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1. Lupus pathogenesis and autoimmunity are exacerbated by high fat diet-induced obesity in MRL/lpr mice

Author

Xin Zhang, William Davis, Jerald Zakem, Zongbing You, Ronak Patel, Juan Meng, Xuhua Shi, Robert James Quinet, Chandana Keshavamurthy, Gitanjali Lobo, Linh Hellmers, Alicia Nicole Ray, Laura E Rivers, Hiba Ali, Therese Posas-Mendoza, and Chad Hille

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Objective SLE is an autoimmune disease characterised by persistent inflammation and autoantibody production. Genetic predisposition and environmental factors such as a high-fat diet (HFD) may contribute to lupus development. However, the immune cell profile and gender difference in response to HFD in lupus have not been reported. Here we investigated the impact of HFD on lupus pathogenesis and autoimmunity using lupus-prone mice.Methods Thirty male and 30 female MRL/lymphoproliferation (lpr) mice were fed with regular diet (RD) or HFD. Body weights were recorded weekly. SLE progression was monitored by skin lesion, urine protein, titres of antidouble-strand DNA (dsDNA) and ANA. At week 14, kidney and skin tissue sections were stained with H&E and periodic acid–Schiff to detect histological kidney index and skin score. Splenocytes were identified by immunofluorescence staining and flow cytometry.Results HFD significantly increased body weight and lipid levels compared with RD (p

Published
2023
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2. Environmental and societal factors associated with COVID-19-related death in people with rheumatic disease: an observational study

