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1. Building Reality Checks into the Translational Pathway for Diagnostic and Prognostic Models

Author

Lendrem, Dennis W, Lendrem, B Clare, Pratt, Arthur G, Tarn, Jessica R, Skelton, Andrew, James, Kathryn, McMeekin, Peter, Linsley, Matt, Gillespie, Colin, Cordell, Heather, Ng, Wan-Fai, and Isaacs, John D

Subjects
Statistics - Applications
Abstract

There has been a significant increase in the number of diagnostic and prognostic models published in the last decade. Testing such models in an independent, external validation cohort gives some assurance the model will transfer to a naturalistic, healthcare setting. Of 2,147 published models in the PubMed database, we found just 120 included some kind of separate external validation cohort. Of these studies not all were sufficiently well documented to allow a judgement about whether that model was likely to transfer to other centres, with other patients, treated by other clinicians, using data scored or analysed by other laboratories. We offer a solution to better characterizing the validation cohort and identify the key steps on the translational pathway for diagnostic and prognostic models.

Published
2018

2. Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Author

Devauchelle-Pensec, Valerie, Dieude, Philippe, Dubost, Jean Jacques, Fauchais, Anne-Laure, Goeb, Vincent, Hachulla, Eric, Larroche, Claire, Le Guern, Véronique, Morel, Jacques, Perdriger, Aleth, Puéchal, Xavier, Rist, Stephanie, Sen, Damien, Sibilia, Jean, Vittecoq, Olivier, Benessiano, Joelle, Tubiana, Sarah, Inamo, Karine, Gaete, Stanie, Batouche, Djilali, Molinari, Domitille, Randrianandrasana, Mickael, Pane, Isabelle, Abbe, Adeline, Baron, Gabriel, Ravaud, Philippe, Gottenberg, Jacques-Eric, Saraux, Alain, Devauchelle-Pensec, Valérie, Hayem, Gilles, Hatron, Pierre, Sene, Damien, Zarnitsky, Charles, Furlan, Valérie, Perrodeau, Elodie, Seror, Raphaele, Mariette, Xavier, Brown, S, Navarro, N Coy, Pitzalis, C, Emery, P, Pavitt, S, Gray, J, Hulme, C, Hall, F, Busch, R, Smith, P, Dawson, L, Bombardieri, M, Ng, W-F, Pease, C, Price, E, Sutcliffe, N, Woods, C, Ruddock, S, Everett, C, Reynolds, C, Skinner, E, Poveda-Gallego, A, Rout, J, Macleod, I, Rauz, S, Bowman, S, Ng, Wan-Fai, Bowman, Simon J, Griffiths, Bridget, Hall, Frances, Bacaba, Elalaine C, Frankland, Helen, Moots, Robert, Chadravarty, Kuntal, Lamabadusuriya, Shamin, Bombardieri, Michele, Pitzalis, Constantino, Sutcliffe, Nurhan, Breston, Celia, Gendi, Nagui, Culfear, Karen, Riddell, Claire, Hamburger, John, Richards, Andrea, Rauz, Saaeh, Brailsford, Sue, Dasgin, Joanne, Logan, Joanne, Mulherin, Diarmuid, Andrews, Jacqueline, Emery, Pau, McManus, Alison, Pease, Colin, Pickles, David, Booth, Alison, Regan, Marian, Kin, Jon King, Holt, Amanda, Dimitroulas, Theodoros, Kadiki, Lucy, Kaur, Daljit, Kitas, George, Khan, Abdul, Cosier, Tracey, Panthakalam, Mintrim, Kell, Lloyd, Mark, Moore, Lisa, Gordon, Esther, Lawson, Cathy, Gupta, Monica, Hunter, John, Stirton, Lesley, Ortiz, Gill, Price, Elizabeth, Pelger, Suzannah, Gorman, Claire, Hans, Balinder, Clunie, Gavin, Lane, Suzanne, Rose, Ginny, Cuckow, Sue, Batley, Michael, Einosas, Ruby, Knight, Susan, Symmons, Deborah, Jones, Beverley, Carr, Andrew, Edgar, Suzanne, Figuereido, Francisco, Foggo, Heather, Lendrem, Dennis, Macleod, Iain, Mitchell, Sheryl, Downie, Christine, Tarn, Jessica, Locke, James, Al-Ali, Shereen, Legg, Sarah, Mirza, Kamran, Hargreaves, Ben, Hetherington, Laura, Jones, Adrian, Lanyon, Peter, Muir, Alice, White, Paula, Young-Min, Steven, Pugmire, Susan, Vadivelu, Saravanan, Cooper, Annie, Watkins, Marianne, Field, Anne, Kaye, Stephen, Mewar, Devesh, Medcalf, Patricia, Tomlinson, Pamela, Whiteside, Debbie, McHugh, Neil, Pauling, John, James, Julie, Dowden, Andrea, Akil, Mohammed, McDermott, Jayne, Godia, Olivia, Coady, David, Kidd, Elizabeth, Palmer, Lynne, Li, Charles, Bartrum, Sarah, Mead, De, Dasgupta, Bhaskar, Katsande, Victoria, Long, Pamela, Vermaak, Erin, Turner, Janet, Chandra, Usha, MacKay, Kirsten, Fedele, Stefano, Ferenkeh-Koroma, Ada, Giles, Ian, Isenberg, David, MaConnell, Helena, Ahwiren, Nyarko, Porter, Stephen, Allcoa, Paul, McLaren, John, Tarn, Jessica R, Howard-Tripp, Nadia, Lendrem, Dennis W, Skelton, Andrew J, James, Katherine, McMeekin, Peter, Hackett, Katie L, Lendrem, B Clare, Casement, John, Pease, Colin T, Emery, Paul, Pitzalis, Costantino, Saravanan, Vadivelu, Johnsen, Svein J A, Norheim, Katrine B, Omdal, Roald, Stocken, Deborah, Everett, Colin, Fernandez, Catherine, and Isaacs, John D

