arthritis, Biology, medicine.disease
Published
2020
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15. Antigen-driven PD-1

Author

Patrick, Maschmeyer, Gitta Anne, Heinz, Christopher Mark, Skopnik, Lisanne, Lutter, Alessio, Mazzoni, Frederik, Heinrich, Sae Lim, von Stuckrad, Lorenz Elias, Wirth, Cam Loan, Tran, René, Riedel, Katrin, Lehmann, Imme, Sakwa, Rolando, Cimaz, Francesco, Giudici, Marcus Alexander, Mall, Philipp, Enghard, Bas, Vastert, Hyun-Dong, Chang, Pawel, Durek, Francesco, Annunziato, Femke, van Wijk, Andreas, Radbruch, Tilmann, Kallinich, and Mir-Farzin, Mashreghi

Subjects
CD4-Positive T-Lymphocytes, Homeodomain Proteins, Gene Expression Profiling, T-Lymphocytes, Programmed Cell Death 1 Receptor, High Mobility Group Proteins, Receptors, Antigen, T-Cell, CD8-Positive T-Lymphocytes, Arthritis, Juvenile, Basic Helix-Loop-Helix Transcription Factors, Humans, RNA-Seq, Antigens, Single-Cell Analysis, T-Box Domain Proteins, Transcriptome, Cells, Cultured
Abstract

T lymphocytes accumulate in inflamed tissues of patients with chronic inflammatory diseases (CIDs) and express pro-inflammatory cytokines upon re-stimulation in vitro. Further, a significant genetic linkage to MHC genes suggests that T lymphocytes play an important role in the pathogenesis of CIDs including juvenile idiopathic arthritis (JIA). However, the functions of T lymphocytes in established disease remain elusive. Here we dissect the transcriptional and the clonal heterogeneity of synovial T lymphocytes in JIA patients by single-cell RNA sequencing combined with T cell receptor profiling on the same cells. We identify clonally expanded subpopulations of T lymphocytes expressing genes reflecting recent activation by antigen in situ. A PD-1

Published
2020

16. Tapering Canakinumab Monotherapy in Patients with Systemic Juvenile Idiopathic Arthritis in Clinical Remission: Results from an Open‐label, Randomized Phase IIIb/IV Study

