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2. Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis

Author

Beretta, Lorenzo, Vigone, Barbara, Pers, Jacques-Olivier, Saraux, Alain, Devauchelle-Pensec, Valérie, Cornec, Divi, Jousse-Joulin, Sandrine, Lauwerys, Bernard, Ducreux, Julie, Maudoux, Anne-Lise, Vasconcelos, Carlos, Tavares, Ana, Neves, Esmeralda, Faria, Raquel, Brandão, Mariana, Campar, Ana, Marinho, António, Farinha, Fátima, Almeida, Isabel, Gonzalez-Gay Mantecón, Miguel Angel, Alonso, Ricardo Blanco, Martínez, Alfonso Corrales, Cervera, Ricard, Rodríguez-Pintó, Ignasi, Espinosa, Gerard, Lories, Rik, De Langhe, Ellen, Hunzelmann, Nicolas, Belz, Doreen, Witte, Torsten, Baerlecken, Niklas, Stummvoll, Georg, Zauner, Michael, Lehner, Michaela, Collantes, Eduardo, Ortega-Castro, Rafaela, Aguirre-Zamorano, Ma Angeles, Escudero-Contreras, Alejandro, Castro-Villegas, Ma Carmen, Ortego, Norberto, Fernández Roldán, María Concepción, Raya, Enrique, Moleón, Inmaculada Jiménez, de Ramon, Enrique, Quintero, Isabel Díaz, Meroni, Pier Luigi, Gerosa, Maria, Schioppo, Tommaso, Artusi, Carolina, Chizzolini, Carlo, Zuber, Aleksandra, Wynar, Donatienne, Kovács, Laszló, Balog, Attila, Deák, Magdolna, Bocskai, Márta, Dulic, Sonja, Kádár, Gabriella, Hiepe, Falk, Gerl, Velia, Thiel, Silvia, Maresca, Manuel Rodriguez, López-Berrio, Antonio, Aguilar-Quesada, Rocío, Navarro-Linares, Héctor, Parodis, Ioannis, Lindblom, Julius, Toro-Domínguez, Daniel, Borghi, Maria O., Castillo, Jessica, Carnero-Montoro, Elena, Enman, Yvonne, Mohan, Chandra, Alarcón-Riquelme, Marta E., Barturen, Guillermo, and Nikolopoulos, Dionysis

Published
2024
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3. Baricitinib in juvenile idiopathic arthritis: an international, phase 3, randomised, double-blind, placebo-controlled, withdrawal, efficacy, and safety trial

Author

Viola, Diego, Spindler, Alberto, Akikusa, Jonathan, Chaitow, Jeffrey, Huemer, Christian, Dehoorne, Joke, Wouters, Carine, Lauwerys, Bernard, Boulanger, Cecile, Saad Magalhães, Claudia, Terreri, Maria, Li, Caifeng, Tang, Xuemei, Feng, Qihua, Yu, Haiguo, Zhou, Zhixuan, Dolezalova, Pavla, Horvath, Rudolf, Herlin, Troels, Glerup, Mia, Quartier Dit Maire, Pierre, Kone Paut, Isabelle, Gervais, Elisabeth, Belot, Alexandre, Name, Investigator, Horneff, Gerd, Minden, Kirsten, Trauzeddel, Ralf, Foeldvari, Ivan, Lutz, Thomas, Helling-Bakki, Astrid, Grulich-Henn, Jürgen, Kümmerle-Deschner, Jasmin, Sawhney, Sujata, Kumar, Sathish, Janarthanan, Mahesh, Amarilyo, Gil, Butbul, Yonatan, Uziel, Yosef, Tirosh, Irit, Harel, Liora, Caorsi, Roberta, Pastore, Serena, Tommasini, Alberto, Alessio, Maria, Breda, Luciana, Cattalini, Marco, Cimaz, Rolando, Giani, Teresa, Simonini, Gabriele, Filocamo, Giovanni, Umebayashi, Hiroaki, Kaneko, Utako, Kawano, Yutaka, Sato, Satoshi, Mori, Masaaki, Shimizu, Masaki, Yamaguchi, Kenichi, Ito, Shuichi, Imagawa, Tomoyuki, Inoue, Natsumi, Yokoyama, Tadafumi, Shabana, Kosuke, Ozeki, Yuka, Kawano, Yoshifumi, Yamasaki, Yuichi, Miyamae, Takako, Vega Cornejo, Gabriel, Rubio Perez, Nadina, Vargas, Edgar, Pacheco-Tena, Cesar, Edmundo Enriquez Sosa, Favio, Smolewska, Elzbieta, Zuber, Zbigniew, Gietka, Piotr, Alexeeva, Ekaterina, Nikishina, Irina, Valieva, Sania, Antón López, Jordi, Murias Loza, Sara, Maria Alcobendas Rueda, Rosa, Calvo Penades, Inmaculada, Grana, Genaro, Lucica Boteanu, Alina, Kasapcopur, Ozgur, Unsal, Erbil, Vaidyanathan Ramanan, Athimalaipet, Lacassagne, Sandrine, Hawley, Daniel, Mahmood, Kamran, Almeida, Beverley, Ramanan, Athimalaipet V, Quartier, Pierre, Okamoto, Nami, Fingerhutová, Šárka, Antón, Jordi, Wang, Zhongkai, Meszaros, Gabriella, Araújo, Joana, Liao, Ran, Keller, Stuart, Brunner, Hermine I, and Ruperto, Nicolino

Published
2023
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4. A Genome‐Wide Association Study Suggests New Susceptibility Loci for Primary Antiphospholipid Syndrome.

Author

Casares‐Marfil, Desiré, Martínez‐Bueno, Manuel, Borghi, Maria Orietta, Pons‐Estel, Guillermo, Beretta, Lorenzo, Vigone, Barbara, Pers, Jacques‐Olivier, Saraux, Alain, Devauchelle‐Pensec, Valérie, Cornec, Divi, Jousse‐Joulin, Sandrine, Lauwerys, Bernard, Ducreux, Julie, Maudoux, Anne‐Lise, Vasconcelos, Carlos, Tavares, Ana, Neves, Esmeralda, Faria, Raquel, Brandão, Mariana, and Campar, Ana

Subjects
NEUROMYELITIS optica, GENOME-wide association studies, GENOMICS, RESEARCH funding, META-analysis, CELLULAR signal transduction, DESCRIPTIVE statistics, CHI-squared test, LONGITUDINAL method, ODDS ratio, GENE expression profiling, SYSTEMIC scleroderma, DISEASE susceptibility, PREGNANCY complications, SJOGREN'S syndrome, CONFIDENCE intervals, ANTIPHOSPHOLIPID syndrome, ALLELES, HLA-B27 antigen
Abstract

Objective: Primary antiphospholipid syndrome (PAPS) is a rare autoimmune disease characterized by the presence of antiphospholipid antibodies and the occurrence of thrombotic events and pregnancy complications. Our study aimed to identify novel genetic susceptibility loci associated with PAPS. Methods: We performed a genome‐wide association study comprising 5,485 individuals (482 affected individuals) of European ancestry. Significant and suggestive independent variants from a meta‐analysis of approximately 7 million variants were evaluated for functional and biological process enrichment. The genetic risk variability for PAPS in different populations was also assessed. Hierarchical clustering, Mahalanobis distance, and Dirichlet Process Mixtures with uncertainty clustering methods were used to assess genetic similarities between PAPS and other immune‐mediated diseases. Results: We revealed genetic associations with PAPS in a regulatory locus within the HLA class II region near HLA‐DRA and in STAT1‐STAT4 with a genome‐wide level of significance; 34 additional suggestive genetic susceptibility loci for PAPS were also identified. The disease risk allele near HLA‐DRA is associated with overexpression of HLA‐DRB6, HLA‐DRB9, HLA‐DQA2, and HLA‐DQB2 in immune cells, vascular tissue, and nervous tissue. This association is independent of the association between PAPS and HLA‐DRB1*1302. Functional analyses highlighted immune‐related pathways in PAPS‐associated loci. The comparison with other immune‐mediated diseases revealed a close genetic relatedness to neuromyelitis optica, systemic sclerosis, and Sjögren syndrome, suggesting co‐localized causal variations close to STAT1‐STAT4, TNPO3, and BLK. Conclusion: This study represents a comprehensive large‐scale genetic analysis for PAPS and provides new insights into the genetic basis and pathophysiology of this rare disease. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Impact of high rheumatoid factor levels on treatment outcomes with certolizumab pegol and adalimumab in patients with rheumatoid arthritis.