Published
2019
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3. Trained Immunity in Primary Sjögren’s Syndrome: Linking Type I Interferons to a Pro-Atherogenic Phenotype

Author

Huijser, Erika, primary, van Helden-Meeuwsen, Cornelia G., additional, Grashof, Dwin G. B., additional, Tarn, Jessica R., additional, Brkic, Zana, additional, Huisman, Josje M. A., additional, Wahadat, M. Javad, additional, van de Werken, Harmen J. G., additional, Lopes, Ana P., additional, van Roon, Joel A. G., additional, van Daele, Paul L. A., additional, Kamphuis, Sylvia, additional, Ng, Wan-Fai, additional, Bekkering, Siroon, additional, Joosten, Leo A. B., additional, Dik, Willem A., additional, and Versnel, Marjan A., additional

Published
2022
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4. Variability of Primary Sjögren's Syndrome Is Driven by Interferon α and Interferon α Blood Levels Are Associated With the Class II HLA–DQ Locus

Author

Trutschel, Diana, Bost, Pierre, Mariette, Xavier, Bondet, Vincent, Llibre, Alba, Posseme, Celine, Charbit, Bruno, Thorball, Christian W., Jonsson, Roland, Lessard, Christopher J., Felten, Renaud, Ng, Wan Fai, Chatenoud, Lucienne, Dumortier, Hélène, Sibilia, Jean, Fellay, Jacques, Brokstad, Karl A., Appel, Silke, Tarn, Jessica R., Quintana‐Murci, Lluis, Mingueneau, Michael, Meyer, Nicolas, Duffy, Darragh, Schwikowski, Benno, Gottenberg, Jacques Eric, Dernis, Emmanuelle, Devauchelle‐Pensec, Valerie, Dieude, Philippe, Dubost, Jean‐Jacques, Fauchais, Anne‐Laure, Goeb, Vincent, Hachulla, Eric, Hatron, Pierre Yves, Larroche, Claire, Le Guern, Véronique, Morel, Jacques, Perdriger, Aleth, Salliot, Carinne, Rist, Stephanie, Saraux, Alain, Vittecoq, Olivier, Nocturne, Gaétane, Ravaud, Philippe, Seror, Raphaèle, Abel, Laurent, Alcover, Andres, Aschard, Hugues, Astrom, Kalla, Bousso, Philippe, Bruhns, Pierre, Cumano, Ana, Demangel, Caroline, Deriano, Ludovic, Di Santo, James, Dromer, Françoise, Eberl, Gérard, Enninga, Jost, Gelpi, Odile, GompertsBoneca, Ivo, Hasan, Milena, Hercberg, Serge, Lantz, Olivier, Leclerc, Claude, Mouquet, Hugo, Pellegrini, Sandra, Pol, Stanislas, Rausell, Antonio, Rogge, Lars, Sakuntabhai, Anavaj, Schwartz, Olivier, Shorte, Spencer, Soumelis, Vassili, Tangy, Frédéric, Tartour, Eric, Toubert, Antoine, Touvier, Mathilde, Ungeheuer, Marie‐Noëlle, Albert, Matthew L., Biomédecine computationelle des systèmes / Computational systems biomedicine, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Universität Zürich [Zürich] = University of Zurich (UZH), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Service de Rhumatologie [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Projet NECESSITY (PN), Hôpitaux Universitaires Paris Sud [AP-HP] (HUPS)-Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Immunologie Translationnelle - Translational Immunology lab, Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Ecole Polytechnique Fédérale de Lausanne (EPFL), Université de Lausanne = University of Lausanne (UNIL), Lausanne University Hospital, University of Bergen (UiB), Oklahoma Medical Research Foundation (OMRF), University of Oklahoma Health Sciences Center (OUHSC), Université de Strasbourg (UNISTRA), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Newcastle University [Newcastle], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Immunologie, Immunopathologie et Chimie Thérapeutique (I2CT), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Biogen Inc. [Cambridge, MA, USA], Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Supported by the Innovative Medicines Initiative 2 Joint Undertaking (JU) (grant 806975). The JU receives support from the European Union’s Horizon 2020 research and innovation program and the European Unionand the European Federation of Pharmaceutical Industries and Associations. This work was also supported by the National Institutes of Health (National Institute of Arthritis and Musculoskeletal Skin Disease grant R01-AR-065953). The Assessment of Systemic Signs and Evolution in Sjögren’s Syndrome(ASSESS) national multicenter prospective cohort was formed in 2006 with aFrench Ministry of Health grant (Programme Hospitalier de Recherche Clinique 2005 P060228). The ASSESS cohort is promoted by the French Society of Rheumatology and receives research grants from the French Society of Rheumatology. Dr. Gottenberg’s work was supported by Bristol Myers Squibbfor transcriptomic analysis of the ASSESS and Norwegian cohorts and by Geneviève Garnier (Association Française du Syndrome de Gougerot-Sjögrenet des syndromes secs). Drs. Trutschel’s and Schwikowski’s work was supported by Geneviève Garnier (Association Française du Syndrome de Gougerot-Sjögren et des syndromes secs)., Milieu Intérieur Consortium, ASSESS study investigators, and NECESSITY Consortium: Emmanuelle Dernis, Valerie Devauchelle-Pensec, Philippe Dieude, Jean-Jacques Dubost, Anne-Laure Fauchais, Vincent Goeb, Eric Hachulla, Pierre Yves Hatron, Claire Larroche, Véronique Le Guern, Jacques Morel, Aleth Perdriger, Carinne Salliot, Stephanie Rist, Alain Saraux, Jean Sibilia, Olivier Vittecoq, Gaétane Nocturne, Philippe Ravaud, Raphaèle Seror, Laurent Abel, Andres Alcover, Hugues Aschard, Kalla Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Odile Gelpi, Ivo GompertsBoneca, Milena Hasan, Serge Hercberg, Olivier Lantz, Claude Leclerc, Hugo Mouquet, Sandra Pellegrini, Stanislas Pol, Antonio Rausell, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis, Frédéric Tangy, Eric Tartour, Antoine Toubert, Mathilde Touvier, Marie-Noëlle Ungeheuer, Matthew L Albert, Darragh Duffy, Lluis Quintana-Murci., European Project: 806975,NECESSITY, Clauss, Isabelle, and NEw Clinical Endpoints in primary Sjögren’s Syndrome: an Interventional Trial based on stratifYing patients - NECESSITY - 0000-00-00 - 0000-00-00 - 806975 - VALID

Subjects
Proteomics, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Sjogren's Syndrome, Rheumatology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, HLA-DQ Antigens, Immunology, Humans, Interferon-alpha, Immunology and Allergy, Prospective Studies
Abstract

