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1. Variable immunodeficiency study: Evaluation of two European cohorts within a variety of clinical phenotypes

Author

Guevara-Hoyer, Kissy et al., Neves, Esmeralda, Gil López, Celia, Recio Hoyas, María José, Fernández Arquero, Miguel, Ramos Amador, José Tomás, Sánchez Ramón, Silvia María, Guevara-Hoyer, Kissy et al., Neves, Esmeralda, Gil López, Celia, Recio Hoyas, María José, Fernández Arquero, Miguel, Ramos Amador, José Tomás, and Sánchez Ramón, Silvia María

Abstract

Introduction: Given the wide heterogeneity of common variable immunodeficiency (CVID), several groups have proposed clinical and immunological classifications to better define follow-up and prognostic algorithms. The present study aims to validate recent clinical and laboratory algorithms, based on different combinations of CVID biomarkers, to provide more personalized treatment and follow-up strategies. Methods: We analysed clinical and immunological features of 80 patients with suspected or diagnosed CVID, in two reference centres of Portugal and Spain. Clinical manifestations were categorized into clinical phenotyping proposed by Chapel et al. [1] that included cytopenia; polyclonal lymphocytic infiltration; unexplained enteropathy; and no disease-related complications. Results: 76% of patients in our cohort entered one of the four categories of clinical phenotyping, without overlap (cytopenia; polyclonal lymphocytic infiltration; unexplained enteropathy; and no disease-related complications). The most prominent phenotype was "cytopenia" (40%) followed by "polyclonal lymphocytic infiltration" (19%). The remaining 24% patients of our cohort had overlap of 2 clinical phenotypes (cytopenia and unexplained enteropathy mainly). A delay of CVID diagnosis in more than 6 years presented 3.7-fold higher risk of developing lymphoproliferation and/or malignancy (p < 0.05), and was associated with increased CD8+CD45RO + T-lymphocytes (p < 0.05). An association between decreased switched-memory B cells with lymphoproliferation and malignancy was observed (p < 0.03 and p < 0.05, respectively). CD4 + T-lymphocytopenia correlated with autoimmune phenotype, with 30% prevalence (p < 0.05). HLA-DR7 expression was related to CVID onset in early life in our patients (13 vs 25 years), and DQ2.5 or DQ2.2 with unexplained enteropathy (p < 0.05). Conclusions: The phenotypic and genetic study is crucial for an adequate clinical orientation of CVID patients. In these two independent cohort, European Federation of Immunological Societies (EFIS), Depto. de Inmunología, Oftalmología y ORL, Fac. de Medicina, TRUE, pub