Author

Zara Izadi, Milena A Gianfrancesco, Gabriela Schmajuk, Lindsay Jacobsohn, Patricia Katz, Stephanie Rush, Clairissa Ja, Tiffany Taylor, Kie Shidara, Maria I Danila, Katherine D Wysham, Anja Strangfeld, Elsa F Mateus, Kimme L Hyrich, Laure Gossec, Loreto Carmona, Saskia Lawson-Tovey, Lianne Kearsley-Fleet, Martin Schaefer, Samar Al-Emadi, Jeffrey A Sparks, Tiffany Y-T Hsu, Naomi J Patel, Leanna Wise, Emily Gilbert, Alí Duarte-García, Maria O Valenzuela-Almada, Manuel F Ugarte-Gil, Lotta Ljung, Carlo A Scirè, Greta Carrara, Eric Hachulla, Christophe Richez, Patrice Cacoub, Thierry Thomas, Maria J Santos, Miguel Bernardes, Rebecca Hasseli, Anne Regierer, Hendrik Schulze-Koops, Ulf Müller-Ladner, Guillermo Pons-Estel, Romina Tanten, Romina E Nieto, Cecilia N Pisoni, Yohana S Tissera, Ricardo Xavier, Claudia D Lopes Marques, Gecilmara C S Pileggi, Philip C Robinson, Pedro M Machado, Emily Sirotich, Jean W Liew, Jonathan S Hausmann, Paul Sufka, Rebecca Grainger, Suleman Bhana, Monique Gore-Massy, Zachary S Wallace, Jinoos Yazdany, Brahim Dahou, Gimena Gómez, Karen Roberts, Roberto M Baez, Vanessa V Castro Coello, María J Haye Salinas, Federico N Maldonado, Alvaro A Reyes, Gelsomina Alle, Hernán Maldonado Ficco, Romina Nieto, Carla Gobbi, Yohana Tissera, Cecilia Pisoni, Alba Paula, Juan A Albiero, Maria M Schmid, Micaela Cosatti, Maria J Gamba, Carlevaris Leandro, María A Cusa, Noelia German, Veronica Bellomio, Lorena Takashima, Mariana Pera, Karina Cogo, Maria S Gálvez Elkin, María A Medina, Veronica Savio, Romina Rojas Tessel, Rodolfo P Alamino, Marina L Werner, Sofía Ornella, Luciana Casalla, Maria de la Vega, María Severina, Mercedes García, Luciana Gonzalez Lucero, Cecilia Romeo, Sebastián Moyano, Tatiana Barbich, Ana Bertoli, Andrea Baños, Sandra Petruzzelli, Carla Matellan, Silvana Conti, Maria A Lazaro, Gustavo F Rodriguez Gil, Fabian Risueño, Maria I Quaglia, Julia Scafati, Natalia L Cuchiaro, Jonathan E Rebak, Susana I Pineda, María E Calvo, Eugenia Picco, Josefina G Yanzi, Pablo Maid, Debora Guaglianone, Julieta S Morbiducci, Sabrina Porta, Natalia Herscovich, José L Velasco Zamora, Boris Kisluk, Maria S Castaños Menescardi, Rosana Gallo, María V Martire, Carla Maldini, Cecilia Goizueta, Sabrina S de la Vega Fernandez, Carolina Aeschlimann, Gisela Subils, Eva Rath, Yves Piette, Mieke Devinck, Bea Maeyaert, Francinne Machado Ribeiro, Sandra L Euzebio Ribeiro, Marcelo Pinheiro, Sebastián Ibáñez, Anne-Marie Chassin Trubert, Lingli Dong, Lui Cajas, Marko Barešić, Branimir Anić, Melanie-Ivana Ćulo, Tea A Pavelić, Kristina K Stranski, Boris Karanovic, Jiri Vencovsky, Marta Píchová, Maria Filkova, Hesham Hamoud, Dimitrios Vassilopoulos, Gabriela M Guzman Melgar, Ho So, Márta Király, Mahdi Vojdanian, Alexandra Balbir Gurman, Fatemah Abutiban, Julija Zepa, Inita Bulina, Loreta Bukauskiene, Beatriz E Zazueta Montiel, Angel A Castillo Ortiz, Erick Zamora Tehozol, David Vega Morales, Diana Cervántes Rosete, Eduardo Martín Nares, Tatiana S Rodriguez Reyna, Marina Rull Gabayet, Deshiré Alpízar Rodríguez, Fedra Irazoque, Xochitl Jimenez, Lenny Geurts van Bon, Theo Zijlstra, Monique Hoekstra, Nasra Al Adhoubi, Babur Salim, Enrique Giraldo, Ariel Salinas, Manuel Ugarte Gil, Jarosław Nowakowski, Richard Conway, Rachael Flood, Geraldine McCarthy, Ioana Felea, Ileana Filipescu, Simona Rednic, Laura Groseanu, Maria M Tamas, Vanda Mlynarikova, Martina Skamlova, Martin Zlnay, Dagmar Mičeková, Lubica Capova, Zelmira Macejova, Emőke Šteňová, Helena Raffayova, Gabriela Belakova, Eva Strakova, Marieta Senčarová, Soňa Žlnayová, Anna Sabová, Daniela Spisakova, Mária Oetterová, Olga Lukacova, Martina Bakosova, Alojzija Hocevar, Natalia de la Torre Rubio, Juan J Alegre Sancho, Montserrat Corteguera Coro, Juan C Cobeta Garcia, Maria C Torres Martin, Jose Campos, Jose A Gomez Puerta, Gozd K Yardimci, Servet Akar, Ozan C Icacan, Selda ÇELİK, Viktoriia Vasylets, Su-Ann Yeoh, Claire Vandevelde, Sasha Dunt, Jane Leeder, Elizabeth Macphie, Rosaria Salerno, Christine Graver, Katie Williams, Sheila O'Reilly, Kirsty Devine, Jennifer Tyler, Elizabeth Warner, James Pilcher, Samir Patel, Elena Nikiphorou, Laura Chadwick, Caroline M Jones, Beverley Harrison, Lucy Thornton, Diana O'Kane, Lucia Fusi, Audrey Low, Sarah Horton, Shraddha Jatwani, Sara Baig, Hammad Bajwa, Vernon Berglund, Angela Dahle, Walter Dorman, Jody Hargrove, Maren Hilton, Nicholas Lebedoff, Susan Leonard, Jennifer Morgan, Emily Pfeifer, Archibald Skemp, Jeffrey Wilson, Anne Wolff, Eduardo Cepeda, Derrick Todd, Denise Hare, Cassandra Calabrese, Christopher Adams, Arezou Khosroshahi, Adam Kilian, Douglas White, Melanie Winter, Theodore Fields, Caroline Siegel, Nicole Daver, Melissa Harvey, Neil Kramer, Concetta Lamore, Suneya Hogarty, Karen Yeter, Faizah Siddique, Byung Ban, Tamar Tanner, Eric Ruderman, William Davis, Robert Quinet, Evangeline Scopelitis, Karen Toribio, Tameka Webb Detiege, Jerald Zakem, Khurram Abbass, Gilbert Kepecs, Lilliam Miranda, Michael Guma, Ammar Haikal, Sushama Mody, Daric Mueller, Arundathi Jayatilleke, JoAnn Zell, Alison Bays, Kathryn Dao, Fatemeh Ezzati, Deborah Parks, David Karp, Guillermo Quiceno, Izadi, Z, Gianfrancesco, M, Schmajuk, G, Jacobsohn, L, Katz, P, Rush, S, Ja, C, Taylor, T, Shidara, K, Danila, M, Wysham, K, Strangfeld, A, Mateus, E, Hyrich, K, Gossec, L, Carmona, L, Lawson-Tovey, S, Kearsley-Fleet, L, Schaefer, M, Al-Emadi, S, Sparks, J, Hsu, T, Patel, N, Wise, L, Gilbert, E, Duarte-Garcia, A, Valenzuela-Almada, M, Ugarte-Gil, M, Ljung, L, Scire, C, Carrara, G, Hachulla, E, Richez, C, Cacoub, P, Thomas, T, Santos, M, Bernardes, M, Hasseli, R, Regierer, A, Schulze-Koops, H, Muller-Ladner, U, Pons-Estel, G, Tanten, R, Nieto, R, Pisoni, C, Tissera, Y, Xavier, R, Lopes Marques, C, Pileggi, G, Robinson, P, Machado, P, Sirotich, E, Liew, J, Hausmann, J, Sufka, P, Grainger, R, Bhana, S, Gore-Massy, M, Wallace, Z, Yazdany, J, Dahou, B, Gomez, G, Roberts, K, Baez, R, Castro Coello, V, Haye Salinas, M, Maldonado, F, Reyes, A, Alle, G, Maldonado Ficco, H, Gobbi, C, Paula, A, Albiero, J, Schmid, M, Cosatti, M, Gamba, M, Leandro, C, Cusa, M, German, N, Bellomio, V, Takashima, L, Pera, M, Cogo, K, Galvez Elkin, M, Medina, M, Savio, V, Rojas Tessel, R, Alamino, R, Werner, M, Ornella, S, Casalla, L, de la Vega, M, Severina, M, Garcia, M, Gonzalez Lucero, L, Romeo, C, Moyano, S, Barbich, T, Bertoli, A, Banos, A, Petruzzelli, S, Matellan, C, Conti, S, Lazaro, M, Rodriguez Gil, G, Risueno, F, Quaglia, M, Scafati, J, Cuchiaro, N, Rebak, J, Pineda, S, Calvo, M, Picco, E, Yanzi, J, Maid, P, Guaglianone, D, Morbiducci, J, Porta, S, Herscovich, N, Velasco Zamora, J, Kisluk, B, Castanos Menescardi, M, Gallo, R, Martire, M, Maldini, C, Goizueta, C, de la Vega Fernandez, S, Aeschlimann, C, Subils, G, Rath, E, Piette, Y, Devinck, M, Maeyaert, B, Machado Ribeiro, F, Euzebio Ribeiro, S, Pinheiro, M, Ibanez, S, Chassin Trubert, A, Dong, L, Cajas, L, Baresic, M, Anic, B, Culo, M, Pavelic, T, Stranski, K, Karanovic, B, Vencovsky, J, Pichova, M, Filkova, M, Hamoud, H, Vassilopoulos, D, Guzman Melgar, G, So, H, Kiraly, M, Vojdanian, M, Balbir Gurman, A, Abutiban, F, Zepa, J, Bulina, I, Bukauskiene, L, Zazueta Montiel, B, Castillo Ortiz, A, Zamora Tehozol, E, Vega Morales, D, Cervantes Rosete, D, Martin Nares, E, Rodriguez Reyna, T, Rull Gabayet, M, Alpizar Rodriguez, D, Irazoque, F, Jimenez, X, Geurts van Bon, L, Zijlstra, T, Hoekstra, M, Al Adhoubi, N, Salim, B, Giraldo, E, Salinas, A, Ugarte Gil, M, Nowakowski, J, Conway, R, Flood, R, Mccarthy, G, Felea, I, Filipescu, I, Rednic, S, Groseanu, L, Tamas, M, Mlynarikova, V, Skamlova, M, Zlnay, M, Micekova, D, Capova, L, Macejova, Z, Stenova, E, Raffayova, H, Belakova, G, Strakova, E, Sencarova, M, Zlnayova, S, Sabova, A, Spisakova, D, Oetterova, M, Lukacova, O, Bakosova, M, Hocevar, A, de la Torre Rubio, N, Alegre Sancho, J, Corteguera Coro, M, Cobeta Garcia, J, Torres Martin, M, Campos, J, Gomez Puerta, J, Yardimci, G, Akar, S, Icacan, O, Celik, S, Vasylets, V, Yeoh, S, Vandevelde, C, Dunt, S, Leeder, J, Macphie, E, Salerno, R, Graver, C, Williams, K, O'Reilly, S, Devine, K, Tyler, J, Warner, E, Pilcher, J, Patel, S, Nikiphorou, E, Chadwick, L, Jones, C, Harrison, B, Thornton, L, O'Kane, D, Fusi, L, Low, A, Horton, S, Jatwani, S, Baig, S, Bajwa, H, Berglund, V, Dahle, A, Dorman, W, Hargrove, J, Hilton, M, Lebedoff, N, Leonard, S, Morgan, J, Pfeifer, E, Skemp, A, Wilson, J, Wolff, A, Cepeda, E, Todd, D, Hare, D, Calabrese, C, Adams, C, Khosroshahi, A, Kilian, A, White, D, Winter, M, Fields, T, Siegel, C, Daver, N, Harvey, M, Kramer, N, Lamore, C, Hogarty, S, Yeter, K, Siddique, F, Ban, B, Tanner, T, Ruderman, E, Davis, W, Quinet, R, Scopelitis, E, Toribio, K, Webb Detiege, T, Zakem, J, Abbass, K, Kepecs, G, Miranda, L, Guma, M, Haikal, A, Mody, S, Mueller, D, Jayatilleke, A, Zell, J, Bays, A, Dao, K, Ezzati, F, Parks, D, Karp, D, Quiceno, G, and Repositório da Universidade de Lisboa