Objective: Primary Sjögren's syndrome (SS) is the second most frequent systemic autoimmune disease, affecting 0.1% of the general population. To characterize the molecular and clinical variabilities among patients with primary SS, we integrated transcriptomic, proteomic, cellular, and genetic data with clinical phenotypes in a cohort of 351 patients with primary SS. Methods: We analyzed blood transcriptomes and genotypes of 351 patients with primary SS who were participants in a multicenter prospective clinical cohort. We replicated the transcriptome analysis in 3 independent cohorts (n = 462 patients). We determined circulating interferon-α (IFNα) and IFNγ protein concentrations using digital single molecular arrays (Simoa). Results: Transcriptome analysis of the prospective cohort showed a strong IFN gene signature in more than half of the patients; this finding was replicated in the 3 independent cohorts. Because gene expression analysis did not discriminate between type I IFN and type II IFN, we used Simoa to demonstrate that the IFN transcriptomic signature was driven by circulating IFNα and not by IFNγ protein levels. IFNα protein levels, detectable in 75% of patients, were significantly associated with clinical and immunologic features of primary SS disease activity at enrollment and with increased frequency of systemic complications over the 5-year follow-up. Genetic analysis revealed a significant association between IFNα protein levels, a major histocompatibility (MHC) class II haplotype, and anti-SSA antibody. Additional cellular analysis revealed that an MHC class II HLA–DQ locus acts through up-regulation of HLA class II molecules on conventional dendritic cells. Conclusion: We identified the predominance of IFNα as a driver of primary SS variability, with IFNα demonstrating an association with HLA gene polymorphisms., Arthritis & Rheumatology, 74 (12), ISSN:2326-5191, ISSN:2326-5205

Published
2022
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5. Trained Immunity in Primary Sjögren’s Syndrome: Linking Type I Interferons to a Pro-Atherogenic Phenotype

Author

CTI, MS Reumatologie/Immunologie/Infectie, Infection & Immunity, Lab Reumatologie/Klinische Immunologie, Huijser, Erika, van Helden-Meeuwsen, Cornelia G., Grashof, Dwin G.B., Tarn, Jessica R., Brkic, Zana, Huisman, Josje M.A., Wahadat, M. Javad, van de Werken, Harmen J.G., Lopes, Ana P., van Roon, Joel A.G., van Daele, Paul L.A., Kamphuis, Sylvia, Ng, Wan Fai, Bekkering, Siroon, Joosten, Leo A.B., Dik, Willem A., Versnel, Marjan A., CTI, MS Reumatologie/Immunologie/Infectie, Infection & Immunity, Lab Reumatologie/Klinische Immunologie, Huijser, Erika, van Helden-Meeuwsen, Cornelia G., Grashof, Dwin G.B., Tarn, Jessica R., Brkic, Zana, Huisman, Josje M.A., Wahadat, M. Javad, van de Werken, Harmen J.G., Lopes, Ana P., van Roon, Joel A.G., van Daele, Paul L.A., Kamphuis, Sylvia, Ng, Wan Fai, Bekkering, Siroon, Joosten, Leo A.B., Dik, Willem A., and Versnel, Marjan A.

Published
2022

6. Trained Immunity in Primary Sjogren's Syndrome: Linking Type I Interferons to a Pro-Atherogenic Phenotype

Author

Huijser, Erika, Helden-Meeuwsen, C.G. van, Grashof, Dwin G.B., Tarn, Jessica R., Brkic, Zana, Huisman, J.M., Bekkering, S., Joosten, L.A.B., Dik, Willem A., Versnel, M.A., Huijser, Erika, Helden-Meeuwsen, C.G. van, Grashof, Dwin G.B., Tarn, Jessica R., Brkic, Zana, Huisman, J.M., Bekkering, S., Joosten, L.A.B., Dik, Willem A., and Versnel, M.A.

Abstract

Contains fulltext : 253395.pdf (Publisher’s version ) (Open Access)