Published
2024

2. Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases

Author

Barturen, Guillermo, Babaei, Sepideh, Catala-Moll, Francesc, Martinez-Bueno, Manuel, Makowska, Zuzanna, Martorell-Marugan, Jordi, Carmona-Saez, Pedro, Toro-Dominguez, Daniel, Carnero-Montoro, Elena, Teruel, Maria, Kerick, Martin, Acosta-Herrera, Marialbert, Le Lann, Lucas, Jamin, Christophe, Rodriguez-Ubreva, Javier, Garcia-Gomez, Antonio, Kageyama, Jorge, Buttgereit, Anne, Hayat, Sikander, Mueller, Joerg, Lesche, Ralf, Hernandez-Fuentes, Maria, Juarez, Maria, Rowley, Tania, White, Ian, Maranon, Concepcion, Gomes Anjos, Tania, Varela, Nieves, Aguilar-Quesada, Rocio, Garrancho, Francisco Javier, Lopez-Berrio, Antonio, Rodriguez Maresca, Manuel, Navarro-Linares, Hector, Almeida, Isabel, Azevedo, Nancy, Brandao, Mariana, Campar, Ana, Faria, Raquel, Farinha, Fatima, Marinho, Antonio, Neves, Esmeralda, Tavares, Ana, Vasconcelos, Carlos, Trombetta, Elena, Montanelli, Gaia, Vigone, Barbara, Alvarez-Errico, Damiana, Li, Tianlu, Thiagaran, Divya, Blanco Alonso, Ricardo, Corrales Martinez, Alfonso, Genre, Fernanda, Lopez Mejias, Raquel, Gonzalez-Gay, Miguel A., Remuzgo, Sara, Ubilla Garcia, Begona, Cervera, Ricard, Espinosa, Gerard, Rodriguez-Pinto, Ignasi, De Langhe, Ellen, Cremer, Jonathan, Lories, Rik, Belz, Doreen, Hunzelmann, Nicolas, Baerlecken, Niklas, Kniesch, Katja, Witte, Torsten, Lehner, Michaela, Stummvoll, Georg, Zauner, Michael, Aguirre-Zamorano, Maria Angeles, Barbarroja, Nuria, Castro-Villegas, Maria Carmen, Collantes-Estevez, Eduardo, de Ramon, Enrique, Diaz Quintero, Isabel, Escudero-Contreras, Alejandro, Fernandez Roldan, Maria Concepcion, Jimenez Gomez, Yolanda, Jimenez Moleon, Inmaculada, Lopez-Pedrera, Rosario, Ortega-Castro, Rafaela, Ortego, Norberto, Raya, Enrique, Artusi, Carolina, Gerosa, Maria, Meroni, Pier Luigi, Schioppo, Tommaso, De Groof, Aurelie, Ducreux, Julie, Lauwerys, Bernard, Maudoux, Anne-Lise, Cornec, Divi, Devauchelle-Pensec, Valerie, Jousse-Joulin, Sandrine, Jouve, Pierre-Emmanuel, Rouviere, Benedicte, Saraux, Alain, Simon, Quentin, Alvarez, Montserrat, Chizzolini, Carlo, Dufour, Aleksandra, Wynar, Donatienne, Balog, Attila, Bocskai, Marta, Deak, Magdolna, Dulic, Sonja, Kadar, Gabriella, Kovacs, Laszlo, Cheng, Qingyu, Gerl, Velia, Hiepe, Falk, Khodadadi, Laleh, Thiel, Silvia, de Rinaldis, Emanuele, Rao, Sambasiva, Benschop, Robert J., Chamberlain, Chris, Dow, Ernst R., Ioannou, Yiannis, Laigle, Laurence, Marovac, Jacqueline, Wojcik, Jerome, Renaudineau, Yves, Borghi, Maria Orietta, Frostegard, Johan, Martin, Javier, Beretta, Lorenzo, Ballestar, Esteban, McDonald, Fiona, Pers, Jacques-Olivier, Alarcon-Riquelme, Marta E., Barturen, Guillermo, Babaei, Sepideh, Catala-Moll, Francesc, Martinez-Bueno, Manuel, Makowska, Zuzanna, Martorell-Marugan, Jordi, Carmona-Saez, Pedro, Toro-Dominguez, Daniel, Carnero-Montoro, Elena, Teruel, Maria, Kerick, Martin, Acosta-Herrera, Marialbert, Le Lann, Lucas, Jamin, Christophe, Rodriguez-Ubreva, Javier, Garcia-Gomez, Antonio, Kageyama, Jorge, Buttgereit, Anne, Hayat, Sikander, Mueller, Joerg, Lesche, Ralf, Hernandez-Fuentes, Maria, Juarez, Maria, Rowley, Tania, White, Ian, Maranon, Concepcion, Gomes Anjos, Tania, Varela, Nieves, Aguilar-Quesada, Rocio, Garrancho, Francisco Javier, Lopez-Berrio, Antonio, Rodriguez Maresca, Manuel, Navarro-Linares, Hector, Almeida, Isabel, Azevedo, Nancy, Brandao, Mariana, Campar, Ana, Faria, Raquel, Farinha, Fatima, Marinho, Antonio, Neves, Esmeralda, Tavares, Ana, Vasconcelos, Carlos, Trombetta, Elena, Montanelli, Gaia, Vigone, Barbara, Alvarez-Errico, Damiana, Li, Tianlu, Thiagaran, Divya, Blanco Alonso, Ricardo, Corrales Martinez, Alfonso, Genre, Fernanda, Lopez Mejias, Raquel, Gonzalez-Gay, Miguel A., Remuzgo, Sara, Ubilla Garcia, Begona, Cervera, Ricard, Espinosa, Gerard, Rodriguez-Pinto, Ignasi, De Langhe, Ellen, Cremer, Jonathan, Lories, Rik, Belz, Doreen, Hunzelmann, Nicolas, Baerlecken, Niklas, Kniesch, Katja, Witte, Torsten, Lehner, Michaela, Stummvoll, Georg, Zauner, Michael, Aguirre-Zamorano, Maria Angeles, Barbarroja, Nuria, Castro-Villegas, Maria Carmen, Collantes-Estevez, Eduardo, de Ramon, Enrique, Diaz Quintero, Isabel, Escudero-Contreras, Alejandro, Fernandez Roldan, Maria Concepcion, Jimenez Gomez, Yolanda, Jimenez Moleon, Inmaculada, Lopez-Pedrera, Rosario, Ortega-Castro, Rafaela, Ortego, Norberto, Raya, Enrique, Artusi, Carolina, Gerosa, Maria, Meroni, Pier Luigi, Schioppo, Tommaso, De Groof, Aurelie, Ducreux, Julie, Lauwerys, Bernard, Maudoux, Anne-Lise, Cornec, Divi, Devauchelle-Pensec, Valerie, Jousse-Joulin, Sandrine, Jouve, Pierre-Emmanuel, Rouviere, Benedicte, Saraux, Alain, Simon, Quentin, Alvarez, Montserrat, Chizzolini, Carlo, Dufour, Aleksandra, Wynar, Donatienne, Balog, Attila, Bocskai, Marta, Deak, Magdolna, Dulic, Sonja, Kadar, Gabriella, Kovacs, Laszlo, Cheng, Qingyu, Gerl, Velia, Hiepe, Falk, Khodadadi, Laleh, Thiel, Silvia, de Rinaldis, Emanuele, Rao, Sambasiva, Benschop, Robert J., Chamberlain, Chris, Dow, Ernst R., Ioannou, Yiannis, Laigle, Laurence, Marovac, Jacqueline, Wojcik, Jerome, Renaudineau, Yves, Borghi, Maria Orietta, Frostegard, Johan, Martin, Javier, Beretta, Lorenzo, Ballestar, Esteban, McDonald, Fiona, Pers, Jacques-Olivier, and Alarcon-Riquelme, Marta E.

Abstract

Objective Clinical heterogeneity, a hallmark of systemic autoimmune diseases, impedes early diagnosis and effective treatment, issues that may be addressed if patients could be classified into groups defined by molecular pattern. This study was undertaken to identify molecular clusters for reclassifying systemic autoimmune diseases independently of clinical diagnosis. Methods Unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data on 955 patients with 7 systemic autoimmune diseases and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed up for 6 or 14 months to validate the results and analyze whether or not cluster assignment changed over time. Results Four clusters were identified and validated. Three were pathologic, representing inflammatory, lymphoid, and interferon patterns. Each included all diagnoses and was defined by genetic, clinical, serologic, and cellular features. A fourth cluster with no specific molecular pattern was associated with low disease activity and included healthy controls. A longitudinal and independent inception cohort showed a relapse-remission pattern, where patients remained in their pathologic cluster, moving only to the healthy one, thus showing that the molecular clusters remained stable over time and that single pathogenic molecular signatures characterized each individual patient. Conclusion Patients with systemic autoimmune diseases can be jointly stratified into 3 stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of nonresponse to therapy, marking a paradigm shift in our view of systemic autoimmune diseases.