Subjects
health care disparity, Immunology, air pollution, cohort analysi, mortality rate, Autoimmune Disease, Article, coronavirus disease 2019, biocontainment, Rheumatology, male, cardiovascular disease, environmental factor, death, geographic distribution, Immunology and Allergy, follow up, controlled study, human, population density, outcome assessment, rheumatic disease, diabetes mellitu, adult, Prevention, market, temperature, mortality, United Kingdom, Europe, aged, female, workplace, Good Health and Well Being, human development, particulate matter 2.5, statistical analysi, North America, incidence, life expectancy, social aspect, COVID-19 Global Rheumatology Alliance Registry, observational study, demographic
Abstract

Published by Elsevier Ltd., Background: Differences in the distribution of individual-level clinical risk factors across regions do not fully explain the observed global disparities in COVID-19 outcomes. We aimed to investigate the associations between environmental and societal factors and country-level variations in mortality attributed to COVID-19 among people with rheumatic disease globally. Methods: In this observational study, we derived individual-level data on adults (aged 18-99 years) with rheumatic disease and a confirmed status of their highest COVID-19 severity level from the COVID-19 Global Rheumatology Alliance (GRA) registry, collected between March 12, 2020, and Aug 27, 2021. Environmental and societal factors were obtained from publicly available sources. The primary endpoint was mortality attributed to COVID-19. We used a multivariable logistic regression to evaluate independent associations between environmental and societal factors and death, after controlling for individual-level risk factors. We used a series of nested mixed-effects models to establish whether environmental and societal factors sufficiently explained country-level variations in death. Findings: 14 044 patients from 23 countries were included in the analyses. 10 178 (72·5%) individuals were female and 3866 (27·5%) were male, with a mean age of 54·4 years (SD 15·6). Air pollution (odds ratio 1·10 per 10 μg/m3 [95% CI 1·01-1·17]; p=0·0105), proportion of the population aged 65 years or older (1·19 per 1% increase [1·10-1·30]; p, MAG is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers K01 AR070585 and K24 AR074534 [JY]). KDW is supported by the Department of Veterans Affairs and the Rheumatology Research Foundation Scientist Development award. JAS is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers K23 AR069688, R03 AR075886, L30 AR066953, P30 AR070253, and P30 AR072577), the Rheumatology Research Foundation (K Supplement Award and R Bridge Award), the Brigham Research Institute, and the R. Bruce and Joan M. Mickey Research Scholar Fund. NJP is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32-AR-007258). AD-G is supported by grants from the Centers for Disease Control and Prevention and the Rheumatology Research Foundation. RH was supported by the Justus-Liebig University Giessen Clinician Scientist Program in Biomedical Research to work on this registry. JY is supported by grants from the National Institutes of Health (K24 AR074534 and P30 AR070155).

Published
2022

3. Lupus pathogenesis and autoimmunity are exacerbated by high fat diet–induced obesity in MRL/lpr mice

Author

Xin Zhang, Juan Meng, Xuhua Shi, Robert Quinet, William Davis, Jerald Zakem, Ronak Patel, Gitanjali Lobo, Linh Hellmers, Alicia Ray, Talon Washington, Chandana Keshavamurthy, Natasha Kumar, Hiba Ali, Swathi Dhulipala, Chad Hille, and Zongbing You

Abstract

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by persistent inflammation and autoantibody production, leading to systemic damage. Genetic predisposition and environmental factors such as high fat diet (HFD)/obesity may contribute to lupus development. In this study, we investigated the impact of HFD in lupus pathogenesis and autoimmunity to reveal the pathological link of HFD and SLE using-lupus prone mice.Methods: Sixty MRL/lpr mice were grouped and fed with a regular diet (RD) or HFD. Their body weights were recorded weekly. SLE progression was monitored by skin lesion, urine protein, and titers of anti-dsDNA and antinuclear antibodies (ANA). Mice were euthanized at week 14. Kidney and skin tissue sections were stained with hematoxylin and eosin (H&E), periodic acid–Schiff (PAS), and Masson's trichrome to detect lupus histopathological lesions and were quantified as kidney index and histological skin score. Immune cells in the spleen were identified by immunofluorescence staining and flow cytometry. Student t test or two-way ANOVA was used for statistical analysis.Results: HFD induced a significant increase in mouse body weight by week 5 and continued until week 14 compared to RD (pppppConclusion: Our results showed that HFD induced an accelerated and exacerbated lupus development and autoimmunity in MRL/lpr mice. Tfh/Treg cells may be the interconnection of HFD and SLE. Interventions of healthy diet or restoring balance of Tfh/Treg cells may improve both lupus symptoms and outcomes in genetically predisposed SLE patients.

Published
2022
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4. Outcomes of COVID-19 in patients with primary systemic vasculitis or polymyalgia rheumatica from the COVID-19 Global Rheumatology Alliance physician registry: a retrospective cohort study