Author

Quartier, P, Alexeeva, E, Tamàs, C, Chasnyk, V, Wulffraat, N, Palmblad, K, Wouters, C, Brunner, H, Marzan, K, Schneider, R, Horneff, G, Martini, A, Anton, J, Wei, X, Slade, A, Ruperto, N, Abrams, K, Emminger, W, Ulbrich, A, Fodor, S, Desomer, L, Lauwerys, B, Brichard, B, Boulanger, C, Levy, G, Goffin, L, Quoc Le, P, Bandeira, M, Feitosa Pelajo, C, Knupp Feitosa, S, Costa, C, Cristine Felix Rodrigues, M, Artur Almeida da Silva, C, Maria Mattei de, L, Kozu, K, Laxer, R, Houghton, K, Tucker, L, Morishita, K, Mogenet, A, Mouy, R, Bader Meunier, B, Meyzer, C, Semeraro, M, Ben‐brahim, O, Kone‐paut, I, Galeotti, C, Rossi, L, Dusser, P, Cherquaoui, B, Belot, A, Duquesne, A, Caroline, F, Audrey, L, Desjonqueres, M, Foeldvari, I, Kienast, A, Willig, B, Barthel, D, Peitz, J, Wintrich, S, Felix Geikowski, T, Carina Schulz, A, Hufnagel, M, Hirdes, M, Kubicki, R, Kirschner, J, Janda, A, Jacob, A, Emerich, C, Raab, A, Ngoumou, G, Minden, K, Lieber, M, von Stuckrad, S, Kuemmerle Deschner, J, Hansmann, S, Schleich, T, Maria Magunia, I, Riethmuller, J, Anders, N, Lehmann, H, de Laffolie, J, Lutz, T, Grulich‐henn, J, Pfeil, J, Helling‐bakki, A, Trauzeddel, R, Haselbusch, D, Kolbeck, H, Weissbarth‐riedel, E, Froehlich, A, Ponyi, A, Garan, D, Orban, I, Sevcic, K, Butbul, Y, Brik, R, Hashkes, P, Toker, O, Haviv, R, Uziel, Y, Moshe, V, Rothschild, M, Harel, L, Amarilyo, G, Tal, R, Hamad Said, M, Tirosh, I, Spielman, S, Gerstein, M, Ravelli, A, Schiappapietra, B, Camilla Varnier, G, Finetti, M, Marasini, M, Caorsi, R, Rosina, S, Federici, S, Pontikaki, I, Luigi Meroni, P, Gerloni, V, Ughi, N, Ubiali, T, Alessio, M, Della Casa, R, Jozef Vastert, S, Frans Swart, J, van Royen‐Kerhof, A, Schatorje, E, Van Iperen‐Schutte, G, Rutkowska‐sak, L, Szczygielska, I, Kwiatkowska, M, Marusak‐banacka, M, Gietka, P, Isaeva, K, Denisova, R, Snegireva, L, Dubko, M, Kostik, M, Buchinskaia, N, Kalashnikova, O, Avrusin, S, Masalova, V, Nunez Cuadros, E, Diez, G, Galindo Zavala, R, Bou Torrent, R, Iglesias, E, Calzada, J, Bittermann, V, Lucica Boteanu, A, Luz Gamir, M, Calvo, I, Lopez, B, Gonzalez, I, Fernandez, L, Clemente Garulo, D, Carlos Lopez Robledillo, J, Merino, R, Alcobendas, R, Remesal, A, Murias, S, Magnusson, B, Kasapcopur, O, Barut, K, Adrovic, A, Sahin, S, Erguven, M, Gozdenur Savci, R, Ozen, S, Demir, S, Bilginer, Y, Serap Avci, Z, Deriz Batu, E, Reiff, A, Ramanatham, A, Brown, D, Shaham, B, Parks, S, Cidon, M, Higgins, G, Spencer, C, Rossette, J, Jones, K, Bout Tabaku, S, Farley, S, Akoghlanian, S, Pierre Quartier, Ekaterina Alexeeva, Constantin Tamàs, Vyacheslav Chasnyk, Nico Wulffraat, Karin Palmblad, Carine Wouters, Hermine Brunner, Katherine Marzan, Rayfel Schneider, Gerd Horneff, Alberto Martini, Jordi Anton, Xiaoling Wei, Alan Slade, Nicolino Ruperto, Ken Abrams, Wolfgang Emminger, Andrea Ulbrich, Sugarka Fodor, Lien Desomer, Bernard Lauwerys, Bénédicte Brichard, Cécile Boulanger, Gabriel Levy, Laurence Goffin, Phu Quoc Le, Marcia Bandeira, Christina Feitosa Pelajo, Sheila Knupp Feitosa, Christianne Costa, Marta Cristine Felix Rodrigues, Clovis Artur Almeida da Silva, Lucia Maria Mattei de, Katia Kozu, Ronald Laxer, Kristin Houghton, Lori Tucker, Kimberly Morishita, Agnes Mogenet, Richard Mouy, Brigitte Bader Meunier, Candice Meyzer, Michaela Semeraro, Ouafa Ben‐Brahim, Isabelle Kone‐Paut, Caroline Galeotti, Linda Rossi, Perrine Dusser, Bilade Cherquaoui, Alexandre Belot, Agnes Duquesne, Freychet Caroline, Laurent Audrey, Marine Desjonqueres, Ivan Foeldvari, Antonia Kienast, Barbara Willig, Deborah Barthel, Joachim Peitz, Stefanie Wintrich, Tilman Felix Geikowski, Anna Carina Schulz, Markus Hufnagel, Marc Hirdes, Rouven Kubicki, Janbernd Kirschner, Ales Janda, Andre Jacob, Cornelia Emerich, Anna Raab, Gonza Ngoumou, Kirsten Minden, Mareike Lieber, Sae‐Lim von Stuckrad, Jasmin Kuemmerle Deschner, Sandra Hansmann, Tom