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1. SICOB-endorsed national Delphi consensus on obesity treatment optimization: focus on diagnosis, pre-operative management, and weight regain/insufficient weight loss approach

Author: Zappa, M. A., Iossa, A., Busetto, L., Chiappetta, S., Greco, F., Lucchese, M., Micanti, F., Mingrone, Geltrude, Navarra, G., Raffaelli, Marco, Altorio, S. F., Angrisani, L., Arcudi, C., Bellini, F., Bernante, P., Berta, R., Capristo, Esmeralda, Carbonelli, M. G., Casella, G., Casella, J. M., Castagneto Gissey, L., Cerbone, M. R., Ciampaglia, F., Ciccoritti, Luigi, Contine, A., Curro, G., D'Alessio, R., De Palma, M., Delle Piane, D., Di Benedetto, N., Di Lorenzo, N., Fantola, G., Farnaz, R., Foletto, M., Forestieri, P., Frittitta, L., Galfrascoli, E., Gentileschi, P., Giardiello, C., Giustacchini, Piero, Giusti, M. P., Grandone, I., Guidone, Caterina, Iaconelli, Amerigo, Lembo, Erminia, Leanza, S., Lezoche, G., Lunardi, C., Martines, G., Marzano, B., Paone, E., Papadia, F. S., Perrone, F., Piazza, L., Pilone, V., Pizzi, P., Rice, M., Rizzi, A., Santini, F., Sarro, G., Schettino, A., Tartaglia, N., Toppino, Piero Maria, Usai, Alessandro, De Luca, Marianna, Mingrone G. (ORCID:0000-0003-2021-528X), Raffaelli M. (ORCID:0000-0002-1259-2491), Capristo E. (ORCID:0000-0002-5753-3495), Ciccoritti L., Giustacchini P., Guidone C., Iaconelli A., Lembo E., Toppino M., Usai A., De Luca M. (ORCID:0000-0002-9996-6563), Zappa, M. A., Iossa, A., Busetto, L., Chiappetta, S., Greco, F., Lucchese, M., Micanti, F., Mingrone, Geltrude, Navarra, G., Raffaelli, Marco, Altorio, S. F., Angrisani, L., Arcudi, C., Bellini, F., Bernante, P., Berta, R., Capristo, Esmeralda, Carbonelli, M. G., Casella, G., Casella, J. M., Castagneto Gissey, L., Cerbone, M. R., Ciampaglia, F., Ciccoritti, Luigi, Contine, A., Curro, G., D'Alessio, R., De Palma, M., Delle Piane, D., Di Benedetto, N., Di Lorenzo, N., Fantola, G., Farnaz, R., Foletto, M., Forestieri, P., Frittitta, L., Galfrascoli, E., Gentileschi, P., Giardiello, C., Giustacchini, Piero, Giusti, M. P., Grandone, I., Guidone, Caterina, Iaconelli, Amerigo, Lembo, Erminia, Leanza, S., Lezoche, G., Lunardi, C., Martines, G., Marzano, B., Paone, E., Papadia, F. S., Perrone, F., Piazza, L., Pilone, V., Pizzi, P., Rice, M., Rizzi, A., Santini, F., Sarro, G., Schettino, A., Tartaglia, N., Toppino, Piero Maria, Usai, Alessandro, De Luca, Marianna, Mingrone G. (ORCID:0000-0003-2021-528X), Raffaelli M. (ORCID:0000-0002-1259-2491), Capristo E. (ORCID:0000-0002-5753-3495), Ciccoritti L., Giustacchini P., Guidone C., Iaconelli A., Lembo E., Toppino M., Usai A., and De Luca M. (ORCID:0000-0002-9996-6563)
Abstract: Purpose: Overweight and obesity affects 60% of adults causing more than 1.2 million deaths across world every year. Fight against involved different specialist figures and multiple are the approved weapons. Aim of the present survey endorsed by the Italian Society of Bariatric Surgery (SICOB) is to reach a national consensus on obesity treatment optimization through a Delphi process. Methods: Eleven key opinion leaders (KOLs) identified 22 statements with a major need of clarification and debate. The explored pathways were: (1) Management of patient candidate to bariatric/metabolic surgery (BMS); (2) Management of patient not eligible for BMS; (3) Management of patient with short-term (2 years) weight regain (WR) or insufficient weight loss (IWL); (4) Management of the patient with medium-term (5 years) WR; and (5) Association between drugs and BMS as WR prevention. The questionnaire was distributed to 65 national experts via an online platform with anonymized results. Results: 54 out of 65 invited panelists (83%) respond. Positive consensus was reached for 18/22 statements (82%); while, negative consensus (s20.4; s21.5) and no consensus (s11.5, s17) were reached for 2 statements, respectively (9%). Conclusion: The Delphi results underline the importance of first-line interdisciplinary management, with large pre-treatment examination, and establish a common opinion on how to properly manage post-operative IWL/WR. Level of evidence V: Report of expert committees.
Published: 2023

2. Mepolizumab for Eosinophilic Granulomatosis with Polyangiitis (EGPA): a European multicenter observational study

Author: Bettiol, A, Urban, M, Dagna, L, Cottin, V, Franceschini, F, Del Giacco, S, Schiavon, F, Neumann, T, Lopalco, G, Novikov, P, Baldini, C, Lombardi, C, Berti, A, Alberici, F, Folci, M, Negrini, S, Sinico, R, Quartuccio, L, Lunardi, C, Parronchi, P, Moosig, F, Espígol-Frigolé, G, Schroeder, J, Kernder, A, Monti, S, Silvagni, E, Crimi, C, Cinetto, F, Fraticelli, P, Roccatello, D, Vacca, A, Mohammad, A, Hellmich, B, Samson, M, Bargagli, E, Cohen Tervaert, J, Ribi, C, Fiori, D, Bello, F, Fagni, F, Moroni, L, Ramirez, G, Nasser, M, Marvisi, C, Toniati, P, Firinu, D, Padoan, R, Egan, A, Seeliger, B, Iannone, F, Salvarani, C, Jayne, D, Prisco, D, Vaglio, A, Emmi, G, Bettiol, Alessandra, Urban, Maria Letizia, Dagna, Lorenzo, Cottin, Vincent, Franceschini, Franco, Del Giacco, Stefano, Schiavon, Franco, Neumann, Thomas, Lopalco, Giuseppe, Novikov, Pavel, Baldini, Chiara, Lombardi, Carlo, Berti, Alvise, Alberici, Federico, Folci, Marco, Negrini, Simone, Sinico, Renato Alberto, Quartuccio, Luca, Lunardi, Claudio, Parronchi, Paola, Moosig, Frank, Espígol-Frigolé, Georgina, Schroeder, Jan, Kernder, Anna Luise, Monti, Sara, Silvagni, Ettore, Crimi, Claudia, Cinetto, Francesco, Fraticelli, Paolo, Roccatello, Dario, Vacca, Angelo, Mohammad, Aladdin J, Hellmich, Bernhard, Samson, Maxime, Bargagli, Elena, Cohen Tervaert, Jan Willem, Ribi, Camillo, Fiori, Davide, Bello, Federica, Fagni, Filippo, Moroni, Luca, Ramirez, Giuseppe Alvise, Nasser, Mouhamad, Marvisi, Chiara, Toniati, Paola, Firinu, Davide, Padoan, Roberto, Egan, Allyson, Seeliger, Benjamin, Iannone, Florenzo, Salvarani, Carlo, Jayne, David, Prisco, Domenico, Vaglio, Augusto, Emmi, Giacomo, Bettiol, A, Urban, M, Dagna, L, Cottin, V, Franceschini, F, Del Giacco, S, Schiavon, F, Neumann, T, Lopalco, G, Novikov, P, Baldini, C, Lombardi, C, Berti, A, Alberici, F, Folci, M, Negrini, S, Sinico, R, Quartuccio, L, Lunardi, C, Parronchi, P, Moosig, F, Espígol-Frigolé, G, Schroeder, J, Kernder, A, Monti, S, Silvagni, E, Crimi, C, Cinetto, F, Fraticelli, P, Roccatello, D, Vacca, A, Mohammad, A, Hellmich, B, Samson, M, Bargagli, E, Cohen Tervaert, J, Ribi, C, Fiori, D, Bello, F, Fagni, F, Moroni, L, Ramirez, G, Nasser, M, Marvisi, C, Toniati, P, Firinu, D, Padoan, R, Egan, A, Seeliger, B, Iannone, F, Salvarani, C, Jayne, D, Prisco, D, Vaglio, A, Emmi, G, Bettiol, Alessandra, Urban, Maria Letizia, Dagna, Lorenzo, Cottin, Vincent, Franceschini, Franco, Del Giacco, Stefano, Schiavon, Franco, Neumann, Thomas, Lopalco, Giuseppe, Novikov, Pavel, Baldini, Chiara, Lombardi, Carlo, Berti, Alvise, Alberici, Federico, Folci, Marco, Negrini, Simone, Sinico, Renato Alberto, Quartuccio, Luca, Lunardi, Claudio, Parronchi, Paola, Moosig, Frank, Espígol-Frigolé, Georgina, Schroeder, Jan, Kernder, Anna Luise, Monti, Sara, Silvagni, Ettore, Crimi, Claudia, Cinetto, Francesco, Fraticelli, Paolo, Roccatello, Dario, Vacca, Angelo, Mohammad, Aladdin J, Hellmich, Bernhard, Samson, Maxime, Bargagli, Elena, Cohen Tervaert, Jan Willem, Ribi, Camillo, Fiori, Davide, Bello, Federica, Fagni, Filippo, Moroni, Luca, Ramirez, Giuseppe Alvise, Nasser, Mouhamad, Marvisi, Chiara, Toniati, Paola, Firinu, Davide, Padoan, Roberto, Egan, Allyson, Seeliger, Benjamin, Iannone, Florenzo, Salvarani, Carlo, Jayne, David, Prisco, Domenico, Vaglio, Augusto, and Emmi, Giacomo
Abstract: Objective: Mepolizumab proved efficacious for eosinophilic granulomatosis with polyangiitis (EGPA, former Churg-Strauss) at the dosage of 300mg/4 weeks in the randomized controlled MIRRA trial. Few successful real-life experiences with the dosage approved for severe eosinophilic asthma (100mg/4 weeks) were recently reported. We retrospectively assessed the effectiveness and safety of mepolizumab 100 and 300mg/4 weeks in a large European EGPA cohort. Methods: We included all EGPA patients treated with mepolizumab at the recruiting centres in 2015-2020. Treatment response was evaluated from month 3 through 24 (T3-T24) after mepolizumab starting. Complete response (CR) was defined as no disease activity (Birmingham Vasculitis Activity Score, BVAS=0) and a prednisone dose ≤4mg/day. Respiratory outcomes included asthma and ear-nose-throat (ENT) exacerbations. Results: We included 203 patients, of whom 191 at stable dosage (158 mepolizumab 100mg/4 weeks, 33 300mg/4 weeks). At T3, 25 patients (12.3%) had a CR. CR rates increased to 30.4% and 35.7% at T12 and T24 and were comparable between mepolizumab 100 and 300mg/4 weeks. Mepolizumab led to a significant reduction in BVAS, prednisone dose, eosinophil counts from T3 through T24, with no significant differences between 100 and 300 mg/4weeks. Eighty-two patients (40.4%) experienced asthma exacerbations [57/158 (36%) on 100mg/4 weeks; 17/33 (52%) on 300mg/4 weeks]. Thirty-one (15.3%) experienced ENT exacerbations. Forty-four patients (21.7%) experienced adverse events, most being non-serious (38/44). Conclusion: Mepolizumab both at 100 and 300mg/4 weeks is effective for EGPA. The two dosages should be compared in the setting of a controlled trial.
Published: 2022

3. The Italian Registry for Primary Immunodeficiencies (Italian Primary Immunodeficiency Network; IPINet): Twenty Years of Experience (1999–2019)

Author: Lougaris, V, Pession, A, Baronio, M, Soresina, A, Rondelli, R, Gazzurelli, L, Benvenuto, A, Martino, S, Gattorno, M, Biondi, A, Zecca, M, Marinoni, M, Fabio, G, Aiuti, A, Marseglia, G, Putti, M, Agostini, C, Lunardi, C, Tommasini, A, Bertolini, P, Gambineri, E, Consolini, R, Matucci, A, Azzari, C, Danieli, M, Paganelli, R, Duse, M, Cancrini, C, Moschese, V, Chessa, L, Spadaro, G, Civino, A, Vacca, A, Cardinale, F, Martire, B, Carpino, L, Trizzino, A, Russo, G, Cossu, F, Badolato, R, Pietrogrande, M, Quinti, I, Rossi, P, Ugazio, A, Pignata, C, Plebani, A, Lougaris V., Pession A., Baronio M., Soresina A., Rondelli R., Gazzurelli L., Benvenuto A., Martino S., Gattorno M., Biondi A., Zecca M., Marinoni M., Fabio G., Aiuti A., Marseglia G., Putti M. C., Agostini C., Lunardi C., Tommasini A., Bertolini P., Gambineri E., Consolini R., Matucci A., Azzari C., Danieli M. G., Paganelli R., Duse M., Cancrini C., Moschese V., Chessa L., Spadaro G., Civino A., Vacca A., Cardinale F., Martire B., Carpino L., Trizzino A., Russo G., Cossu F., Badolato R., Pietrogrande M. C., Quinti I., Rossi P., Ugazio A., Pignata C., Plebani A., Lougaris, V, Pession, A, Baronio, M, Soresina, A, Rondelli, R, Gazzurelli, L, Benvenuto, A, Martino, S, Gattorno, M, Biondi, A, Zecca, M, Marinoni, M, Fabio, G, Aiuti, A, Marseglia, G, Putti, M, Agostini, C, Lunardi, C, Tommasini, A, Bertolini, P, Gambineri, E, Consolini, R, Matucci, A, Azzari, C, Danieli, M, Paganelli, R, Duse, M, Cancrini, C, Moschese, V, Chessa, L, Spadaro, G, Civino, A, Vacca, A, Cardinale, F, Martire, B, Carpino, L, Trizzino, A, Russo, G, Cossu, F, Badolato, R, Pietrogrande, M, Quinti, I, Rossi, P, Ugazio, A, Pignata, C, Plebani, A, Lougaris V., Pession A., Baronio M., Soresina A., Rondelli R., Gazzurelli L., Benvenuto A., Martino S., Gattorno M., Biondi A., Zecca M., Marinoni M., Fabio G., Aiuti A., Marseglia G., Putti M. C., Agostini C., Lunardi C., Tommasini A., Bertolini P., Gambineri E., Consolini R., Matucci A., Azzari C., Danieli M. G., Paganelli R., Duse M., Cancrini C., Moschese V., Chessa L., Spadaro G., Civino A., Vacca A., Cardinale F., Martire B., Carpino L., Trizzino A., Russo G., Cossu F., Badolato R., Pietrogrande M. C., Quinti I., Rossi P., Ugazio A., Pignata C., and Plebani A.
Abstract: Primary immunodeficiencies (PIDs) are heterogeneous disorders, characterized by variable clinical and immunological features. National PID registries offer useful insights on the epidemiology, diagnosis, and natural history of these disorders. In 1999, the Italian network for primary immunodeficiencies (IPINet) was established. We report on data collected from the IPINet registry after 20 years of activity. A total of 3352 pediatric and adult patients affected with PIDs are registered in the database. In Italy, a regional distribution trend of PID diagnosis was observed. Based on the updated IUIS classification of 2019, PID distribution in Italy showed that predominantly antibody deficiencies account for the majority of cases (63%), followed by combined immunodeficiencies with associated or syndromic features (22.5%). The overall age at diagnosis was younger for male patients. The minimal prevalence of PIDs in Italy resulted in 5.1 per 100.000 habitants. Mortality was similar to other European registries (4.2%). Immunoglobulin replacement treatment was prescribed to less than one third of the patient cohort. Collectively, this is the first comprehensive description of the PID epidemiology in Italy.
Published: 2020

4. Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Author: Ghofrani, H.-A. Gomez Sanchez, M.-A. Humbert, M. Pittrow, D. Simonneau, G. Gall, H. Grünig, E. Klose, H. Halank, M. Langleben, D. Snijder, R.J. Escribano Subias, P. Mielniczuk, L.M. Lange, T.J. Vachiéry, J.-L. Wirtz, H. Helmersen, D.S. Tsangaris, I. Barberá, J.A. Pepke-Zaba, J. Boonstra, A. Rosenkranz, S. Ulrich, S. Steringer-Mascherbauer, R. Delcroix, M. Jansa, P. Šimková, I. Giannakoulas, G. Klotsche, J. Williams, E. Meier, C. Hoeper, M.M. Caneva, J. Tuhay, G. Diez, M. Talavera, M.L. Acosta, A. Vulcano, N. Bosio, M. Maldonado, L. Deleo, S. Melatini, L. Keogh, A. Kotlyar, E. Feenstra, J. Dwyer, N. Adams, H. Stevens, W. Steele, P. Proudman, S. Minson, R. Reeves, G. Lavender, M. Ng, B. Mackenzie, M. Barry, L. Gruenberger, M. Huber, C. Lang, I. Tilea, I. Sadushi-Kolici, R. Löffler-Ragg, J. Feistmantl, L.-T. Evrard, P. Louis, R. Guiot, J. Naldi, M. De Pauw, M. Mehta, S. Camacho, R.C. Tovar, P.P. Londoño, A. Campo, F. Garcia, P. Lema, C. Orozco-Levi, M. Martinez, W. Gomez, J.E. Nielsen-Kudsk, J.E. Mellemkjaer, S. Anton, L. Altraja, A. Vihinen, T. Vasankari, T. Sitbon, O. Cottin, V. Têtu, L. Noël-Savina, E. Shearman, N. Tayler, S. Olzik, I. Kulka, C. Grimminger, J. Simon, M. Nolde, A. Oqueka, T. Harbaum, L. Egenlauf, B. Ewert, R. Schulz, C. Regotta, S. Kramer, T. Knoop-Busch, S. Gerhardt, F. Konstantinides, S. Pitsiou, G. Stanopoulos, I. Sourla, E. Mouratoglou, S. Karvounis, H. Pappas, A. Georgopoulos, D. Fanaridis, M. Mitrouska, I. Michalis, L. Pappas, K. Kotsia, A. Gaine, S. Vizza, C.D. Manzi, G. Poscia, R. Badagliacca, R. Agostoni, P. Bruno, N. Farina, S. D'Alto, M. Argiento, P. Correra, A. Di Marco, G.M. Cresci, C. Vannucchi, V. Torricelli, E. Garcea, A. Pesci, A. Sardella, L. Paciocco, G. Pane, F. D'Armini, A.M. Pin, M. Grazioli, V. Massola, G. Sciortino, A. Prediletto, R. Bauleo, C. Airò, E. Ndreu, R. Pavlickova, I. Lunardi, C. Mulè, M. Farruggio, S. Costa, S. Galgano, G. Petruzzi, M. De Luca, A. Lombardi, F. Roncon, L. Conte, L. Picariello, C. Wirtz, G. and Ghofrani, H.-A. Gomez Sanchez, M.-A. Humbert, M. Pittrow, D. Simonneau, G. Gall, H. Grünig, E. Klose, H. Halank, M. Langleben, D. Snijder, R.J. Escribano Subias, P. Mielniczuk, L.M. Lange, T.J. Vachiéry, J.-L. Wirtz, H. Helmersen, D.S. Tsangaris, I. Barberá, J.A. Pepke-Zaba, J. Boonstra, A. Rosenkranz, S. Ulrich, S. Steringer-Mascherbauer, R. Delcroix, M. Jansa, P. Šimková, I. Giannakoulas, G. Klotsche, J. Williams, E. Meier, C. Hoeper, M.M. Caneva, J. Tuhay, G. Diez, M. Talavera, M.L. Acosta, A. Vulcano, N. Bosio, M. Maldonado, L. Deleo, S. Melatini, L. Keogh, A. Kotlyar, E. Feenstra, J. Dwyer, N. Adams, H. Stevens, W. Steele, P. Proudman, S. Minson, R. Reeves, G. Lavender, M. Ng, B. Mackenzie, M. Barry, L. Gruenberger, M. Huber, C. Lang, I. Tilea, I. Sadushi-Kolici, R. Löffler-Ragg, J. Feistmantl, L.-T. Evrard, P. Louis, R. Guiot, J. Naldi, M. De Pauw, M. Mehta, S. Camacho, R.C. Tovar, P.P. Londoño, A. Campo, F. Garcia, P. Lema, C. Orozco-Levi, M. Martinez, W. Gomez, J.E. Nielsen-Kudsk, J.E. Mellemkjaer, S. Anton, L. Altraja, A. Vihinen, T. Vasankari, T. Sitbon, O. Cottin, V. Têtu, L. Noël-Savina, E. Shearman, N. Tayler, S. Olzik, I. Kulka, C. Grimminger, J. Simon, M. Nolde, A. Oqueka, T. Harbaum, L. Egenlauf, B. Ewert, R. Schulz, C. Regotta, S. Kramer, T. Knoop-Busch, S. Gerhardt, F. Konstantinides, S. Pitsiou, G. Stanopoulos, I. Sourla, E. Mouratoglou, S. Karvounis, H. Pappas, A. Georgopoulos, D. Fanaridis, M. Mitrouska, I. Michalis, L. Pappas, K. Kotsia, A. Gaine, S. Vizza, C.D. Manzi, G. Poscia, R. Badagliacca, R. Agostoni, P. Bruno, N. Farina, S. D'Alto, M. Argiento, P. Correra, A. Di Marco, G.M. Cresci, C. Vannucchi, V. Torricelli, E. Garcea, A. Pesci, A. Sardella, L. Paciocco, G. Pane, F. D'Armini, A.M. Pin, M. Grazioli, V. Massola, G. Sciortino, A. Prediletto, R. Bauleo, C. Airò, E. Ndreu, R. Pavlickova, I. Lunardi, C. Mulè, M. Farruggio, S. Costa, S. Galgano, G. Petruzzi, M. De Luca, A. Lombardi, F. Roncon, L. Conte, L. Picariello, C. Wirtz, G.
Abstract: Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial [CHEST-2]). Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified. © 2020 The Authors
Published: 2021

5. Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Author: Ghofrani, H.A., Gomez Sanchez, M.-A. (Miguel-Angel), Humbert, M., Pittrow, D. (David), Simonneau, G. (Gérald), Gall, H. (Henning), Grünig, E. (Ekkehard), Klose, H. (Hans), Halank, M. (Michael), Langleben, D. (David), Snijder, R., Escribano Subías, P. (Pilar), Mielniczuk, L.M. (Lisa M.), Lange, T.J. (Tobias J.), Vachiéry, J.-L. (Jean-Luc), Wirtz, H. (Hubert), Helmersen, D.S. (Douglas S.), Tsangaris, I. (Iraklis), Barberá, J.A. (Joan A.), Pepke-Zaba, J. (Joanna), Boonstra, A. (Anco), Rosenkranz, S. (Stephan), Ulrich, S. (Silvia), Steringer-Mascherbauer, R. (Regina), Delcroix, M. (Marion), Jansa, P. (Pavel), Šimková, I. (Iveta), Giannakoulas, G. (George), Klotsche, J. (Jens), Williams, E. (Evgenia), Meier, C. (Christian), Hoeper, M.M. (Marius M.), Caneva, J. (Jorge), Tuhay, G. (Graciela), Diez, M. (Mirta), Talavera, M.L. (Maria Lujan), Acosta, A. (Adriana), Vulcano, N. (Norberto), Bosio, M. (Martin), Maldonado, L. (Lorena), Deleo, S. (Sabino), Melatini, L. (Luciano), Keogh, A. (Anne), Kotlyar, E. (Eugene), Feenstra, J. (John), Dwyer, N. (Nathan), Adams, H. (Heath), Stevens, W. (Wendy), Steele, P. (Peter), Proudman, S. (Susanna), Minson, R. (Robert), Reeves, G. (Glenn), Lavender, M. (Melanie), Ng, B. (Benjamin), Mackenzie, M. (Michele), Barry, L. (Lisa), Gruenberger, M. (Margarethe), Huber, C. (Charlotte), Lang, I. (Irene), Tilea, I. (Ioana), Sadushi-Kolici, R. (Roela), Löffler-Ragg, J. (Judith), Feistmantl, L.-T. (Lisa-Theresa), Evrard, P. (Patrick), Louis, R. (Renaud), Guiot, J. (Julien), Naldi, M. (Marco), De Pauw, M. (Michel), Mehta, S. (Sanjay), Camacho, R.C. (Rafael Conde), Tovar, P.P. (Patricia Parada), Londoño, A. (Alejandro), Campo, F. (Felipe), Garcia, P. (Paula), Lema, C. (Camila), Orozco-Levi, M. (Mauricio), Martinez, W. (William), Gomez, J.E. (Juan Esteban), Nielsen-Kudsk, J.E. (Jens Erik), Mellemkjaer, S. (Soren), Anton, L. (Ly), Altraja, A. (Alan), Vihinen, T. (Tapani), Vasankari, T. (Tuija), Sitbon, O. (Olivier), Cottin, V. (Vincent), Têtu, L. (Laurent), Noël-Savina, E. (Elise), Shearman, N. (Nicole), Tayler, S. (Susanne), Olzik, I. (Ilona), Kulka, C. (Christine), Grimminger, J. (Jan), Simon, M. (Marcel), Nolde, A. (Anna), Oqueka, T. (Tim), Harbaum, L. (Lars), Egenlauf, B. (Benjamin), Ewert, R. (Ralf), Schulz, C. (Christian), Regotta, S. (Sabine), Kramer, T. (Tilmann), Knoop-Busch, S. (Susanne), Gerhardt, F. (Felix), Konstantinides, S. (Stavros), Pitsiou, G. (Georgia), Stanopoulos, I. (Ioannis), Sourla, E. (Evdokia), Mouratoglou, S. (Sofia), Karvounis, H.I., Pappas, A. (Athanasios), Georgopoulos, D. (Dimitrios), Fanaridis, M. (Michail), Mitrouska, I. (Ioanna), Michalis, L.K. (Lampros), Pappas, K. (Konstantinos), Kotsia, A. (Anna), Gaine, S. (Sean), Vizza, C.D. (Carmine Dario), Manzi, G. (Giovanna), Poscia, R. (Roberto), Badagliacca, R. (Roberto), Agostoni, P. (Piergiuseppe), Bruno, N. (Noemi), Farina, S. (Stefania), D'Alto, M. (Michele), Argiento, P. (Paola), Correra, A. (Anna), Di Marco, G.M. (Giovanni Maria), Cresci, C. (Chiara), Vannucchi, V. (Vieri), Torricelli, E. (Elena), Garcea, A. (Alessio), Pesci, A. (Alberto), Sardella, L. (Luca), Paciocco, G. (Giuseppe), Pane, F. (Federico), D'Armini, A.M. (Andrea Maria), Pin, M. (Maurizio), Grazioli, V. (Valentina), Massola, G. (Giulia), Sciortino, A. (Antonio), Prediletto, R. (Renato), Bauleo, C. (Carolina), Airò, E. (Edoardo), Ndreu, R. (Rudina), Pavlickova, I. (Ivana), Lunardi, C. (Claudio), Mulè, M. (Massimiliano), Farruggio, S. (Silvia), Costa, S. (Serena), Galgano, G. (Giuseppe), Petruzzi, M. (Mario), De Luca, A. (Anna), Lombardi, F. (Francesco), Roncon, L. (Loris), Conte, L. (Luca), Picariello, C. (Claudio), Wirtz, G. (Gil), Alexandre, M. (Myriam), Vonk Noordegraaf, A. (Anton), Boogaard, H. (H.), Mager, J. (J.), Reesink, H.J. (Herre), Toorn, L.M. (Leon) van den, Boomars, K.A.T. (Karin), Andreassen, A.K. (Arne K.), Castro, G. (Graça), Tania, G. (Gonçalves), Baptista, R. (Rui), Marinho, A. (António), Shiang, T. (Teresa), Oliveira, A. (Ana), Coutinho, D. (Daniel), Sousa, J. (Joana), Loureiro, M.J. (Maria José), Repolho, D. (Débora), Martins Jesus, S.M. (Susana Maria), Capinha, M. (Marta), Agostinho, J. (João), Cardoso, T. (Tania), Rocha, A. (Andreia), Espinha, M. (Mafalda), Ivanov, K.I. (Kyundyul Ivanovich), Alexeeva, D.E. (Dalyana Eduardovna), Batalina, M.V. (Marina Vadimovna), Hegya, D.V. (Daria Viktorovna), Zvereva, T.N. (Tatyana Nikolaevna), Avdeev, S.N. (Sergey Nikolaevich), Tsareva, N.A. (Natalia Anatolievna), Galyavich, A.S. (Albert Sarvatovich), Nikolaevich, B.A. (Bykov Aleksander), Filippov, E.V. (Evgeny Vladimirovich), Yakovleva, O.E. (Olga Eduardovna), Pavlova, O.B. (Olga Borisovna), Skripkina, E.S. (Elena Sergeevna), Martynyuk, T.V. (Tamila Vitalievna), Bukatova, I.F. (Irina Fedorovna), Tregubova, A.V. (Anna Viktorovna), Platonov, D.Y. (Dmitry Yurievich), Kolomeytseva, T.M. (Tatyana Mikhaylovna), Al Dalaan, A. (Abdullah), Abdelsayed, A.A. (Abeer Abeer), Weheba, I. (Ihab), Saleemi, S. (Sarferaz), Sakkijha, H. (Hussam), Bohacekova, M. (Marcela), Valkovicova, T. (Tatiana), Farkasova, I. (Iveta), Quezada, C.A. (Carlos Andres), Piccari, L. (Lucilla), Blanco, I. (Isabel), Sebastian, L. (Laura), Roman, A. (Antonio), Lopez, M. (Manuel), Otero, R. (Remedios), Elias, T. (Teresa), Jara, L. (Luis), Asencio, I. (Isabel), Arjona, J.J. (Josefa Jiménez), Almagro, R.M. (Raúl Menor), Cárdenas, S.L. (Salvador López), García, S.A. (Salvador Alcaraz), Rodríguez, P.V. (Patricia Villanueva), Lopez, R. (Raquel), Garcia, A. (Alberto), Avilés, F.F. (Francisco Fernandez), De La Pava, S. (Sebastian), Yotti, R. (Raquel), Peñate, G.P. (Gregorio Pérez), Marrero, F.L. (Fernando León), Cifrián Martínez, J.M. (José Manuel), Martinez-Meñaca, A. (Amaya), Alonso, L.P. (Lecue Pilar), Rozas, S.F. (Sonia Fernandez), Fernandez, D.I. (David Iturbe), Cuesta, V.M. (Victor Mora), Söderberg, S. (Stefan), Bartfay, S.-E. (Sven-Erik), Rundqvist, B. (Bengt), Alfetlawi, M. (Monthir), Wodlin, P. (Peter), Schwarz, E.I. (Esther Irene), Speich, R. (Rudolf), Lador, F. (Frédéric), Rochat, T. (Thierry), Gasche-Soccal, P. (Paola), Hsu, C.-H. (Chih-Hsin), Lin, T.-H. (Tsung-Hsien), Su, H.-M. (Ho-Ming), Lai, W.-T. (Wen-Ter), Chu, C.Y. (Chun Yuan), Hsu, P.-C. (Po-Chao), Voon, W.-C. (Wen-Chol), Yen, H.-W. (Hsueh-Wei), Yih-Jer Wu, J. (Jacob), Wu, S.-H. (Shu-Hao), Huang, W.-P. (Wen-Pin), Fong, M.-C. (Man-Cai), Huang, C.-L. (Chien-Lung), Kuo, P.-H. (Ping-Hung), Lin, Y.-H. (Yen-Hung), Lin, J.-L. (Jiunn-Lee), Hung, C.-S. (Chi-Sheng), Wu, C.-K. (Cho-Kai), Sung, S.-H. (Shih-Hsien), Huang, W.-C. (Wei-Chun), Cheng, C.-C. (Chin-Chang), Kuo, S.-H. (Shu-Hung), Wang, W.-H. (Wen-Hwa), Ho, W.-J. (Wan-Jing), Hsu, T.-S. (Tsu-Shiu), Mutlu, B. (Bülent), Atas, H. (Halil), Ongen, G. (Gul), Un, Z. (Zeynep), Okumus, G. (Gulfer), Hanta, I. (Ismail), Corris, P. (Paul), Peacock, A. (Andrew), Church, C. (Colin), Toshner, M. (Mark), Newnham, M. (Michael), Ghofrani, H.A., Gomez Sanchez, M.-A. (Miguel-Angel), Humbert, M., Pittrow, D. (David), Simonneau, G. (Gérald), Gall, H. (Henning), Grünig, E. (Ekkehard), Klose, H. (Hans), Halank, M. (Michael), Langleben, D. (David), Snijder, R., Escribano Subías, P. (Pilar), Mielniczuk, L.M. (Lisa M.), Lange, T.J. (Tobias J.), Vachiéry, J.-L. (Jean-Luc), Wirtz, H. (Hubert), Helmersen, D.S. (Douglas S.), Tsangaris, I. (Iraklis), Barberá, J.A. (Joan A.), Pepke-Zaba, J. (Joanna), Boonstra, A. (Anco), Rosenkranz, S. (Stephan), Ulrich, S. (Silvia), Steringer-Mascherbauer, R. (Regina), Delcroix, M. (Marion), Jansa, P. (Pavel), Šimková, I. (Iveta), Giannakoulas, G. (George), Klotsche, J. (Jens), Williams, E. (Evgenia), Meier, C. (Christian), Hoeper, M.M. (Marius M.), Caneva, J. (Jorge), Tuhay, G. (Graciela), Diez, M. (Mirta), Talavera, M.L. (Maria Lujan), Acosta, A. (Adriana), Vulcano, N. (Norberto), Bosio, M. (Martin), Maldonado, L. (Lorena), Deleo, S. (Sabino), Melatini, L. (Luciano), Keogh, A. (Anne), Kotlyar, E. (Eugene), Feenstra, J. (John), Dwyer, N. (Nathan), Adams, H. (Heath), Stevens, W. (Wendy), Steele, P. (Peter), Proudman, S. (Susanna), Minson, R. (Robert), Reeves, G. (Glenn), Lavender, M. (Melanie), Ng, B. (Benjamin), Mackenzie, M. (Michele), Barry, L. (Lisa), Gruenberger, M. (Margarethe), Huber, C. (Charlotte), Lang, I. (Irene), Tilea, I. (Ioana), Sadushi-Kolici, R. (Roela), Löffler-Ragg, J. (Judith), Feistmantl, L.-T. (Lisa-Theresa), Evrard, P. (Patrick), Louis, R. (Renaud), Guiot, J. (Julien), Naldi, M. (Marco), De Pauw, M. (Michel), Mehta, S. (Sanjay), Camacho, R.C. (Rafael Conde), Tovar, P.P. (Patricia Parada), Londoño, A. (Alejandro), Campo, F. (Felipe), Garcia, P. (Paula), Lema, C. (Camila), Orozco-Levi, M. (Mauricio), Martinez, W. (William), Gomez, J.E. (Juan Esteban), Nielsen-Kudsk, J.E. (Jens Erik), Mellemkjaer, S. (Soren), Anton, L. (Ly), Altraja, A. (Alan), Vihinen, T. (Tapani), Vasankari, T. (Tuija), Sitbon, O. (Olivier), Cottin, V. (Vincent), Têtu, L. (Laurent), Noël-Savina, E. (Elise), Shearman, N. (Nicole), Tayler, S. (Susanne), Olzik, I. (Ilona), Kulka, C. (Christine), Grimminger, J. (Jan), Simon, M. (Marcel), Nolde, A. (Anna), Oqueka, T. (Tim), Harbaum, L. (Lars), Egenlauf, B. (Benjamin), Ewert, R. (Ralf), Schulz, C. (Christian), Regotta, S. (Sabine), Kramer, T. (Tilmann), Knoop-Busch, S. (Susanne), Gerhardt, F. (Felix), Konstantinides, S. (Stavros), Pitsiou, G. (Georgia), Stanopoulos, I. (Ioannis), Sourla, E. (Evdokia), Mouratoglou, S. (Sofia), Karvounis, H.I., Pappas, A. (Athanasios), Georgopoulos, D. (Dimitrios), Fanaridis, M. (Michail), Mitrouska, I. (Ioanna), Michalis, L.K. (Lampros), Pappas, K. (Konstantinos), Kotsia, A. (Anna), Gaine, S. (Sean), Vizza, C.D. (Carmine Dario), Manzi, G. (Giovanna), Poscia, R. (Roberto), Badagliacca, R. (Roberto), Agostoni, P. (Piergiuseppe), Bruno, N. (Noemi), Farina, S. (Stefania), D'Alto, M. (Michele), Argiento, P. (Paola), Correra, A. (Anna), Di Marco, G.M. (Giovanni Maria), Cresci, C. (Chiara), Vannucchi, V. (Vieri), Torricelli, E. (Elena), Garcea, A. (Alessio), Pesci, A. (Alberto), Sardella, L. (Luca), Paciocco, G. (Giuseppe), Pane, F. (Federico), D'Armini, A.M. (Andrea Maria), Pin, M. (Maurizio), Grazioli, V. (Valentina), Massola, G. (Giulia), Sciortino, A. (Antonio), Prediletto, R. (Renato), Bauleo, C. (Carolina), Airò, E. (Edoardo), Ndreu, R. (Rudina), Pavlickova, I. (Ivana), Lunardi, C. (Claudio), Mulè, M. (Massimiliano), Farruggio, S. (Silvia), Costa, S. (Serena), Galgano, G. (Giuseppe), Petruzzi, M. (Mario), De Luca, A. (Anna), Lombardi, F. (Francesco), Roncon, L. (Loris), Conte, L. (Luca), Picariello, C. (Claudio), Wirtz, G. (Gil), Alexandre, M. (Myriam), Vonk Noordegraaf, A. (Anton), Boogaard, H. (H.), Mager, J. (J.), Reesink, H.J. (Herre), Toorn, L.M. (Leon) van den, Boomars, K.A.T. (Karin), Andreassen, A.K. (Arne K.), Castro, G. (Graça), Tania, G. (Gonçalves), Baptista, R. (Rui), Marinho, A. (António), Shiang, T. (Teresa), Oliveira, A. (Ana), Coutinho, D. (Daniel), Sousa, J. (Joana), Loureiro, M.J. (Maria José), Repolho, D. (Débora), Martins Jesus, S.M. (Susana Maria), Capinha, M. (Marta), Agostinho, J. (João), Cardoso, T. (Tania), Rocha, A. (Andreia), Espinha, M. (Mafalda), Ivanov, K.I. (Kyundyul Ivanovich), Alexeeva, D.E. (Dalyana Eduardovna), Batalina, M.V. (Marina Vadimovna), Hegya, D.V. (Daria Viktorovna), Zvereva, T.N. (Tatyana Nikolaevna), Avdeev, S.N. (Sergey Nikolaevich), Tsareva, N.A. (Natalia Anatolievna), Galyavich, A.S. (Albert Sarvatovich), Nikolaevich, B.A. (Bykov Aleksander), Filippov, E.V. (Evgeny Vladimirovich), Yakovleva, O.E. (Olga Eduardovna), Pavlova, O.B. (Olga Borisovna), Skripkina, E.S. (Elena Sergeevna), Martynyuk, T.V. (Tamila Vitalievna), Bukatova, I.F. (Irina Fedorovna), Tregubova, A.V. (Anna Viktorovna), Platonov, D.Y. (Dmitry Yurievich), Kolomeytseva, T.M. (Tatyana Mikhaylovna), Al Dalaan, A. (Abdullah), Abdelsayed, A.A. (Abeer Abeer), Weheba, I. (Ihab), Saleemi, S. (Sarferaz), Sakkijha, H. (Hussam), Bohacekova, M. (Marcela), Valkovicova, T. (Tatiana), Farkasova, I. (Iveta), Quezada, C.A. (Carlos Andres), Piccari, L. (Lucilla), Blanco, I. (Isabel), Sebastian, L. (Laura), Roman, A. (Antonio), Lopez, M. (Manuel), Otero, R. (Remedios), Elias, T. (Teresa), Jara, L. (Luis), Asencio, I. (Isabel), Arjona, J.J. (Josefa Jiménez), Almagro, R.M. (Raúl Menor), Cárdenas, S.L. (Salvador López), García, S.A. (Salvador Alcaraz), Rodríguez, P.V. (Patricia Villanueva), Lopez, R. (Raquel), Garcia, A. (Alberto), Avilés, F.F. (Francisco Fernandez), De La Pava, S. (Sebastian), Yotti, R. (Raquel), Peñate, G.P. (Gregorio Pérez), Marrero, F.L. (Fernando León), Cifrián Martínez, J.M. (José Manuel), Martinez-Meñaca, A. (Amaya), Alonso, L.P. (Lecue Pilar), Rozas, S.F. (Sonia Fernandez), Fernandez, D.I. (David Iturbe), Cuesta, V.M. (Victor Mora), Söderberg, S. (Stefan), Bartfay, S.-E. (Sven-Erik), Rundqvist, B. (Bengt), Alfetlawi, M. (Monthir), Wodlin, P. (Peter), Schwarz, E.I. (Esther Irene), Speich, R. (Rudolf), Lador, F. (Frédéric), Rochat, T. (Thierry), Gasche-Soccal, P. (Paola), Hsu, C.-H. (Chih-Hsin), Lin, T.-H. (Tsung-Hsien), Su, H.-M. (Ho-Ming), Lai, W.-T. (Wen-Ter), Chu, C.Y. (Chun Yuan), Hsu, P.-C. (Po-Chao), Voon, W.-C. (Wen-Chol), Yen, H.-W. (Hsueh-Wei), Yih-Jer Wu, J. (Jacob), Wu, S.-H. (Shu-Hao), Huang, W.-P. (Wen-Pin), Fong, M.-C. (Man-Cai), Huang, C.-L. (Chien-Lung), Kuo, P.-H. (Ping-Hung), Lin, Y.-H. (Yen-Hung), Lin, J.-L. (Jiunn-Lee), Hung, C.-S. (Chi-Sheng), Wu, C.-K. (Cho-Kai), Sung, S.-H. (Shih-Hsien), Huang, W.-C. (Wei-Chun), Cheng, C.-C. (Chin-Chang), Kuo, S.-H. (Shu-Hung), Wang, W.-H. (Wen-Hwa), Ho, W.-J. (Wan-Jing), Hsu, T.-S. (Tsu-Shiu), Mutlu, B. (Bülent), Atas, H. (Halil), Ongen, G. (Gul), Un, Z. (Zeynep), Okumus, G. (Gulfer), Hanta, I. (Ismail), Corris, P. (Paul), Peacock, A. (Andrew), Church, C. (Colin), Toshner, M. (Mark), and Newnham, M. (Michael)
Abstract: Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3
Published: 2021
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6. Risk of acute arterial and venous thromboembolic events in Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss syndrome)