Published
2021

3. A new molecular classification to drive precision treatment strategies in primary Sjogren's syndrome

Author

Soret, Perrine, Le Dantec, Christelle, Desvaux, Emiko, Foulquier, Nathan, Chassagnol, Bastien, Hubert, Sandra, Jamin, Christophe, Barturen, Guillermo, Desachy, Guillaume, Devauchelle-Pensec, Valerie, Boudjeniba, Cheiema, Cornec, Divi, Saraux, Alain, Jousse-Joulin, Sandrine, Barbarroja, Nuria, Rodriguez-Pinto, Ignasi, De Langhe, Ellen, Beretta, Lorenzo, Chizzolini, Carlo, Kovacs, Laszlo, Witte, Torsten, Bettacchioli, Eleonore, Buttgereit, Anne, Makowska, Zuzanna, Lesche, Ralf, Orietta Borghi, Maria, Martin, Javier, Courtade-Gaiani, Sophie, Xuereb, Laura, Guedj, Mickael, Moingeon, Philippe, Alarcon-Riquelme, Marta E., Laigle, Laurence, Pers, Jacques-Olivier, Vigone, Barbara, Lauwerys, Bernard, Ducreux, Julie, Maudoux, Anne-Lise, Vasconcelos, Carlos, Tavares, Ana, Neves, Esmeralda, Faria, Raquel, Brandao, Mariana, Campar, Ana, Marinho, Antonio, Farinha, Fatima, Almeida, Isabel, Gonzalez-Gay Mantecon, Miguel Angel, Alonso, Ricardo Blanco, Martinez, Alfonso Corrales, Cervera, Ricard, Espinosa, Gerard, Lories, Rik, Hunzelmann, Nicolas, Belz, Doreen, Baerlecken, Niklas, Stummvoll, Georg, Zauner, Michael, Lehner, Michaela, Collantes, Eduardo, Ortega-Castro, Rafaela, Angeles Aguirre-Zamorano, Ma, Carmen Castro-Villegas, Ma, Jimenez Gomez, Yolanda, Ortego, Norberto, Fernandez Roldan, Maria Concepcion, Raya, Enrique, Moleon, Inmaculada Jimenez, de Ramon, Enrique, Quintero, Isabel Diaz, Meroni, Pier Luigi, Gerosa, Maria, Schioppo, Tommaso, Artusi, Carolina, Dulic, Sonja, Kadar, Gabriella, Hiepe, Falk, Gerl, Velia, Thiel, Silvia, Maresca, Manuel Rodriguez, Lopez-Berrio, Antonio, Aguilar-Quesada, Rocio, Navarro-Linares, Hector, Ioannou, Yiannis, Chamberlain, Chris, Marovac, Jacqueline, Alarcon Riquelme, Marta, Gomes Anjos, Tania, Maranon, Concepcion, Le Lann, Lucas, Simon, Quentin, Rouviere, Benedicte, Varela, Nieves, Muchmore, Brian, Dufour, Aleksandra, Alvarez, Montserrat, Cremer, Jonathan, Lopez-Pedrera, Chary, Ger, Velia, Khodadadi, Laleh, Cheng, Qingyu, De Groof, Aurelie, Trombetta, Elena, Li, Tianlu, Alvarez-Errico, Damiana, Kniesch, Katja, Azevedo, Nancy, Rao, Sambasiva, Jouve, Pierre-Emmanuel, Soret, Perrine, Le Dantec, Christelle, Desvaux, Emiko, Foulquier, Nathan, Chassagnol, Bastien, Hubert, Sandra, Jamin, Christophe, Barturen, Guillermo, Desachy, Guillaume, Devauchelle-Pensec, Valerie, Boudjeniba, Cheiema, Cornec, Divi, Saraux, Alain, Jousse-Joulin, Sandrine, Barbarroja, Nuria, Rodriguez-Pinto, Ignasi, De Langhe, Ellen, Beretta, Lorenzo, Chizzolini, Carlo, Kovacs, Laszlo, Witte, Torsten, Bettacchioli, Eleonore, Buttgereit, Anne, Makowska, Zuzanna, Lesche, Ralf, Orietta Borghi, Maria, Martin, Javier, Courtade-Gaiani, Sophie, Xuereb, Laura, Guedj, Mickael, Moingeon, Philippe, Alarcon-Riquelme, Marta E., Laigle, Laurence, Pers, Jacques-Olivier, Vigone, Barbara, Lauwerys, Bernard, Ducreux, Julie, Maudoux, Anne-Lise, Vasconcelos, Carlos, Tavares, Ana, Neves, Esmeralda, Faria, Raquel, Brandao, Mariana, Campar, Ana, Marinho, Antonio, Farinha, Fatima, Almeida, Isabel, Gonzalez-Gay Mantecon, Miguel Angel, Alonso, Ricardo Blanco, Martinez, Alfonso Corrales, Cervera, Ricard, Espinosa, Gerard, Lories, Rik, Hunzelmann, Nicolas, Belz, Doreen, Baerlecken, Niklas, Stummvoll, Georg, Zauner, Michael, Lehner, Michaela, Collantes, Eduardo, Ortega-Castro, Rafaela, Angeles Aguirre-Zamorano, Ma, Carmen Castro-Villegas, Ma, Jimenez Gomez, Yolanda, Ortego, Norberto, Fernandez Roldan, Maria Concepcion, Raya, Enrique, Moleon, Inmaculada Jimenez, de Ramon, Enrique, Quintero, Isabel Diaz, Meroni, Pier Luigi, Gerosa, Maria, Schioppo, Tommaso, Artusi, Carolina, Dulic, Sonja, Kadar, Gabriella, Hiepe, Falk, Gerl, Velia, Thiel, Silvia, Maresca, Manuel Rodriguez, Lopez-Berrio, Antonio, Aguilar-Quesada, Rocio, Navarro-Linares, Hector, Ioannou, Yiannis, Chamberlain, Chris, Marovac, Jacqueline, Alarcon Riquelme, Marta, Gomes Anjos, Tania, Maranon, Concepcion, Le Lann, Lucas, Simon, Quentin, Rouviere, Benedicte, Varela, Nieves, Muchmore, Brian, Dufour, Aleksandra, Alvarez, Montserrat, Cremer, Jonathan, Lopez-Pedrera, Chary, Ger, Velia, Khodadadi, Laleh, Cheng, Qingyu, De Groof, Aurelie, Trombetta, Elena, Li, Tianlu, Alvarez-Errico, Damiana, Kniesch, Katja, Azevedo, Nancy, Rao, Sambasiva, and Jouve, Pierre-Emmanuel