Schleich, Ines Maria Magunia, Joachim Riethmuller, Nicole Anders, Hartwig Lehmann, Jan de Laffolie, Thomas Lutz, Juergen Grulich‐Henn, Johannes Pfeil, Astrid Helling‐Bakki, Ralf Trauzeddel, Daniel Haselbusch, Henryk Kolbeck, Elisabeth Weissbarth‐Riedel, Anja Froehlich, Andrea Ponyi, Diana Garan, Ilonka Orban, Krisztina Sevcic, Yonatan Butbul, Riva Brik, Philip Hashkes, Ori Toker, Ruby Haviv, Yosef Uziel, Rubi Haviv, Veronica Moshe, Michal Rothschild, Liora Harel, Gil Amarilyo, Rotem Tal, Mohamad Hamad Said, Irit Tirosh, Shiri Spielman, Maya Gerstein, Angelo Ravelli, Benedetta Schiappapietra, Giulia Camilla Varnier, Martina Finetti, Maurizio Marasini, Roberta Caorsi, Silvia Rosina, Silvia Federici, Irene Pontikaki, Pier Luigi Meroni, Valeri Gerloni, Nicola Ughi, Tania Ubiali, Maria Alessio, Roberto Della Casa, Sebastiaan Jozef Vastert, Joost Frans Swart, A. van Royen‐Kerhof, Ellen Schatorje, G. Van Iperen‐Schutte, Lidia Rutkowska‐Sak, Izabela Szczygielska, Malgorzata Kwiatkowska, Maria Marusak‐Banacka, Piotr Gietka, Kseniya Isaeva, Rina Denisova, Ludmila Snegireva, Margarita Dubko, Mikhail Kostik, Natalia Buchinskaia, Olga Kalashnikova, Sergey Avrusin, Vera Masalova, Esmeralda Nunez Cuadros, Gisela Diez, Rocio Galindo Zavala, Rosa Bou Torrent, Estibaliz Iglesias, Joan Calzada, Violeta Bittermann, Alina Lucica Boteanu, Maria Luz Gamir, Inmaculada Calvo, Berta Lopez, Isabel Gonzalez, Laura Fernandez, Daniel Clemente Garulo, Juan Carlos Lopez Robledillo, Rosa Merino, Rosa Alcobendas, Agustin Remesal, Sara Murias, Bo Magnusson, Ozgur Kasapcopur, Kenan Barut, Amra Adrovic, Sezgin Sahin, Muferet Erguven, Refia Gozdenur Savci, Seza Ozen, Selcan Demir, Yelda Bilginer, Zehra Serap Avci, Ezgi Deriz Batu, Andreas Reiff, Anusha Ramanatham, Diana Brown, Bracha Shaham, Shirley Parks, Michal Cidon, Gloria Higgins, Charles Spencer, Jenny Rossette, Karla Jones, Sharon Bout Tabaku, Shelli Farley, Shoghik Akoghlanian, Quartier, P, Alexeeva, E, Tamàs, C, Chasnyk, V, Wulffraat, N, Palmblad, K, Wouters, C, Brunner, H, Marzan, K, Schneider, R, Horneff, G, Martini, A, Anton, J, Wei, X, Slade, A, Ruperto, N, Abrams, K, Emminger, W, Ulbrich, A, Fodor, S, Desomer, L, Lauwerys, B, Brichard, B, Boulanger, C, Levy, G, Goffin, L, Quoc Le, P, Bandeira, M, Feitosa Pelajo, C, Knupp Feitosa, S, Costa, C, Cristine Felix Rodrigues, M, Artur Almeida da Silva, C, Maria Mattei de, L, Kozu, K, Laxer, R, Houghton, K, Tucker, L, Morishita, K, Mogenet, A, Mouy, R, Bader Meunier, B, Meyzer, C, Semeraro, M, Ben‐brahim, O, Kone‐paut, I, Galeotti, C, Rossi, L, Dusser, P, Cherquaoui, B, Belot, A, Duquesne, A, Caroline, F, Audrey, L, Desjonqueres, M, Foeldvari, I, Kienast, A, Willig, B, Barthel, D, Peitz, J, Wintrich, S, Felix Geikowski, T, Carina Schulz, A, Hufnagel, M, Hirdes, M, Kubicki, R, Kirschner, J, Janda, A, Jacob, A, Emerich, C, Raab, A, Ngoumou, G, Minden, K, Lieber, M, von Stuckrad, S, Kuemmerle Deschner, J, Hansmann, S, Schleich, T, Maria Magunia, I, Riethmuller, J, Anders, N, Lehmann, H, de Laffolie, J, Lutz, T, Grulich‐henn, J, Pfeil, J, Helling‐bakki, A, Trauzeddel, R, Haselbusch, D, Kolbeck, H, Weissbarth‐riedel, E, Froehlich, A, Ponyi, A, Garan, D, Orban, I, Sevcic, K, Butbul, Y, Brik, R, Hashkes, P, Toker, O, Haviv, R, Uziel, Y, Moshe, V, Rothschild, M, Harel, L, Amarilyo, G, Tal, R, Hamad Said, M, Tirosh, I, Spielman, S, Gerstein, M, Ravelli, A, Schiappapietra, B, Camilla Varnier, G, Finetti, M, Marasini, M, Caorsi, R, Rosina, S, Federici, S, Pontikaki, I, Luigi Meroni, P, Gerloni, V, Ughi, N, Ubiali, T, Alessio, M, Della Casa, R, Jozef Vastert, S, Frans Swart, J, van Royen‐Kerhof, A, Schatorje, E, Van Iperen‐Schutte, G, Rutkowska‐sak, L, Szczygielska, I, Kwiatkowska, M, Marusak‐banacka, M, Gietka, P, Isaeva, K, Denisova, R, Snegireva, L, Dubko, M, Kostik, M, Buchinskaia, N, Kalashnikova, O, Avrusin, S, Masalova, V, Nunez