Author

Smolen, Josef S, Taylor, Peter C, Tanaka, Yoshiya, Takeuchi, Tsutomu, Hashimoto, Motomu, Cara, Carlos, Lauwerys, Bernard, Tilt, Nicola, Ufuktepe, Baran, Xavier, Ricardo M, Balsa, Alejandro, Curtis, Jeffrey R, Mikuls, Ted R, and Weinblatt, Michael

Subjects
ANTI-inflammatory agents, CERTOLIZUMAB pegol, DATA analysis, PATIENT safety, RESEARCH funding, RHEUMATOID arthritis, AUTOANTIBODIES, STATISTICAL sampling, BLIND experiment, RANDOMIZED controlled trials, DESCRIPTIVE statistics, DRUG monitoring, ADALIMUMAB, DRUG efficacy, STATISTICS, COMPARATIVE studies
Abstract

Objectives To assess the impact of baseline RF level on drug concentrations and efficacy of certolizumab pegol [CZP; TNF inhibitor (TNFi) without a crystallizable fragment (Fc)] and adalimumab (ADA; Fc-containing TNFi) in patients with RA. Methods The phase 4 EXXELERATE study (NCT01500278) was a 104-week, randomized, single-blind (double-blind until week 12; investigator-blind thereafter), head-to-head study of CZP vs ADA in patients with RA. In this post hoc analysis, we report drug concentration and efficacy outcomes stratified by baseline RF quartile (≤Q3 or >Q3). Results Baseline data by RF quartiles were available for 453 CZP-randomized and 454 ADA-randomized patients (≤Q3: ≤204 IU/ml; >Q3: >204 IU/ml). From week 12, the area under the curve (AUC) of ADA concentration was lower in patients with RF >204 IU/ml vs patients with RF ≤204 IU/ml; the AUC of CZP concentration was similar in patients with RF ≤204 IU/ml and >204 IU/ml. For patients with RF ≤204 IU/ml, disease activity score (DAS28)-CRP was similar between CZP- and ADA-treated patients through week 104. For patients with RF >204 IU/ml, mean DAS28-CRP was lower in CZP- vs ADA-treated patients at week 104. The proportion of patients with RF >204 IU/ml achieving DAS28-CRP low disease activity at week 104 was greater in CZP- vs ADA-treated patients. Conclusion CZP was associated with maintained drug concentration and efficacy in patients with RA and high RF and may therefore be a more suitable therapeutic option than TNFis with an Fc fragment in these patients. Trial registration Clinicaltrials.gov, http://clinicaltrials.gov , NCT01500278 [ABSTRACT FROM AUTHOR]

Published
2024
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6. Two Broad Categories Overlapping With Rheumatoid Arthritis Observed in Synovial Biopsies from Patients With Juvenile Idiopathic Arthritis.

Author

Triaille, Clément, Tilman, Gaëlle, Baert, Charlotte A., Sokolova, Tatiana, Loriot, Axelle, Nzeusseu‐Toukap, Adrien, Meric de Bellefon, Laurent, Galant, Christine, Boulanger, Cécile, Fonseca, Joao E., Bouzin, Caroline, Durez, Patrick, Lauwerys, Bernard R., and Limaye, Nisha

Subjects
BIOPSY, JUVENILE idiopathic arthritis, SYNOVIAL membranes, MACROPHAGES, T cells, RHEUMATOID arthritis, DESCRIPTIVE statistics, RNA, GENE expression, IMMUNOHISTOCHEMISTRY, HYPERTROPHY, GENE expression profiling, DATA analysis software, SEQUENCE analysis, B cells
Abstract

Objective: The objective is to characterize transcriptomic profiles and immune cell composition and distribution in juvenile idiopathic arthritis (JIA) synovial biopsies, assess for associations of these features with clinical parameters, and compare JIA and rheumatoid arthritis (RA) synovial features. Methods: RNA sequencing (RNASeq) was performed on 24 samples, with pathway analysis and inference of relative abundance of immune cell subsets based on gene expression data. Two multiplex fluorescence immunohistochemistry (IHC) panels were performed on 28 samples (including 13 on which RNASeq was performed), staining for CD206− classical and CD206+ nonclassical macrophages, and CD8+ and CD4+ T and B lymphocytes. Data were compared to a published series of early RA synovial biopsies. Results: Pathway analysis of the most variably expressed genes (n = 339) identified a B and plasma cell signature as the main driver of heterogeneity in JIA synovia, with strong overlap between JIA and RA synovitis. Multiplex IHC confirmed heterogeneity of immune cell infiltration. M1‐like macrophage–rich synovial lining was associated with greater lining hypertrophy and higher (CD45+) pan–immune cell and CD8+ T cell infiltration. Conclusion: Our study indicates significant similarities between JIA and RA synovitis. Similar to RA, JIA synovia may be broadly categorized into two groups: (1) those with an inflammatory/adaptive immune transcriptomic signature, M1‐like macrophage and CD8+ T cell infiltration, and thicker, M1‐like macrophage–rich synovial lining, and (2) those with an M2‐like macrophage transcriptomic signature, greater M2/M1‐like macrophage ratios, and thinner, M2‐like macrophage–rich synovial lining. Synovial features were not significantly associated with clinical parameters, likely because of group size and heterogeneity. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Transcriptomic profiling and immuno‐histological characterization of synovial biopsies in juvenile idiopathic arthritis (JIA) suggest two broad categories, with significant overlap with rheumatoid arthritis (RA)

Author

Triaille, Clément, primary, Tilman, Gaëlle, additional, Baert, Charlotte A., additional, Sokolova, Tatiana, additional, Loriot, Axelle, additional, Nzeusseu‐Toukap, Adrien, additional, Meric de Bellefon, Laurent, additional, Galant, Christine, additional, Boulanger, Cécile, additional, Fonseca, Joao E., additional, Bouzin, Caroline, additional, Durez, Patrick, additional, Lauwerys, Bernard R, additional, and Limaye, Nisha, additional

Published
2024
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8. P106 Do high rheumatoid factor titres impact response to tumour necrosis factor inhibitors? Comparison of certolizumab pegol and adalimumab in patients with rheumatoid arthritis and high titres of rheumatoid factor: a post hoc analysis of a phase 4 trial.

Author

Smolen, Josef S, primary, Taylor, Peter C, additional, Tanaka, Yoshiya, additional, Cara, Carlos, additional, Lauwerys, Bernard, additional, Xavier, Ricardo, additional, Curtis, Jeffrey R, additional, Mikuls, Ted R, additional, and Weinblatt, Michael, additional

Published
2024
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9. Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis

Author

Parodis, Ioannis, primary, Lindblom, Julius, additional, Toro-Domínguez, Daniel, additional, Beretta, Lorenzo, additional, Borghi, Maria O., additional, Castillo, Jessica, additional, Carnero-Montoro, Elena, additional, Enman, Yvonne, additional, Mohan, Chandra, additional, Alarcón-Riquelme, Marta E., additional, Barturen, Guillermo, additional, Nikolopoulos, Dionysis, additional, Vigone, Barbara, additional, Pers, Jacques-Olivier, additional, Saraux, Alain, additional, Devauchelle-Pensec, Valérie, additional, Cornec, Divi, additional, Jousse-Joulin, Sandrine, additional, Lauwerys, Bernard, additional, Ducreux, Julie, additional, Maudoux, Anne-Lise, additional, Vasconcelos, Carlos, additional, Tavares, Ana, additional, Neves, Esmeralda, additional, Faria, Raquel, additional, Brandão, Mariana, additional, Campar, Ana, additional, Marinho, António, additional, Farinha, Fátima, additional, Almeida, Isabel, additional, Gonzalez-Gay Mantecón, Miguel Angel, additional, Alonso, Ricardo Blanco, additional, Martínez, Alfonso Corrales, additional, Cervera, Ricard, additional, Rodríguez-Pintó, Ignasi, additional, Espinosa, Gerard, additional, Lories, Rik, additional, De Langhe, Ellen, additional, Hunzelmann, Nicolas, additional, Belz, Doreen, additional, Witte, Torsten, additional, Baerlecken, Niklas, additional, Stummvoll, Georg, additional, Zauner, Michael, additional, Lehner, Michaela, additional, Collantes, Eduardo, additional, Ortega-Castro, Rafaela, additional, Aguirre-Zamorano, Ma Angeles, additional, Escudero-Contreras, Alejandro, additional, Castro-Villegas, Ma Carmen, additional, Ortego, Norberto, additional, Fernández Roldán, María Concepción, additional, Raya, Enrique, additional, Moleón, Inmaculada Jiménez, additional, de Ramon, Enrique, additional, Quintero, Isabel Díaz, additional, Meroni, Pier Luigi, additional, Gerosa, Maria, additional, Schioppo, Tommaso, additional, Artusi, Carolina, additional, Chizzolini, Carlo, additional, Zuber, Aleksandra, additional, Wynar, Donatienne, additional, Kovács, Laszló, additional, Balog, Attila, additional, Deák, Magdolna, additional, Bocskai, Márta, additional, Dulic, Sonja, additional, Kádár, Gabriella, additional, Hiepe, Falk, additional, Gerl, Velia, additional, Thiel, Silvia, additional, Maresca, Manuel Rodriguez, additional, López-Berrio, Antonio, additional, Aguilar-Quesada, Rocío, additional, and Navarro-Linares, Héctor, additional

Published
2024
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10. Transancestral mapping and genetic load in systemic lupus erythematosus.