Published
2022

8. Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Author

Tarn, Jessica R, Howard-Tripp, Nadia, Lendrem, Dennis W, Mariette, Xavier, Saraux, Alain, Devauchelle-Pensec, Valerie, Seror, Raphaele, Skelton, Andrew J, James, Katherine, McMeekin, Peter, Al-Ali, Shereen, Hackett, Kate, Lendrem, B Clare, Hargreaves, Ben, Casement, John, Mitchell, Sheryl, Bowman, Simon J, Price, Elizabeth, Pease, Colin T, Emery, Paul, Lanyon, Peter, Hunter, John, Gupta, Monica, Bombardieri, Michele, Sutcliffe, Nurhan, Pitzalis, Costantino, McLaren, John, Cooper, Annie, Regan, Marian, Giles, Ian, Isenberg, David, Saravanan, Vadivelu, Coady, David, Dasgupta, Bhaskar, McHugh, Neil, Young-Min, Steven, Moots, Robert, Gendi, Nagui, Akil, Mohammed, Griffiths, Bridget, Johnsen, Svein J A, Norheim, Katrine B, Omdal, Roald, Stocken, Deborah, Everett, Colin, Fernandez, Catherine, Isaacs, John D, Gottenberg, Jacques-Eric, Ng, Wan-Fai, Dieude, Philippe, Dubost, Jean Jacques, Fauchais, Anne-Laure, Goeb, Vincent, Hachulla, Eric, Larroche, Claire, Le Guern, Véronique, Morel, Jacques, Perdriger, Aleth, Puéchal, Xavier, Rist, Stephanie, Sen, Damien, Sibilia, Jean, Vittecoq, Olivier, Benessiano, Joelle, Tubiana, Sarah, Inamo, Karine, Gaete, Stanie, Batouche, Djilali, Molinari, Domitille, Randrianandrasana, Mickael, Pane, Isabelle, Abbe, Adeline, Baron, Gabriel, Ravaud, Philippe, Dubost, Jean-Jacques, Rist, Stéphanie, Devauchelle-Pensec, Valérie, Hayem, Gilles, Hatron, Pierre, Sene, Damien, Zarnitsky, Charles, Furlan, Valérie, Perrodeau, Elodie, Brown, S, Navarro, N Coy, Pitzalis, C, Emery, P, Pavitt, S, Gray, J, Hulme, C, Hall, F, Busch, R, Smith, P, Dawson, L, Bombardieri, M, Ng, W-F, Pease, C, Price, E, Sutcliffe, N, Woods, C, Ruddock, S, Everett, C, Reynolds, C, Skinner, E, Poveda-Gallego, A, Rout, J, Macleod, I, Rauz, S, Bowman, S, Hall, Frances, Bacaba, Elalaine C, Frankland, Helen, Chadravarty, Kuntal, Lamabadusuriya, Shamin, Pitzalis, Constantino, Breston, Celia, Culfear, Karen, Riddell, Claire, Hamburger, John, Richards, Andrea, Rauz, Saaeh, Brailsford, Sue, Dasgin, Joanne, Logan, Joanne, Mulherin, Diarmuid, Andrews, Jacqueline, Emery, Pau, McManus, Alison, Pease, Colin, Pickles, David, Booth, Alison, Kin, Jon King, Holt, Amanda, Dimitroulas, Theodoros, Kadiki, Lucy, Kaur, Daljit, Kitas, George, Khan, Abdul, Cosier, Tracey, Panthakalam, Mintrim, Kell, Lloyd, Mark, Moore, Lisa, Gordon, Esther, Lawson, Cathy, Stirton, Lesley, Ortiz, Gill, Pelger, Suzannah, Gorman, Claire, Hans, Balinder, Clunie, Gavin, Lane, Suzanne, Rose, Ginny, Cuckow, Sue, Batley, Michael, Einosas, Ruby, Knight, Susan, Symmons, Deborah, Jones, Beverley, Carr, Andrew, Edgar, Suzanne, Figuereido, Francisco, Foggo, Heather, Lendrem, Dennis, Macleod, Iain, Downie, Christine, Tarn, Jessica, Locke, James, Legg, Sarah, Mirza, Kamran, Hetherington, Laura, Jones, Adrian, Muir, Alice, White, Paula, Pugmire, Susan, Vadivelu, Saravanan, Watkins, Marianne, Field, Anne, Kaye, Stephen, Mewar, Devesh, Medcalf, Patricia, Tomlinson, Pamela, Whiteside, Debbie, Pauling, John, James, Julie, Dowden, Andrea, McDermott, Jayne, Godia, Olivia, Kidd, Elizabeth, Palmer, Lynne, Li, Charles, Bartrum, Sarah, Mead, De, Katsande, Victoria, Long, Pamela, Vermaak, Erin, Turner, Janet, Chandra, Usha, MacKay, Kirsten, Fedele, Stefano, Ferenkeh-Koroma, Ada, MaConnell, Helena, Ahwiren, Nyarko, Porter, Stephen, and Allcoa, Paul