Abstract

There is currently no approved treatment for primary Sjogren's syndrome, a disease that primarily affects adult women. The difficulty in developing effective therapies is -in part- because of the heterogeneity in the clinical manifestation and pathophysiology of the disease. Finding common molecular signatures among patient subgroups could improve our understanding of disease etiology, and facilitate the development of targeted therapeutics. Here, we report, in a cross-sectional cohort, a molecular classification scheme for Sjogren's syndrome patients based on the multi-omic profiling of whole blood samples from a European cohort of over 300 patients, and a similar number of age and gender-matched healthy volunteers. Using transcriptomic, genomic, epigenetic, cytokine expression and flow cytometry data, combined with clinical parameters, we identify four groups of patients with distinct patterns of immune dysregulation. The biomarkers we identify can be used by machine learning classifiers to sort future patients into subgroups, allowing the re-evaluation of response to treatments in clinical trials. Sjogren's syndrome, a disease that primarily affects women, is poorly understood. Here, the authors combine data from a large cohort of patients and healthy controls to identify biomarkers that distinguish patient subgroups to improve our understanding of the disease and facilitate drug development.

Published
2021

4. Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases.

Author

UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Alarcón-Riquelme, Marta E, Benschop, Robert J, Balog, Attila, Bocskai, Márta, Deák, Magdolna, Dulic, Sonja, Kádár, Gabriella, Kovács, László, Cheng, Qingyu, Gerl, Velia, Hiepe, Falk, Khodadadi, Laleh, Thiel, Silvia, de Rinaldis, Emanuele, Rao, Sambasiva, Chamberlain, Chris, Dufour, Aleksandra, Dow, Ernst R, Ioannou, Yiannis, Laigle, Laurence, Marovac, Jacqueline, Wojcik, Jerome, Renaudineau, Yves, Borghi, Maria Orietta, Frostegård, Johan, Martín, Javier, Beretta, Lorenzo, Ballestar, Esteban, McDonald, Fiona, Pers, Jacques-Olivier, Wynar, Donatienne, Barturen, Guillermo, Babaei, Sepideh, Català-Moll, Francesc, Martínez-Bueno, Manuel, Makowska, Zuzanna, Martorell-Marugán, Jordi, Carmona-Sáez, Pedro, Toro-Domínguez, Daniel, Carnero-Montoro, Elena, Teruel, María, Kerick, Martin, Acosta-Herrera, Marialbert, Le Lann, Lucas, Jamin, Christophe, Rodríguez-Ubreva, Javier, García-Gómez, Antonio, Kageyama, Jorge, Buttgereit, Anne, Hayat, Sikander, Mueller, Joerg, Lesche, Ralf, Hernandez-Fuentes, Maria, Juarez, Maria, Rowley, Tania, White, Ian, Marañón, Concepción, Gomes Anjos, Tania, Varela, Nieves, Aguilar-Quesada, Rocío, Garrancho, Francisco Javier, López-Berrio, Antonio, Rodriguez Maresca, Manuel, Navarro-Linares, Héctor, Almeida, Isabel, Azevedo, Nancy, Brandão, Mariana, Campar, Ana, Faria, Raquel, Farinha, Fátima, Marinho, António, Neves, Esmeralda, Tavares, Ana, Vasconcelos, Carlos, Trombetta, Elena, Montanelli, Gaia, Vigone, Barbara, Alvarez-Errico, Damiana, Li, Tianlu, Thiagaran, Divya, Blanco Alonso, Ricardo, Corrales Martínez, Alfonso, Genre, Fernanda, López Mejías, Raquel, Gonzalez-Gay, Miguel A, Remuzgo, Sara, Ubilla Garcia, Begoña, Cervera, Ricard, Espinosa, Gerard, Rodríguez-Pintó, Ignasi, De Langhe, Ellen, Cremer, Jonathan, Lories, Rik, Belz, Doreen, Hunzelmann, Nicolas, Baerlecken, Niklas, Kniesch, Katja, Witte, Torsten, Lehner, Michaela, Stummvoll, Georg, Zauner, Michael, Aguirre-Zamorano, Maria Angeles, Barbarroja, Nuria, Castro-Villegas, Maria Carmen, Collantes-Estevez, Eduardo, de Ramon, Enrique, Díaz Quintero, Isabel, Escudero-Contreras, Alejandro, Fernández Roldán, María Concepción, Jiménez Gómez, Yolanda, Jiménez Moleón, Inmaculada, Lopez-Pedrera, Rosario, Ortega-Castro, Rafaela, Ortego, Norberto, Raya, Enrique, Artusi, Carolina, Gerosa, Maria, Meroni, Pier Luigi, Schioppo, Tommaso, De Groof, Aurélie, Ducreux, Julie, Lauwerys, Bernard, Maudoux, Anne-Lise, Cornec, Divi, Devauchelle-Pensec, Valérie, Jousse-Joulin, Sandrine, Jouve, Pierre-Emmanuel, Rouvière, Bénédicte, Saraux, Alain, Simon, Quentin, Alvarez, Montserrat, Chizzolini, Carlo, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Alarcón-Riquelme, Marta E, Benschop, Robert J, Balog, Attila, Bocskai, Márta, Deák, Magdolna, Dulic, Sonja, Kádár, Gabriella, Kovács, László, Cheng, Qingyu, Gerl, Velia, Hiepe, Falk, Khodadadi, Laleh, Thiel, Silvia, de Rinaldis, Emanuele, Rao, Sambasiva, Chamberlain, Chris, Dufour, Aleksandra, Dow, Ernst R, Ioannou, Yiannis, Laigle, Laurence, Marovac, Jacqueline, Wojcik, Jerome, Renaudineau, Yves, Borghi, Maria Orietta, Frostegård, Johan, Martín, Javier, Beretta, Lorenzo, Ballestar, Esteban, McDonald, Fiona, Pers, Jacques-Olivier, Wynar, Donatienne, Barturen, Guillermo, Babaei, Sepideh, Català-Moll, Francesc, Martínez-Bueno, Manuel, Makowska, Zuzanna, Martorell-Marugán, Jordi, Carmona-Sáez, Pedro, Toro-Domínguez, Daniel, Carnero-Montoro, Elena, Teruel, María, Kerick, Martin, Acosta-Herrera, Marialbert, Le Lann, Lucas, Jamin, Christophe, Rodríguez-Ubreva, Javier, García-Gómez, Antonio, Kageyama, Jorge, Buttgereit, Anne, Hayat, Sikander, Mueller, Joerg, Lesche, Ralf, Hernandez-Fuentes, Maria, Juarez, Maria, Rowley, Tania, White, Ian, Marañón, Concepción, Gomes Anjos, Tania, Varela, Nieves, Aguilar-Quesada, Rocío, Garrancho, Francisco Javier, López-Berrio, Antonio, Rodriguez Maresca, Manuel, Navarro-Linares, Héctor, Almeida, Isabel, Azevedo, Nancy, Brandão, Mariana, Campar, Ana, Faria, Raquel, Farinha, Fátima, Marinho, António, Neves, Esmeralda, Tavares, Ana, Vasconcelos, Carlos, Trombetta, Elena, Montanelli, Gaia, Vigone, Barbara, Alvarez-Errico, Damiana, Li, Tianlu, Thiagaran, Divya, Blanco Alonso, Ricardo, Corrales Martínez, Alfonso, Genre, Fernanda, López Mejías, Raquel, Gonzalez-Gay, Miguel A, Remuzgo, Sara, Ubilla Garcia, Begoña, Cervera, Ricard, Espinosa, Gerard, Rodríguez-Pintó, Ignasi, De Langhe, Ellen, Cremer, Jonathan, Lories, Rik, Belz, Doreen, Hunzelmann, Nicolas, Baerlecken, Niklas, Kniesch, Katja, Witte, Torsten, Lehner, Michaela, Stummvoll, Georg, Zauner, Michael, Aguirre-Zamorano, Maria Angeles, Barbarroja, Nuria, Castro-Villegas, Maria Carmen, Collantes-Estevez, Eduardo, de Ramon, Enrique, Díaz Quintero, Isabel, Escudero-Contreras, Alejandro, Fernández Roldán, María Concepción, Jiménez Gómez, Yolanda, Jiménez Moleón, Inmaculada, Lopez-Pedrera, Rosario, Ortega-Castro, Rafaela, Ortego, Norberto, Raya, Enrique, Artusi, Carolina, Gerosa, Maria, Meroni, Pier Luigi, Schioppo, Tommaso, De Groof, Aurélie, Ducreux, Julie, Lauwerys, Bernard, Maudoux, Anne-Lise, Cornec, Divi, Devauchelle-Pensec, Valérie, Jousse-Joulin, Sandrine, Jouve, Pierre-Emmanuel, Rouvière, Bénédicte, Saraux, Alain, Simon, Quentin, Alvarez, Montserrat, and Chizzolini, Carlo