Author

Maria Sol Castaños Menescardi, Mercedes García, Elena Nikiphorou, Ulf Müller-Ladner, Rita Pinheiro Torres, Cassandra Calabrese, Nasra Al-Adhoubi, Sandra Lucia Euzebio Ribeiro, Kaley Beins, Puja Mehta, José Luis Velasco Zamora, Lorena Takashima, Loreta Bukauskiene, Derrick Todd, Gozd Kubra Yardimci, Samia Araujo de Sousa Studart, Ariel Salinas, Babur Salim, Martin Schaefer, Sarah Horton, Bea Maeyaert, Andrea M Seet, Beverley Harrison, Vernon Berglund, Douglas White, Archibald Skemp, Vanessa Castro Coello, Susan Leonard, Guillermo Quiceno, Geraldine McCarthy, Neil Kramer, Reinhard E. Voll, Helena Raffayova, Lianne Kearsley-Fleet, Hernán Maldonado Ficco, Emily L Gilbert, Samir Patel, Arezou Khosroshahi, Boris Karanovic, Jaroslaw Nowakowski, Dagmar Miceková, Márta Király, Saskia Lawson-Tovey, Alison Bays, Katie Williams, Pablo Maid, Montserrat Corteguera Coro, Anna Anna Sabová, Noelia German, Rosana Gallo, María Alejandra Cusa, Philip Robinson, Natalia Herscovich, Branimir Anic, Lorna Neill, Sara Baig, James Pilcher, Lucia Fusi, Jerald Zakem, Eugenia Picco, Monique Hoekstra, Michael S. Putman, Veronica Bellomio, Martina Skamlova, Daniela Spisakova, Caroline Mulvaney Jones, Ezzati Fatemeh, Sona Žlnayová, Silvana Conti, Eva Strakova, Jose A Gomez Puerta, Kristin M D’Silva, Marko Barešic, Yohana Tissera, Roberto Miguel Baez, Theodore Fields, Rachael Flood, Josefina Gallino Yanzi, Fatemah Abutiban, Henrique Ataide Mariz, Martin Zlnay, Mariana Luís, Mariana Pera, Robert Quinet, Claire Vandevelde, Richard Conway, Lubica Capova, Rodolfo Perez Alamino, Romina Nieto, Deborah Parks, Denise Hare, Audrey Low, Faizah Siddique, Zachary S. Wallace, Tiffany Y-T Hsu, Tameka Webb-Detiege, Sheila O'Reilly, Tatiana Barbich, Theo Zijlstra, Kathryn Dao, Luca Quartuccio, Cecilia Pisoni, Maria Isabel Quaglia, Zelmira Macejova, Laure Gossec, Jean W Liew, JoAnn Zell, Tiffany Y.T. Hsu, Rebecca Hasseli, Zara Izadi, Francinne Machado Ribeiro, Christopher Adams, Laura Chadwick, Naomi J Patel, Maria Carmen Torres Martin, Emoke Štenová, Fedra Irazoque, Natalia Lili Cuchiaro, Selda Çelik, Maria Isabel Haye Salinas, Alexandra Balbir-Gurman, Lucy Thornton, Shraddha Jatwani, Jane Leeder, Jeffrey A. Sparks, Pedro Machado, Elizabeth Macphie, Alojzija Hocevar, Melanie Winter, Christopher Hill, Carolina Aeschlimann, Loreto Carmona, Viktoriia Vasylets, Jose Campos, Jiri Vencovsky, Romina Tanten, Karina Cogo, Emily Pfeifer, Zachary S Wallace, Erick Zamora Tehozol, David F L Liew, Christine Graver, Cecilia Romeo, Lenny Geurts-van Bon, Alvaro Andres Reyes Torres, Arundathi Jayatilleke, Lui Cajas, Ana Bertoli, María Victoria Martire, Pascal Chazerain, Boris Kisluk, Anne Wolff, Alba Paula, Maria Marcela Schmid, Marieta Sencarová, Manuel F. Ugarte-Gil, Concetta Lamore, Veronica Savio, Emily Sirotich, Nicole Daver, Inita Bulina, Maria Filkova, Samar Al-Emadi, Jennifer Tyler, Ho So, Anne-Marie Chassin-Trubert, Leanna Wise, Davide Rozza, Yves Piette, Sabrina Solange de la Vega Fernandez, Eva Rath, Angel Alejandro Castillo Ortiz, Simona Rednic, Stéphane Bally, Kimme L Hyrich, Eric Ruderman, Gabriela Maria Guzman Melgar, Diana Cervántes Rosete, Alí Duarte-García, Juan Carlos Cobeta Garcia, Vanda Mlynarikova, Byung Ban, David Karp, Juan José Alegre Sancho, Carlevaris Leandro, Tamar Tanner, Gisela Subils, Susana Isabel Pineda, Ileana Filipescu, Lilliam Miranda, Karen Toribio Toribio, Karen Roberts, María Severina, Maria Valenzuela Almada, Kristin M. D’Silva, Tea Ahel Pavelic, Federico Nicolas Maldonado, Lingli Dong, Kirsty Devine, Ammar Haikal, Sebastian E Sattui, María J. Haye Salinas, Karen Yeter, Jennifer Morgan, Maria Julieta Gamba, Carla Matellan, Juan Alejandro Albiero, Angela Dahle, Martina Bakosova, Julija Zepa, Luciana Casalla, Jonathan S. Hausmann, Andrea Baños, William Davis, Elsa F Mateus, Kristina Kovacevic Stranski, Lindsay Jacobsohn, Milena A. Gianfrancesco, Daric Mueller, Eduardo Cepeda, Tatiana Sofia Rodriguez-Reyna, Sarah L. Mackie, Mahdi Vojdanian, Julieta Silvana Morbiducci, Enrique Giraldo, Gustavo Fabián Rodriguez Gil, Ivana Romina Rojas Tessel, Laura Groseanu, Carla Gobbi, Anja Strangfeld, Maria Soledad Gálvez Elkin, Alexandre Tj Maria, Adam Kilian, Marina Laura Werner, Sebastián Ibáñez, Sushama Mody, Melissa Harvey, Sofía Ornella, Melanie-Ivana Culo, Gabriela Belakova, Luciana Gonzalez Lucero, Marcelo Pinheiro, Natalia de la Torre-Rubio, Sasha Dunt, Khurram Abbass, Jeffrey A Sparks, Beatriz Zaueta, Elizabeth Warner, Servet Akar, Maren Hilton, Evangeline Scopelitis, Julia Scafati, Jeffrey Wilson, Marta Píchová, Rosana Quintana, Mária Oetterová, Diana O'Kane, Paul Sufka, Jinoos Yazdany, Mieke Devinck, Eduardo Martín Nares, Michael Guma, Gimena Gomez, Nicholas Lebedoff, Su-Ann Yeoh, Suneya Hogarty, Sandra Petruzzelli, Ma. Alicia Lazaro, Marina Rull Gabayet, Nafice Costa Araujo, Bimba F Hoyer, Maria Magdelena Tamas, Cecilia Goizueta, María Alejandra Medina, David Vega, Xochitl Jimenez, Rebecca Grainger, Micaela Cosatti, Gilbert Kepecs, Jonathan Eliseo Rebak, Walter Dorman, Dimitrios Vassilopoulos, Ann Knight, Maria de la Vega, Deshiré Alpízar-Rodríguez, Caroline Siegel, Ozan Cemal Icacan, María Elena Calvo, Sabrina Porta, Hesham Hamoud, Sandra Lucia Euzebio Ribeirio, Maxime Samson, Suleman Bhana, Gelsomina Alle, Ioana Felea, Sebastián Moyano, Rosaria Salerno, Carla Maldini, Jody Hargrove, Brahim Dahou, Fabian Risueño, Debora Guaglianone, Olga Lukacova, and Hammad Bajwa

Subjects
Aging, medicine.medical_specialty, Immunology, Autoimmune Disease, Polymyalgia rheumatica, Rheumatology, Clinical Research, Internal medicine, medicine, Immunology and Allergy, Global Rheumatology Alliance, business.industry, Arthritis, Inflammatory and immune system, Evaluation of treatments and therapeutic interventions, Retrospective cohort study, Articles, Odds ratio, medicine.disease, Comorbidity, Giant cell arteritis, 6.1 Pharmaceuticals, business, Vasculitis, Systemic vasculitis
Abstract