Cuadros, E, Diez, G, Galindo Zavala, R, Bou Torrent, R, Iglesias, E, Calzada, J, Bittermann, V, Lucica Boteanu, A, Luz Gamir, M, Calvo, I, Lopez, B, Gonzalez, I, Fernandez, L, Clemente Garulo, D, Carlos Lopez Robledillo, J, Merino, R, Alcobendas, R, Remesal, A, Murias, S, Magnusson, B, Kasapcopur, O, Barut, K, Adrovic, A, Sahin, S, Erguven, M, Gozdenur Savci, R, Ozen, S, Demir, S, Bilginer, Y, Serap Avci, Z, Deriz Batu, E, Reiff, A, Ramanatham, A, Brown, D, Shaham, B, Parks, S, Cidon, M, Higgins, G, Spencer, C, Rossette, J, Jones, K, Bout Tabaku, S, Farley, S, Akoghlanian, S, Pierre Quartier, Ekaterina Alexeeva, Constantin Tamàs, Vyacheslav Chasnyk, Nico Wulffraat, Karin Palmblad, Carine Wouters, Hermine Brunner, Katherine Marzan, Rayfel Schneider, Gerd Horneff, Alberto Martini, Jordi Anton, Xiaoling Wei, Alan Slade, Nicolino Ruperto, Ken Abrams, Wolfgang Emminger, Andrea Ulbrich, Sugarka Fodor, Lien Desomer, Bernard Lauwerys, Bénédicte Brichard, Cécile Boulanger, Gabriel Levy, Laurence Goffin, Phu Quoc Le, Marcia Bandeira, Christina Feitosa Pelajo, Sheila Knupp Feitosa, Christianne Costa, Marta Cristine Felix Rodrigues, Clovis Artur Almeida da Silva, Lucia Maria Mattei de, Katia Kozu, Ronald Laxer, Kristin Houghton, Lori Tucker, Kimberly Morishita, Agnes Mogenet, Richard Mouy, Brigitte Bader Meunier, Candice Meyzer, Michaela Semeraro, Ouafa Ben‐Brahim, Isabelle Kone‐Paut, Caroline Galeotti, Linda Rossi, Perrine Dusser, Bilade Cherquaoui, Alexandre Belot, Agnes Duquesne, Freychet Caroline, Laurent Audrey, Marine Desjonqueres, Ivan Foeldvari, Antonia Kienast, Barbara Willig, Deborah Barthel, Joachim Peitz, Stefanie Wintrich, Tilman Felix Geikowski, Anna Carina Schulz, Markus Hufnagel, Marc Hirdes, Rouven Kubicki, Janbernd Kirschner, Ales Janda, Andre Jacob, Cornelia Emerich, Anna Raab, Gonza Ngoumou, Kirsten Minden, Mareike Lieber, Sae‐Lim von Stuckrad, Jasmin Kuemmerle Deschner, Sandra Hansmann, Tom Schleich, Ines Maria Magunia, Joachim Riethmuller, Nicole Anders, Hartwig Lehmann, Jan de Laffolie, Thomas Lutz, Juergen Grulich‐Henn, Johannes Pfeil, Astrid Helling‐Bakki, Ralf Trauzeddel, Daniel Haselbusch, Henryk Kolbeck, Elisabeth Weissbarth‐Riedel, Anja Froehlich, Andrea Ponyi, Diana Garan, Ilonka Orban, Krisztina Sevcic, Yonatan Butbul, Riva Brik, Philip Hashkes, Ori Toker, Ruby Haviv, Yosef Uziel, Rubi Haviv, Veronica Moshe, Michal Rothschild, Liora Harel, Gil Amarilyo, Rotem Tal, Mohamad Hamad Said, Irit Tirosh, Shiri Spielman, Maya Gerstein, Angelo Ravelli, Benedetta Schiappapietra, Giulia Camilla Varnier, Martina Finetti, Maurizio Marasini, Roberta Caorsi, Silvia Rosina, Silvia Federici, Irene Pontikaki, Pier Luigi Meroni, Valeri Gerloni, Nicola Ughi, Tania Ubiali, Maria Alessio, Roberto Della Casa, Sebastiaan Jozef Vastert, Joost Frans Swart, A. van Royen‐Kerhof, Ellen Schatorje, G. Van Iperen‐Schutte, Lidia Rutkowska‐Sak, Izabela Szczygielska, Malgorzata Kwiatkowska, Maria Marusak‐Banacka, Piotr Gietka, Kseniya Isaeva, Rina Denisova, Ludmila Snegireva, Margarita Dubko, Mikhail Kostik, Natalia Buchinskaia, Olga Kalashnikova, Sergey Avrusin, Vera Masalova, Esmeralda Nunez Cuadros, Gisela Diez, Rocio Galindo Zavala, Rosa Bou Torrent, Estibaliz Iglesias, Joan Calzada, Violeta Bittermann, Alina Lucica Boteanu, Maria Luz Gamir, Inmaculada Calvo, Berta Lopez, Isabel Gonzalez, Laura Fernandez, Daniel Clemente Garulo, Juan Carlos Lopez Robledillo, Rosa Merino, Rosa Alcobendas, Agustin Remesal, Sara Murias, Bo Magnusson, Ozgur Kasapcopur, Kenan Barut, Amra Adrovic, Sezgin Sahin, Muferet Erguven, Refia Gozdenur Savci, Seza Ozen, Selcan Demir, Yelda Bilginer, Zehra Serap Avci, Ezgi Deriz Batu, Andreas Reiff, Anusha Ramanatham, Diana Brown, Bracha Shaham, Shirley Parks, Michal Cidon, Gloria Higgins, Charles Spencer, Jenny Rossette, Karla Jones, Sharon Bout Tabaku, Shelli Farley, and Shoghik Akoghlanian