Abstract

OBJECTIVE: Clinical heterogeneity, a hallmark of systemic autoimmune diseases, impedes early diagnosis and effective treatment, issues that may be addressed if patients could be classified into groups defined by molecular pattern. This study was undertaken to identify molecular clusters for reclassifying systemic autoimmune diseases independently of clinical diagnosis. METHODS: Unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data on 955 patients with 7 systemic autoimmune diseases and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed up for 6 or 14 months to validate the results and analyze whether or not cluster assignment changed over time. RESULTS: Four clusters were identified and validated. Three were pathologic, representing "inflammatory," "lymphoid," and "interferon" patterns. Each included all diagnoses and was defined by genetic, clinical, serologic, and cellular features. A fourth cluster with no specific molecular pattern was associated with low disease activity and included healthy controls. A longitudinal and independent inception cohort showed a relapse-remission pattern, where patients remained in their pathologic cluster, moving only to the healthy one, thus showing that the molecular clusters remained stable over time and that single pathogenic molecular signatures characterized each individual patient. CONCLUSION: Patients with systemic autoimmune diseases can be jointly stratified into 3 stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of nonresponse to therapy, marking a paradigm shift in our view of systemic autoimmune diseases.

Published
2021

5. Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases

Author

Barturen, Guillermo, Babaei, Sepideh, Catala-Moll, Francesc, Martinez-Bueno, Manuel, Makowska, Zuzanna, Martorell-Marugan, Jordi, Carmona-Saez, Pedro, Toro-Dominguez, Daniel, Carnero-Montoro, Elena, Teruel, Maria, Kerick, Martin, Acosta-Herrera, Marialbert, Le Lann, Lucas, Jamin, Christophe, Rodriguez-Ubreva, Javier, Garcia-Gomez, Antonio, Kageyama, Jorge, Buttgereit, Anne, Hayat, Sikander, Mueller, Joerg, Lesche, Ralf, Hernandez-Fuentes, Maria, Juarez, Maria, Rowley, Tania, White, Ian, Maranon, Concepcion, Gomes Anjos, Tania, Varela, Nieves, Aguilar-Quesada, Rocio, Garrancho, Francisco Javier, Lopez-Berrio, Antonio, Rodriguez Maresca, Manuel, Navarro-Linares, Hector, Almeida, Isabel, Azevedo, Nancy, Brandao, Mariana, Campar, Ana, Faria, Raquel, Farinha, Fatima, Marinho, Antonio, Neves, Esmeralda, Tavares, Ana, Vasconcelos, Carlos, Trombetta, Elena, Montanelli, Gaia, Vigone, Barbara, Alvarez-Errico, Damiana, Li, Tianlu, Thiagaran, Divya, Blanco Alonso, Ricardo, Corrales Martinez, Alfonso, Genre, Fernanda, Lopez Mejias, Raquel, Gonzalez-Gay, Miguel A., Remuzgo, Sara, Ubilla Garcia, Begona, Cervera, Ricard, Espinosa, Gerard, Rodriguez-Pinto, Ignasi, De Langhe, Ellen, Cremer, Jonathan, Lories, Rik, Belz, Doreen, Hunzelmann, Nicolas, Baerlecken, Niklas, Kniesch, Katja, Witte, Torsten, Lehner, Michaela, Stummvoll, Georg, Zauner, Michael, Aguirre-Zamorano, Maria Angeles, Barbarroja, Nuria, Castro-Villegas, Maria Carmen, Collantes-Estevez, Eduardo, de Ramon, Enrique, Diaz Quintero, Isabel, Escudero-Contreras, Alejandro, Fernandez Roldan, Maria Concepcion, Jimenez Gomez, Yolanda, Jimenez Moleon, Inmaculada, Lopez-Pedrera, Rosario, Ortega-Castro, Rafaela, Ortego, Norberto, Raya, Enrique, Artusi, Carolina, Gerosa, Maria, Meroni, Pier