Author

Langefeld, Carl D, Ainsworth, Hannah C, Cunninghame Graham, Deborah S, Kelly, Jennifer A, Comeau, Mary E, Marion, Miranda C, Howard, Timothy D, Ramos, Paula S, Croker, Jennifer A, Morris, David L, Sandling, Johanna K, Almlöf, Jonas Carlsson, Acevedo-Vásquez, Eduardo M, Alarcón, Graciela S, Babini, Alejandra M, Baca, Vicente, Bengtsson, Anders A, Berbotto, Guillermo A, Bijl, Marc, Brown, Elizabeth E, Brunner, Hermine I, Cardiel, Mario H, Catoggio, Luis, Cervera, Ricard, Cucho-Venegas, Jorge M, Dahlqvist, Solbritt Rantapää, D'Alfonso, Sandra, Da Silva, Berta Martins, de la Rúa Figueroa, Iñigo, Doria, Andrea, Edberg, Jeffrey C, Endreffy, Emőke, Esquivel-Valerio, Jorge A, Fortin, Paul R, Freedman, Barry I, Frostegård, Johan, García, Mercedes A, de la Torre, Ignacio García, Gilkeson, Gary S, Gladman, Dafna D, Gunnarsson, Iva, Guthridge, Joel M, Huggins, Jennifer L, James, Judith A, Kallenberg, Cees GM, Kamen, Diane L, Karp, David R, Kaufman, Kenneth M, Kottyan, Leah C, Kovács, László, Laustrup, Helle, Lauwerys, Bernard R, Li, Quan-Zhen, Maradiaga-Ceceña, Marco A, Martín, Javier, McCune, Joseph M, McWilliams, David R, Merrill, Joan T, Miranda, Pedro, Moctezuma, José F, Nath, Swapan K, Niewold, Timothy B, Orozco, Lorena, Ortego-Centeno, Norberto, Petri, Michelle, Pineau, Christian A, Pons-Estel, Bernardo A, Pope, Janet, Raj, Prithvi, Ramsey-Goldman, Rosalind, Reveille, John D, Russell, Laurie P, Sabio, José M, Aguilar-Salinas, Carlos A, Scherbarth, Hugo R, Scorza, Raffaella, Seldin, Michael F, Sjöwall, Christopher, Svenungsson, Elisabet, Thompson, Susan D, Toloza, Sergio MA, Truedsson, Lennart, Tusié-Luna, Teresa, Vasconcelos, Carlos, Vilá, Luis M, Wallace, Daniel J, Weisman, Michael H, Wither, Joan E, Bhangale, Tushar, Oksenberg, Jorge R, Rioux, John D, Gregersen, Peter K, Syvänen, Ann-Christine, Rönnblom, Lars, Criswell, Lindsey A, Jacob, Chaim O, Sivils, Kathy L, Tsao, Betty P, Schanberg, Laura E, and Behrens, Timothy W

Subjects
Humans, Lupus Erythematosus, Systemic, HLA Antigens, Logistic Models, Case-Control Studies, Mutagenesis, Insertional, Age of Onset, Sequence Deletion, Genetic Load, Multifactorial Inheritance, Polymorphism, Single Nucleotide, African Continental Ancestry Group, American Native Continental Ancestry Group, European Continental Ancestry Group, Hispanic Americans, Lupus Erythematosus, Systemic, Mutagenesis, Insertional, Polymorphism, Single Nucleotide
Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P

Published
2017

11. Molecular subtypes explain lupus epigenomic heterogeneity unveiling new regulatory genetic risk variants.

Author

Castellini-Pérez, Olivia, Povedano, Elena, Barturen, Guillermo, Martínez-Bueno, Manuel, Iakovliev, Andrii, Kerick, Martin, López-Domínguez, Raúl, Marañón, Concepción, Martín, Javier, Ballestar, Esteban, Beretta, Lorenzo, Vigone, Barbara, Pers, Jacques‐Olivier, Saraux, Alain, Devauchelle‐Pensec, Valérie, Cornec, Divi, Jousse‐Joulin, Sandrine, Lauwerys, Bernard, Ducreux, Julie, and Maudoux, Anne‐Lise

Published
2024
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12. Association of Combined Anti‐Ro52/TRIM21 and Anti‐Ro60/SSA Antibodies With Increased Sjögren Disease Severity Through Interferon Pathway Activation.

Author

Bettacchioli, Eléonore, Saraux, Alain, Tison, Alice, Cornec, Divi, Dueymes, Maryvonne, Foulquier, Nathan, Hillion, Sophie, Roguedas‐Contios, Anne‐Marie, Benyoussef, Anas‐Alexis, Alarcon‐Riquelme, Marta E., Pers, Jacques‐Olivier, Devauchelle‐Pensec, Valérie, Beretta, Lorenzo, Vigone, Barbara, Jousse‐Joulin, Sandrine, Lauwerys, Bernard, Ducreux, Julie, Maudoux, Anne‐Lise, Vasconcelos, Carlos, and Tavares, Ana

Subjects
RNA analysis, LEUCOPENIA, RESEARCH funding, AUTOANTIBODIES, IMMUNOGLOBULINS, LYMPHOPENIA, CELLULAR signal transduction, SEVERITY of illness index, DESCRIPTIVE statistics, BLOOD sedimentation, INTERFERONS, LONGITUDINAL method, HYPERGAMMAGLOBULINEMIA, GENE expression profiling, ARTHRITIS, SJOGREN'S syndrome, INFLAMMATION, BIOMARKERS, SEQUENCE analysis, SYMPTOMS
Abstract

Objective: The biologic diagnosis of primary Sjögren disease (SjD) mainly relies on anti‐Ro60/SSA antibodies, whereas the significance of anti‐Ro52/TRIM21 antibodies currently remains unclear. The aim of this study was to characterize the clinical, serological, biologic, transcriptomic, and interferon profiles of patients with SjD according to their anti‐Ro52/TRIM21 antibody status. Methods: Patients with SjD from the European PRECISESADS (n = 376) and the Brittany Diagnostic Suspicion of primitive Sjögren's Syndrome (DIApSS); (n = 146) cohorts were divided into four groups: double negative (Ro52−/Ro60−), isolated anti‐Ro52/TRIM21 positive (Ro52+), isolated anti‐Ro60/SSA positive (Ro60+), and double‐positive (Ro52+/Ro60+) patients. Clinical information; EULAR Sjögren Syndrome Disease Activity Index, a score representing systemic activity; and biologic markers associated with disease severity were evaluated. Transcriptome data obtained from whole blood by RNA sequencing and type I and II interferon signatures were analyzed for PRECISESADS patients. Results: In the DIApSS cohort, Ro52+/Ro60+ patients showed significantly more parotidomegaly (33.3% vs 0%–11%) along with higher β2‐microglobulin (P = 0.0002), total immunoglobulin (P < 0.0001), and erythrocyte sedimentation rate levels (P = 0.002) as well as rheumatoid factor (RF) positivity (66.2% vs 20.8%–25%) compared to other groups. The PRECISESADS cohort corroborated these observations, with increased arthritis (P = 0.046), inflammation (P = 0.005), hypergammaglobulinemia (P < 0.0001), positive RF (P < 0.0001), leukopenia (P = 0.004), and lymphopenia (P = 0.009) in Ro52+/Ro60+ patients. Cumulative EULAR Sjögren Syndrome Disease Activity Index results further confirmed these disparities (P = 0.002). Transcriptome analysis linked anti‐Ro52/TRIM21 antibody positivity to interferon pathway activation as an underlying cause for these clinical correlations. Conclusion: These results suggest that the combination of anti‐Ro52/TRIM21 and anti‐Ro60/SSA antibodies is associated with a clinical, biologic, and transcriptional profile linked to greater disease severity in SjD through the potentiation of the interferon pathway activation by anti‐Ro52/TRIM21 antibodies. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Patterns and determinants of response to novel therapies in juvenile and adult-onset polyarthritis.

Author

Triaille, Clément, Quartier, Pierre, Somer, Lien De, Durez, Patrick, Lauwerys, Bernard R, Verschueren, Patrick, Taylor, Peter C, and Wouters, Carine

Subjects
BIOTHERAPY, DRUG efficacy, BIOMARKERS, JUVENILE idiopathic arthritis, INDIVIDUALIZED medicine, PATIENT-centered care, ANTIRHEUMATIC agents, TREATMENT effectiveness, RHEUMATOID arthritis, AGE factors in disease, DISEASE management, ADULTS
Abstract

Biologic and targeted synthetic DMARDs (b/tsDMARDs) have revolutionized the management of multiple rheumatic inflammatory conditions. Among these, polyarticular JIA (pJIA) and RA display similarities in terms of disease pathophysiology and response pattern to b/tsDMARDs. Indeed, the therapeutic efficacy of novel targeted drugs is variable among individual patients, in both RA and pJIA. The mechanisms and determinants of this heterogeneous response are diverse and complex, such that the development of true 'precision'-medicine strategies has proven highly challenging. In this review, we will discuss pathophysiological, patient-specific, drug-specific and environmental factors contributing to individual therapeutic response in pJIA in comparison with what is known in RA. Although some biomarkers have been identified that stratify with respect to the likelihood of either therapeutic response or non-response, few have proved useful in clinical practice so far, likely due to the complexity of treatment–response mechanisms. Consequently, we propose a pragmatic, patient-centred and clinically based approach, i.e. personalized instead of biomarker-based precision medicine in JIA. [ABSTRACT FROM AUTHOR]

Published
2024
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15. Deep sequencing reveals a DAP1 regulatory haplotype that potentiates autoimmunity in systemic lupus erythematosus

Author

Raj, Prithvi, Song, Ran, Zhu, Honglin, Riediger, Linley, Jun, Dong-Jae, Liang, Chaoying, Arana, Carlos, Zhang, Bo, Gao, Yajing, Wakeland, Benjamin E., Dozmorov, Igor, Zhou, Jinchun, Kelly, Jennifer A., Lauwerys, Bernard R., Guthridge, Joel M., Olsen, Nancy J., Nath, Swapan K., Pasare, Chandrashekhar, van Oers, Nicolai, Gilkeson, Gary, Tsao, Betty P., Gaffney, Patrick M., Gregersen, Peter K., James, Judith A., Zuo, Xiaoxia, Karp, David R., Li, Quan-Zhen, and Wakeland, Edward K.