Summary Background Patients with primary systemic vasculitis or polymyalgia rheumatica might be at a high risk for poor COVID-19 outcomes due to the treatments used, the potential organ damage cause by primary systemic vasculitis, and the demographic factors associated with these conditions. We therefore aimed to investigate factors associated with COVID-19 outcomes in patients with primary systemic vasculitis or polymyalgia rheumatica. Methods In this retrospective cohort study, adult patients (aged ≥18 years) diagnosed with COVID-19 between March 12, 2020, and April 12, 2021, who had a history of primary systemic vasculitis (antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis, giant cell arteritis, Behcet's syndrome, or other vasculitis) or polymyalgia rheumatica, and were reported to the COVID-19 Global Rheumatology Alliance registry were included. To assess COVID-19 outcomes in patients, we used an ordinal COVID-19 severity scale, defined as: (1) no hospitalisation; (2) hospitalisation without supplemental oxygen; (3) hospitalisation with any supplemental oxygen or ventilation; or (4) death. Multivariable ordinal logistic regression analyses were used to estimate odds ratios (ORs), adjusting for age, sex, time period, number of comorbidities, smoking status, obesity, glucocorticoid use, disease activity, region, and medication category. Analyses were also stratified by type of rheumatic disease. Findings Of 1202 eligible patients identified in the registry, 733 (61·0%) were women and 469 (39·0%) were men, and their mean age was 63·8 years (SD 17·1). A total of 374 (31·1%) patients had polymyalgia rheumatica, 353 (29·4%) had ANCA-associated vasculitis, 183 (15·2%) had giant cell arteritis, 112 (9·3%) had Behcet's syndrome, and 180 (15·0%) had other vasculitis. Of 1020 (84·9%) patients with outcome data, 512 (50·2%) were not hospitalised, 114 (11·2%) were hospitalised and did not receive supplemental oxygen, 239 (23·4%) were hospitalised and received ventilation or supplemental oxygen, and 155 (15·2%) died. A higher odds of poor COVID-19 outcomes were observed in patients who were older (per each additional decade of life OR 1·44 [95% CI 1·31–1·57]), were male compared with female (1·38 [1·05–1·80]), had more comorbidities (per each additional comorbidity 1·39 [1·23–1·58]), were taking 10 mg/day or more of prednisolone compared with none (2·14 [1·50–3·04]), or had moderate, or high or severe disease activity compared with those who had disease remission or low disease activity (2·12 [1·49–3·02]). Risk factors varied among different disease subtypes. Interpretation Among patients with primary systemic vasculitis and polymyalgia rheumatica, severe COVID-19 outcomes were associated with variable and largely unmodifiable risk factors, such as age, sex, and number of comorbidities, as well as treatments, including high-dose glucocorticoids. Our results could be used to inform mitigation strategies for patients with these diseases. Funding American College of Rheumatology and the European Alliance of Associations for Rheumatology.

Published
2021
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5. Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry

Author

Anja, Strangfeld, Martin, Schäfer, Milena, A Gianfrancesco, Saskia, Lawson-Tovey, Jean, W Liew, Lotta, Ljung, Elsa, F Mateus, Christophe, Richez, Maria, J Santos, Gabriela, Schmajuk, Carlo, A Scirè, Emily, Sirotich, Jeffrey, A Sparks, Paul, Sufka, Thierry, Thomas, Laura, Trupin, Zachary, S Wallace, Sarah, Al-Adely, Javier, Bachiller-Corral, Suleman, Bhana, Patrice, Cacoub, Loreto, Carmona, Ruth, Costello, Wendy, Costello, Laure, Gossec, Rebecca, Grainger, Eric, Hachulla, Rebecca, Hasseli, Jonathan, S Hausmann, Kimme, L Hyrich, Zara, Izadi, Lindsay, Jacobsohn, Patricia, Katz, Lianne, Kearsley-Fleet, Philip, C Robinson, Jinoos, Yazdany, Pedro, M Machado, COVID-19 Global Rheumatology Alliance, COVID-19 Global Rheumatology Alliance Consortium Collaborators: COVID-19 Global Rheumatology Alliance Consortium, Brahim, Dahou, Marcelo, Pinheiro, Francinne, M Ribeiro, Anne-Marie, Chassin-Trubert, Sebastián, Ibáñez, Lingli, Dong, Lui, Cajas, Hesham, Hamoud, Jérôme, Avouac, Véronique, Belin, Raphaël, Borie, Pascal, Chazerain, Xavier, Chevalier, Pascal, Claudepierre, Gaëlle, Clavel, Marie-Eve, Colette-Cedoz, Bernard, Combe, Elodie, Constant, Nathalie, Costedoat-Chalumeau, Marie, Desmurs, Valérie, Devauchelle-Pensec, Mathilde, Devaux, Robin, Dhote, Yannick, Dieudonné, Fanny, Domont, Pierre-Marie, Duret, Mikaël, Ebbo, Esther, Ebstein, Soumaya El Mahou, Bruno, Fautrel, Renaud, Felten, René-Marc, Flipo, Violaine, Foltz, Antoine, Froissart, Joris, Galland, Véronique, Gaud-Listrat, Sophie, Georgin-Lavialle, Aude, Giraud-Morelet, Jeanine, S Giraudet-Le Quitrec, Philippe, Goupille, Sophie, Govindaraju-Audouard, Franck, Grados, Séverine, Guillaume-Czitrom, Marion, Hermet, Ambre, Hittinger-Roux, Christophe, Hudry, Isabelle, Kone-Paut, Sylvain La Batide Alanore, Pierre, Lafforgue, Sophie, Lahalle, Isabelle, Lambrecht, Vincent, Langlois, Jean-Paul, Larbre, Emmanuel, Ledoult, Christophe, Leroux, Frédéric, Liote, Alexandre TJ Maria, Hubert, Marotte, Arsène, Mekinian, Isabelle, Melki, Laurent, Messer, Catherine, Michel, Gauthier, Morel, Jacques, Morel, Marie-Noelle, Paris-Havard, Edouard, Pertuiset, Thao, Pham, Myriam, Renard, Sabine, Revuz, Sébastien, Rivière, Clémentine, Rousselin, Christian, Roux, Diane, Rouzaud, Jérémie, Sellam, Raphaele, Seror, Amelie, Servettaz, Vincent, Sobanski, Christelle, Sordet, Lionnel, Spielmann, Nathalie, Tieulié, Alice, Tison, Sophie, Trijau, Alexandre, Virone, Ursula, Warzocha, Daniel, Wendling, Frederik, N Albach, Peer, Aries, Elvira, Decker, Urs, Hartmann, Joerg, Henes, Bimba, F Hoyer, Andreas, Krause, Klaus, Krüger, Hanns-Martin, Lorenz, Ulf, Müller-Ladner, Alexander, Pfeil, Anne, Regierer, Jutta, G Richter, Markus, Rihl, Tim, Schmeiser, Hendrik, Schulze-Koops, Christof, Specker, Reinhard, E Voll, Stephanie, Werner, Gabriela MG Melgar, Mahdi, Vojdanian, Andreoli, Laura, Elena, Bartoloni-Bocci, Maurizio, Benucci, Francesco, Campanaro, Marta, Caprioli, Davide, Carboni, Greta, Carrara, Edoardo, Cipolletta, Chiara, Crotti, Gloria, Dallagiacoma, Paola, Faggioli, Rosario, Foti, Franceschini, Franco, Fredi, Micaela, Giacomo, Guidelli, Florenzo, Iannone, Gianpiero, Landolfi, Caludia, Lomater, Ceciclia, Nalli, Simone, Parisi, Luca, Quartuccio, Bernd, Raffeiner, Rossella, Reggia, Marta, Riva, Nicoletta, Romeo, Cinzia, Rotondo, Ettore, Silvagni, Luigi, Sinigaglia, Ilaria, Tinazzi, Anna, Zanetti, Giovanni, Zanframundo, Fatemah, Abutiban, Deshiré, Alpízar-Rodríguez, Marina, R Gabayet, Fedra, Irazoque, Xochitl, Jimenez, Eduardo, Martín, Angel AC Ortiz, Tatiana, S Rodriguez-Reyna, Diana, C Rosete, Erick AZ Tehozol, David, Vega, Beatriz, Zaueta, Nasra, Al-Adhoubi, Babur, Salim, Enrique, Giraldo, Ariel, Salinas, Manuel, Ugarte-Gil, Diogo, Almeida, Miguel, Bernardes, Rita, C Machado, Maria, Rato, Samar, Al-Emadi, Richard, Conway, Rachael, Flood, Juan, J Alegre-Sancho, Montserrat, C Coro, Natalia de la Torre-Rubio, Jose, C Esteban, Maria del Martin, Jose, G Puerta, Johan, Back, Maryam, Dastmalchi, Brigitte, Dupré, Emma, Grenholm, Aase, Hensvold, Ann, Knight, Servet, Akar, Ozan, C Icacan, Laura, Chadwick, Kirsty, Devine, Sasha, Dunt, Lucia, Fusi, Caroline, M Jones, Elizabeth, Macphie, Elena, Nikiphorou, Diana, O'Kane, Sheila, O'Reilly, Samir, Patel, Rosaria, Salerno, Lucy, Thornton, Jenny, Tyler, Claire, Vandevelde, Elizabeth, Warner, Su-Ann, Yeoh, Sara, Baig, Hammad, Bajwa, Byung, Ban, Vernon, Berglund, Cassandra, Calabrese, Kristin, D'Silva, Angela, Dahle, Kathryn, Dao, Nicole, Daver, William, Davis, Walter, Dorman, Ezzati, Fatemeh, Theodore, Fields, Jody, Hargrove, Melissa, Harvey, Maren, Hilton, Tiffany, Hsu, Arundathi, Jayatilleke, David, Karp, Gilbert, Kepecs, Neil, Kramer, Concetta, Lamore, Nicholas, Lebedoff, Susan, Leonard, Sushama, Mody, Jennifer, Morgan, Emily, Pfeifer, Guillermo, Quiceno, Robert, Quinet, Elliot, Rosenstein, Eric, Ruderman, Evangeline, Scopelitis, Naomi, Serling-Boyd, Faizah, Siddique, Archibald, Skemp, Jeffrey, Sparks, Derrick, Todd, Karen, T Toribio, Rachel, Wallwork, Tameka, Webb-Detiege, Douglas, White, Jeffrey, Wilson, Melanie, Winter, Leanna, Wise, Anne, Wolff, Kristen, Young, Jerald, Zakem, Joann, Zell, and Kurt Zimmerman, Leibniz Forschungsinstitut für Molekulare Pharmakolgie = Leibniz Institute for Molecular Pharmacology [Berlin, Allemagne] (FMP), Leibniz Association, University of California, University of Manchester [Manchester], Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Umeå University, EULAR standing committee of People with Arthritis/Rheumatism in Europe (PARE), CHU Bordeaux [Bordeaux], Club Rhumatismes et Inflammation, Faculdade de Medicina [Lisboa], Universidade de Lisboa (ULISBOA), Università degli Studi di Ferrara (UniFE), McMaster University [Hamilton, Ontario], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), INSERM U1059, SAINBIOSE - Santé, Ingénierie, Biologie, Saint-Etienne (SAINBIOSE-ENSMSE), Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Ingénierie et Santé (CIS-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Universidad de Alcalá - University of Alcalá (UAH), Service de rhumatologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Otago [Dunedin, Nouvelle-Zélande], Université de Lille, Technische Hochschule Mittelhessen - University of Applied Sciences [Giessen] (THM), University of Queensland [Brisbane], University College of London [London] (UCL), Repositório da Universidade de Lisboa, University of California (UC), Universidade de Lisboa = University of Lisbon (ULISBOA), Università degli Studi di Ferrara = University of Ferrara (UniFE), Santé Ingénierie Biologie Saint-Etienne (SAINBIOSE), Centre Ingénierie et Santé (CIS-ENSMSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Strangfeld, A, Schafer, M, Gianfrancesco, M, Lawson-Tovey, S, Liew, J, Ljung, L, Mateus, E, Richez, C, Santos, M, Schmajuk, G, Scire, C, Sirotich, E, Sparks, J, Sufka, P, Thomas, T, Trupin, L, Wallace, Z, Al-Adely, S, Bachiller-Corral, J, Bhana, S, Cacoub, P, Carmona, L, Costello, R, Costello, W, Gossec, L, Grainger, R, Hachulla, E, Hasseli, R, Hausmann, J, Hyrich, K, Izadi, Z, Jacobsohn, L, Katz, P, Kearsley-Fleet, L, Robinson, P, Yazdany, J, Machado, P, and HAL-SU, Gestionnaire