Luigi, Schioppo, Tommaso, De Groof, Aurelie, Ducreux, Julie, Lauwerys, Bernard, Maudoux, Anne-Lise, Cornec, Divi, Devauchelle-Pensec, Valerie, Jousse-Joulin, Sandrine, Jouve, Pierre-Emmanuel, Rouviere, Benedicte, Saraux, Alain, Simon, Quentin, Alvarez, Montserrat, Chizzolini, Carlo, Dufour, Aleksandra, Wynar, Donatienne, Balog, Attila, Bocskai, Marta, Deak, Magdolna, Dulic, Sonja, Kadar, Gabriella, Kovacs, Laszlo, Cheng, Qingyu, Gerl, Velia, Hiepe, Falk, Khodadadi, Laleh, Thiel, Silvia, de Rinaldis, Emanuele, Rao, Sambasiva, Benschop, Robert J., Chamberlain, Chris, Dow, Ernst R., Ioannou, Yiannis, Laigle, Laurence, Marovac, Jacqueline, Wojcik, Jerome, Renaudineau, Yves, Borghi, Maria Orietta, Frostegard, Johan, Martin, Javier, Beretta, Lorenzo, Ballestar, Esteban, McDonald, Fiona, Pers, Jacques-Olivier, Alarcon-Riquelme, Marta E., Barturen, Guillermo, Babaei, Sepideh, Catala-Moll, Francesc, Martinez-Bueno, Manuel, Makowska, Zuzanna, Martorell-Marugan, Jordi, Carmona-Saez, Pedro, Toro-Dominguez, Daniel, Carnero-Montoro, Elena, Teruel, Maria, Kerick, Martin, Acosta-Herrera, Marialbert, Le Lann, Lucas, Jamin, Christophe, Rodriguez-Ubreva, Javier, Garcia-Gomez, Antonio, Kageyama, Jorge, Buttgereit, Anne, Hayat, Sikander, Mueller, Joerg, Lesche, Ralf, Hernandez-Fuentes, Maria, Juarez, Maria, Rowley, Tania, White, Ian, Maranon, Concepcion, Gomes Anjos, Tania, Varela, Nieves, Aguilar-Quesada, Rocio, Garrancho, Francisco Javier, Lopez-Berrio, Antonio, Rodriguez Maresca, Manuel, Navarro-Linares, Hector, Almeida, Isabel, Azevedo, Nancy, Brandao, Mariana, Campar, Ana, Faria, Raquel, Farinha, Fatima, Marinho, Antonio, Neves, Esmeralda, Tavares, Ana, Vasconcelos, Carlos, Trombetta, Elena, Montanelli, Gaia, Vigone, Barbara, Alvarez-Errico, Damiana, Li, Tianlu, Thiagaran, Divya, Blanco Alonso, Ricardo, Corrales Martinez, Alfonso, Genre, Fernanda, Lopez Mejias, Raquel, Gonzalez-Gay, Miguel A., Remuzgo, Sara, Ubilla Garcia, Begona, Cervera, Ricard, Espinosa, Gerard, Rodriguez-Pinto, Ignasi, De Langhe, Ellen, Cremer, Jonathan, Lories, Rik, Belz, Doreen, Hunzelmann, Nicolas, Baerlecken, Niklas, Kniesch, Katja, Witte, Torsten, Lehner, Michaela, Stummvoll, Georg, Zauner, Michael, Aguirre-Zamorano, Maria Angeles, Barbarroja, Nuria, Castro-Villegas, Maria Carmen, Collantes-Estevez, Eduardo, de Ramon, Enrique, Diaz Quintero, Isabel, Escudero-Contreras, Alejandro, Fernandez Roldan, Maria Concepcion, Jimenez Gomez, Yolanda, Jimenez Moleon, Inmaculada, Lopez-Pedrera, Rosario, Ortega-Castro, Rafaela, Ortego, Norberto, Raya, Enrique, Artusi, Carolina, Gerosa, Maria, Meroni, Pier Luigi, Schioppo, Tommaso, De Groof, Aurelie, Ducreux, Julie, Lauwerys, Bernard, Maudoux, Anne-Lise, Cornec, Divi, Devauchelle-Pensec, Valerie, Jousse-Joulin, Sandrine, Jouve, Pierre-Emmanuel, Rouviere, Benedicte, Saraux, Alain, Simon, Quentin, Alvarez, Montserrat, Chizzolini, Carlo, Dufour, Aleksandra, Wynar, Donatienne, Balog, Attila, Bocskai, Marta, Deak, Magdolna, Dulic, Sonja, Kadar, Gabriella, Kovacs, Laszlo, Cheng, Qingyu, Gerl, Velia, Hiepe, Falk, Khodadadi, Laleh, Thiel, Silvia, de Rinaldis, Emanuele, Rao, Sambasiva, Benschop, Robert J., Chamberlain, Chris, Dow, Ernst R., Ioannou, Yiannis, Laigle, Laurence, Marovac, Jacqueline, Wojcik, Jerome, Renaudineau, Yves, Borghi, Maria Orietta, Frostegard, Johan, Martin, Javier, Beretta, Lorenzo, Ballestar, Esteban, McDonald, Fiona, Pers, Jacques-Olivier, and Alarcon-Riquelme, Marta E.