Subjects
medicine.medical_specialty, business.industry, Immunology, Hydroxychloroquine, Placebo, Article, Rheumatology, B700, Clinical trial, B900, Internal medicine, Cohort, Immunology and Allergy, Medicine, Observational study, Rituximab, business, Depression (differential diagnoses), medicine.drug
Abstract

Summary Background Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjogren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. Methods We did hierarchical cluster analysis using five common symptoms associated with primary Sjogren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjogren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. Findings In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. Interpretation Stratification on the basis of patient-reported symptoms of patients with primary Sjogren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. Funding UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology. Video Abstract Download : Download video (77MB) Symptom-based stratification of patients with Sjogren's syndrome

Published
2019

9. Interleukin-22 and associated genes are targets of microRNAs dysregulated

Author

Tarn, Jessica R., Nordmark, Gunnel, Gillespie, Colin, Al-Ali, Shereen, James, Katherine, Mitchell, Sheryl, Bowman, Simon, Griffiths, Bridget, Johnsen, Svein Joar Auglaend, Norheim, Katrine, Backlin, Carin, Rönnblom, Lars, Eloranta, Maija-Leena, Omdal, Roald, Young, David Alan, Ng, Wan-Fai, Tarn, Jessica R., Nordmark, Gunnel, Gillespie, Colin, Al-Ali, Shereen, James, Katherine, Mitchell, Sheryl, Bowman, Simon, Griffiths, Bridget, Johnsen, Svein Joar Auglaend, Norheim, Katrine, Backlin, Carin, Rönnblom, Lars, Eloranta, Maija-Leena, Omdal, Roald, Young, David Alan, and Ng, Wan-Fai

Published
2018

11. Systems Biology in 874 Patients with Primary Sjogren's Syndrome Indicates the Predominant Role of Interferon Alpha Compared to Interferon Gamma, Its Association with Systemic Complications, and a New Aspect of the Genetic Contribution of HLA

Author

Bost, Pierre, Mariette, Xavier, Bondet, Vincent, Llibre, Alba, Posseme, Celine, Charbit, Bruno, Thorball, Christian, Jonsson, Roland, Lessard, Chris, Felten, Renaud, Ng, Fai, Silvis, K., Chatenoud, Lucienne, Dumortier, Helene, Jacques Fellay, Brostadt, Karl A., Appel, Silke, Tarn, Jessica R., Quintana-Murci, Lluis, Minguenau, Michael, Meyer, Nicolas, Duffy, Darragh, Schwikowski, Benno, and Gottenberg, Jacques-Eric

12. Variability of Primary Sjogren's Syndrome Is Driven by Interferon alpha and Interferon alpha Blood Levels Are Associated With the Class II HLA-DQ Locus

Author

Trutschel, Diana, Bost, Pierre, Mariette, Xavier, Bondet, Vincent, Llibre, Alba, Posseme, Celine, Charbit, Bruno, Thorball, Christian W., Jonsson, Roland, Lessard, Christopher J., Felten, Renaud, Ng, Wan Fai, Chatenoud, Lucienne, Dumortier, Helene, Sibilia, Jean, Fellay, Jacques, Brokstad, Karl A., Appel, Silke, Tarn, Jessica R., Quintana-Murci, Lluis, Mingueneau, Michael, Meyer, Nicolas, Duffy, Darragh, Schwikowski, Benno, and Gottenberg, Jacques Eric

Subjects
disease-activity, signatures, pathways, innate, cells, autoantibody production, clinical phenotypes
Abstract