Subjects
Male, 0301 basic medicine, Aging, antirheumatic agents, Epidemiology, Azathioprine, Comorbidity, Disease, Global Health, Cardiovascular, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Odds Ratio, Immunology and Allergy, Registries, AcademicSubjects/MED00360, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, glucocorticoids, Middle Aged, health care, 3. Good health, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Letter to the Editor (Other), 6.1 Pharmaceuticals, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Public Health and Health Services, Female, epidemiology, Rituximab, medicine.drug, medicine.medical_specialty, Clinical Sciences, Immunology, autoimmune disease, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Autoimmune Disease, General Biochemistry, Genetics and Molecular Biology, Antibodies, Antineutrophil Cytoplasmic, 03 medical and health sciences, Rheumatology, Sulfasalazine, Rheumatic Diseases, Internal medicine, medicine, Humans, autoimmune diseases, outcome assessment, Aged, Rheumatology and Autoimmunity, 030203 arthritis & rheumatology, Reumatologi och inflammation, SARS-CoV-2, business.industry, Arthritis, Evaluation of treatments and therapeutic interventions, COVID-19, Odds ratio, medicine.disease, Arthritis & Rheumatology, Good Health and Well Being, 030104 developmental biology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, COVID-19 Global Rheumatology Alliance, antirheumatic agent, glucocorticoid, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ., Objectives: To determine factors associated with COVID-19-related death in people with rheumatic diseases. Methods: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category. Results: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death. Conclusion: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants.

Published
2021
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6. Dysregulation of T follicular cells and antibody responses in high fat-diet associated lupus development in MRL/lpr mice

Author

Xin Zhang, Juan Meng, Xuhua Shi, Ronak Patel, Alicia Ray, Linh Hellmers, William Davis, Jerald Zakem, Chandana Keshavamurthy, Zongbing You, and Robert Quinet

Subjects
Immunology, Immunology and Allergy
Abstract

Background/Purpose Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by persistent inflammation, autoantibodies production, and organ damage. Genetic predisposition and environmental factors such as fat diet/obesity contribute to lupus pathogenesis. Here, we investigated the role of immune cells, especially T follicular helper (Tfh) cells and T regulatory (Treg) cells, in bridging obesity and SLE manifestations using lupus prone mice. Methods Fifty MRL/lpr mice were fed and grouped in a regular diet (RD) or high fat diet (HFD). Body weights and skin lesions were recorded weekly. Urine protein, serum IgG, anti-dsDNA antibody (Ab), and anti-nuclear Ab were detected. At week 14, kidney and skin biopsy were collected for H&E and PAS staining for histopathological lesions and quantified as kidney index and skin score. Immune cells in spleen were examined by flow cytometry and confirmed by slides staining. Results HFD induced a significant increase in body weight than RD (p Conclusion HFD induced an exacerbated lupus development with dysregulated Tfh/Treg cells associated with increased of anti-dsDNA Ab in MRL/lpr mice, suggesting the central role of Tfh/Treg cells in linking HFD to autoimmunity in SLE. Intervention of healthy diet or restoring balance of Tfh/Treg cells may improve lupus symptoms and outcomes in genetically predisposed individual. Supported by None