Published
2020
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16. Current laboratory and clinical practices in reporting and interpreting anti-nuclear antibody indirect immunofluorescence (ANA IIF) patterns: results of an international survey

Author

Van Hoovels, Lieve, Broeders, Sylvia, Chan, Edward K. L., Andrade, Luis, de Melo Cruvinel, Wilson, Damoiseaux, Jan, Viander, Markku, Herold, Manfred, Coucke, Wim, Heijnen, Ingmar, Bogdanos, Dimitrios, Calvo-Alén, Jaime, Eriksson, Catharina, Kozmar, Ana, Kuhi, Liisa, Bonroy, Carolien, Lauwerys, Bernard, Schouwers, Sofie, Lutteri, Laurence, Vercammen, Martine, Mayer, Miroslav, Patel, Dina, Egner, William, Puolakka, Kari, Tesija-Kuna, Andrea, Shoenfeld, Yehuda, de Sousa, Maria José Rego, Hoyos, Marcos Lopez, Radice, Antonella, and Bossuyt, Xavier

Published
2020
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17. Baricitinib in juvenile idiopathic arthritis: an international, phase 3, randomised, double-blind, placebo-controlled, withdrawal, efficacy, and safety trial

Author

Ramanan, Athimalaipet V, primary, Quartier, Pierre, additional, Okamoto, Nami, additional, Foeldvari, Ivan, additional, Spindler, Alberto, additional, Fingerhutová, Šárka, additional, Antón, Jordi, additional, Wang, Zhongkai, additional, Meszaros, Gabriella, additional, Araújo, Joana, additional, Liao, Ran, additional, Keller, Stuart, additional, Brunner, Hermine I, additional, Ruperto, Nicolino, additional, Viola, Diego, additional, Akikusa, Jonathan, additional, Chaitow, Jeffrey, additional, Huemer, Christian, additional, Dehoorne, Joke, additional, Wouters, Carine, additional, Lauwerys, Bernard, additional, Boulanger, Cecile, additional, Saad Magalhães, Claudia, additional, Terreri, Maria, additional, Li, Caifeng, additional, Tang, Xuemei, additional, Feng, Qihua, additional, Yu, Haiguo, additional, Zhou, Zhixuan, additional, Dolezalova, Pavla, additional, Horvath, Rudolf, additional, Herlin, Troels, additional, Glerup, Mia, additional, Quartier Dit Maire, Pierre, additional, Kone Paut, Isabelle, additional, Gervais, Elisabeth, additional, Belot, Alexandre, additional, Name, Investigator, additional, Horneff, Gerd, additional, Minden, Kirsten, additional, Trauzeddel, Ralf, additional, Lutz, Thomas, additional, Helling-Bakki, Astrid, additional, Grulich-Henn, Jürgen, additional, Kümmerle-Deschner, Jasmin, additional, Sawhney, Sujata, additional, Kumar, Sathish, additional, Janarthanan, Mahesh, additional, Amarilyo, Gil, additional, Butbul, Yonatan, additional, Uziel, Yosef, additional, Tirosh, Irit, additional, Harel, Liora, additional, Caorsi, Roberta, additional, Pastore, Serena, additional, Tommasini, Alberto, additional, Alessio, Maria, additional, Breda, Luciana, additional, Cattalini, Marco, additional, Cimaz, Rolando, additional, Giani, Teresa, additional, Simonini, Gabriele, additional, Filocamo, Giovanni, additional, Umebayashi, Hiroaki, additional, Kaneko, Utako, additional, Kawano, Yutaka, additional, Sato, Satoshi, additional, Mori, Masaaki, additional, Shimizu, Masaki, additional, Yamaguchi, Kenichi, additional, Ito, Shuichi, additional, Imagawa, Tomoyuki, additional, Inoue, Natsumi, additional, Yokoyama, Tadafumi, additional, Shabana, Kosuke, additional, Ozeki, Yuka, additional, Kawano, Yoshifumi, additional, Yamasaki, Yuichi, additional, Miyamae, Takako, additional, Vega Cornejo, Gabriel, additional, Rubio Perez, Nadina, additional, Vargas, Edgar, additional, Pacheco-Tena, Cesar, additional, Edmundo Enriquez Sosa, Favio, additional, Smolewska, Elzbieta, additional, Zuber, Zbigniew, additional, Gietka, Piotr, additional, Alexeeva, Ekaterina, additional, Nikishina, Irina, additional, Valieva, Sania, additional, Antón López, Jordi, additional, Murias Loza, Sara, additional, Maria Alcobendas Rueda, Rosa, additional, Calvo Penades, Inmaculada, additional, Grana, Genaro, additional, Lucica Boteanu, Alina, additional, Kasapcopur, Ozgur, additional, Unsal, Erbil, additional, Vaidyanathan Ramanan, Athimalaipet, additional, Lacassagne, Sandrine, additional, Hawley, Daniel, additional, Mahmood, Kamran, additional, and Almeida, Beverley, additional

Published
2023
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18. Disease activity drives transcriptomic heterogeneity in early untreated rheumatoid synovitis

Author

Triaille, Clément, primary, Tilman, Gaëlle, additional, Sokolova, Tatiana, additional, Loriot, Axelle, additional, Marchandise, Joelle, additional, De Montjoye, Stéphanie, additional, Nzeusseu-Toukap, Adrien, additional, Méric de Bellefon, Laurent, additional, Bouzin, Caroline, additional, Galant, Christine, additional, Durez, Patrick, additional, Lauwerys, Bernard R, additional, and Limaye, Nisha, additional

Published
2023
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19. Abatacept as Monotherapy and in Combination With Methotrexate in Patients With Juvenile Idiopathic Arthritis: Analysis of 2 Phase III Trials

Author

Ruperto, Nicolino, primary, Lovell, Daniel J., additional, Berman, Alberto, additional, Anton, Jordi, additional, Viola, Diego O., additional, Lauwerys, Bernard, additional, Rama, Maria E., additional, Bohnsack, John, additional, Breedt, Johannes, additional, Fischbach, Michel, additional, Lutz, Thomas, additional, Minden, Kirsten, additional, Ally, Mahmood, additional, Rubio-Pérez, Nadina, additional, Gervais, Elisabeth, additional, Van Zyl, Riana, additional, Wong, Robert, additional, Askelson, Margarita, additional, Martini, Alberto, additional, and Brunner, Hermine I., additional

Published
2023
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25. Standardisation of synovial biopsy analyses in rheumatic diseases: a consensus of the EULAR Synovitis and OMERACT Synovial Tissue Biopsy Groups

Author

Najm, Aurélie, Le Goff, Benoît, Orr, Carl, Thurlings, Rogier, Cañete, Juan D., Humby, Frances, Alivernini, Stefano, Manzo, Antonio, Just, Søren Andreas, Romão, Vasco C., Krenn, Veit, Müller-Ladner, Ulf, Addimanda, Olga, Tas, Sander W., Stoenoiu, Maria, Meric de Bellefon, Laurent, Durez, Patrick, Strand, Vibeke, Wechalekar, Mihir D., Fonseca, Joao E., Lauwerys, Bernard, Fearon, Ursula, Veale, Douglas J., and on behalf of EULAR Synovitis Study Group and OMERACT Synovial Tissue Special Interest Group

Published
2018
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26. Correction to: Standardisation of synovial biopsy analyses in rheumatic diseases: a consensus of the EULAR Synovitis and OMERACT Synovial Tissue Biopsy Groups

Author

Najm, Aurélie, Le Goff, Benoît, Orr, Carl, Thurlings, Rogier, Cañete, Juan D., Humby, Frances, Alivernini, Stefano, Manzo, Antonio, Just, Søren Andreas, Romão, Vasco C., Krenn, Veit, Müller-Ladner, Ulf, Addimanda, Olga, Tas, Sander W., Stoenoiu, Maria, de Bellefon, Laurent Meric, Durez, Patrick, Strand, Vibeke, Wechalekar, Mihir D., Fonseca, Joao E., Lauwerys, Bernard, Fearon, Ursula, Veale, Douglas J., and on behalf of EULAR Synovitis Study Group and OMERACT Synovial Tissue Special Interest Group

Published
2018
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28. Subcutaneous golimumab for children with active polyarticular-course juvenile idiopathic arthritis: results of a multicentre, double-blind, randomised-withdrawal trial