Abstract

Objective: To evaluate the efficacy and safety of 2 canakinumab monotherapy tapering regimens in order to maintain complete clinical remission in children with systemic juvenile idiopathic arthritis (JIA). Methods: The study was designed as a 2-part phase IIIb/IV open-label, randomized trial. In the first part, patients received 4 mg/kg of canakinumab subcutaneously every 4 weeks and discontinued glucocorticoids and/or methotrexate as appropriate. Patients in whom clinical remission was achieved (inactive disease for at least 24 weeks) with canakinumab monotherapy were entered into the second part of the trial, in which they were randomized 1:1 into 1 of 2 treatment arms. In arm 1, the dose of canakinumab was reduced from 4 mg/kg to 2 mg/kg and then to 1 mg/kg, followed by discontinuation. In arm 2, the 4 mg/kg dose interval was prolonged from every 4 weeks, to every 8 weeks, and then to every 12 weeks, followed by discontinuation. In both arms, canakinumab exposure could be reduced provided systemic JIA remained in clinical remission for 24 weeks with each step. The primary objective was to assess whether >40% of randomized patients in either arm maintained clinical remission of systemic JIA for 24 weeks in the first part of the study. Results: In part 1 of the study, 182 patients were enrolled, with 75 of those patients randomized before entering part 2 of the trial. Among the 75 randomized patients, clinical remission was maintained for 24 weeks in 27 (71%) of 38 patients in arm 1 (2 mg/kg every 4 weeks) and 31 (84%) of 37 patients in arm 2 (4 mg/kg every 8 weeks) (P ≤ 0.0001 for arm 1 versus arm 2 among those meeting the 40% threshold). Overall, 25 (33%) of 75 patients discontinued canakinumab, and clinical remission was maintained for at least 24 weeks in all 25 of these patients. No new safety signals were identified. Conclusion: Reduction of canakinumab exposure may be feasible in patients who have achieved clinical remission of systemic JIA, but consisten