Author: Bettiol, A, Sinico, R, Schiavon, F, Monti, S, Bozzolo, E, Franceschini, F, Govoni, M, Lunardi, C, Guida, G, Lopalco, G, Paolazzi, G, Vacca, A, Gregorini, G, Leccese, P, Piga, M, Conti, F, Fraticelli, P, Quartuccio, L, Alberici, F, Salvarani, C, Bettio, S, Negrini, S, Selmi, C, Sciascia, S, Moroni, G, Colla, L, Manno, C, Urban, M, Vannacci, A, Pozzi, M, Fabbrini, P, Polti, S, Felicetti, M, Marchi, M, Padoan, R, Delvino, P, Caporali, R, Montecucco, C, Dagna, L, Cariddi, A, Toniati, P, Tamanini, S, Furini, F, Bortoluzzi, A, Tinazzi, E, Delfino, L, Badiu, I, Rolla, G, Venerito, V, Iannone, F, Berti, A, Bortolotti, R, Racanelli, V, Jeannin, G, Padula, A, Cauli, A, Priori, R, Gabrielli, A, Bond, M, Tedesco, M, Pazzola, G, Tomietto, P, Pellecchio, M, Marvisi, C, Maritati, F, Palmisano, A, Dejaco, C, Willeit, J, Kiechl, S, Olivotto, I, Willeit, P, Prisco, D, Vaglio, A, Emmi, G, Bettiol, Alessandra, Sinico, Renato Alberto, Schiavon, Franco, Monti, Sara, Bozzolo, Enrica Paola, Franceschini, Franco, Govoni, Marcello, Lunardi, Claudio, Guida, Giuseppe, Lopalco, Giuseppe, Paolazzi, Giuseppe, Vacca, Angelo, Gregorini, Gina, Leccese, Pietro, Piga, Matteo, Conti, Fabrizio, Fraticelli, Paolo, Quartuccio, Luca, Alberici, Federico, Salvarani, Carlo, Bettio, Silvano, Negrini, Simone, Selmi, Carlo, Sciascia, Savino, Moroni, Gabriella, Colla, Loredana, Manno, Carlo, Urban, Maria Letizia, Vannacci, Alfredo, Pozzi, Maria Rosa, Fabbrini, Paolo, Polti, Stefano, Felicetti, Mara, Marchi, Maria Rita, Padoan, Roberto, Delvino, Paolo, Caporali, Roberto, Montecucco, Carlomaurizio, Dagna, Lorenzo, Cariddi, Adriana, Toniati, Paola, Tamanini, Silvia, Furini, Federica, Bortoluzzi, Alessandra, Tinazzi, Elisa, Delfino, Lorenzo, Badiu, Iuliana, Rolla, Giovanni, Venerito, Vincenzo, Iannone, Florenzo, Berti, Alvise, Bortolotti, Roberto, Racanelli, Vito, Jeannin, Guido, Padula, Angela, Cauli, Alberto, Priori, Roberta, Gabrielli, Armando, Bond, Milena, Tedesco, Martina, Pazzola, Giulia, Tomietto, Paola, Pellecchio, Marco, Marvisi, Chiara, Maritati, Federica, Palmisano, Alessandra, Dejaco, Christian, Willeit, Johann, Kiechl, Stefan, Olivotto, Iacopo, Willeit, Peter, Prisco, Domenico, Vaglio, Augusto, Emmi, Giacomo, Bettiol, A, Sinico, R, Schiavon, F, Monti, S, Bozzolo, E, Franceschini, F, Govoni, M, Lunardi, C, Guida, G, Lopalco, G, Paolazzi, G, Vacca, A, Gregorini, G, Leccese, P, Piga, M, Conti, F, Fraticelli, P, Quartuccio, L, Alberici, F, Salvarani, C, Bettio, S, Negrini, S, Selmi, C, Sciascia, S, Moroni, G, Colla, L, Manno, C, Urban, M, Vannacci, A, Pozzi, M, Fabbrini, P, Polti, S, Felicetti, M, Marchi, M, Padoan, R, Delvino, P, Caporali, R, Montecucco, C, Dagna, L, Cariddi, A, Toniati, P, Tamanini, S, Furini, F, Bortoluzzi, A, Tinazzi, E, Delfino, L, Badiu, I, Rolla, G, Venerito, V, Iannone, F, Berti, A, Bortolotti, R, Racanelli, V, Jeannin, G, Padula, A, Cauli, A, Priori, R, Gabrielli, A, Bond, M, Tedesco, M, Pazzola, G, Tomietto, P, Pellecchio, M, Marvisi, C, Maritati, F, Palmisano, A, Dejaco, C, Willeit, J, Kiechl, S, Olivotto, I, Willeit, P, Prisco, D, Vaglio, A, Emmi, G, Bettiol, Alessandra, Sinico, Renato Alberto, Schiavon, Franco, Monti, Sara, Bozzolo, Enrica Paola, Franceschini, Franco, Govoni, Marcello, Lunardi, Claudio, Guida, Giuseppe, Lopalco, Giuseppe, Paolazzi, Giuseppe, Vacca, Angelo, Gregorini, Gina, Leccese, Pietro, Piga, Matteo, Conti, Fabrizio, Fraticelli, Paolo, Quartuccio, Luca, Alberici, Federico, Salvarani, Carlo, Bettio, Silvano, Negrini, Simone, Selmi, Carlo, Sciascia, Savino, Moroni, Gabriella, Colla, Loredana, Manno, Carlo, Urban, Maria Letizia, Vannacci, Alfredo, Pozzi, Maria Rosa, Fabbrini, Paolo, Polti, Stefano, Felicetti, Mara, Marchi, Maria Rita, Padoan, Roberto, Delvino, Paolo, Caporali, Roberto, Montecucco, Carlomaurizio, Dagna, Lorenzo, Cariddi, Adriana, Toniati, Paola, Tamanini, Silvia, Furini, Federica, Bortoluzzi, Alessandra, Tinazzi, Elisa, Delfino, Lorenzo, Badiu, Iuliana, Rolla, Giovanni, Venerito, Vincenzo, Iannone, Florenzo, Berti, Alvise, Bortolotti, Roberto, Racanelli, Vito, Jeannin, Guido, Padula, Angela, Cauli, Alberto, Priori, Roberta, Gabrielli, Armando, Bond, Milena, Tedesco, Martina, Pazzola, Giulia, Tomietto, Paola, Pellecchio, Marco, Marvisi, Chiara, Maritati, Federica, Palmisano, Alessandra, Dejaco, Christian, Willeit, Johann, Kiechl, Stefan, Olivotto, Iacopo, Willeit, Peter, Prisco, Domenico, Vaglio, Augusto, and Emmi, Giacomo
Published: 2021

7. Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Author: Ghofrani, HA, Gomez Sanchez, MA, Humbert, M, Pittrow, D, Simonneau, G, Gall, H, Grünig, E, Klose, H, Halank, M, Langleben, D, Snijder, RJ, Escribano Subias, P, Mielniczuk, LM, Lange, TJ, Vachiéry, JL, Wirtz, H, Helmersen, DS, Tsangaris, I, Barberá, JA, Pepke-Zaba, J, Boonstra, Andre, Rosenkranz, S, Ulrich, S, Steringer-Mascherbauer, R, Delcroix, M, Jansa, P, Šimková, I, Giannakoulas, G, Klotsche, J, Williams, E, Meier, C, Hoeper, MM, Caneva, J, Tuhay, G, Diez, M, Talavera, ML, Acosta, A, Vulcano, N, Bosio, M, Maldonado, L, Deleo, S, Melatini, L, Keogh, A, Kotlyar, E, Feenstra, J, Dwyer, N, Adams, H, Stevens, W, Steele, P, Proudman, S, Minson, R, Reeves, G, Lavender, M, Ng, B, MacKenzie, M, Barry, L, Gruenberger, M, Huber, C, Lang, I, Tilea, I, Sadushi-Kolici, R, Löffler-Ragg, J, Feistmantl, LT, Evrard, P, Louis, R, Guiot, J, Naldi, M, Pauw, M, Mehta, S, Camacho, RC, Tovar, PP, Londoño, A, Campo, F, Garcia, P, Lema, C, Orozco-Levi, M, Martinez, W, Gomez, JE, Nielsen-Kudsk, JE, Mellemkjaer, S, Anton, L, Altraja, A, Vihinen, T, Vasankari, T, Sitbon, O, Cottin, V, Têtu, L, Noël-Savina, E, Shearman, N, Tayler, S, Olzik, I, Kulka, C, Grimminger, J, Simon, M, Nolde, A, Oqueka, T, Harbaum, L, Egenlauf, B, Ewert, R, Schulz, C, Regotta, S, Kramer, T, Knoop-Busch, S, Gerhardt, F, Konstantinides, S, Pitsiou, G, Stanopoulos, I, Sourla, E, Mouratoglou, S, Karvounis, H, Pappas, A, Georgopoulos, D, Fanaridis, M, Mitrouska, I, Michalis, L, Pappas, K, Kotsia, A, Gaine, S, Vizza, CD, Manzi, G, Poscia, R, Badagliacca, R, Agostoni, P, Bruno, N, Farina, S, D'Alto, M, Argiento, P, Correra, A, Di Marco, GM, Cresci, C, Vannucchi, V, Torricelli, E, Garcea, A, Pesci, A, Sardella, L, Paciocco, G, Pane, F, D'Armini, AM, Pin, M, Grazioli, V, Massola, G, Sciortino, A, Prediletto, R, Bauleo, C, Airò, E, Ndreu, R, Pavlickova, I, Lunardi, C, Mulè, M, Farruggio, S, Costa, S, Galgano, G, Petruzzi, M, Luca, A, Lombardi, F, Roncon, L, Conte, L, Picariello, C, Wirtz, G, Alexandre, M, Vonk-Noordegraaf, A, van den Boogaard, H, Mager, J, Reesink, H, van den Toorn, Leon, Boomars, Karin, Andreassen, AK, Castro, G, Tania, G, Baptista, R, Marinho, A, Shiang, T, Oliveira, A, Coutinho, D, Sousa, J, Loureiro, MJ, Repolho, D, Martins Jesus, SM, Capinha, M, Agostinho, J, Cardoso, T, Rocha, A, Espinha, M, Ivanov, KI, Alexeeva, DE, Batalina, MV, Hegya, DV, Zvereva, TN, Avdeev, SN, Tsareva, NA, Galyavich, AS, Nikolaevich, BA, Filippov, EV, Yakovleva, OE, Pavlova, OB, Skripkina, ES, Martynyuk, TV, Bukatova, IF, Tregubova, AV, Platonov, DY, Kolomeytseva, TM, Al Dalaan, A, Abdelsayed, AA, Weheba, I, Saleemi, S, Sakkijha, H, Bohacekova, M, Valkovicova, T, Farkasova, I, Quezada, CA, Piccari, L, Blanco, I, Sebastian, L, Roman, A, Lopez, M, Otero, R, Elias, T, Jara, L, Asencio, I, Arjona, JJ, Almagro, RM, Cárdenas, SL, García, SA, Rodríguez, PV, Lopez, R, Garcia, A, Avilés, FF, De La Pava, S, Yotti, R, Peñate, GP, Marrero, FL, Cifrián Martínez, JM, Martinez-Meñaca, A, Alonso, LP, Rozas, SF, Fernandez, DI, Cuesta, VM, Söderberg, S, Bartfay, SE, Rundqvist, B, Alfetlawi, M, Wodlin, P, Schwarz, EI, Speich, R, Lador, F, Rochat, T, Gasche-Soccal, P, Hsu, CH, Lin, TH, Su, HM, Lai, WT, Chu, CY, Hsu, PC, Voon, WC, Yen, HW, Yih-Jer Wu, J, Wu, SH, Huang, WP, Fong, MC, Huang, CL, Kuo, PH, Lin, YH, Lin, JL, Hung, CS, Wu, CK, Sung, SH, Huang, WC, Cheng, CC, Kuo, SH, Wang, WH, Ho, WJ, Hsu, TS, Mutlu, B, Atas, H, Ongen, G, Un, Z, Okumus, G, Hanta, I, Corris, P, Peacock, A, Church, C, Toshner, M, Ghofrani, HA, Gomez Sanchez, MA, Humbert, M, Pittrow, D, Simonneau, G, Gall, H, Grünig, E, Klose, H, Halank, M, Langleben, D, Snijder, RJ, Escribano Subias, P, Mielniczuk, LM, Lange, TJ, Vachiéry, JL, Wirtz, H, Helmersen, DS, Tsangaris, I, Barberá, JA, Pepke-Zaba, J, Boonstra, Andre, Rosenkranz, S, Ulrich, S, Steringer-Mascherbauer, R, Delcroix, M, Jansa, P, Šimková, I, Giannakoulas, G, Klotsche, J, Williams, E, Meier, C, Hoeper, MM, Caneva, J, Tuhay, G, Diez, M, Talavera, ML, Acosta, A, Vulcano, N, Bosio, M, Maldonado, L, Deleo, S, Melatini, L, Keogh, A, Kotlyar, E, Feenstra, J, Dwyer, N, Adams, H, Stevens, W, Steele, P, Proudman, S, Minson, R, Reeves, G, Lavender, M, Ng, B, MacKenzie, M, Barry, L, Gruenberger, M, Huber, C, Lang, I, Tilea, I, Sadushi-Kolici, R, Löffler-Ragg, J, Feistmantl, LT, Evrard, P, Louis, R, Guiot, J, Naldi, M, Pauw, M, Mehta, S, Camacho, RC, Tovar, PP, Londoño, A, Campo, F, Garcia, P, Lema, C, Orozco-Levi, M, Martinez, W, Gomez, JE, Nielsen-Kudsk, JE, Mellemkjaer, S, Anton, L, Altraja, A, Vihinen, T, Vasankari, T, Sitbon, O, Cottin, V, Têtu, L, Noël-Savina, E, Shearman, N, Tayler, S, Olzik, I, Kulka, C, Grimminger, J, Simon, M, Nolde, A, Oqueka, T, Harbaum, L, Egenlauf, B, Ewert, R, Schulz, C, Regotta, S, Kramer, T, Knoop-Busch, S, Gerhardt, F, Konstantinides, S, Pitsiou, G, Stanopoulos, I, Sourla, E, Mouratoglou, S, Karvounis, H, Pappas, A, Georgopoulos, D, Fanaridis, M, Mitrouska, I, Michalis, L, Pappas, K, Kotsia, A, Gaine, S, Vizza, CD, Manzi, G, Poscia, R, Badagliacca, R, Agostoni, P, Bruno, N, Farina, S, D'Alto, M, Argiento, P, Correra, A, Di Marco, GM, Cresci, C, Vannucchi, V, Torricelli, E, Garcea, A, Pesci, A, Sardella, L, Paciocco, G, Pane, F, D'Armini, AM, Pin, M, Grazioli, V, Massola, G, Sciortino, A, Prediletto, R, Bauleo, C, Airò, E, Ndreu, R, Pavlickova, I, Lunardi, C, Mulè, M, Farruggio, S, Costa, S, Galgano, G, Petruzzi, M, Luca, A, Lombardi, F, Roncon, L, Conte, L, Picariello, C, Wirtz, G, Alexandre, M, Vonk-Noordegraaf, A, van den Boogaard, H, Mager, J, Reesink, H, van den Toorn, Leon, Boomars, Karin, Andreassen, AK, Castro, G, Tania, G, Baptista, R, Marinho, A, Shiang, T, Oliveira, A, Coutinho, D, Sousa, J, Loureiro, MJ, Repolho, D, Martins Jesus, SM, Capinha, M, Agostinho, J, Cardoso, T, Rocha, A, Espinha, M, Ivanov, KI, Alexeeva, DE, Batalina, MV, Hegya, DV, Zvereva, TN, Avdeev, SN, Tsareva, NA, Galyavich, AS, Nikolaevich, BA, Filippov, EV, Yakovleva, OE, Pavlova, OB, Skripkina, ES, Martynyuk, TV, Bukatova, IF, Tregubova, AV, Platonov, DY, Kolomeytseva, TM, Al Dalaan, A, Abdelsayed, AA, Weheba, I, Saleemi, S, Sakkijha, H, Bohacekova, M, Valkovicova, T, Farkasova, I, Quezada, CA, Piccari, L, Blanco, I, Sebastian, L, Roman, A, Lopez, M, Otero, R, Elias, T, Jara, L, Asencio, I, Arjona, JJ, Almagro, RM, Cárdenas, SL, García, SA, Rodríguez, PV, Lopez, R, Garcia, A, Avilés, FF, De La Pava, S, Yotti, R, Peñate, GP, Marrero, FL, Cifrián Martínez, JM, Martinez-Meñaca, A, Alonso, LP, Rozas, SF, Fernandez, DI, Cuesta, VM, Söderberg, S, Bartfay, SE, Rundqvist, B, Alfetlawi, M, Wodlin, P, Schwarz, EI, Speich, R, Lador, F, Rochat, T, Gasche-Soccal, P, Hsu, CH, Lin, TH, Su, HM, Lai, WT, Chu, CY, Hsu, PC, Voon, WC, Yen, HW, Yih-Jer Wu, J, Wu, SH, Huang, WP, Fong, MC, Huang, CL, Kuo, PH, Lin, YH, Lin, JL, Hung, CS, Wu, CK, Sung, SH, Huang, WC, Cheng, CC, Kuo, SH, Wang, WH, Ho, WJ, Hsu, TS, Mutlu, B, Atas, H, Ongen, G, Un, Z, Okumus, G, Hanta, I, Corris, P, Peacock, A, Church, C, and Toshner, M
Abstract: Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial [CHEST-2]). Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified.
Published: 2021

8. MEPOLIZUMAB FOR EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS (EGPA): A RETROSPECTIVE REAL-WORLD EUROPEAN STUDY ON 142 PATIENTS

Author: Bettiol, A, Urban, M, Alberici, F, Agostini, C, Baldini, C, Bozzolo, E, Cameli, P, Crimi, N, Del Giacco, S, Egan, A, Espigol-Frigole, G, Felicetti, M, Folci, M, Fraticelli, P, Govoni, M, Kernder, A, Lombardi, C, Lopalco, G, Lunardi, C, Mohammad, A, Moosig, F, Negrini, S, Neumann, T, Novikov, P, Paolazzi, G, Parronchi, P, Quartuccio, L, Racanelli, V, Salvarani, C, Samson, M, Schroeder, J, Sciascia, S, Sinico, R, Terrier, B, Toniati, P, Prisco, D, Vaglio, A, Emmi, G, A Bettiol, ML Urban, F Alberici, C Agostini, C Baldini, E Bozzolo, P Cameli, N Crimi, S Del Giacco, A Egan, G Espigol-Frigole, M Felicetti, M Folci, P Fraticelli, M Govoni, A Kernder, C Lombardi, G Lopalco, C Lunardi, AJ Mohammad, F Moosig, S Negrini, T Neumann, P Novikov, G Paolazzi, P Parronchi, L Quartuccio, V Racanelli, C Salvarani, M Samson, J Schroeder, S Sciascia, RA Sinico, B Terrier, P Toniati, D Prisco, A Vaglio, G Emmi, Bettiol, A, Urban, M, Alberici, F, Agostini, C, Baldini, C, Bozzolo, E, Cameli, P, Crimi, N, Del Giacco, S, Egan, A, Espigol-Frigole, G, Felicetti, M, Folci, M, Fraticelli, P, Govoni, M, Kernder, A, Lombardi, C, Lopalco, G, Lunardi, C, Mohammad, A, Moosig, F, Negrini, S, Neumann, T, Novikov, P, Paolazzi, G, Parronchi, P, Quartuccio, L, Racanelli, V, Salvarani, C, Samson, M, Schroeder, J, Sciascia, S, Sinico, R, Terrier, B, Toniati, P, Prisco, D, Vaglio, A, Emmi, G, A Bettiol, ML Urban, F Alberici, C Agostini, C Baldini, E Bozzolo, P Cameli, N Crimi, S Del Giacco, A Egan, G Espigol-Frigole, M Felicetti, M Folci, P Fraticelli, M Govoni, A Kernder, C Lombardi, G Lopalco, C Lunardi, AJ Mohammad, F Moosig, S Negrini, T Neumann, P Novikov, G Paolazzi, P Parronchi, L Quartuccio, V Racanelli, C Salvarani, M Samson, J Schroeder, S Sciascia, RA Sinico, B Terrier, P Toniati, D Prisco, A Vaglio, and G Emmi
Abstract: Background: Evidence on the efficacy of Mepolizumab (MEPO) in Eosinophilic Granulomatosis with Polyangiitis (EGPA) is scarce [1]. Objectives: To assess the efficacy and safety of MEPO in real-life clinical practice. Methods: We retrospectively included patients diagnosed with EGPA and treated with MEPO (100 or 300 mg/month). MEPO efficacy was evaluated in the first 12 months in terms of systemic disease and asthma control. The occurrence of any adverse event (AE) was recorded. Results: 142 patients were included (38% males; median age 46.4 (IQR 36.7-54.4); 110 and 32 on MEPO 100 and 300 mg/month, respectively). General, ear-nose-throat, pulmonary, and neurological symptoms significantly decreased during treatment (table 1). MEPO accounted for a significant reduction in the BVAS (figure 1) and for a steroid sparing effect (figure 2). The proportion of patients with asthma attacks decreased by 90% at 12 months compared to t0, and asthma-related emergency accesses dropped from 17.4% to 2.3%. Overall, 21.1% of patients had a non-serious AE.
Published: 2020

9. GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways.

Author: Vicente E., Mumbach M.R., Granja J., Beretta L., Simeon C.P., Carreira P., Ortego-Centeno N., Castellvi I., Bossini-Castillo L., Carmona F.D., Orozco G., Hunzelmann N., Distler J.H.W., Franke A., Lunardi C., Moroncini G., Gabrielli A., de Vries-Bouwstra J., Wijmenga C., Koeleman B.P.C., Nordin A., Padyukov L., Hoffmann-Vold A.-M., Lie B., Rios R., Callejas J.L., Vargas-Hitos J.A., Garcia-Portales R., Camps M.T., Fernandez-Nebro A., Gonzalez-Escribano M.F., Garcia-Hernandez F.J., Castillo M.J., Aguirre M.A., Gomez-Gracia I., Fernandez-Gutierrez B., Rodriguez-Rodriguez L., Garcia de la Pena P., Andreu J.L., Fernandez de Castro M., Lopez-Longo F.J., Martinez L., Fonollosa, Guillen A., Espinosa G., Tolosa C., Pros A., Rodriguez-Carballeira M., Narvaez F.J., Rubio-Rivas M., Ortiz-Santamaria, Madronero A.B., Gonzalez-Gay M.A., Diaz B., Trapiella L., Sousa A., Egurbide M.V., Fanlo-Mateo P., Saez-Comet L., Diaz F., Hernandez, Beltran E., Roman-Ivorra J.A., Grau E., Alegre-Sancho J.J., Freire M., Blanco-Garcia F.J., Oreiro N., Witte T., Kreuter A., Riemekasten G., Airo P., Magro C., Voskuyl A.E., Vonk M.C., Hesselstrand R., Proudman S., Stevens W., Nikpour M., Zochling J., Sahhar J., Roddy J., Nash P., Tymms K., Rischmueller M., Lester S., Vyse T., Herrick A.L., Worthington J., Denton C.P., Allanore Y., Brown M.A., Radstake T.R.D.J., Fonseca C., Chang H.Y., Mayes M.D., Martin J., Lopez-Isac E., Acosta-Herrera M., Kerick M., Assassi S., Satpathy A.T., Vicente E., Mumbach M.R., Granja J., Beretta L., Simeon C.P., Carreira P., Ortego-Centeno N., Castellvi I., Bossini-Castillo L., Carmona F.D., Orozco G., Hunzelmann N., Distler J.H.W., Franke A., Lunardi C., Moroncini G., Gabrielli A., de Vries-Bouwstra J., Wijmenga C., Koeleman B.P.C., Nordin A., Padyukov L., Hoffmann-Vold A.-M., Lie B., Rios R., Callejas J.L., Vargas-Hitos J.A., Garcia-Portales R., Camps M.T., Fernandez-Nebro A., Gonzalez-Escribano M.F., Garcia-Hernandez F.J., Castillo M.J., Aguirre M.A., Gomez-Gracia I., Fernandez-Gutierrez B., Rodriguez-Rodriguez L., Garcia de la Pena P., Andreu J.L., Fernandez de Castro M., Lopez-Longo F.J., Martinez L., Fonollosa, Guillen A., Espinosa G., Tolosa C., Pros A., Rodriguez-Carballeira M., Narvaez F.J., Rubio-Rivas M., Ortiz-Santamaria, Madronero A.B., Gonzalez-Gay M.A., Diaz B., Trapiella L., Sousa A., Egurbide M.V., Fanlo-Mateo P., Saez-Comet L., Diaz F., Hernandez, Beltran E., Roman-Ivorra J.A., Grau E., Alegre-Sancho J.J., Freire M., Blanco-Garcia F.J., Oreiro N., Witte T., Kreuter A., Riemekasten G., Airo P., Magro C., Voskuyl A.E., Vonk M.C., Hesselstrand R., Proudman S., Stevens W., Nikpour M., Zochling J., Sahhar J., Roddy J., Nash P., Tymms K., Rischmueller M., Lester S., Vyse T., Herrick A.L., Worthington J., Denton C.P., Allanore Y., Brown M.A., Radstake T.R.D.J., Fonseca C., Chang H.Y., Mayes M.D., Martin J., Lopez-Isac E., Acosta-Herrera M., Kerick M., Assassi S., and Satpathy A.T.
Abstract: Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.Copyright © 2019, The Author(s).
Published: 2019

10. GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways.

Author: Vicente E., Mumbach M.R., Granja J., Beretta L., Simeon C.P., Carreira P., Ortego-Centeno N., Castellvi I., Bossini-Castillo L., Carmona F.D., Orozco G., Hunzelmann N., Distler J.H.W., Franke A., Lunardi C., Moroncini G., Gabrielli A., de Vries-Bouwstra J., Wijmenga C., Koeleman B.P.C., Nordin A., Padyukov L., Hoffmann-Vold A.-M., Lie B., Rios R., Callejas J.L., Vargas-Hitos J.A., Garcia-Portales R., Camps M.T., Fernandez-Nebro A., Gonzalez-Escribano M.F., Garcia-Hernandez F.J., Castillo M.J., Aguirre M.A., Gomez-Gracia I., Fernandez-Gutierrez B., Rodriguez-Rodriguez L., Garcia de la Pena P., Andreu J.L., Fernandez de Castro M., Lopez-Longo F.J., Martinez L., Fonollosa, Guillen A., Espinosa G., Tolosa C., Pros A., Rodriguez-Carballeira M., Narvaez F.J., Rubio-Rivas M., Ortiz-Santamaria, Madronero A.B., Gonzalez-Gay M.A., Diaz B., Trapiella L., Sousa A., Egurbide M.V., Fanlo-Mateo P., Saez-Comet L., Diaz F., Hernandez, Beltran E., Roman-Ivorra J.A., Grau E., Alegre-Sancho J.J., Freire M., Blanco-Garcia F.J., Oreiro N., Witte T., Kreuter A., Riemekasten G., Airo P., Magro C., Voskuyl A.E., Vonk M.C., Hesselstrand R., Proudman S., Stevens W., Nikpour M., Zochling J., Sahhar J., Roddy J., Nash P., Tymms K., Rischmueller M., Lester S., Vyse T., Herrick A.L., Worthington J., Denton C.P., Allanore Y., Brown M.A., Radstake T.R.D.J., Fonseca C., Chang H.Y., Mayes M.D., Martin J., Lopez-Isac E., Acosta-Herrera M., Kerick M., Assassi S., Satpathy A.T., Vicente E., Mumbach M.R., Granja J., Beretta L., Simeon C.P., Carreira P., Ortego-Centeno N., Castellvi I., Bossini-Castillo L., Carmona F.D., Orozco G., Hunzelmann N., Distler J.H.W., Franke A., Lunardi C., Moroncini G., Gabrielli A., de Vries-Bouwstra J., Wijmenga C., Koeleman B.P.C., Nordin A., Padyukov L., Hoffmann-Vold A.-M., Lie B., Rios R., Callejas J.L., Vargas-Hitos J.A., Garcia-Portales R., Camps M.T., Fernandez-Nebro A., Gonzalez-Escribano M.F., Garcia-Hernandez F.J., Castillo M.J., Aguirre M.A., Gomez-Gracia I., Fernandez-Gutierrez B., Rodriguez-Rodriguez L., Garcia de la Pena P., Andreu J.L., Fernandez de Castro M., Lopez-Longo F.J., Martinez L., Fonollosa, Guillen A., Espinosa G., Tolosa C., Pros A., Rodriguez-Carballeira M., Narvaez F.J., Rubio-Rivas M., Ortiz-Santamaria, Madronero A.B., Gonzalez-Gay M.A., Diaz B., Trapiella L., Sousa A., Egurbide M.V., Fanlo-Mateo P., Saez-Comet L., Diaz F., Hernandez, Beltran E., Roman-Ivorra J.A., Grau E., Alegre-Sancho J.J., Freire M., Blanco-Garcia F.J., Oreiro N., Witte T., Kreuter A., Riemekasten G., Airo P., Magro C., Voskuyl A.E., Vonk M.C., Hesselstrand R., Proudman S., Stevens W., Nikpour M., Zochling J., Sahhar J., Roddy J., Nash P., Tymms K., Rischmueller M., Lester S., Vyse T., Herrick A.L., Worthington J., Denton C.P., Allanore Y., Brown M.A., Radstake T.R.D.J., Fonseca C., Chang H.Y., Mayes M.D., Martin J., Lopez-Isac E., Acosta-Herrera M., Kerick M., Assassi S., and Satpathy A.T.
Abstract: Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.Copyright © 2019, The Author(s).
Published: 2019

11. GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways

Author: Lopez-Isac, E, Acosta-Herrera, M, Kerick, M, Assassi, S, Satpathy, AT, Granja, J, Mumbach, MR, Beretta, L, Simeon, CP, Carreira, P, Ortego-Centeno, N, Castellvi, I, Bossini-Castillo, L, David Carmona, F, Orozco, G, Hunzelmann, N, Distler, JHW, Franke, A, Lunardi, C, Moroncini, G, Gabrielli, A, de Vries-Bouwstra, J, Wijmenga, C, Koeleman, BPC, Nordin, A, Padyukov, L, Hoffmann-Vold, A-M, Lie, B, Rios, R, Callejas, JL, Vargas-Hitos, JA, Garcia-Portales, R, Camps, MT, Fernandez-Nebro, A, Gonzalez-Escribano, MF, Garcia-Hernandez, FJ, Castillo, MJ, Aguirre, MA, Gomez-Gracia, I, Fernandez-Gutierrez, B, Rodriguez-Rodriguez, L, Garcia de la Pena, P, Vicente, E, Andreu, JL, Fernandez de Castro, M, Lopez-Longo, FJ, Martinez, L, Fonollosa, V, Guillen, A, Espinosa, G, Tolosa, C, Pros, A, Rodriguez-Carballeira, M, Narvaez, FJ, Rubio-Rivas, M, Ortiz-Santamaria, V, Madronero, AB, Gonzalez-Gay, MA, Diaz, B, Trapiella, L, Sousa, A, Egurbide, MV, Fanlo-Mateo, P, Saez-Comet, L, Diaz, F, Hernandez, V, Beltran, E, Roman-Ivorra, JA, Grau, E, Alegre-Sancho, JJ, Freire, M, Blanco-Garcia, FJ, Oreiro, N, Witte, T, Kreuter, A, Riemekasten, G, Airo, P, Magro, C, Voskuyl, AE, Vonk, MC, Hesselstrand, R, Proudman, S, Stevens, W, Nikpour, M, Zochling, J, Sahhar, J, Roddy, J, Nash, P, Tymms, K, Rischmueller, M, Lester, S, Vyse, T, Herrick, AL, Worthington, J, Denton, CP, Allanore, Y, Brown, MA, Radstake, TRDJ, Fonseca, C, Chang, HY, Mayes, MD, Martin, J, Lopez-Isac, E, Acosta-Herrera, M, Kerick, M, Assassi, S, Satpathy, AT, Granja, J, Mumbach, MR, Beretta, L, Simeon, CP, Carreira, P, Ortego-Centeno, N, Castellvi, I, Bossini-Castillo, L, David Carmona, F, Orozco, G, Hunzelmann, N, Distler, JHW, Franke, A, Lunardi, C, Moroncini, G, Gabrielli, A, de Vries-Bouwstra, J, Wijmenga, C, Koeleman, BPC, Nordin, A, Padyukov, L, Hoffmann-Vold, A-M, Lie, B, Rios, R, Callejas, JL, Vargas-Hitos, JA, Garcia-Portales, R, Camps, MT, Fernandez-Nebro, A, Gonzalez-Escribano, MF, Garcia-Hernandez, FJ, Castillo, MJ, Aguirre, MA, Gomez-Gracia, I, Fernandez-Gutierrez, B, Rodriguez-Rodriguez, L, Garcia de la Pena, P, Vicente, E, Andreu, JL, Fernandez de Castro, M, Lopez-Longo, FJ, Martinez, L, Fonollosa, V, Guillen, A, Espinosa, G, Tolosa, C, Pros, A, Rodriguez-Carballeira, M, Narvaez, FJ, Rubio-Rivas, M, Ortiz-Santamaria, V, Madronero, AB, Gonzalez-Gay, MA, Diaz, B, Trapiella, L, Sousa, A, Egurbide, MV, Fanlo-Mateo, P, Saez-Comet, L, Diaz, F, Hernandez, V, Beltran, E, Roman-Ivorra, JA, Grau, E, Alegre-Sancho, JJ, Freire, M, Blanco-Garcia, FJ, Oreiro, N, Witte, T, Kreuter, A, Riemekasten, G, Airo, P, Magro, C, Voskuyl, AE, Vonk, MC, Hesselstrand, R, Proudman, S, Stevens, W, Nikpour, M, Zochling, J, Sahhar, J, Roddy, J, Nash, P, Tymms, K, Rischmueller, M, Lester, S, Vyse, T, Herrick, AL, Worthington, J, Denton, CP, Allanore, Y, Brown, MA, Radstake, TRDJ, Fonseca, C, Chang, HY, Mayes, MD, and Martin, J
Abstract: Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.
Published: 2019

12. IDENTIFICATION OF FOUR NEW SHARED SUSCEPTIBILITY GENES IN SYSTEMIC SCLEROSIS AND CROHN¿S DISEASE THROUGH A CROSS-DISEASE META-GWAS

Author: González-Serna, David, Ochoa, Eguzkine, López-Isac, Elena, Julià, A., Degenhardt, Frauke, van Beelen Granlund, A, Carreira, PE, Simeón, Carmen P., Ortego-Centeno, N., González-Gay, M. A., Vicente, Esther, Beltrán, E., Alegre-Sancho, Juan-José, Spanish Scleroderma Group, Beretta, L., Santaniello, A, Lunardi, C., Hunzelmann, Nicolas, Riemekasten, G, Witte, T, Distler, J.H.W., Kreuter, A., Airó, P, Koeleman, B. P., Voskuyl, AE, de Vries-Bouwstra, Jeska, Radstake, Timothy R. D. J., Wijmenga, C, Assassi, S., Franke, Andre, Marsal, Sara, Mayes, Maureen D., Martín, J., Márquez A, González-Serna, David, Ochoa, Eguzkine, López-Isac, Elena, Julià, A., Degenhardt, Frauke, van Beelen Granlund, A, Carreira, PE, Simeón, Carmen P., Ortego-Centeno, N., González-Gay, M. A., Vicente, Esther, Beltrán, E., Alegre-Sancho, Juan-José, Spanish Scleroderma Group, Beretta, L., Santaniello, A, Lunardi, C., Hunzelmann, Nicolas, Riemekasten, G, Witte, T, Distler, J.H.W., Kreuter, A., Airó, P, Koeleman, B. P., Voskuyl, AE, de Vries-Bouwstra, Jeska, Radstake, Timothy R. D. J., Wijmenga, C, Assassi, S., Franke, Andre, Marsal, Sara, Mayes, Maureen D., Martín, J., and Márquez A
Published: 2019

13. GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways.

Author: Universidad de Salamanca, Ministerio de Economía y Competitividad (España), Junta de Andalucía, Ministerio de Educación, Cultura y Deporte (España), Instituto de Salud Carlos III, Howard Hughes Medical Institute, Federal Ministry of Education and Research (Germany), López-Isac, Elena, Acosta-Herrera, Marialbert, Kerick M, Assassi, S., Satpathy AT, Granja J, Mumbach, Maxwell R., Beretta L, Simeón, Carmen P., Carreira P, Ortego-Centeno, N., Castellví, I., Bossini-Castillo, L., Carmona, F.D., Orozco, Gisela, Hunzelmann, Nicolas, Distler, J.H.W., Franke, Andre, Lunardi, C., Moroncini, G, Gabrielli, Armando, de Vries-Bouwstra, Jeska, Wijmenga, C, Koeleman, B. P., Nordin, A, Padyukov, L, Hoffmann-Vold, A. M., Lie, B, European Scleroderma Group¿, Proudman, S, Stevens, W, Nikpour, M, Australian Scleroderma Interest Group (ASIG), Vyse, T, Herrick, Ariane L., Worthington, J, Denton, CP, Allanore, Y, Brown, MA, Radstake, Timothy R. D. J., Fonseca, C., Chang, HY, Mayes, Maureen D., Martín, J., Universidad de Salamanca, Ministerio de Economía y Competitividad (España), Junta de Andalucía, Ministerio de Educación, Cultura y Deporte (España), Instituto de Salud Carlos III, Howard Hughes Medical Institute, Federal Ministry of Education and Research (Germany), López-Isac, Elena, Acosta-Herrera, Marialbert, Kerick M, Assassi, S., Satpathy AT, Granja J, Mumbach, Maxwell R., Beretta L, Simeón, Carmen P., Carreira P, Ortego-Centeno, N., Castellví, I., Bossini-Castillo, L., Carmona, F.D., Orozco, Gisela, Hunzelmann, Nicolas, Distler, J.H.W., Franke, Andre, Lunardi, C., Moroncini, G, Gabrielli, Armando, de Vries-Bouwstra, Jeska, Wijmenga, C, Koeleman, B. P., Nordin, A, Padyukov, L, Hoffmann-Vold, A. M., Lie, B, European Scleroderma Group¿, Proudman, S, Stevens, W, Nikpour, M, Australian Scleroderma Interest Group (ASIG), Vyse, T, Herrick, Ariane L., Worthington, J, Denton, CP, Allanore, Y, Brown, MA, Radstake, Timothy R. D. J., Fonseca, C., Chang, HY, Mayes, Maureen D., and Martín, J.
Abstract: Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.
Published: 2019

14. A CROSS-DISEASE META-GWAS IDENTIFIES IRF1, STAT3 AND ZBTB9-BAK1 AS NEW SHARED SUSCEPTIBILITY LOCI IN SYSTEMIC SCLEROSIS AND CROHN¿S DISEASE

Author: González-Serna, David, Ochoa, Eguzkine, López-Isac, Elena, Julià, A., Degenhardt, Frauke, van Beelen Granlund,, A., Carreira, P.E., Simeón, Carmen P., Ortego-Centeno, N., González-Gay, M. A., Vicente, Esther, Beltrán, E., Alegre-Sancho, Juan-José, Beretta, L., Santaniello, A., Lunardi, C., Hunzelmann, Nicolas, Riemekasten, .G, Witte, T., Distler, J.H.W., Kreuter, A., Airó, P., Koeleman, BPC, Voskuyl, T..A.E., de Vries-Bouwstra, Jeska, Radstake, Timothy R. D. J., Wijmenga, C., Assassi, S.., Franke, Andre, Marsal, Sara, Mayes, Maureen D., Martín, J., Márquez, A., González-Serna, David, Ochoa, Eguzkine, López-Isac, Elena, Julià, A., Degenhardt, Frauke, van Beelen Granlund,, A., Carreira, P.E., Simeón, Carmen P., Ortego-Centeno, N., González-Gay, M. A., Vicente, Esther, Beltrán, E., Alegre-Sancho, Juan-José, Beretta, L., Santaniello, A., Lunardi, C., Hunzelmann, Nicolas, Riemekasten, .G, Witte, T., Distler, J.H.W., Kreuter, A., Airó, P., Koeleman, BPC, Voskuyl, T..A.E., de Vries-Bouwstra, Jeska, Radstake, Timothy R. D. J., Wijmenga, C., Assassi, S.., Franke, Andre, Marsal, Sara, Mayes, Maureen D., Martín, J., and Márquez, A.
Published: 2019

15. NEW SYSTEMIC SCLEROSIS RISK LOCI IDENTIFIED THROUGH A META-GWAS STRATEGY

Author: Lopez-Isac, E., Acosta-Herrera, M., Assassi, S., Simeon, C. P., Carreira, P. E., Castellvi, I., Ortego-Centeno, N., Beretta, L., Lunardi, C., Gabrielli, A., Moroncini, G., Hunzelmann, N., Witte, T., Distler, J. H., Franke, A., Voskuyl, A. E., de Vries-Bouwstra, J., Wijmenga, C., Hesselstrand, R., Nordin, A., Hoffmann-Vold, A. -M., Herrick, A., Worthington, J., Denton, C. P., Brown, M. A., Allanore, Y., Radstake, T. R., Fonseca, C., Mayes, M. D., Martin, J., Lopez-Isac, E., Acosta-Herrera, M., Assassi, S., Simeon, C. P., Carreira, P. E., Castellvi, I., Ortego-Centeno, N., Beretta, L., Lunardi, C., Gabrielli, A., Moroncini, G., Hunzelmann, N., Witte, T., Distler, J. H., Franke, A., Voskuyl, A. E., de Vries-Bouwstra, J., Wijmenga, C., Hesselstrand, R., Nordin, A., Hoffmann-Vold, A. -M., Herrick, A., Worthington, J., Denton, C. P., Brown, M. A., Allanore, Y., Radstake, T. R., Fonseca, C., Mayes, M. D., and Martin, J.
Published: 2018