Author

Brunner, Hermine I, Ruperto, Nicolino, Tzaribachev, Nikolay, Horneff, Gerd, Chasnyk, Vyacheslav G, Panaviene, Violeta, Abud-Mendoza, Carlos, Reiff, Andreas, Alexeeva, Ekaterina, Rubio-Pérez, Nadina, Keltsev, Vladimir, Kingsbury, Daniel J, del Rocio Maldonado Velázquez, Maria, Nikishina, Irina, Silverman, Earl D, Joos, Rik, Smolewska, Elzbieta, Bandeira, Márcia, Minden, Kirsten, van Royen-Kerkhof, Annet, Emminger, Wolfgang, Foeldvari, Ivan, Lauwerys, Bernard R, Sztajnbok, Flavio, Gilmer, Keith E, Xu, Zhenhua, Leu, Jocelyn H, Kim, Lilianne, Lamberth, Sarah L, Loza, Matthew J, Lovell, Daniel J, and Martini, Alberto

Published
2018
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29. Synovial tissue research: a state-of-the-art review

Author

Orr, Carl, Vieira-Sousa, Elsa, Boyle, David L., Buch, Maya H., Buckley, Christopher D., Cañete, Juan D., Catrina, Anca I., Choy, Ernest H. S., Emery, Paul, Fearon, Ursula, Filer, Andrew, Gerlag, Danielle, Humby, Frances, Isaacs, John D., Just, Søren A., Lauwerys, Bernard R., Goff, Benoit Le, Manzo, Antonio, McGarry, Trudy, McInnes, Iain B., Najm, Aurélie, Pitzalis, Constantino, Pratt, Arthur, Smith, Malcolm, Tak, Paul P., Tas, Sander W., Thurlings, Rogier, Fonseca, João E., and Veale, Douglas J.

Published
2018
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30. Deciphering transcriptomic heterogeneity in rheumatoid arthritis synovium

Author

UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - Faculté de médecine et médecine dentaire, Limaye, Nisha, Lauwerys, Bernard, Marbaix, Etienne, Coulie, Pierre, Durez, Patrick, Brichard, Bénédicte, Demoulin, Jean-Baptiste, Lories, Rik, Richez, Christophe, Triaille, Clément, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - Faculté de médecine et médecine dentaire, Limaye, Nisha, Lauwerys, Bernard, Marbaix, Etienne, Coulie, Pierre, Durez, Patrick, Brichard, Bénédicte, Demoulin, Jean-Baptiste, Lories, Rik, Richez, Christophe, and Triaille, Clément

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by a predominant joint involvement. RA encompasses a wide spectrum of clinical disease severity spanning from limited, indolent oligoarticular involvement to severe, polyarticular destructive disease. Therapeutic armamentarium has greatly increased these last decades to involve drugs specifically targeting key inflammatory effectors. Again, response to therapy displays a wide heterogeneity across individuals, with some patients entering remission after 1st-line therapy while others suffer from “multi-resistant” RA. Importantly, accurate predictors of response to therapy are lacking. The target tissue of RA -the synovium- is the seat of alterations involving immune and resident cells. Just as clinical characteristics, features of synovial inflammation in RA are widely heterogenous from a cellular and molecular point-of-view. The development of minimally invasive biopsies techniques has enabled to study clinical correlates of synovial tissue heterogeneity in large cohorts of RA patients. While confounding factors (i.e. disease duration, ongoing treatment) may partially account for these variations, it remains unclear whether RA endotypes (commonly named “pathotypes”) can be defined based on synovial inflammatory pattern. The clinical benefit of defining such RA subgroups with different prognosis/response to therapy is evident and would represent a great step toward the grail of precision-medicine. Nevertheless, clinician scientists ought to temper their enthusiasm with a critical approach. In this thesis, I first explored the intra-patient heterogeneity (that is, across pairs of large and small joints) of synovial inflammatory features. I have shown that T cells infiltration and expression of TCR-signaling genes (and other RA-related pathways) are largely similar between pairs of joints from the same individuals. These observations have pathophysiological but also methodological impli, (MED - Sciences médicales) -- UCL, 2022

Published
2022

31. ERRATUM: Synovial tissue research: a state-of-the-art review

Author

Orr, Carl, Vieira-Sousa, Elsa, Boyle, David L., Buch, Maya H., Buckley, Christopher D., Cañete, Juan D., Catrina, Anca I., Choy, Ernest H. S., Emery, Paul, Fearon, Ursula, Filer, Andrew, Gerlag, Danielle, Humby, Frances, Isaacs, John D., Just, Søren A., Lauwerys, Bernard R., Le Goff, Benoit, Manzo, Antonio, McGarry, Trudy, McInnes, Iain B., Najm, Aurélie, Pitzalis, Constantino, Pratt, Arthur, Smith, Malcolm, Tak, Paul P., Thurlings, Rogier, Fonseca, João E., and Veale, Douglas J.

Published
2017
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32. sj-doc-2-tab-10.1177_1759720X221087650 – Supplemental material for Pharmacovigilance pregnancy data in a large population of patients with chronic inflammatory disease exposed to certolizumab pegol

Author

Clowse, Megan, Fischer-Betz, Rebecca, Nelson-Piercy, Catherine, Scheuerle, Angela E., Stephan, Brigitte, Dubinsky, Marla, Kumke, Thomas, Kasliwal, Rachna, Lauwerys, Bernard, and Förger, Frauke

Subjects
FOS: Clinical medicine, 110604 Sports Medicine, FOS: Health sciences, 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified, 110314 Orthopaedics
Abstract

Supplemental material, sj-doc-2-tab-10.1177_1759720X221087650 for Pharmacovigilance pregnancy data in a large population of patients with chronic inflammatory disease exposed to certolizumab pegol by Megan Clowse, Rebecca Fischer-Betz, Catherine Nelson-Piercy, Angela E. Scheuerle, Brigitte Stephan, Marla Dubinsky, Thomas Kumke, Rachna Kasliwal, Bernard Lauwerys and Frauke Förger in Therapeutic Advances in Musculoskeletal Disease

Published
2022
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33. sj-docx-1-tab-10.1177_1759720X221087650 – Supplemental material for Pharmacovigilance pregnancy data in a large population of patients with chronic inflammatory disease exposed to certolizumab pegol

Author

Clowse, Megan, Fischer-Betz, Rebecca, Nelson-Piercy, Catherine, Scheuerle, Angela E., Stephan, Brigitte, Dubinsky, Marla, Kumke, Thomas, Kasliwal, Rachna, Lauwerys, Bernard, and Förger, Frauke

Subjects
FOS: Clinical medicine, 110604 Sports Medicine, FOS: Health sciences, 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified, 110314 Orthopaedics
Abstract

Supplemental material, sj-docx-1-tab-10.1177_1759720X221087650 for Pharmacovigilance pregnancy data in a large population of patients with chronic inflammatory disease exposed to certolizumab pegol by Megan Clowse, Rebecca Fischer-Betz, Catherine Nelson-Piercy, Angela E. Scheuerle, Brigitte Stephan, Marla Dubinsky, Thomas Kumke, Rachna Kasliwal, Bernard Lauwerys and Frauke Förger in Therapeutic Advances in Musculoskeletal Disease

Published
2022
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34. A new molecular classification to drive precision treatment strategies in primary Sjögren’s syndrome