Published
2022
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7. Lupus pathogenesis and autoimmunity are exacerbated by high fat diet-induced obesity in mice

Author

Xin Zhang, Juan Meng, Xuhua Shi, Hiba Ali, Linh Hellmers, Neeha Mathew, Talon Washington, Robert Quinet, William Davis, Jerald Zakem, Chandana Keshavamurthy, and Zongbing You

Subjects
Immunology, Immunology and Allergy
Abstract

Objectives System lupus erythematosus (SLE)patients have increased prevalence of metabolic syndrome. Our previous data showed that circulating Tfh (Tfh) cells were increased in SLE patients and correlated to their disease activities. Here, we investigated the pathophysiologic link between fat-diet induced obesity and SLE and underlying mechanism using MRL/lpr lupus prone mice. Methods Twenty MRL/lpr mice were fed with a regular diet (RD) or high fat diet (HFD, 60% calories comprised of fat). Body weight and skin lesion were recorded weekly. Urine protein using Bradford assay was assessed. Blood was collected for IgG, anti-dsDNA and anti-nuclear antibody (ANA) detection. At the end of experiment of week 14, kidney and skin biopsy were embedded in paraffin for H&E, PAS, and Masson’s staining to detect lupus histopathological lesions and quantified as kidney index based on fibrinoid necrosis, periglomerular infiltrate, and inflammatory dermatitis. Spleen paraffin specimens were stained for Tfh cells markers. Results Obesity was achieved with a significant difference of mouse body weight in HFD groups by week 3 (p Conclusion Our results demonstrated that HFD-induced obesity with increase Tfh cells contributes to the acceleration of SLE progression and metabolic abnormalities. Changing eating habit or interventions reducing obesity could improve both SLE symptoms and metabolic inflammation, especially in genetically predisposed individuals.

Published
2020
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8. Small Molecule Inhibitor suppresses Tfh cell development in germinal center and reduces the severity of inflammation in a collagen-induced arthritis mouse model

Author

Xin Zhang, Nitasha Bhatia, Frank Migliore, Linh Hellmers, Gbemi Olayemi, Cara Mcleod, Jerald Zakem, William Davis, and Robert Quinet

Subjects
Immunology, Immunology and Allergy
Abstract

Background Rheumatoidarthritis (RA) is a autoimmune disease characterized by the accumulation of inflammatory cells in the joints, leading to hyperproliferation of synovial cells and tissue destruction. Our previous data showed autoreactive B cells could be induced by T follicular helper (Tfh) cells to undergo clonal expansion with in germinal center (GC), and ultimately differentiate into autoantibody producing plasma cells in RA. Here, we further investigated the role of Tfh cells in RA pathogenesis and the therapeutic effect of a small molecule inhibitor targeting Tfh cells (SMI-Tfh) in collagen-induced arthritis (CIA)mouse model. Methods CIA model was induced by immunization with chicken type II collagen in DBA/1 mice. Disease progression was monitored daily by the paw swollenness. Following the onset of clinical arthritis, mice were treated with SMI-Tfh. At the end of the study, blood, spleen, and affected paws were collected. Pathological changes were examined by H&E staining of tissue sections. Immunofluorescent histochemistry (IHC) staining and flow cytometry analysis were used to identify Tfh cells (CD4+CXCR5+ICOS+) in spleen and blood. Results Arthritis onset was developed at day 21 and with peak on day 42 after initial immunization. Destruction of articular cartilage, increased inflammatory cells and Tfh infiltration were observed in the synovial tissue. Mice treated with SMI-Tfh had significantly reduced Tfh cells in GC of the spleen (p Conclusion SMI-Tfh selectively inhibits GC-Tfh cells in the spleen and abrogates the severity of inflammatory arthritis. It may serve as a novel therapy by interfering with autoreactive GC-Tfh cells development in RA.

Published
2019
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9. Selective inhibition of Tfh cells by a small molecule inhibitor abrogates progression of experimental inflammatory arthritis

Author

Xin Zhang, Frank Migliore, Linh Hellmers, Sedrick Bradley, Jerald Zakem, William Davis, Zongbing You, and Robert Quinet

Subjects
Immunology, Immunology and Allergy
Abstract

Background Rheumatoidarthritis (RA) is an inflammatory autoimmune disease characterized by T cell infiltration in the joints and autoantibody production. T follicular helper (Tfh) cells are a unique subset of CD4+ T cells regulating antibody production in B cell follicle. Our previous studies have showed that increased circulating Tfh cells were correlated with anti-CCP antibody titer and disease activity in active RA patients, indicating that Tfh cells may play an important role in RA pathogenesis. Here we investigate the therapeutic potential of a small molecule inhibitor targeting Tfh cells (SMI-Tfh) in mice with collagen-induced arthritis (CIA). Methods CIA was induced in DBA/1 mice by immunization with chicken type II collagen. Following the onset of clinical arthritis, mice were treated with SMI-Tfh (50mg/kg/day) for 10 days. Arthritis progression was monitored daily and recorded by the paw swollenness. Blood, spleen, and affected paws were collected at the end of the study. Tfh cells were examined and defined by CD4+CXCR5+ICOS+via flow cytometry and further confirmed by immunohistochemistry staining in spleen. Results Mice developed arthritis four weeks after immunization with type II collagen. Treatment with SMI-Tfh significantly reduced the disease progression/activity in mice with CIA. SMI-Tfh significantly inhibited the frequency of Tfh cells in spleen (P0.05). Conclusion The small molecule inhibitor SMI-Tfh selectively inhibits Tfh cells and abrogates progression/activity of inflammatory arthritis in CIA mouse model. Treatment with SMI-Tfh in CIA mice provides a potential strategy for joint protection and may be beneficial in RA patients.

Published
2018
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10. The distinct role of Tfh and Th17 cells and their interplay in the pathogenesis of rheumatoid arthritis

Author

Xin Zhang, Frank Migliore, Magdalena Budziakowska, Quretul Quresh, Jerald Zakem, Tamika Webb-Detiege, Willam Davis, Zongbing You, and Robert Quinet

Subjects
Immunology, Immunology and Allergy
Abstract

Objectives Rheumatoid Arthritis (RA) is an autoimmune disease characterized by the presence of autoantibodies and chronic inflammation in synovium leading to joint destruction. Recently Tfh and Th17 cells have emerged as novel T cell subsets controlling autoimmunity. Our previous data showed that circulating Tfh (cTfh) and circulating Th17 (cTh17) cells were increased in RA patients. Here, we further investigated their role and interplay in the pathogenesis in RA. Design and Methods Peripheral blood was collected from 61 RA patients and 61 healthy donors. RA patients were divided into remission (2.6) based on disease activity score. Clinic parameters including RF, anti-CCP, ESR and CRP were obtained. The frequencies of cTfh and cTh17 cells were measured by flow cytometry. Serum IL-21 and IL-17 were detected by ELISA. Correlations of the frequency of cTfh/IL-21 with cTh17/IL-17 and clinic parameters were statistically determined. Results The increased frequency of cTfh cells significantly correlated with the level of anti-CCP antibody (p Conclusion Tfh cells may be involved in RA pathogenesis by inducing generation of autoantibody producing plasma cells, while cTh17 cells largely related to inflammation. Tfh cells and its cytokine IL-21 may also steer T cell differentiation into Th17 cells which secrete the pro-inflammatory cytokine IL-17 and contribute to inflammation in RA.