Abstract

Objective Clinical heterogeneity, a hallmark of systemic autoimmune diseases, impedes early diagnosis and effective treatment, issues that may be addressed if patients could be classified into groups defined by molecular pattern. This study was undertaken to identify molecular clusters for reclassifying systemic autoimmune diseases independently of clinical diagnosis. Methods Unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data on 955 patients with 7 systemic autoimmune diseases and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed up for 6 or 14 months to validate the results and analyze whether or not cluster assignment changed over time. Results Four clusters were identified and validated. Three were pathologic, representing inflammatory, lymphoid, and interferon patterns. Each included all diagnoses and was defined by genetic, clinical, serologic, and cellular features. A fourth cluster with no specific molecular pattern was associated with low disease activity and included healthy controls. A longitudinal and independent inception cohort showed a relapse-remission pattern, where patients remained in their pathologic cluster, moving only to the healthy one, thus showing that the molecular clusters remained stable over time and that single pathogenic molecular signatures characterized each individual patient. Conclusion Patients with systemic autoimmune diseases can be jointly stratified into 3 stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of nonresponse to therapy, marking a paradigm shift in our view of systemic autoimmune diseases.

Published
2021

6. A new molecular classification to drive precision treatment strategies in primary Sjogren's syndrome

Author

Soret, Perrine, Le Dantec, Christelle, Desvaux, Emiko, Foulquier, Nathan, Chassagnol, Bastien, Hubert, Sandra, Jamin, Christophe, Barturen, Guillermo, Desachy, Guillaume, Devauchelle-Pensec, Valerie, Boudjeniba, Cheiema, Cornec, Divi, Saraux, Alain, Jousse-Joulin, Sandrine, Barbarroja, Nuria, Rodriguez-Pinto, Ignasi, De Langhe, Ellen, Beretta, Lorenzo, Chizzolini, Carlo, Kovacs, Laszlo, Witte, Torsten, Bettacchioli, Eleonore, Buttgereit, Anne, Makowska, Zuzanna, Lesche, Ralf, Orietta Borghi, Maria, Martin, Javier, Courtade-Gaiani, Sophie, Xuereb, Laura, Guedj, Mickael, Moingeon, Philippe, Alarcon-Riquelme, Marta E., Laigle, Laurence, Pers, Jacques-Olivier, Vigone, Barbara, Lauwerys, Bernard, Ducreux, Julie, Maudoux, Anne-Lise, Vasconcelos, Carlos, Tavares, Ana, Neves, Esmeralda, Faria, Raquel, Brandao, Mariana, Campar, Ana, Marinho, Antonio, Farinha, Fatima, Almeida, Isabel, Gonzalez-Gay Mantecon, Miguel Angel, Alonso, Ricardo Blanco, Martinez, Alfonso Corrales, Cervera, Ricard, Espinosa, Gerard, Lories, Rik, Hunzelmann, Nicolas, Belz, Doreen, Baerlecken, Niklas, Stummvoll, Georg, Zauner, Michael, Lehner, Michaela, Collantes, Eduardo, Ortega-Castro, Rafaela, Angeles Aguirre-Zamorano, Ma, Carmen Castro-Villegas, Ma, Jimenez Gomez, Yolanda, Ortego, Norberto, Fernandez Roldan, Maria Concepcion, Raya, Enrique, Moleon, Inmaculada Jimenez, de Ramon, Enrique, Quintero, Isabel Diaz, Meroni, Pier Luigi, Gerosa, Maria, Schioppo, Tommaso, Artusi, Carolina, Dulic, Sonja, Kadar, Gabriella, Hiepe, Falk, Gerl, Velia, Thiel, Silvia, Maresca, Manuel Rodriguez, Lopez-Berrio, Antonio, Aguilar-Quesada, Rocio, Navarro-Linares, Hector, Ioannou, Yiannis, Chamberlain, Chris, Marovac, Jacqueline, Alarcon Riquelme, Marta, Gomes Anjos, Tania, Maranon, Concepcion, Le Lann, Lucas, Simon, Quentin, Rouviere, Benedicte, Varela, Nieves, Muchmore, Brian, Dufour, Aleksandra, Alvarez, Montserrat, Cremer, Jonathan, Lopez-Pedrera, Chary, Ger, Velia, Khodadadi, Laleh, Cheng, Qingyu, De Groof, Aurelie, Trombetta, Elena, Li, Tianlu, Alvarez-Errico, Damiana, Kniesch, Katja, Azevedo, Nancy, Rao, Sambasiva, Jouve, Pierre-Emmanuel, Soret, Perrine, Le Dantec, Christelle, Desvaux, Emiko, Foulquier, Nathan, Chassagnol, Bastien, Hubert, Sandra, Jamin, Christophe, Barturen, Guillermo, Desachy, Guillaume, Devauchelle-Pensec, Valerie, Boudjeniba, Cheiema, Cornec, Divi, Saraux, Alain, Jousse-Joulin, Sandrine, Barbarroja, Nuria, Rodriguez-Pinto, Ignasi, De Langhe, Ellen, Beretta, Lorenzo, Chizzolini, Carlo, Kovacs, Laszlo, Witte, Torsten, Bettacchioli, Eleonore, Buttgereit, Anne, Makowska, Zuzanna, Lesche, Ralf, Orietta Borghi, Maria, Martin, Javier, Courtade-Gaiani, Sophie, Xuereb, Laura, Guedj, Mickael, Moingeon, Philippe, Alarcon-Riquelme, Marta E., Laigle, Laurence, Pers, Jacques-Olivier, Vigone, Barbara, Lauwerys, Bernard, Ducreux, Julie, Maudoux, Anne-Lise, Vasconcelos, Carlos, Tavares, Ana, Neves, Esmeralda, Faria, Raquel, Brandao, Mariana, Campar, Ana, Marinho, Antonio, Farinha, Fatima, Almeida, Isabel, Gonzalez-Gay Mantecon, Miguel Angel, Alonso, Ricardo Blanco, Martinez, Alfonso Corrales, Cervera, Ricard, Espinosa, Gerard, Lories, Rik, Hunzelmann, Nicolas, Belz, Doreen, Baerlecken, Niklas, Stummvoll, Georg, Zauner, Michael, Lehner, Michaela, Collantes, Eduardo, Ortega-Castro, Rafaela, Angeles Aguirre-Zamorano, Ma, Carmen Castro-Villegas, Ma, Jimenez Gomez, Yolanda, Ortego, Norberto, Fernandez Roldan, Maria Concepcion, Raya, Enrique, Moleon, Inmaculada Jimenez, de Ramon, Enrique, Quintero, Isabel Diaz, Meroni, Pier Luigi, Gerosa, Maria, Schioppo, Tommaso, Artusi, Carolina, Dulic, Sonja, Kadar, Gabriella, Hiepe, Falk, Gerl, Velia, Thiel, Silvia, Maresca, Manuel Rodriguez, Lopez-Berrio, Antonio, Aguilar-Quesada, Rocio, Navarro-Linares, Hector, Ioannou, Yiannis, Chamberlain, Chris, Marovac, Jacqueline, Alarcon Riquelme, Marta, Gomes Anjos, Tania, Maranon, Concepcion, Le Lann, Lucas, Simon, Quentin, Rouviere, Benedicte, Varela, Nieves, Muchmore, Brian, Dufour, Aleksandra, Alvarez, Montserrat, Cremer, Jonathan, Lopez-Pedrera, Chary, Ger, Velia, Khodadadi, Laleh, Cheng, Qingyu, De Groof, Aurelie, Trombetta, Elena, Li, Tianlu, Alvarez-Errico, Damiana, Kniesch, Katja, Azevedo, Nancy, Rao, Sambasiva, and Jouve, Pierre-Emmanuel