Author

Soret, Perrine, Le Dantec, Christelle, Desvaux, Emiko, Foulquier, Nathan, Chassagnol, Bastien, Hubert, Sandra, Christophe, Jamin, Barturen, Guillermo, Desachy, Guillaume, Devauchelle-Pensec, Valérie, Boudjeniba, Cheïma, Cornec, Divi, Saraux, Alain, Jousse-Joulin, Sandrine, Barbarroja, Nuria, Rodríguez-Pintó, Ignasi, de Langhe, Ellen, Beretta, Lorenzo, Chizzolini, Carlo, Kovács, László, Witte, Torsten, Bettacchioli, Eléonore, Buttgereit, Anne, Makowska, Zuzanna, Lesche, Ralf, Borghi, Maria Orietta, Martin, Javier, Courtade-Gaiani, Sophie, Xuereb, Laura, Guedj, Mickaël, Moingeon, Philippe, Alarcón-Riquelme, Marta, Laigle, Laurence, Pers, Jacques-Olivier, Vigone, Barbara, Lauwerys, Bernard, Maudoux, Anne-Lise, Vasconcelos, Carlos, Tavares, Ana, Faria, Raquel, Brandão, Mariana, Campar, Ana, Marinho, António, Farinha, Fátima, Almeida, Isabel, Gonzalez-Gay Mantecón, Miguel Angel, Blanco Alonso, Ricardo, Corrales Martínez, Alfonso, Cervera, Ricard, Espinosa, Gerard, Lories, Rik, Hunzelmann, Nicolas, Belz, Doreen, Baerlecken, Niklas, Stummvoll, Georg, Zauner, Michael, Lehner, Michaela, Collantes, Eduardo, Ortega-Castro, Rafaela, Aguirre-Zamorano, Ma Angeles, Escudero-Contreras, Alejandro, Castro-Villegas, Ma Carmen, Jiménez Gómez, Yolanda, Ortego, Norberto, Fernández Roldán, María Concepción, Raya, Enrique, Jiménez Moleón, Inmaculada, de Ramon, Enrique, Díaz Quintero, Isabel, Meroni, Pier Luigi, Gerosa, Maria, Schioppo, Tommaso, Artusi, Carolina, Zuber, Aleksandra, Wynar, Donatienne, Balog, Attila, Deák, Magdolna, Bocskai, Márta, Dulic, Sonja, Kádár, Gabriella, Hiepe, Falk, Thiel, Silvia, Rodriguez Maresca, Manuel, López-Berrio, Antonio, Aguilar-Quesada, Rocío, Navarro-Linares, Héctor, Ioannou, Yiannis, Chamberlain, Chris, Marovac, Jacqueline, Alarcón Riquelme, Marta, Gomes Anjos, Tania, Marañón, Concepción, Le Lann, Lucas, Simon, Quentin, Rouvière, Bénédicte, Varela, Nieves, Muchmore, Brian, Dufour, Aleksandra, Alvarez, Montserrat, Cremer, Jonathan, Lopez-Pedrera, Chary, Gerl, Velia, Khodadadi, Laleh, Cheng, Qingyu, de Groof, Aurélie, Ducreux, Julie, Trombetta, Elena, Li, Tianlu, Alvarez-Errico, Damiana, Kniesch, Katja, Azevedo, Nancy, Neves, Esmeralda, Rao, Sambasiva, Jouve, Pierre-Emmanuel, Institut de Recherches Internationales Servier [Suresnes] (IRIS), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Centre for Genomics and Oncological Reearch (GENYO), CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Instituto Maimonides de Investigación Biomédica de Cordoba (IMIBIC), Universidad de Córdoba = University of Córdoba [Córdoba]-Hospital Universitario Reina Sofía, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Maggiore Hospital, IRCCS Foundation, Milano, Department of Pathology and Immunology [Geneva, Switzerland], Université de Genève = University of Geneva (UNIGE), University of Szeged [Szeged], Clinic for Immunology and Rhematology, Hannover Medical School, Hanover, Germany, Hôpital Morvan - CHRU de Brest (CHU - BREST ), Pharmaceuticals Division Bayer Pharma Aktiengesellschaft, Università degli Studi di Milano = University of Milan (UNIMI), Instituto de Parasitología y Biomedicina 'López-Neyra' (IPBLN), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Granada = University of Granada (UGR), and Michel, Geneviève

Subjects
MESH: Databases, Protein, MESH: Inflammation, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Flow Cytometry, MESH: Cross-Sectional Studies, MESH: DNA Methylation, MESH: Computer Simulation, cell cycle, chronic lymphocytic leukemia, liquid chromatography-tandem mass spectrometry, splicing, MESH: Autoantibodies, MESH: Interferons, MESH: RNA-Seq, MESH: Cohort Studies, MESH: Databases, Genetic, MESH: Cytokines, MESH: Humans, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, MESH: Transcriptome, MESH: Adult, MESH: Chemokines, MESH: Male, MESH: Proteome, MESH: Sjogren's Syndrome, MESH: Genome-Wide Association Study, MESH: Biomarkers, MESH: Multigene Family, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Female, MESH: Computational Biology
Abstract

International audience; Abstract There is currently no approved treatment for primary Sjögren’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 Sjögren’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.

Published
2021
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36. Rate and Clinical Presentation of Macrophage Activation Syndrome in Patients With Systemic Juvenile Idiopathic Arthritis Treated With Canakinumab

Author

Grom, Alexei A., Ilowite, Norman T., Pascual, Virginia, Brunner, Hermine I., Martini, Alberto, Lovell, Daniel, Ruperto, Nicolino, Leon, Karolynn, Lheritier, Karine, Abrams, Ken, Cuttica, Ruben, Emminger, Wolfgang, Goffin, Laurence, Joos, Rik, Lauwerys, Bernard, Wouters, Carine, Hilário, Maria Odete Esteves, de Oliveira, Sheila Knupp Feitosa, Len, Claudio, Radominski, Sebastiao, Sztajnbok, Flavio Roberto, Haddad, Elie, Hofer, Michael, Houghton, Kristin, Huber, Adam, Saurenmann, Traudel, Schneider, Rayfel, Tucker, Lori, Bader-Meunier, Brigitte, Desjonqueres, Marine, Fischbach, Michel, Kone-Paut, Isabelle, Marie, Isabelle, Mogenet, Agnes, Mouy, Richard, Quartier, Pierre, Berner, Reinhard, Foeldvari, Ivan, Foell, Dirk, Frosch, Michael, Haas, Johannes-Peter, Horneff, Gerd, Hufnagel, Markus, Kallinich, Tilmann, Kuemmerle-Deschner, Jasmin, Lehmann, Hartwig, Lutz, Thomas, Thon, Angelika, Trauzeddel, Ralf, Tzaribachev, Nikolay, Weibarth-Riedel, Elisabeth, Chrousos, Georgios, Trachana, Maria, Vougiouka, Olga, Constantin, Tamas, Barash, Judith, Berkun, Yackov, Brik, Riva, Harel, Liora, Nahum, Amit, Pade, Shay, Uziel, Yosef, Alessio, Maria, Cimaz, Rolando, Corona, Fabrizia, Gerloni, Valeria, Wulffraat, N. M., Ferrandiz, Manuel, Rutkowska-Sak, Lidia, Alekseeva, Ekaterina, Chasnyk, Vyacheslav, Nasonov, Evgeny, Stanislav, Marina, Anton, Jordi, Calvo, Inmaculada, Gamir, Mari Luz, Robledillos, Juan Carlos, Magnusson, Bo, Erguven, Muferet, Kasapcopur, Ozgur, Ozdogan, Huri, Ozen, Seza, Unsal, Erbil, Chieng, Alice, Foster, Helen, McCann, Liza, Ramanan, Athimalaip, Southwood, Taunton, Wilkinson, Nicholas, Woo, Patricia, Higgins, Gloria Christine, Kingsbury, Daniel, Lopez-Benitez, Jorge, Marzan, Katherine, Morris, Paula, Natter, Marc, and Schikler, Kenneth Noel

Published
2016
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37. Canakinumab improves patient-reported outcomes in children and adults with autoinflammatory recurrent fever syndromes: results from the CLUSTER trial

Author

Lachmann, Helen J., primary, Lauwerys, Bernard, additional, Miettunen, Paivi, additional, Kallinich, Tilmann, additional, Jansson, Annette, additional, Rosner, Itzhak, additional, Manna, Raffaele, additional, Murias, Sara, additional, Savic, Sinisa, additional, Smeets, Serge, additional, De Benedetti, Fabrizio, additional, and Simon, Anna, additional

Published
2021
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40. PXK locus in systemic lupus erythematosus: fine mapping and functional analysis reveals novel susceptibility gene ABHD6

Author

Oparina, Nina Y, Delgado-Vega, Angelica M, Martinez-Bueno, Manuel, Magro-Checa, César, Fernández, Concepción, Castro, Rafaela Ortega, Pons-Estel, Bernardo A, DʼAlfonso, Sandra, Sebastiani, Gian Domenico, Witte, Torsten, Lauwerys, Bernard R, Endreffy, Emoke, Kovács, László, Escudero, Alejandro, López-Pedrera, Chary, Vasconcelos, Carlos, da Silva, Berta Martins, Frostegård, Johan, Truedsson, Lennart, Martin, Javier, Raya, Enrique, Ortego-Centeno, Norberto, de los Angeles Aguirre, Maria, de Ramón Garrido, Enrique, Palma, María-Jesús Castillo, Alarcon-Riquelme, Marta E, and Kozyrev, Sergey V

Published
2015
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42. Molecular Signatures of Kidney Antibody–Secreting Cells in Lupus Patients With Active Nephritis Upon Immunosuppressive Therapy

Author

Crickx, Etienne, primary, Tamirou, Farah, additional, Huscenot, Tessa, additional, Costedoat‐Chalumeau, Nathalie, additional, Rabant, Marion, additional, Karras, Alexandre, additional, Robbins, Ailsa, additional, Fadeev, Tatiana, additional, Le Guern, Véronique, additional, Remy, Philippe, additional, Hummel, Aurélie, additional, Aydin, Selda, additional, Lauwerys, Bernard, additional, Weill, Jean‐Claude, additional, Reynaud, Claude‐Agnès, additional, Houssiau, Frédéric, additional, and Mahévas, Matthieu, additional

Published
2021
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43. Serum calprotectin (S100A8/A9): a promising biomarker in diagnosis and follow-up in different subgroups of juvenile idiopathic arthritis

Author

La, Céline, primary, Lê, Phu Quoc, additional, Ferster, Alina, additional, Goffin, Laurence, additional, Spruyt, Delphine, additional, Lauwerys, Bernard, additional, Durez, Patrick, additional, Boulanger, Cecile, additional, Sokolova, Tatiana, additional, Rasschaert, Joanne, additional, and Badot, Valérie, additional

Published
2021
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44. Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