16. NEW SYSTEMIC SCLEROSIS RISK LOCI IDENTIFIED THROUGH A META-GWAS STRATEGY

Author: Lopez-Isac, E., Acosta-Herrera, M., Assassi, S., Simeon, C. P., Carreira, P. E., Castellvi, I., Ortego-Centeno, N., Beretta, L., Lunardi, C., Gabrielli, A., Moroncini, G., Hunzelmann, N., Witte, T., Distler, J. H., Franke, A., Voskuyl, A. E., de Vries-Bouwstra, J., Wijmenga, C., Hesselstrand, R., Nordin, A., Hoffmann-Vold, A. -M., Herrick, A., Worthington, J., Denton, C. P., Brown, M. A., Allanore, Y., Radstake, T. R., Fonseca, C., Mayes, M. D., Martin, J., Lopez-Isac, E., Acosta-Herrera, M., Assassi, S., Simeon, C. P., Carreira, P. E., Castellvi, I., Ortego-Centeno, N., Beretta, L., Lunardi, C., Gabrielli, A., Moroncini, G., Hunzelmann, N., Witte, T., Distler, J. H., Franke, A., Voskuyl, A. E., de Vries-Bouwstra, J., Wijmenga, C., Hesselstrand, R., Nordin, A., Hoffmann-Vold, A. -M., Herrick, A., Worthington, J., Denton, C. P., Brown, M. A., Allanore, Y., Radstake, T. R., Fonseca, C., Mayes, M. D., and Martin, J.
Published: 2018

17. International consensus: What else can we do to improve diagnosis and therapeutic strategies in patients affected by autoimmune rheumatic diseases (rheumatoid arthritis, spondyloarthritides, systemic sclerosis, systemic lupus erythematosus, antiphospholipid syndrome and Sjogren's syndrome)?: The unmet needs and the clinical grey zone in autoimmune disease management

Author: Giacomelli, R. Afeltra, A. Alunno, A. Baldini, C. Bartoloni-Bocci, E. Berardicurti, O. Carubbi, F. Cauli, A. Cervera, R. Ciccia, F. Cipriani, P. Conti, F. De Vita, S. Di Benedetto, P. Doria, A. Drosos, A.A. Favalli, E.G. Gandolfo, S. Gatto, M. Grembiale, R.D. Liakouli, V. Lories, R. Lubrano, E. Lunardi, C. Margiotta, D.P.E. Massaro, L. Meroni, P. Minniti, A. Navarini, L. Pendolino, M. Perosa, F. Pers, J.-O. Prete, M. Priori, R. Puppo, F. Quartuccio, L. Ruffatti, A. Ruscitti, P. Russo, B. Sarzi-Puttini, P. Shoenfeld, Y. Somarakis, G.A. Spinelli, F.R. Tinazzi, E. Triolo, G. Ursini, F. Valentini, G. Valesini, G. Vettori, S. Vitali, C. Tzioufas, A.G. and Giacomelli, R. Afeltra, A. Alunno, A. Baldini, C. Bartoloni-Bocci, E. Berardicurti, O. Carubbi, F. Cauli, A. Cervera, R. Ciccia, F. Cipriani, P. Conti, F. De Vita, S. Di Benedetto, P. Doria, A. Drosos, A.A. Favalli, E.G. Gandolfo, S. Gatto, M. Grembiale, R.D. Liakouli, V. Lories, R. Lubrano, E. Lunardi, C. Margiotta, D.P.E. Massaro, L. Meroni, P. Minniti, A. Navarini, L. Pendolino, M. Perosa, F. Pers, J.-O. Prete, M. Priori, R. Puppo, F. Quartuccio, L. Ruffatti, A. Ruscitti, P. Russo, B. Sarzi-Puttini, P. Shoenfeld, Y. Somarakis, G.A. Spinelli, F.R. Tinazzi, E. Triolo, G. Ursini, F. Valentini, G. Valesini, G. Vettori, S. Vitali, C. Tzioufas, A.G.
Abstract: Autoimmune diseases are a complex set of diseases characterized by immune system activation and, although many progresses have been done in the last 15 years, several unmet needs in the management of these patients may be still identified. Recently, a panel of international Experts, divided in different working groups according to their clinical and scientific expertise, were asked to identify, debate and formulate a list of key unmet needs within the field of rheumatology, serving as a roadmap for research as well as support for clinicians. After a systematic review of the literature, the results and the discussions from each working group were summarised in different statements. Due to the differences among the diseases and their heterogeneity, a large number of statements was produced and voted by the Experts to reach a consensus in a plenary session. At all the steps of this process, including the initial discussions by the steering committee, the identification of the unmet needs, the expansion of the working group and finally the development of statements, a large agreement was attained. This work confirmed that several unmet needs may be identified and despite the development of new therapeutic strategies as well as a better understanding of the effects of existing therapies, many open questions still remain in this field, suggesting a research agenda for the future and specific clinical suggestions which may allow physicians to better manage those clinical conditions still lacking of scientific clarity. © 2017
Published: 2017

18. An MIF Promoter Polymorphism Is Associated with Susceptibility to Pulmonary Arterial Hypertension in Diffuse Cutaneous Systemic Sclerosis

Author: Bossini-Castillo, L., Campillo-Davo, D., Lopez-Isac, E., Carmona, F.D., Simeon, C.P., Carreira, P., Callejas-Rubio, J.L., Castellvi, I., Fernandez-Nebro, A., Rodriguez-Rodriguez, L., Rubio-Rivas, M., Garcia-Hernandez, F.J., Madronero, A.B., Beretta, L., Santaniello, A., Lunardi, C., Airo, P., Hoffmann-Vold, A.M., Kreuter, A., Riemekasten, G., Witte, T. de, Hunzelmann, N., Vonk, M.C., Voskuyl, A.E., Vries-Bouwstra, J. de, Shiels, P., Herrick, A., Worthington, J., Radstake, T., Martin, J., Bossini-Castillo, L., Campillo-Davo, D., Lopez-Isac, E., Carmona, F.D., Simeon, C.P., Carreira, P., Callejas-Rubio, J.L., Castellvi, I., Fernandez-Nebro, A., Rodriguez-Rodriguez, L., Rubio-Rivas, M., Garcia-Hernandez, F.J., Madronero, A.B., Beretta, L., Santaniello, A., Lunardi, C., Airo, P., Hoffmann-Vold, A.M., Kreuter, A., Riemekasten, G., Witte, T. de, Hunzelmann, N., Vonk, M.C., Voskuyl, A.E., Vries-Bouwstra, J. de, Shiels, P., Herrick, A., Worthington, J., Radstake, T., and Martin, J.
Abstract: Contains fulltext : 178011.pdf (publisher's version ) (Closed access), OBJECTIVE: Systemic sclerosis (SSc) is a fibrotic immune-mediated disease of unknown etiology. Among its clinical manifestations, pulmonary involvement is the leading cause of mortality in patients with SSc. However, the genetic factors involved in lung complication are not well defined. We aimed to review the association of the MIF gene, which encodes a cytokine implicated in idiopathic pulmonary hypertension among other diseases, with the susceptibility and clinical expression of SSc, in addition to testing the association of this polymorphism with SSc-related pulmonary involvement. METHODS: A total of 4392 patients with SSc and 16,591 unaffected controls from 6 cohorts of European origin were genotyped for the MIF promoter variant rs755622. An inverse variance method was used to metaanalyze the data. RESULTS: A statistically significant increase of the MIF rs755622*C allele frequency compared with controls was observed in the subgroups of patients with diffuse cutaneous SSc (dcSSc) and with pulmonary arterial hypertension (PAH) independently (dcSSc: p = 3.20E-2, OR 1.13; PAH: p = 2.19E-02, OR 1.32). However, our data revealed a stronger effect size with the subset of patients with SSc showing both clinical manifestations (dcSSc with PAH: p = 6.91E-3, OR 2.05). CONCLUSION: We reviewed the association of the MIF rs755622*C allele with SSc and described a phenotype-specific association of this variant with the susceptibility to develop PAH in patients with dcSSc.
Published: 2017

19. A MIF PROMOTER POLYMORPHISM IS ASSOCIATED WITH THE SUSCEPTIBILITY TO PULMONARY ARTERIAL HYPERTENSION IN DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS PATIENTS

Author: Lopez-Isac, E., Bossini-Castillo, L., Campillo-Davo, D., Carmona, F. D., Simeon, C. P., Carreira, P., Callejas-Rubio, J. L., Castellvi, I., Fernandez-Nebro, A., Rodriguez-Rodriguez, L., Rubio Rivas, M., Garcia Hernandez, F. J., Madronero, A. B., Beretta, L., Santaniello, A., Lunardi, C., Airo, P., Hoffmann-Vold, A-M., Kreuter, A., Riemekasten, G., Witte, T., Hunzelmann, N., Vonk, M. C., Voskuyl, A. E., Bouwstra, J. D. V., Shiels, P., Herrick, A., Worthington, J., Radstake, T. R. D. J., Martin, J., Lopez-Isac, E., Bossini-Castillo, L., Campillo-Davo, D., Carmona, F. D., Simeon, C. P., Carreira, P., Callejas-Rubio, J. L., Castellvi, I., Fernandez-Nebro, A., Rodriguez-Rodriguez, L., Rubio Rivas, M., Garcia Hernandez, F. J., Madronero, A. B., Beretta, L., Santaniello, A., Lunardi, C., Airo, P., Hoffmann-Vold, A-M., Kreuter, A., Riemekasten, G., Witte, T., Hunzelmann, N., Vonk, M. C., Voskuyl, A. E., Bouwstra, J. D. V., Shiels, P., Herrick, A., Worthington, J., Radstake, T. R. D. J., and Martin, J.
Published: 2017

20. An MIF Promoter Polymorphism Is Associated with Susceptibility to Pulmonary Arterial Hypertension in Diffuse Cutaneous Systemic Sclerosis

Author: Bossini-Castillo, L., Campillo-Davo, D., Lopez-Isac, E., Carmona, F.D., Simeon, C.P., Carreira, P., Callejas-Rubio, J.L., Castellvi, I., Fernandez-Nebro, A., Rodriguez-Rodriguez, L., Rubio-Rivas, M., Garcia-Hernandez, F.J., Madronero, A.B., Beretta, L., Santaniello, A., Lunardi, C., Airo, P., Hoffmann-Vold, A.M., Kreuter, A., Riemekasten, G., Witte, T. de, Hunzelmann, N., Vonk, M.C., Voskuyl, A.E., Vries-Bouwstra, J. de, Shiels, P., Herrick, A., Worthington, J., Radstake, T., Martin, J., Bossini-Castillo, L., Campillo-Davo, D., Lopez-Isac, E., Carmona, F.D., Simeon, C.P., Carreira, P., Callejas-Rubio, J.L., Castellvi, I., Fernandez-Nebro, A., Rodriguez-Rodriguez, L., Rubio-Rivas, M., Garcia-Hernandez, F.J., Madronero, A.B., Beretta, L., Santaniello, A., Lunardi, C., Airo, P., Hoffmann-Vold, A.M., Kreuter, A., Riemekasten, G., Witte, T. de, Hunzelmann, N., Vonk, M.C., Voskuyl, A.E., Vries-Bouwstra, J. de, Shiels, P., Herrick, A., Worthington, J., Radstake, T., and Martin, J.
Abstract: Contains fulltext : 178011.pdf (publisher's version ) (Closed access), OBJECTIVE: Systemic sclerosis (SSc) is a fibrotic immune-mediated disease of unknown etiology. Among its clinical manifestations, pulmonary involvement is the leading cause of mortality in patients with SSc. However, the genetic factors involved in lung complication are not well defined. We aimed to review the association of the MIF gene, which encodes a cytokine implicated in idiopathic pulmonary hypertension among other diseases, with the susceptibility and clinical expression of SSc, in addition to testing the association of this polymorphism with SSc-related pulmonary involvement. METHODS: A total of 4392 patients with SSc and 16,591 unaffected controls from 6 cohorts of European origin were genotyped for the MIF promoter variant rs755622. An inverse variance method was used to metaanalyze the data. RESULTS: A statistically significant increase of the MIF rs755622*C allele frequency compared with controls was observed in the subgroups of patients with diffuse cutaneous SSc (dcSSc) and with pulmonary arterial hypertension (PAH) independently (dcSSc: p = 3.20E-2, OR 1.13; PAH: p = 2.19E-02, OR 1.32). However, our data revealed a stronger effect size with the subset of patients with SSc showing both clinical manifestations (dcSSc with PAH: p = 6.91E-3, OR 2.05). CONCLUSION: We reviewed the association of the MIF rs755622*C allele with SSc and described a phenotype-specific association of this variant with the susceptibility to develop PAH in patients with dcSSc.
Published: 2017

21. An MIF Promoter Polymorphism Is Associated with Susceptibility to Pulmonary Arterial Hypertension in Diffuse Cutaneous Systemic Sclerosis

Author: Bossini-Castillo, L., Campillo-Davo, D., Lopez-Isac, E., Carmona, F.D., Simeon, C.P., Carreira, P., Callejas-Rubio, J.L., Castellvi, I., Fernandez-Nebro, A., Rodriguez-Rodriguez, L., Rubio-Rivas, M., Garcia-Hernandez, F.J., Madronero, A.B., Beretta, L., Santaniello, A., Lunardi, C., Airo, P., Hoffmann-Vold, A.M., Kreuter, A., Riemekasten, G., Witte, T. de, Hunzelmann, N., Vonk, M.C., Voskuyl, A.E., Vries-Bouwstra, J. de, Shiels, P., Herrick, A., Worthington, J., Radstake, T., Martin, J., Bossini-Castillo, L., Campillo-Davo, D., Lopez-Isac, E., Carmona, F.D., Simeon, C.P., Carreira, P., Callejas-Rubio, J.L., Castellvi, I., Fernandez-Nebro, A., Rodriguez-Rodriguez, L., Rubio-Rivas, M., Garcia-Hernandez, F.J., Madronero, A.B., Beretta, L., Santaniello, A., Lunardi, C., Airo, P., Hoffmann-Vold, A.M., Kreuter, A., Riemekasten, G., Witte, T. de, Hunzelmann, N., Vonk, M.C., Voskuyl, A.E., Vries-Bouwstra, J. de, Shiels, P., Herrick, A., Worthington, J., Radstake, T., and Martin, J.
Abstract: Contains fulltext : 178011.pdf (publisher's version ) (Closed access), OBJECTIVE: Systemic sclerosis (SSc) is a fibrotic immune-mediated disease of unknown etiology. Among its clinical manifestations, pulmonary involvement is the leading cause of mortality in patients with SSc. However, the genetic factors involved in lung complication are not well defined. We aimed to review the association of the MIF gene, which encodes a cytokine implicated in idiopathic pulmonary hypertension among other diseases, with the susceptibility and clinical expression of SSc, in addition to testing the association of this polymorphism with SSc-related pulmonary involvement. METHODS: A total of 4392 patients with SSc and 16,591 unaffected controls from 6 cohorts of European origin were genotyped for the MIF promoter variant rs755622. An inverse variance method was used to metaanalyze the data. RESULTS: A statistically significant increase of the MIF rs755622*C allele frequency compared with controls was observed in the subgroups of patients with diffuse cutaneous SSc (dcSSc) and with pulmonary arterial hypertension (PAH) independently (dcSSc: p = 3.20E-2, OR 1.13; PAH: p = 2.19E-02, OR 1.32). However, our data revealed a stronger effect size with the subset of patients with SSc showing both clinical manifestations (dcSSc with PAH: p = 6.91E-3, OR 2.05). CONCLUSION: We reviewed the association of the MIF rs755622*C allele with SSc and described a phenotype-specific association of this variant with the susceptibility to develop PAH in patients with dcSSc.
Published: 2017

22. A MIF PROMOTER POLYMORPHISM IS ASSOCIATED WITH THE SUSCEPTIBILITY TO PULMONARY ARTERIAL HYPERTENSION IN DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS PATIENTS

Author: Lopez-Isac, E., Bossini-Castillo, L., Campillo-Davo, D., Carmona, F. D., Simeon, C. P., Carreira, P., Callejas-Rubio, J. L., Castellvi, I., Fernandez-Nebro, A., Rodriguez-Rodriguez, L., Rubio Rivas, M., Garcia Hernandez, F. J., Madronero, A. B., Beretta, L., Santaniello, A., Lunardi, C., Airo, P., Hoffmann-Vold, A-M., Kreuter, A., Riemekasten, G., Witte, T., Hunzelmann, N., Vonk, M. C., Voskuyl, A. E., Bouwstra, J. D. V., Shiels, P., Herrick, A., Worthington, J., Radstake, T. R. D. J., Martin, J., Lopez-Isac, E., Bossini-Castillo, L., Campillo-Davo, D., Carmona, F. D., Simeon, C. P., Carreira, P., Callejas-Rubio, J. L., Castellvi, I., Fernandez-Nebro, A., Rodriguez-Rodriguez, L., Rubio Rivas, M., Garcia Hernandez, F. J., Madronero, A. B., Beretta, L., Santaniello, A., Lunardi, C., Airo, P., Hoffmann-Vold, A-M., Kreuter, A., Riemekasten, G., Witte, T., Hunzelmann, N., Vonk, M. C., Voskuyl, A. E., Bouwstra, J. D. V., Shiels, P., Herrick, A., Worthington, J., Radstake, T. R. D. J., and Martin, J.
Published: 2017