Abstract

There is currently no approved treatment for primary Sjogren's syndrome, a disease that primarily affects adult women. The difficulty in developing effective therapies is -in part- because of the heterogeneity in the clinical manifestation and pathophysiology of the disease. Finding common molecular signatures among patient subgroups could improve our understanding of disease etiology, and facilitate the development of targeted therapeutics. Here, we report, in a cross-sectional cohort, a molecular classification scheme for Sjogren's syndrome patients based on the multi-omic profiling of whole blood samples from a European cohort of over 300 patients, and a similar number of age and gender-matched healthy volunteers. Using transcriptomic, genomic, epigenetic, cytokine expression and flow cytometry data, combined with clinical parameters, we identify four groups of patients with distinct patterns of immune dysregulation. The biomarkers we identify can be used by machine learning classifiers to sort future patients into subgroups, allowing the re-evaluation of response to treatments in clinical trials. Sjogren's syndrome, a disease that primarily affects women, is poorly understood. Here, the authors combine data from a large cohort of patients and healthy controls to identify biomarkers that distinguish patient subgroups to improve our understanding of the disease and facilitate drug development.

Published
2021

7. Multi-center harmonization of flow cytometers in the context of the European 'PRECISESADS' project.

Author

UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, Jamin, Christophe, Le Lann, Lucas, Alvarez-Errico, Damiana, Barbarroja, Nuria, Cantaert, Tineke, Ducreux, Julie, Dufour, Aleksandra Maria, Gerl, Velia, Kniesch, Katja, Neves, Esmeralda, Trombetta, Elena, Alarcón-Riquelme, Marta, Marañon, Concepción, Pers, Jacques-Olivier, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, Jamin, Christophe, Le Lann, Lucas, Alvarez-Errico, Damiana, Barbarroja, Nuria, Cantaert, Tineke, Ducreux, Julie, Dufour, Aleksandra Maria, Gerl, Velia, Kniesch, Katja, Neves, Esmeralda, Trombetta, Elena, Alarcón-Riquelme, Marta, Marañon, Concepción, and Pers, Jacques-Olivier

Abstract

The innovative medicine initiative project called PRECISESADS will study 2.500 individuals affected by systemic autoimmune diseases (SADs) and controls. Among extensive OMICS approaches, multi-parameter flow cytometry analyses will be performed in eleven different centers. Therefore, the integration of all data in common bioinformatical and biostatistical investigations requires a fine mirroring of all instruments. We describe here the procedure elaborated to achieve this prerequisite. One flow cytometer chosen as reference instrument fixed the mean fluorescence intensities (MFIs) of 8 different fluorochrome-conjugated antibodies (Abs) using VersaComp Ab capture beads. The ten other centers adjusted their own PMT voltages to reach the same MFIs. Subsequently, all centers acquired Rainbow 8-peak beads data on a daily basis to follow the stability of their instrument overtime. One blood sample has been dispatched and concomitantly stained in all centers. Comparison of leukocytes frequencies and cell surface marker MFIs demonstrated the close sensitivity of all flow cytometers, allowing a multicenter analysis. The effective multi-center harmonization enables the constitution of a workable wide flow cytometry database for the identification of specific molecular signatures in individuals with SADs.

Published
2016

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