Author

Teruel, María, Barturen, Guillermo, Martínez Bueno, Manuel, Castellini Pérez, Olivia, Barroso Gil, Miguel, Povedano, Elena, Kerick, Martin, Català Moll, Francesc, Makowska, Zuzanna, Buttgereit, Anne, Beretta, Lorenzo, Chizzolini, Carlo, Zuber, Aleksandra, Wynar, Donatienne, Kovács, Laszló, Balog, Attila, Deák, Magdolna, Bocskai, Márta, Dulic, Sonja, Kádár, Gabriella, Hiepe, Falk, Gerl, Velia, Thiel, Silvia, Rodriguez Maresca, Manuel, López Berrio, Antonio, Aguilar Quesada, Rocío, Navarro Linares, Héctor, Alvarez, Montserrat, Álvarez Errico, Damiana, Azevedo, Nancy, Barbarroja, Nuria, Cheng, Qingyu, Cremer, Jonathan, Groof, Aurélie de, Langhe, Ellen de, Ducreux, Julie, Dufour, Aleksandra, Hernández Fuentes, María, Khodadadi, Laleh, Kniesch, Katja, Li, Tianlu, López Pedrera, Chary, Marañón, Concepción, Muchmore, Brian, Neves, Esmeralda, Rouvière, Bénédicte, Simon, Quentin, Trombetta, Elena, Varela, Nieves, Witte, Torsten, Pers, Jacques-olivier, Ballestar, Esteban, Martin, Javier, Carnero Montoro, Elena, Alarcón Riquelme, Marta, Precisesads Clinical Consortium, Precisesads Flow Cytometry Study Group, Vigone, Barbara, Pers, Jacques Olivier, Saraux, Alain, Devauchelle-Pensec, Valérie, Cornec, Divi, Jousse-Joulin, Sandrine, Lauwerys, Bernard, Maudoux, Anne-lise, Vasconcelos, Carlos, Tavares, Ana, Faria, Raquel, Brandão, Mariana, Campar, Ana, Marinho, António, Farinha, Fátima, Almeida, Isabel, Gonzalez-Gay Mantecón, Miguel Ángel, Blanco Alonso, Ricardo, Corrales Martínez, Alfonso, Cervera, Ricard, Rodríguez Pintó, Ignasi, Espinosa, Gerard, Lories, Rik, Hunzelmann, Nicolas, Belz, Doreen, Baerlecken, Niklas, Stummvoll, Georg, Zauner, Michael, Lehner, Michaela, Collantes, Eduardo, Ortega Castro, Rafaela, Aguirre Zamorano, Mª Angeles, Escudero Contreras, Alejandro, Castro Villegas, Mª Carmen, Ortego, Norberto, Fernández Roldán, María Concepción, Raya, Enrique, Jiménez Moleón, Inmaculada, Ramon, Enrique de, Díaz Quintero, Isabel, Meroni, Pier Luigi, Gerosa, Maria, Schioppo, Tommaso, Artusi, Carolina, PRECISESADS Clinical Consortium, PRECISESADS Flow Cytometry Study Group, [Teruel,M, Barturen,G, Martínez-Bueno,M, Castellini-Pérez,O, Barroso-Gil,M, Povedano,E, Marañón,C, Carnero-Montoro,E, Alarcón-Riquelme,ME] GENYO, Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain. [Kerick,M, Martin,J] IPBLN-CSIC, Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científcas, Granada, Spain. [Català-Moll,F, Ballestar,E] Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), Badalona, Barcelona, Spain. [Català-Moll,F, Ballestar,E] IDIBELL, Bellvitge Biomedical Research Institute L’Hospitalet de Llobregat, Barcelona, Spain. [Makowska,Z, Buttgereit,A] Pharmaceuticals Division, Bayer Pharma Aktiengesellschaft, Berlin, Germany. [Pers,JO] Université de Brest, INSERM, Labex IGO, CHU de Brest, Brest, France.[Alarcón-Riquelme,ME] Institute for Environmental Medicine, Karolinska Institutet, Solna, Sweden., and Funding for the preparation of this manuscript has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement nº 115,565, resources composed of the financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and the EFPIA companies’ in kind contribution. MT is supported by a Spanish grant from Health Department, Junta de Andalucía (PI/0017/2016) and through the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806975. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. EC-M was funded by the Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness (FJCI_2014_20652). We thank Ralf Lesche for the production of RNASeq data and Marc Torres Ciuró for design support.

Subjects
Epigenomics, Male, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation [Medical Subject Headings], Autoimmune diseases, Gene Expression, Quantitative trait, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Interferons [Medical Subject Headings], 0302 clinical medicine, Rheumatic diseases, HLA Antigens, Genetics, Regulation of gene expression, 0303 health sciences, education.field_of_study, Multidisciplinary, Malalties autoimmunitàries, Molecular medicine, Epigenetic, Autoanticuerpos, Genomics, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genomics::Epigenomics [Medical Subject Headings], 3. Good health, Sjogren's Syndrome, DNA methylation, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::DNA Methylation [Medical Subject Headings], Medicine, Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Histocompatibility Antigens::HLA Antigens [Medical Subject Headings], Epigenetics, Female, Phenomena and Processes::Genetic Phenomena::Genetic Variation [Medical Subject Headings], Extracellular matrix organization, Science, Population, Check Tags::Male [Medical Subject Headings], Human leukocyte antigen, Biology, Variación genética, Article, 03 medical and health sciences, Rheumatology, Enfermedades autoinmunes, Diseases::Immune System Diseases::Autoimmune Diseases [Medical Subject Headings], Immunogenetics, Diseases::Immune System Diseases::Autoimmune Diseases::Arthritis, Rheumatoid::Sjogren's Syndrome [Medical Subject Headings], Humans, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies [Medical Subject Headings], education, Gene, 030304 developmental biology, Autoantibodies, 030203 arthritis & rheumatology, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, Genetic [Medical Subject Headings], Genetic Variation, DNA Methylation, Epigenètica, Check Tags::Female [Medical Subject Headings], Gene Expression Regulation, Epigenómica, Síndrome de Sjögren, Interferons, Expresión génica
Abstract

Funding for the preparation of this manuscript has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115,565, resources composed of the financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and the EFPIA companies' in kind contribution. MT is supported by a Spanish grant from Health Department, Junta de Andalucia (PI/0017/2016) and through the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806975. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. EC-M was funded by the Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness (FJCI_2014_20652). We thank Ralf Lesche for the production of RNASeq data and Marc Torres Ciuro for design support., Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population., Innovative Medicines Initiative Joint Undertaking from the European Union's Seventh Framework Program (FP7/2007-2013) 115,565, EFPIA companies, Junta de Andalucia PI/0017/2016, Innovative Medicines Initiative 2 Joint Undertaking 806975 European Union's Horizon 2020 research and innovation programme, EFPIA, Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness FJCI_2014_20652

Published
2021

45. 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

46. Molecular Signatures of Kidney Antibody-Secreting Cells in Lupus Patients With Active Nephritis Upon Immunosuppressive Therapy.

Author

UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Service de rhumatologie, Crickx, Etienne, Tamirou, Farah, Huscenot, Tessa, Costedoat-Chalumeau, Nathalie, Rabant, Marion, Karras, Alexandre, Robbins, Ailsa, Fadeev, Tatiana, Le Guern, Véronique, Remy, Philippe, Hummel, Aurélie, Aydin, Selda, Lauwerys, Bernard, Weill, Jean-Claude, Reynaud, Claude-Agnès, Houssiau, Frédéric, Mahévas, Matthieu, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service d'anatomie pathologique, UCL - (SLuc) Service de rhumatologie, Crickx, Etienne, Tamirou, Farah, Huscenot, Tessa, Costedoat-Chalumeau, Nathalie, Rabant, Marion, Karras, Alexandre, Robbins, Ailsa, Fadeev, Tatiana, Le Guern, Véronique, Remy, Philippe, Hummel, Aurélie, Aydin, Selda, Lauwerys, Bernard, Weill, Jean-Claude, Reynaud, Claude-Agnès, Houssiau, Frédéric, and Mahévas, Matthieu

Abstract

OBJECTIVE: This study was undertaken to characterize kidney and urine antibody-secreting cells (ASCs) from patients with active lupus nephritis, before and after induction therapy. METHODS: We included patients with biopsy-proven active lupus nephritis and performed anti-CD138 staining of kidney biopsy samples to visualize ASCs. We performed single-cell gene expression profiling on sorted ASCs from fresh biopsy samples using multiplex reverse transcriptase-polymerase chain reaction. We used a gene set that allowed for the study of ASC maturation from plasmablasts to long-lived plasma cells. We quantified urine ASCs from untreated patients with lupus nephritis at diagnosis and after 6 months of prospective follow-up during induction therapy. RESULTS: The number of kidney CD138+ ASCs in 46 untreated patients with lupus nephritis was correlated with a low estimated glomerular filtration rate and with tubulointerstitial damage. Most kidney ASCs from 3 untreated patients had a plasmablast molecular signature; in contrast, in 4 patients with refractory lupus nephritis, the kidney ASCs were mainly long-lived plasma cells, representing an ASC transcriptional profile similar to that in the bone marrow of 2 healthy donors. Some urine ASCs with a plasmablast signature were detected in patients with untreated active lupus nephritis. The presence of urine ASCs at 6 months was associated with treatment failure. CONCLUSION: Our results suggest potential for ASC-directed therapy in refractory lupus nephritis.

Published
2021

47. Serum calprotectin (S100A8/A9): a promising biomarker in diagnosis and follow-up in different subgroups of juvenile idiopathic arthritis.