Published
2017
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11. Fibromyalgia: can online cognitive behavioral therapy help?

Author

Gwendoline, Menga, Sharon, Ing, Omar, Khan, Bobby, Dupre, Adriana C, Dornelles, Anika, Alarakhia, William, Davis, Jerald, Zakem, Tamika, Webb-Detiege, Eve, Scopelitis, and Robert, Quinet

Subjects
Original Research
Abstract

Cognitive behavioral therapy (CBT) has proven useful in treating fibromyalgia, depression, and anxiety. Computerized delivery of CBT allows increased access to such therapy. This study assessed the effect of internet-based CBT on Fibromyalgia Impact Questionnaire (FIQ) composite scores and tender point assessments.This 12-week randomized controlled trial included patients ≥18 years of age with 1990 American College of Rheumatology criteria for fibromyalgia and mild to moderate depression and anxiety. A total of 56 subjects were randomized into either a 6-week internet-based CBT group (MoodGYM) or a control group (standard care). We evaluated patients in both groups at 1-, 6-, and 12-week follow-up. The primary outcome measure was change in FIQ composite score. A secondary outcome measure was change in tender point assessment.The mean age of study participants was 55 years, and 88% were female. Mean FIQ scores were significantly lower in the MoodGYM group compared to the control group (P0.05 for group differences at 6 and 12 weeks). Mean tender point scores were also significantly lower in the MoodGYM group (P0.001 at 6 and 12 weeks). We found no significant difference in the FIQ scores across the 3 timepoints in the MoodGYM group, but tender points showed a significant negative trend from baseline to 12-week follow-up.Patients in the internet-based MoodGYM CBT program had lower FIQ and tender point scores at 6- and 12-week follow-up. Internet-based CBT could be beneficial in the treatment of mild to moderate depression and anxiety in patients with fibromyalgia by allowing increased access to CBT.

Published
2014

12. A novel paradigm in the clinical context of rheumatoid arthritis: role of Tfh and Th17 Cells in autoimmunity

Author

Xin Zhang, Magdalena Budziakowska, Arif Shahzad, Jerald Zakem, Zongbing You, William Davis, and Robert Quinet

Subjects
Immunology, Immunology and Allergy
Abstract

Introduction Rheumatoid Arthritis (RA) is an autoimmune disease characterized by chronic inflammation of synovium causing progressive joint destruction. Recently, T follicular helper (Tfh) cells and Th17 cells have emerged as novel T cell subsets controlling autoimmunity. Identifying their roles may break the traditional Th1/Th2 axis dichotomy and bridge knowledge gap of T cell lineages on RA immunopathogenesis. We examined the frequency of circulating Tfh (cTfh) and cTh17 cells in RA patients, and investigated their correlation with disease activity, autoantibody level, and inflammation. Methods Peripheral blood was collected from 51 RA patients and healthy donors. RA patients were divided into remission (2.6) based on disease activity score (DAS-28). Clinic parameters including Rheumatoid Factor (RF), Anti-CCP, ESR and CRP were obtained. The frequency of cTfh, cTh17 cells, and plasmablasts were measured by flow cytometry. Correlation of the frequency of cTfh and cTh17 cells with DAS-28, plasmablasts, and clinic parameters were statistically determined. Results Both cTfh and cTh17 cells were significantly increased in RA patients, expecially in active patients comparing to healthy donors (p Conclusions Tfh cells may contribute to B cell differentiation and autoantibody production, while Th17 cells may involve in the inflamation and pathogenesis of RA. Thus, disrupting the signals provided by Tfh and Th17 cells may offer new therapeutic stategies for active RA patients.

Published
2016
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13. Identification of follicular helper T cells as a novel cell population potentially involved in the pathogenesis of Rheumatoid Arthritis (HUM3P.251)

Author

Xin Zhang, Shikha Singla, Jerry Pound, Jerald Zakem, Kismet Collin, Tamika Webb-Detiege, William Davis, and Robert Quinet

Subjects
Immunology, Immunology and Allergy
Abstract

Background. RA is an autoimmune disease characterized by chronic inflammation of the synovium, causing progressive joint destruction. The treatment for RA is largely based on the clinic manifestations, which are remote from the fundamental pathophysiologic defects. Identification of cellular subsets or biomarkers is a necessary first step toward more accurate prognosis and better therapeutic decisions. Here, we identified a novel T cell subset, follicular helper T cells (Tfh) in RA patients, and examined the hypothesis that Tfh cells may account for RA pathogenesis by providing a fostering environment for self-reactive B cells, resulting in autoantibody production. Methods. Peripheral blood was collected from 26 RA patients and healthy donors. Synovial fluid from actively inflamed joints of RA patients was also collected. Clinical disease activity (DAS-28) and serum laboratory results were obtained. Tfh cells were defined by their signature surface markers via flow cytometry. IL-21 expression and plasmablasts were measured by intracellular staining. Results. A novel T cell subset with Tfh cell signature molecule and cytokine was expanded in the peripheral blood of active RA patients. The percentage of Tfh cells correlated positively with the level of pathogenic auto-antibody (anti-CCP) and disease activity. Conclusions. Circulating Tfh cells may serve as a biomarker of pathogenesis in RA patients. Targeting RA-Tfh cells may provide earlier and precise treatment strategies.

Published
2015
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14. Circulating T helper cells with T follicular helper cell phenotype renders the autoantibody generation in patients with systemic lupus erythematosus (HUM7P.304)

Author

Xin Zhang, Elvira Lindwall, Carl Gauthier, Minzi Chen, Omar Khan, Yong Sung Choi, Jerald Zakem, and Robert Quinet

Subjects
Immunology, Immunology and Allergy
Abstract

SLE is a chronic autoimmune disease characterized by autoreactive B cells and autoantibody production. Follicular helper T (Tfh) cells, a T cell subset located in the germinal center (GC) of lymphoid organs, is a key participant regulating B cell tolerance and antibody production. To identify the role of circulating Tfh (cTfh) cells in SLE, we examined their phenotype and function on supporting antibody production, and their correlation with autoantibody level and disease activity. Peripheral blood was collected from 29 SLE patients and age/gender-matched healthy donors. Tonsils from non-SLE controls were used to extract GC-Tfh cells. Tfh cells were defined by their signature surface markers (CXCR5, ICOS, CD57, and PD-1) via flow cytometry. IL-21 expression was measured by real-time PCR and intracellular staining. Tfh cells, non-Tfh cells were purified by MACS columns and co-cultured with B cells. IgG in the culture supernatant was detected by ELISA. Our results showed that cTfh cells in SLE patients expressed GC-Tfh signature molecules and IL-21 and were capable of driving B cells differentiate into plasma cells in vitro. The elevated frequency of cTfh cells correlated positively with levels of circulating plasmablasts, serum anti-dsDNA Ab and ANA. Our data suggests that the increased cTfh cells in SLE patients share phenotypic and functional properties with GC-Tfh cells. Tfh cells may serve as perpetrator to the pathogenesis in SLE patients and target for novel treatment.

Published
2014
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