Published
2021

17. Antigen-driven PD-1+TOX+EOMES+ and PD-1+TOX+BHLHE40+ synovial T lymphocytes regulate chronic inflammation in situ

Author

Femke van Wijk, Christopher Mark Skopnik, Bas Vastert, Katrin Lehmann, Gitta Anne Heinz, Patrick Maschmeyer, Philipp Enghard, René Riedel, Sae Lim von Stuckrad, Cam Loan Tran, Hyun-Dong Chang, Frederik Heinrich, Alessio Mazzoni, Francesco Giudici, Lorenz Elias Wirth, Marcus A. Mall, Andreas Radbruch, Lisanne Lutter, Francesco Annunziato, Mir-Farzin Mashreghi, Imme Sakwa, Tilmann Kallinich, Rolando Cimaz, and Pawel Durek

Subjects
education.field_of_study, biology, Population, Arthritis, Inflammation, Major histocompatibility complex, medicine.disease, Pathogenesis, Immune system, Antigen, Immunology, biology.protein, medicine, medicine.symptom, education, CD8
Abstract

Introduction/AbstractT lymphocytes accumulate in inflamed tissues of patients with chronic inflammatory diseases (CIDs) and express pro-inflammatory cytokines upon re-stimulation in vitro1–29. Further, a significant genetic linkage to MHC genes suggests that T lymphocytes play an important role in the pathogenesis of CIDs including juvenile idiopathic arthritis (JIA)30–33. However, the functions of T lymphocytes in established disease remain elusive. Here we dissect the heterogeneity of synovial T lymphocytes in JIA patients by single cell RNA-sequencing. We identify subpopulations of T lymphocytes expressing genes reflecting recent activation by antigen in situ. A PD-1+TOX+EOMES+ population of CD4+ T lymphocytes expressed immune regulatory genes and chemoattractant genes for myeloid cells. A PD-1+TOX+BHLHE40+ population of CD4+, and a mirror population of CD8+ T lymphocytes expressed genes driving inflammation, and genes supporting B lymphocyte activation. This analysis points out that multiple types of T lymphocytes have to be targeted for therapeutic regeneration of tolerance in arthritis.

Published
2019
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18. Regulation of Fatty Acid Oxidation by Twist 1 in the Metabolic Adaptation of T Helper Lymphocytes to Chronic Inflammation

Author

Kristyna Hradilkova, Tilmann Kallinich, Pawel Durek, Anne Sae Lim von Stuckrad, Kirsten Minden, Patrick Maschmeyer, Olena Husak, Hyun-Dong Chang, Heidi Schliemann, Andreas Radbruch, Kerstin Westendorf, and Joachim R. Grün

Subjects
0301 basic medicine, medicine.medical_specialty, animal structures, Cell Survival, Immunology, Programmed Cell Death 1 Receptor, Arthritis, Inflammation, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Oxygen Consumption, Rheumatology, Internal medicine, Synovial Fluid, medicine, Immunology and Allergy, Synovial fluid, Animals, Humans, Glycolysis, Lactic Acid, Beta oxidation, chemistry.chemical_classification, Reactive oxygen species, Fatty Acids, Twist-Related Protein 1, Nuclear Proteins, T-Lymphocytes, Helper-Inducer, Th1 Cells, medicine.disease, Pediatric Rheumatology, Arthritis, Juvenile, 030104 developmental biology, Endocrinology, chemistry, Original Article, medicine.symptom, Energy Metabolism, Reactive Oxygen Species, Oxidation-Reduction, Etomoxir, Ex vivo, 030215 immunology
Abstract