Author

UCL - (SLuc) Service de rhumatologie, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service d'hématologie et d'oncologie pédiatrique, La, Céline, Lê, Phu Quoc, Ferster, Alina, Goffin, Laurence, Spruyt, Delphine, Lauwerys, Bernard, Durez, Patrick, Boulanger, Cecile, Sokolova, Tatiana, Rasschaert, Joanne, Badot, Valérie, UCL - (SLuc) Service de rhumatologie, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service d'hématologie et d'oncologie pédiatrique, La, Céline, Lê, Phu Quoc, Ferster, Alina, Goffin, Laurence, Spruyt, Delphine, Lauwerys, Bernard, Durez, Patrick, Boulanger, Cecile, Sokolova, Tatiana, Rasschaert, Joanne, and Badot, Valérie

Abstract

In the management of juvenile idiopathic arthritis (JIA), there is a lack of diagnostic and prognostic biomarkers. This study assesses the use of serum calprotectin (sCal) as a marker to monitor disease activity, and as a classification and prognosis tool of response to treatment or risk of flares in patients with JIA. Eighty-one patients with JIA from the CAP48 multicentric cohort were included in this study, as well as 11 non-paediatric healthy controls. An ELISA method was used to quantify sCal with a commercial kit. Patients with an active disease compared with healthy controls and with patients with inactive disease showed an eightfold and a twofold increased level of sCal, respectively. sCal was found to be correlated with the C-reactive protein (CRP) and even more strongly with the erythrocyte sedimentation rate. Evolution of DAS28 scores correlated well with evolution of sCal, as opposed to evolution of CRP. With regard to CRP, sCal could differentiate forms with active oligoarthritis from polyarthritis and systemic forms. However, sCal brought an added value compared with the CRP as a prognosis marker. Indeed, patients with active disease and reaching minimal disease activity (according to Juvenile Arthritis Disease Activity Score) at 6 months following the test had higher sCal levels, while patients with inactive disease had higher sCal levels if a flare was observed up to 3-9 months following the test. This study confirms the potential uses of sCal as a biomarker in the diagnosis and follow-up of JIA.

Published
2021

48. Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial.

Author

UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Humby, Frances, Durez, Patrick, Buch, Maya H, Lewis, Myles J, Rizvi, Hasan, Rivellese, Felice, Nerviani, Alessandra, Giorli, Giovanni, Mahto, Arti, Montecucco, Carlomaurizio, Lauwerys, Bernard, Ng, Nora, Ho, Pauline, Bombardieri, Michele, Romão, Vasco C, Verschueren, Patrick, Kelly, Stephen, Sainaghi, Pier Paolo, Gendi, Nagui, Dasgupta, Bhaskar, Cauli, Alberto, Reynolds, Piero, Cañete, Juan D, Moots, Robert, Taylor, Peter C, Edwards, Christopher J, Isaacs, John, Sasieni, Peter, Choy, Ernest, Pitzalis, Costantino, R4RA collaborative group, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Humby, Frances, Durez, Patrick, Buch, Maya H, Lewis, Myles J, Rizvi, Hasan, Rivellese, Felice, Nerviani, Alessandra, Giorli, Giovanni, Mahto, Arti, Montecucco, Carlomaurizio, Lauwerys, Bernard, Ng, Nora, Ho, Pauline, Bombardieri, Michele, Romão, Vasco C, Verschueren, Patrick, Kelly, Stephen, Sainaghi, Pier Paolo, Gendi, Nagui, Dasgupta, Bhaskar, Cauli, Alberto, Reynolds, Piero, Cañete, Juan D, Moots, Robert, Taylor, Peter C, Edwards, Christopher J, Isaacs, John, Sasieni, Peter, Choy, Ernest, Pitzalis, Costantino, and R4RA collaborative group

Abstract

Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis, 40% of patients show poor clinical response, which is mechanistically still unexplained. Because more than 50% of patients with rheumatoid arthritis have low or absent CD20 B cells-the target for rituximab-in the main disease tissue (joint synovium), we hypothesised that, in these patients, the IL-6 receptor inhibitor tocilizumab would be more effective. The aim of this trial was to compare the effect of tocilizumab with rituximab in patients with rheumatoid arthritis who had an inadequate response to anti-tumour necrosis factor (TNF) stratified for synovial B-cell status. This study was a 48-week, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial (rituximab vs tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis; R4RA) done in 19 centres across five European countries (the UK, Belgium, Italy, Portugal, and Spain). Patients aged 18 years or older who fulfilled the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for rheumatoid arthritis and were eligible for treatment with rituximab therapy according to UK National Institute for Health and Care Excellence guidelines were eligible for inclusion in the trial. To inform balanced stratification, following a baseline synovial biopsy, patients were classified histologically as B-cell poor or rich. Patients were then randomly assigned (1:1) centrally in block sizes of six and four to receive two 1000 mg rituximab infusions at an interval of 2 weeks (rituximab group) or 8 mg/kg tocilizumab infusions at 4-week intervals (tocilizumab group). To enhance the accuracy of the stratification of B-cell poor and B-cell rich patients, baseline synovial biopsies from all participants were subjected to RNA sequencing and reclassified by B-cell molecular signature. The study was powered to test the superiority of tocilizumab o

Published
2021

49. Atypical phenotype? The answer’s in the genotype: AGS caused by a novel RNASEH2C variant combined with XLA caused by a BTK deficiency.

Author

UCL - (SLuc) Service de rhumatologie, UCL - (SLuc) Service d'hématologie et d'oncologie pédiatrique, UCL - SSS/IREC/PEDI-Pôle de Pédiatrie, UCL - (SLuc) Département de pédiatrie, Boulanger, Cécile, Chatzis, Olga, Nolf, Delphine, Brichard, Bénédicte, Lauwerys, Bernard, Nassogne, Marie-Cécile, Limaye, Nisha, UCL - (SLuc) Service de rhumatologie, UCL - (SLuc) Service d'hématologie et d'oncologie pédiatrique, UCL - SSS/IREC/PEDI-Pôle de Pédiatrie, UCL - (SLuc) Département de pédiatrie, Boulanger, Cécile, Chatzis, Olga, Nolf, Delphine, Brichard, Bénédicte, Lauwerys, Bernard, Nassogne, Marie-Cécile, and Limaye, Nisha

Abstract

DEAR EDITOR, The feasibility of testing multiple genes at once using Next Generation Sequencing, particularly Whole Exome Sequencing (WES), has expanded the phenotypic spectrum associated with many disease genes. Distinguishing atypical presentation from combined gene effects and incidental from causal findings can however be challenging, particularly when composite phenotypes are themselves extremely rare. [...]

Published
2021

50. PKR regulation by phosphorylation and antiviral activity of the PKR-ADAR1 axis

Author

UCL - SSS/DDUV/VIRO - Virologie, UCL - Faculté de pharmacie et des sciences biomédicales, Michiels, Thomas, Vikkula, Miikka, Decottignies, Anabelle, Van Baren, Nicolas, Lauwerys, Bernard, Meurs, Eliane, Vanderplasschen, Alain, Cesaro, Teresa, UCL - SSS/DDUV/VIRO - Virologie, UCL - Faculté de pharmacie et des sciences biomédicales, Michiels, Thomas, Vikkula, Miikka, Decottignies, Anabelle, Van Baren, Nicolas, Lauwerys, Bernard, Meurs, Eliane, Vanderplasschen, Alain, and Cesaro, Teresa

Abstract

Protein kinase RNA-activated (PKR) and Double-stranded RNA-specific adenosine deaminase (ADAR1) are two double stranded RNA binding proteins, respectively involved in the antiviral response to viruses and in the metabolism of dsRNA molecules. PKR is a cellular protein kinase, that in response to dsRNA molecules generated during viral infections, gets activated and phosphorylates the translation initiation factor, eIF2a, leading to translational shutoff and apoptosis. As PKR thereby acts as a potent antiviral effector, many viruses evolved mechanisms to counteract its antiviral response. Previous studies showed that Theiler’s murine encephalomyelitis virus (TMEV), a cardiovirus belonging to the Picornaviridae family, can block PKR activation through the activity of its Leader (L) protein, an accessory protein of the virus known to block IFN gene transcription and perturb nucleocytoplasmic trafficking. In the first part of this thesis I contributed to a work showing that the L protein likely renders PKR insensitive to dsRNA molecules, possibly through the activation of cellular kinases. Next, we analyzed PKR phosphorylation modifications in the hope to identify potential phosphorylation sites responsible for PKR inhibition by TMEV L. We observed that the Ser6 residue located 3aa before the first double-stranded RNA binding motif (DRBM1) of PKR could be phosphorylated. A phospho-mimetic mutation of this site was inhibiting PKR activation after poly(I:C) transfection or viral infection, especially when combined to a phospho-mimetic mutation of the Ser97 residue, located 3aa before the second double- stranded RNA binding motif (DRBM2). We propose a model according to which phosphorylation occurring upstream of DRBMs would tighten the interaction of the DRBMs with the catalytic domain, blocking PKR in a closed conformation, and making it unable to be activated. ADAR1 is an editing enzyme, causing deamination of adenosines into inosines in dsRNA molecules, thus destabilizi, (BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 2021

Published
2021

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