Objective Primary Sjogren's syndrome (SS) is the second most frequent systemic autoimmune disease, affecting 0.1% of the general population. To characterize the molecular and clinical variabilities among patients with primary SS, we integrated transcriptomic, proteomic, cellular, and genetic data with clinical phenotypes in a cohort of 351 patients with primary SS. Methods We analyzed blood transcriptomes and genotypes of 351 patients with primary SS who were participants in a multicenter prospective clinical cohort. We replicated the transcriptome analysis in 3 independent cohorts (n = 462 patients). We determined circulating interferon-alpha (IFN alpha) and IFN gamma protein concentrations using digital single molecular arrays (Simoa). Results Transcriptome analysis of the prospective cohort showed a strong IFN gene signature in more than half of the patients; this finding was replicated in the 3 independent cohorts. Because gene expression analysis did not discriminate between type I IFN and type II IFN, we used Simoa to demonstrate that the IFN transcriptomic signature was driven by circulating IFN alpha and not by IFN gamma protein levels. IFN alpha protein levels, detectable in 75% of patients, were significantly associated with clinical and immunologic features of primary SS disease activity at enrollment and with increased frequency of systemic complications over the 5-year follow-up. Genetic analysis revealed a significant association between IFN alpha protein levels, a major histocompatibility (MHC) class II haplotype, and anti-SSA antibody. Additional cellular analysis revealed that an MHC class II HLA-DQ locus acts through up-regulation of HLA class II molecules on conventional dendritic cells. Conclusion We identified the predominance of IFN alpha as a driver of primary SS variability, with IFN alpha demonstrating an association with HLA gene polymorphisms.

13. Variability of Primary Sjögren's Syndrome Is Driven by Interferon-α and Interferon-α Blood Levels Are Associated With the Class II HLA-DQ Locus.

Author

Trutschel D, Bost P, Mariette X, Bondet V, Llibre A, Posseme C, Charbit B, Thorball CW, Jonsson R, Lessard CJ, Felten R, Ng WF, Chatenoud L, Dumortier H, Sibilia J, Fellay J, Brokstad KA, Appel S, Tarn JR, Quintana-Murci L, Mingueneau M, Meyer N, Duffy D, Schwikowski B, and Gottenberg JE

Subjects
Humans, Interferon-alpha, Proteomics, Prospective Studies, HLA-DQ Antigens genetics, Sjogren's Syndrome
Abstract

Objective: Primary Sjögren's syndrome (SS) is the second most frequent systemic autoimmune disease, affecting 0.1% of the general population. To characterize the molecular and clinical variabilities among patients with primary SS, we integrated transcriptomic, proteomic, cellular, and genetic data with clinical phenotypes in a cohort of 351 patients with primary SS., Methods: We analyzed blood transcriptomes and genotypes of 351 patients with primary SS who were participants in a multicenter prospective clinical cohort. We replicated the transcriptome analysis in 3 independent cohorts (n = 462 patients). We determined circulating interferon-α (IFNα) and IFNγ protein concentrations using digital single molecular arrays (Simoa)., Results: Transcriptome analysis of the prospective cohort showed a strong IFN gene signature in more than half of the patients; this finding was replicated in the 3 independent cohorts. Because gene expression analysis did not discriminate between type I IFN and type II IFN, we used Simoa to demonstrate that the IFN transcriptomic signature was driven by circulating IFNα and not by IFNγ protein levels. IFNα protein levels, detectable in 75% of patients, were significantly associated with clinical and immunologic features of primary SS disease activity at enrollment and with increased frequency of systemic complications over the 5-year follow-up. Genetic analysis revealed a significant association between IFNα protein levels, a major histocompatibility (MHC) class II haplotype, and anti-SSA antibody. Additional cellular analysis revealed that an MHC class II HLA-DQ locus acts through up-regulation of HLA class II molecules on conventional dendritic cells., Conclusion: We identified the predominance of IFNα as a driver of primary SS variability, with IFNα demonstrating an association with HLA gene polymorphisms., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Published
2022
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14. Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials.

Author

Tarn JR, Howard-Tripp N, Lendrem DW, Mariette X, Saraux A, Devauchelle-Pensec V, Seror R, Skelton AJ, James K, McMeekin P, Al-Ali S, Hackett KL, Lendrem BC, Hargreaves B, Casement J, Mitchell S, Bowman SJ, Price E, Pease CT, Emery P, Lanyon P, Hunter J, Gupta M, Bombardieri M, Sutcliffe N, Pitzalis C, McLaren J, Cooper A, Regan M, Giles I, Isenberg D, Saravanan V, Coady D, Dasgupta B, McHugh N, Young-Min S, Moots R, Gendi N, Akil M, Griffiths B, Johnsen SJA, Norheim KB, Omdal R, Stocken D, Everett C, Fernandez C, Isaacs JD, Gottenberg JE, and Ng WF

Abstract

Background: Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response., Methods: We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab., Findings: In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo., Interpretation: Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases., Funding: UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology. VIDEO ABSTRACT., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Published
2019
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