OBJECTIVE Inflamed tissue is characterized by low availability of oxygen and nutrients. Yet CD4+ T helper lymphocytes persist over time in such tissue and probably contribute to the chronicity of inflammation. This study was undertaken to analyze the metabolic adaptation of these cells to the inflamed environment. METHODS Synovial and blood CD4+ T cells isolated ex vivo from patients with juvenile idiopathic arthritis (JIA) and murine CD4+ T cells were either stimulated once or stimulated repeatedly. Their dependency on particular metabolic pathways for survival was then analyzed using pharmacologic inhibitors. The role of the transcription factor Twist 1 was investigated by determining lactate production and oxygen consumption in Twist1-sufficient and Twist1-deficient murine T cells. The dependency of these murine cells on particular metabolic pathways was analyzed using pharmacologic inhibitors. RESULTS Programmed death 1 (PD-1)+ T helper cells in synovial fluid samples from patients with JIA survived via fatty acid oxidation (mean ± SEM survival of 3.4 ± 2.85% in the presence of etomoxir versus 60 ± 7.08% in the absence of etomoxir on day 4 of culture) (P < 0.0002; n = 6) and expressed the E-box-binding transcription factor TWIST1 (2-14-fold increased expression) (P = 0.0156 versus PD-1- T helper cells; n = 6). Repeatedly restimulated murine T helper cells, which expressed Twist1 as well, needed Twist1 to survive via fatty acid oxidation. In addition, Twist1 protected the cells against reactive oxygen species. CONCLUSION Our findings indicate that TWIST1 is a master regulator of metabolic adaptation of T helper cells to chronic inflammation and a target for their selective therapeutic elimination.

Published
2018

19. Juvenile arthritis caused by a novel FAMIN (LACC1) mutation in two children with systemic and extended oligoarticular course

Author

Hella Luksch, Peter Krawitz, Patrick Hundsdoerfer, Kirsten Minden, Angela Rösen-Wolff, Sae-Lim von Stuckrad, Tilmann Kallinich, and Anne Thorwarth

Subjects
0301 basic medicine, medicine.medical_specialty, Arthritis, Case Report, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::619 Gynäkologie, Pädiatrie, Geriatrie, medicine.disease_cause, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Systemic juvenile idiopathic arthritis, Internal medicine, medicine, Humans, Immunology and Allergy, Juvenile, Exome, Genetic Predisposition to Disease, Pediatrics, Perinatology, and Child Health, Child, Frameshift Mutation, 030203 arthritis & rheumatology, Mutation, Systemic juvenile idiopathic arthritis Exome sequencing, business.industry, Homozygote, Intracellular Signaling Peptides and Proteins, Proteins, Inflammasome, Exome sequencing, FAMIN, LACC1, medicine.disease, Phenotype, Arthritis, Juvenile, Pedigree, 030104 developmental biology, FAMIN, LACC1, Pediatrics, Perinatology and Child Health, Immunology, Female, business, medicine.drug
Abstract

Background The pathophysiological origin of juvenile idiopathic arthritis (JIA) is largely unknown. However, individuals with presumably pathogenic mutations in FAMIN have been reported, associating this gene with a rare subtype of this disorder. FAMIN, that is formerly also referred to as LACC1 or C13orf31, has recently been shown to play a crucial role in immune-metabolic functions and is involved in regulation of inflammasome activation and promotion of ROS production. Case presentation We describe two siblings with severe familial forms of juvenile arthritis in which whole-exome-sequencing revealed a novel homozygous frameshift mutation (NM_153218.2:c.827delC¸. p.(T276fs*2) in FAMIN. Conclusions The observation of a new deleterious mutation adds further evidence that pathogenic mutations in FAMIN are causal for a monogenic form of JIA. Furthermore the associated phenotype is not restricted to systemic JIA, but can also be found in other forms of familial juvenile arthritis.

Published
2016
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