23. An MIF Promoter Polymorphism Is Associated with Susceptibility to Pulmonary Arterial Hypertension in Diffuse Cutaneous Systemic Sclerosis

Author: Martín, J. [0000-0002-2202-0622], Bossini-Castillo, L., Campillo-Davó, D., López-Isac, Elena, Carmona, F.D., Simeón, Carmen P., Carreira, P., Callejas-Rubio, J. L., Castellví, I., Fernández-Nebro, Antonio, Rodríguez-Rodríguez, Luis, Rubio-Rivas, M., García-Hernández, Francisco José, Madroñero, A.B., Beretta, L., Santaniello, Alessandro, Lunardi, C., Airó, Paolo, Hoffmann-Vold, A. M., Kreuter, A., Riemekasten, G., Witte, Torsten, Hunzelmann, Nicolas, Vonk, Madelon C., Voskuyl, Alexandre E., de Vries-Bouwstra, Jeska, Shiels, Paul G., Herrick, A., Worthington, J., Radstake, T. R., Martín, J., Spanish Scleroderma Group, Martín, J. [0000-0002-2202-0622], Bossini-Castillo, L., Campillo-Davó, D., López-Isac, Elena, Carmona, F.D., Simeón, Carmen P., Carreira, P., Callejas-Rubio, J. L., Castellví, I., Fernández-Nebro, Antonio, Rodríguez-Rodríguez, Luis, Rubio-Rivas, M., García-Hernández, Francisco José, Madroñero, A.B., Beretta, L., Santaniello, Alessandro, Lunardi, C., Airó, Paolo, Hoffmann-Vold, A. M., Kreuter, A., Riemekasten, G., Witte, Torsten, Hunzelmann, Nicolas, Vonk, Madelon C., Voskuyl, Alexandre E., de Vries-Bouwstra, Jeska, Shiels, Paul G., Herrick, A., Worthington, J., Radstake, T. R., Martín, J., and Spanish Scleroderma Group
Abstract: OBJECTIVE: Systemic sclerosis (SSc) is a fibrotic immune-mediated disease of unknown etiology. Among its clinical manifestations, pulmonary involvement is the leading cause of mortality in patients with SSc. However, the genetic factors involved in lung complication are not well defined. We aimed to review the association of the MIF gene, which encodes a cytokine implicated in idiopathic pulmonary hypertension among other diseases, with the susceptibility and clinical expression of SSc, in addition to testing the association of this polymorphism with SSc-related pulmonary involvement. METHODS: A total of 4392 patients with SSc and 16,591 unaffected controls from 6 cohorts of European origin were genotyped for the MIF promoter variant rs755622. An inverse variance method was used to metaanalyze the data. RESULTS: A statistically significant increase of the MIF rs755622*C allele frequency compared with controls was observed in the subgroups of patients with diffuse cutaneous SSc (dcSSc) and with pulmonary arterial hypertension (PAH) independently (dcSSc: p = 3.20E-2, OR 1.13; PAH: p = 2.19E-02, OR 1.32). However, our data revealed a stronger effect size with the subset of patients with SSc showing both clinical manifestations (dcSSc with PAH: p = 6.91E-3, OR 2.05). CONCLUSION: We reviewed the association of the MIF rs755622*C allele with SSc and described a phenotype-specific association of this variant with the susceptibility to develop PAH in patients with dcSSc.
Published: 2017

24. S.13.1 Safety and efficacy of rituximab in SSc: an analysis from the European Scleroderma Trial and Research Group

Author: Jordan, S., Distler, J., Maurer, B., Allanore, Y., Van Laar, J., Distler, O., Fraticelli, P., Pomponio, G., Gabrielli, B., Riboldi, P., Ferraccioli, G., Valentini, G., Bombardieri, S., Malorni, W., Gerli, R., Lunardi, C., Faggioli, P., Corvetta, A., Gabrielli, A., Ghassemi, P., Baron, M., Blati, M., Kapoor, M., Della Rossa, A., Casigliani, S., Doveri, M., D'Ascanio, A., Tavoni, A., Bazzichi, L., Jordan, S., Distler, J., Maurer, B., Allanore, Y., Van Laar, J., Distler, O., Fraticelli, P., Pomponio, G., Gabrielli, B., Riboldi, P., Ferraccioli, G., Valentini, G., Bombardieri, S., Malorni, W., Gerli, R., Lunardi, C., Faggioli, P., Corvetta, A., Gabrielli, A., Ghassemi, P., Baron, M., Blati, M., Kapoor, M., Della Rossa, A., Casigliani, S., Doveri, M., D'Ascanio, A., Tavoni, A., and Bazzichi, L.
Abstract: Objectives. Objective of this multicentre, observational study was to assess effects and safety of rituximab (RTX) using the European Scleroderma Trial and Research Group (EUSTAR) cohort. Methods. EUSTAR centres were asked to provide specific data about SSc patients treated with RTX. Primary endpoints were predefined for different disease manifestations and compared between baseline and follow-up. Normally distributed data, analysed by paired t-test, are shown as mean (s.d.), and non-parametric data, analysed by Wilcoxon matched paired signed-rank test, are shown as median and interquartile range. Results. Data on 72 SSc patients treated with RTX were captured from 27 EUSTAR centres (51 females/21 males, 52 diffuse/19 limited, age 51 (44-60) years, disease duration 6 (3-10) years, 47 anti-Scl-70 positive). The most frequent RTX application scheme was 1000 mg × 2 within 2 weeks (57/72 patients). Co-treatment with other immunosuppressive drugs was reported in 28 patients. The modified Rodnan skin score (mRSS) significantly decreased vs baseline at 7 (5-9) months follow-up (n = 47, 18.2 + 10.9 vs 14.5 + 9.9, P = 0.0002). This was true for both patients with later disease stages and also for patients with earlier, extended skin fibrosis (dSSc with mRSS >16 at baseline, n = 26; 26.5 + 6.8 vs 20.4 + 8.9, P < 0.0001, reduction by 29.9%). S-HAQ was unchanged, but the European SSc activity score improved after rituximab treatment [n = 10; 3.7 (2.6-6.4) vs 1.7 (0.9-2.5), P = 0.01]. RTX had no effects on lung fibrosis (FVC, DLCO, TLC, HRCT score) in n = 11 patients with evidence for SSc-ILD. In SSc-polyarthritis patients, the DAS-28 declined at 6 months follow-up without reaching statistical significance [n = 8; 4.8 (2.5-7.5) vs 3.7 (2.6-6.6); p = 0.3]. Of 8, 5patients were RF and/or anti-CCP antibody positive. Similar results were obtained for secondary outcome measures (tender and swollen joint count, VAS, CRP, ESR). Additional positive effects of RTX were seen on SSc-relate
Published: 2017

25. Nailfold Videocapillaroscopic Features and Other Clinical Risk Factors for Digital Ulcers in Systemic Sclerosis: A Multicenter, Prospective Cohort Study

Author: Cutolo, M. Herrick, A.L. Distler, O. Becker, M.O. Beltran, E. Carpentier, P. Ferri, C. Inanç, M. Vlachoyiannopoulos, P. Chadha-Boreham, H. Cottreel, E. Pfister, T. Rosenberg, D. Torres, J.V. Smith, V. Erlacher, L. Hirschl, M. Kiener, H.P. Pilger, E. Blockmans, D. Wautrecht, J.-C. Becvár, R. Frances, C. Lok, C. Sparsa, A. Hachulla, E. Quere, I. Allanore, Y. Agard, C. Riemekasten, G. Hunzelmann, N. Stücker, M. Ahmadi-Simab, K. Sunderkötter, C. Wohlrab, J. Müller-Ladner, U. Schneider, M. Vlachoyianopoulos, P. Vassilopoulos, D. Drosos, A. Antonopoulos, A. Balbir-Gurman, A. Langevitz, P. Rosner, I. Levy, Y. Bombardieri, S. Ferraccioli, G. Mazzuca, S. Grassi, W. Lunardi, C. Airó, P. Riccieri, V. Voskuyl, A.E. Schuerwegh, A. Santos, L. Rodrigues, A.C. Grilo, A. Amaral, M.C. Román Ivorra, J.A. Castellvi, I. Spertini, F. Müller, R. Oksel, F. Turkcapar, N. Herrick, A. Denton, C. McHugh, N. Chattopadhyay, C. Hall, F. Buch, M. on behalf of the CAP Study Investigators and Cutolo, M. Herrick, A.L. Distler, O. Becker, M.O. Beltran, E. Carpentier, P. Ferri, C. Inanç, M. Vlachoyiannopoulos, P. Chadha-Boreham, H. Cottreel, E. Pfister, T. Rosenberg, D. Torres, J.V. Smith, V. Erlacher, L. Hirschl, M. Kiener, H.P. Pilger, E. Blockmans, D. Wautrecht, J.-C. Becvár, R. Frances, C. Lok, C. Sparsa, A. Hachulla, E. Quere, I. Allanore, Y. Agard, C. Riemekasten, G. Hunzelmann, N. Stücker, M. Ahmadi-Simab, K. Sunderkötter, C. Wohlrab, J. Müller-Ladner, U. Schneider, M. Vlachoyianopoulos, P. Vassilopoulos, D. Drosos, A. Antonopoulos, A. Balbir-Gurman, A. Langevitz, P. Rosner, I. Levy, Y. Bombardieri, S. Ferraccioli, G. Mazzuca, S. Grassi, W. Lunardi, C. Airó, P. Riccieri, V. Voskuyl, A.E. Schuerwegh, A. Santos, L. Rodrigues, A.C. Grilo, A. Amaral, M.C. Román Ivorra, J.A. Castellvi, I. Spertini, F. Müller, R. Oksel, F. Turkcapar, N. Herrick, A. Denton, C. McHugh, N. Chattopadhyay, C. Hall, F. Buch, M. on behalf of the CAP Study Investigators
Abstract: Objective: To identify nailfold videocapillaroscopic features and other clinical risk factors for new digital ulcers (DUs) during a 6-month period in patients with systemic sclerosis (SSc). Methods: In this multicenter, prospective, observational cohort study, the videoCAPillaroscopy (CAP) study, we evaluated 623 patients with SSc from 59 centers (14 countries). Patients were stratified into 2 groups: a DU history group and a no DU history group. At enrollment, patients underwent detailed nailfold videocapillaroscopic evaluation and assessment of demographic characteristics, DU status, and clinical and SSc characteristics. Risk factors for developing new DUs were assessed using univariable and multivariable logistic regression (MLR) analyses. Results: Of the 468 patients in the DU history group (mean ± SD age 54.0 ± 13.7 years), 79.5% were female, 59.8% had limited cutaneous SSc, and 22% developed a new DU during follow-up. The strongest risk factors for new DUs identified by MLR in the DU history group included the mean number of capillaries per millimeter in the middle finger of the dominant hand, the number of DUs (categorized as 0, 1, 2, or ≥3), and the presence of critical digital ischemia. The receiver operating characteristic (ROC) of the area under the curve (AUC) of the final MLR model was 0.738 (95% confidence interval [95% CI] 0.681–0.795). Internal validation through bootstrap generated a ROC AUC of 0.633 (95% CI 0.510–0.756). Conclusion: This international prospective study, which included detailed nailfold videocapillaroscopic evaluation and extensive clinical characterization of patients with SSc, identified the mean number of capillaries per millimeter in the middle finger of the dominant hand, the number of DUs at enrollment, and the presence of critical digital ischemia at enrollment as risk factors for the development of new DUs. © 2016, American College of Rheumatology
Published: 2016

26. Brief Report: IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies

Author: Lopez-Isac, E., Martin, J.E., Assassi, S., Simeon, C.P., Carreira, P., Ortego-Centeno, N., Freire, M., Beltran, E., Narvaez, J., Alegre-Sancho, J.J., Fernandez-Gutierrez, B., Balsa, A., Ortiz, A.M., Gonzalez-Gay, M.A., Beretta, L., Santaniello, A., Bellocchi, C., Lunardi, C., Moroncini, G., Gabrielli, A., Witte, T. de, Hunzelmann, N., Distler, J.H., Riekemasten, G., Mil, A.H.V. van der Helm-va, Vries-Bouwstra, J. de, Magro-Checa, C., Voskuyl, A.E., Vonk, M.C., Molberg, O., Merriman, T., Hesselstrand, R., Nordin, A., Padyukov, L., Herrick, A., Eyre, S., Koeleman, B.P.C., Denton, C.P., Fonseca, C., Radstake, T.R., Worthington, J., Mayes, M.D., Martin, J., Lopez-Isac, E., Martin, J.E., Assassi, S., Simeon, C.P., Carreira, P., Ortego-Centeno, N., Freire, M., Beltran, E., Narvaez, J., Alegre-Sancho, J.J., Fernandez-Gutierrez, B., Balsa, A., Ortiz, A.M., Gonzalez-Gay, M.A., Beretta, L., Santaniello, A., Bellocchi, C., Lunardi, C., Moroncini, G., Gabrielli, A., Witte, T. de, Hunzelmann, N., Distler, J.H., Riekemasten, G., Mil, A.H.V. van der Helm-va, Vries-Bouwstra, J. de, Magro-Checa, C., Voskuyl, A.E., Vonk, M.C., Molberg, O., Merriman, T., Hesselstrand, R., Nordin, A., Padyukov, L., Herrick, A., Eyre, S., Koeleman, B.P.C., Denton, C.P., Fonseca, C., Radstake, T.R., Worthington, J., Mayes, M.D., and Martin, J.
Abstract: Contains fulltext : 172048.pdf (publisher's version ) (Closed access), OBJECTIVE: Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc-RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc-RA loci through an interdisease meta-genome-wide association (meta-GWAS) strategy. METHODS: The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case-control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls. RESULTS: This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P < 5 x 10(-6) ) that also showed evidence of association in the disease-specific GWAS scans. These loci included several genomic regions not previously reported as shared loci, as well as several risk factors that were previously found to be associated with both diseases. Follow-up analyses of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these 2 diseases (Pcombined = 3.29 x 10(-12) ). Analysis of the biologic relevance of the known SSc-RA shared loci identified the type I interferon and interleukin-12 signaling pathways as the main common etiologic factors. CONCLUSION: This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.
Published: 2016

27. Brief Report: IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies

Author: Lopez-Isac, E., Martin, J.E., Assassi, S., Simeon, C.P., Carreira, P., Ortego-Centeno, N., Freire, M., Beltran, E., Narvaez, J., Alegre-Sancho, J.J., Fernandez-Gutierrez, B., Balsa, A., Ortiz, A.M., Gonzalez-Gay, M.A., Beretta, L., Santaniello, A., Bellocchi, C., Lunardi, C., Moroncini, G., Gabrielli, A., Witte, T. de, Hunzelmann, N., Distler, J.H., Riekemasten, G., Mil, A.H.V. van der Helm-va, Vries-Bouwstra, J. de, Magro-Checa, C., Voskuyl, A.E., Vonk, M.C., Molberg, O., Merriman, T., Hesselstrand, R., Nordin, A., Padyukov, L., Herrick, A., Eyre, S., Koeleman, B.P.C., Denton, C.P., Fonseca, C., Radstake, T.R., Worthington, J., Mayes, M.D., Martin, J., Lopez-Isac, E., Martin, J.E., Assassi, S., Simeon, C.P., Carreira, P., Ortego-Centeno, N., Freire, M., Beltran, E., Narvaez, J., Alegre-Sancho, J.J., Fernandez-Gutierrez, B., Balsa, A., Ortiz, A.M., Gonzalez-Gay, M.A., Beretta, L., Santaniello, A., Bellocchi, C., Lunardi, C., Moroncini, G., Gabrielli, A., Witte, T. de, Hunzelmann, N., Distler, J.H., Riekemasten, G., Mil, A.H.V. van der Helm-va, Vries-Bouwstra, J. de, Magro-Checa, C., Voskuyl, A.E., Vonk, M.C., Molberg, O., Merriman, T., Hesselstrand, R., Nordin, A., Padyukov, L., Herrick, A., Eyre, S., Koeleman, B.P.C., Denton, C.P., Fonseca, C., Radstake, T.R., Worthington, J., Mayes, M.D., and Martin, J.
Abstract: Contains fulltext : 172048.pdf (publisher's version ) (Closed access), OBJECTIVE: Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc-RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc-RA loci through an interdisease meta-genome-wide association (meta-GWAS) strategy. METHODS: The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case-control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls. RESULTS: This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P < 5 x 10(-6) ) that also showed evidence of association in the disease-specific GWAS scans. These loci included several genomic regions not previously reported as shared loci, as well as several risk factors that were previously found to be associated with both diseases. Follow-up analyses of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these 2 diseases (Pcombined = 3.29 x 10(-12) ). Analysis of the biologic relevance of the known SSc-RA shared loci identified the type I interferon and interleukin-12 signaling pathways as the main common etiologic factors. CONCLUSION: This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.
Published: 2016

28. Brief Report: IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies

Author: Lopez-Isac, E., Martin, J.E., Assassi, S., Simeon, C.P., Carreira, P., Ortego-Centeno, N., Freire, M., Beltran, E., Narvaez, J., Alegre-Sancho, J.J., Fernandez-Gutierrez, B., Balsa, A., Ortiz, A.M., Gonzalez-Gay, M.A., Beretta, L., Santaniello, A., Bellocchi, C., Lunardi, C., Moroncini, G., Gabrielli, A., Witte, T. de, Hunzelmann, N., Distler, J.H., Riekemasten, G., Mil, A.H.V. van der Helm-va, Vries-Bouwstra, J. de, Magro-Checa, C., Voskuyl, A.E., Vonk, M.C., Molberg, O., Merriman, T., Hesselstrand, R., Nordin, A., Padyukov, L., Herrick, A., Eyre, S., Koeleman, B.P.C., Denton, C.P., Fonseca, C., Radstake, T.R., Worthington, J., Mayes, M.D., Martin, J., Lopez-Isac, E., Martin, J.E., Assassi, S., Simeon, C.P., Carreira, P., Ortego-Centeno, N., Freire, M., Beltran, E., Narvaez, J., Alegre-Sancho, J.J., Fernandez-Gutierrez, B., Balsa, A., Ortiz, A.M., Gonzalez-Gay, M.A., Beretta, L., Santaniello, A., Bellocchi, C., Lunardi, C., Moroncini, G., Gabrielli, A., Witte, T. de, Hunzelmann, N., Distler, J.H., Riekemasten, G., Mil, A.H.V. van der Helm-va, Vries-Bouwstra, J. de, Magro-Checa, C., Voskuyl, A.E., Vonk, M.C., Molberg, O., Merriman, T., Hesselstrand, R., Nordin, A., Padyukov, L., Herrick, A., Eyre, S., Koeleman, B.P.C., Denton, C.P., Fonseca, C., Radstake, T.R., Worthington, J., Mayes, M.D., and Martin, J.
Abstract: Contains fulltext : 172048.pdf (publisher's version ) (Closed access), OBJECTIVE: Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc-RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc-RA loci through an interdisease meta-genome-wide association (meta-GWAS) strategy. METHODS: The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case-control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls. RESULTS: This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P < 5 x 10(-6) ) that also showed evidence of association in the disease-specific GWAS scans. These loci included several genomic regions not previously reported as shared loci, as well as several risk factors that were previously found to be associated with both diseases. Follow-up analyses of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these 2 diseases (Pcombined = 3.29 x 10(-12) ). Analysis of the biologic relevance of the known SSc-RA shared loci identified the type I interferon and interleukin-12 signaling pathways as the main common etiologic factors. CONCLUSION: This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.
Published: 2016

29. IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies

Author: Junta de Andalucía, Ministerio de Economía y Competitividad (España), Ministerio de Educación, Cultura y Deporte (España), European Commission, Dutch Association for Institutional Research, Dutch Arthritis Foundation, National Institutes of Health (US), National Institute of Allergy and Infectious Diseases (US), National Center for Research Resources (US), National Institute of Arthritis and Musculoskeletal and Skin Diseases (US), Department of Defense (US), Martín, J. [0000-0002-2202-0622], López-Isac, Elena, Martin, J. E., Assassi, S., Simeón, Carmen P., Carreira, P., Ortego-Centeno, N., Freire, María del Carmen, Beltrán, E., Narváez, Javier, Alegre-Sancho, Juan-José, Fernández-Gutiérrez, B., Balsa, Alejandro, Ortiz, Ana María, González-Gay, M. A., Beretta, L., Santaniello, Alessandro, Bellocchi, Chiara, Lunardi, C., Moroncini, Gianluca, Gabrielli, Armando, Witte, Torsten, Hunzelmann, Nicolas, Distler, J. H., Riekemasten, Gabriella, van der Helm-Van Mil, Annette H. M., de Vries-Bouwstra, Jeska, Magro-Checa, Cesar, Voskuyl, Alexandre E., Vonk, Madelon C., Molberg, Oyvind, Merriman, Tony, Hesselstrand, R., Nordin, A., Padyukov, Leonid, Herrick, A., Eyre, Steve, Koeleman, B. P., Denton, C., Fonseca, C., Radstake, T. R., Worthington, J., Mayes, Maureen D., Martín, J., Junta de Andalucía, Ministerio de Economía y Competitividad (España), Ministerio de Educación, Cultura y Deporte (España), European Commission, Dutch Association for Institutional Research, Dutch Arthritis Foundation, National Institutes of Health (US), National Institute of Allergy and Infectious Diseases (US), National Center for Research Resources (US), National Institute of Arthritis and Musculoskeletal and Skin Diseases (US), Department of Defense (US), Martín, J. [0000-0002-2202-0622], López-Isac, Elena, Martin, J. E., Assassi, S., Simeón, Carmen P., Carreira, P., Ortego-Centeno, N., Freire, María del Carmen, Beltrán, E., Narváez, Javier, Alegre-Sancho, Juan-José, Fernández-Gutiérrez, B., Balsa, Alejandro, Ortiz, Ana María, González-Gay, M. A., Beretta, L., Santaniello, Alessandro, Bellocchi, Chiara, Lunardi, C., Moroncini, Gianluca, Gabrielli, Armando, Witte, Torsten, Hunzelmann, Nicolas, Distler, J. H., Riekemasten, Gabriella, van der Helm-Van Mil, Annette H. M., de Vries-Bouwstra, Jeska, Magro-Checa, Cesar, Voskuyl, Alexandre E., Vonk, Madelon C., Molberg, Oyvind, Merriman, Tony, Hesselstrand, R., Nordin, A., Padyukov, Leonid, Herrick, A., Eyre, Steve, Koeleman, B. P., Denton, C., Fonseca, C., Radstake, T. R., Worthington, J., Mayes, Maureen D., and Martín, J.
Abstract: Objective. Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc-RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc-RA loci through an interdisease meta-genome-wide association (meta-GWAS) strategy. Methods. The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case-control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls. Results. This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P<5 x 10(-6)) that also showed evidence of association in the disease-specific GWAS scans. These loci included several genomic regions not previously reported as shared loci, as well as several risk factors that were previously found to be associated with both diseases. Follow-up analyses of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these 2 diseases (P-combined=3.29 x 10(-12)). Analysis of the biologic relevance of the known SSc-RA shared loci identified the type I interferon and interleukin-12 signaling pathways as the main common etiologic factors. Conclusion. This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.
Published: 2016

30. Nailfold Videocapillaroscopic Features and Other Clinical Risk Factors for Digital Ulcers in Systemic Sclerosis: A Multicenter, Prospective Cohort Study

Author: Cutolo, Maurizio, Herrick, Ariane L., Distler, Oliver, Becker, Mike O., Beltran, Emma, Carpentier, Patrick, Ferri, Clodoveo, Inanç, Murat, Vlachoyiannopoulos, Panayioti, Chadha Boreham, Harbajan, Cottreel, Emmanuelle, Pfister, Thoma, Rosenberg, Daniel, Torres, Juan V., Smith, Vanessa, Becker, Mike, Erlacher, L., Hirschl, M., Kiener, H. P., Pilger, E., Smith, V., Blockmans, D., Wautrecht, J. C., Becvár, R., Carpentier, P., Frances, C., Lok, C., Sparsa, A., Hachulla, E., Quere, I., Allanore, Y., Agard, C., Riemekasten, G., Hunzelmann, N., Stücker, M., Ahmadi Simab, K., Sunderkötter, C., Wohlrab, J., Müller Ladner, U., Schneider, M., Vlachoyianopoulos, P., Vassilopoulos, D., Drosos, A., Antonopoulos, A., Balbir Gurman, A., Langevitz, P., Rosner, I., Levy, Y., Cutolo, M., Bombardieri, S., Ferraccioli, Gianfranco, Mazzuca, S., Grassi, W., Lunardi, C., Airó, P., Riccieri, V., Voskuyl, A. E., Schuerwegh, A., Santos, L., Rodrigues, A. C., Grilo, A., Amaral, M. C., Román Ivorra, J. A., Castellvi, I., Distler, O., Spertini, F., Müller, R., Inanç, M., Oksel, F., Turkcapar, N., Herrick, A., Denton, C., Mchugh, N., Chattopadhyay, C., Hall, F., Buch, M., Ferraccioli, Gianfranco (ORCID:0000-0001-6246-2428), Cutolo, Maurizio, Herrick, Ariane L., Distler, Oliver, Becker, Mike O., Beltran, Emma, Carpentier, Patrick, Ferri, Clodoveo, Inanç, Murat, Vlachoyiannopoulos, Panayioti, Chadha Boreham, Harbajan, Cottreel, Emmanuelle, Pfister, Thoma, Rosenberg, Daniel, Torres, Juan V., Smith, Vanessa, Becker, Mike, Erlacher, L., Hirschl, M., Kiener, H. P., Pilger, E., Smith, V., Blockmans, D., Wautrecht, J. C., Becvár, R., Carpentier, P., Frances, C., Lok, C., Sparsa, A., Hachulla, E., Quere, I., Allanore, Y., Agard, C., Riemekasten, G., Hunzelmann, N., Stücker, M., Ahmadi Simab, K., Sunderkötter, C., Wohlrab, J., Müller Ladner, U., Schneider, M., Vlachoyianopoulos, P., Vassilopoulos, D., Drosos, A., Antonopoulos, A., Balbir Gurman, A., Langevitz, P., Rosner, I., Levy, Y., Cutolo, M., Bombardieri, S., Ferraccioli, Gianfranco, Mazzuca, S., Grassi, W., Lunardi, C., Airó, P., Riccieri, V., Voskuyl, A. E., Schuerwegh, A., Santos, L., Rodrigues, A. C., Grilo, A., Amaral, M. C., Román Ivorra, J. A., Castellvi, I., Distler, O., Spertini, F., Müller, R., Inanç, M., Oksel, F., Turkcapar, N., Herrick, A., Denton, C., Mchugh, N., Chattopadhyay, C., Hall, F., Buch, M., and Ferraccioli, Gianfranco (ORCID:0000-0001-6246-2428)
Abstract: Objective: To identify nailfold videocapillaroscopic features and other clinical risk factors for new digital ulcers (DUs) during a 6-month period in patients with systemic sclerosis (SSc). Methods: In this multicenter, prospective, observational cohort study, the videoCAPillaroscopy (CAP) study, we evaluated 623 patients with SSc from 59 centers (14 countries). Patients were stratified into 2 groups: a DU history group and a no DU history group. At enrollment, patients underwent detailed nailfold videocapillaroscopic evaluation and assessment of demographic characteristics, DU status, and clinical and SSc characteristics. Risk factors for developing new DUs were assessed using univariable and multivariable logistic regression (MLR) analyses. Results: Of the 468 patients in the DU history group (mean ± SD age 54.0 ± 13.7 years), 79.5% were female, 59.8% had limited cutaneous SSc, and 22% developed a new DU during follow-up. The strongest risk factors for new DUs identified by MLR in the DU history group included the mean number of capillaries per millimeter in the middle finger of the dominant hand, the number of DUs (categorized as 0, 1, 2, or ≥3), and the presence of critical digital ischemia. The receiver operating characteristic (ROC) of the area under the curve (AUC) of the final MLR model was 0.738 (95% confidence interval [95% CI] 0.681–0.795). Internal validation through bootstrap generated a ROC AUC of 0.633 (95% CI 0.510–0.756). Conclusion: This international prospective study, which included detailed nailfold videocapillaroscopic evaluation and extensive clinical characterization of patients with SSc, identified the mean number of capillaries per millimeter in the middle finger of the dominant hand, the number of DUs at enrollment, and the presence of critical digital ischemia at enrollment as risk factors for the development of new DUs.
Published: 2016

31. Confirmation of CCR6 as a risk factor for anti-topoisomerase I antibodies in systemic sclerosis

Author: Ochoa, E., Martin, J.E., Assasi, S., Beretta, L., Carreira, P., Guillen, A., Simeon, C.P., Koumakis, E., Dieude, P., Allanore, Y., Garcia-Hernandez, F.J., Espinosa, G., Castellvi, I., Trapiella, J.L., Rodriguez, L., Gonzalez-Gay, M.A., Egurbide, M.V., Saez, L., Callejas-Rubio, J.L., Vargas-Hitos, J.A., Hunzelmann, N., Riemekasten, G., Witte, T. de, Distler, J.H., Kreuter, A., Lunardi, C., Santaniello, A., Tan, F.K., Shiels, P.G., Herrick, A., Worthington, J., Vonk, M.C., Koeleman, B.P.C., Radstake, T.R., Mayes, M.D., et al., Ochoa, E., Martin, J.E., Assasi, S., Beretta, L., Carreira, P., Guillen, A., Simeon, C.P., Koumakis, E., Dieude, P., Allanore, Y., Garcia-Hernandez, F.J., Espinosa, G., Castellvi, I., Trapiella, J.L., Rodriguez, L., Gonzalez-Gay, M.A., Egurbide, M.V., Saez, L., Callejas-Rubio, J.L., Vargas-Hitos, J.A., Hunzelmann, N., Riemekasten, G., Witte, T. de, Distler, J.H., Kreuter, A., Lunardi, C., Santaniello, A., Tan, F.K., Shiels, P.G., Herrick, A., Worthington, J., Vonk, M.C., Koeleman, B.P.C., Radstake, T.R., Mayes, M.D., and et al.
Abstract: Item does not contain fulltext, OBJECTIVES: The current knowledge of the influence of systemic sclerosis (SSc) risk loci in the clinical sub-phenotypes is still limited. The main limitation lies in the low frequency of some sub-phenotypes which could be solved by replication studies in independent cohorts and meta-analysis between studies. In this regard, CCR6 gene variants have been recently associated with anti-topoisomerase I positive (ATA+) production in SSc patients in a candidate gene study. This gene has been proposed to have a critical role in IL-17-driven autoimmunity in human diseases. METHODS: In order to confirm the association between CCR6 and ATA+ SSc patients, we performed an independent replication study in populations of European ancestry. We studied two CCR6 genetic variants (rs968334 and rs3093024) in a total of 901 ATA+ SSc cases, 3,258 ATA- SSc cases and 7,865 healthy controls and compared allelic frequencies for those SNPs in ATA+ SSc with healthy controls and also with ATA- SSc patients. RESULTS: The comparison performed between ATA+ SSc patients and healthy controls showed significant association with SNP rs968334 (p=4.88 x 10-2, OR=1.11). When we compared ATA+ SSc cases with ATA- SSc, both SNPs, rs3093024 and rs968334, showed significant associations (p=2.89 x 10-2, OR=1.13; p=1.69 x 10-2, OR=1.15). Finally, in order to increase even more sample size and statistical power, we meta-analysed our study with the previous reported and found a significant association between SNP rs3093024 and ATA+ SSc patients (p=1.00 x 10-4, OR=1.16) comparing with healthy controls. CONCLUSIONS: Our work confirms the association of CCR6 gene and ATA+ SSc patients.
Published: 2015

32. Confirmation of CCR6 as a risk factor for anti-topoisomerase I antibodies in systemic sclerosis

Author: Ochoa, E., Martin, J. -E., Assassi, S., Beretta, L., Carreira, P., Guillen, A., Simeon, C. P., Koumakis, E., Dieude, P., Allanore, Y., Garcia-Hernandez, F. J., Espinosa, G., Castellvi, I., Trapiella, J. L., Rodriguez, L., Gonzalez-Gay, M. A., Egurbide, M. V., Saez, L., Callejas-Rubio, J. L., Vargas-Hitos, J. A., Hunzelmann, N., Riemekasten, G., Witte, T., Distler, J. H. W., Kreuter, A., Lunardi, C., Santaniello, A., Tan, F. K., Shiels, P. G., Herrick, A., Worthington, J., Vonk, M. C., Koeleman, B. P., Radstake, T. R. D. J., Mayes, M. D., Martin, J., Ochoa, E., Martin, J. -E., Assassi, S., Beretta, L., Carreira, P., Guillen, A., Simeon, C. P., Koumakis, E., Dieude, P., Allanore, Y., Garcia-Hernandez, F. J., Espinosa, G., Castellvi, I., Trapiella, J. L., Rodriguez, L., Gonzalez-Gay, M. A., Egurbide, M. V., Saez, L., Callejas-Rubio, J. L., Vargas-Hitos, J. A., Hunzelmann, N., Riemekasten, G., Witte, T., Distler, J. H. W., Kreuter, A., Lunardi, C., Santaniello, A., Tan, F. K., Shiels, P. G., Herrick, A., Worthington, J., Vonk, M. C., Koeleman, B. P., Radstake, T. R. D. J., Mayes, M. D., and Martin, J.
Abstract: Objective. The current knowledge of the influence of systemic sclerosis (SSc) risk loci in the clinical sub-phenotypes is still limited. The main limitation lies in the low frequency of some sub-phenotypes which could be solved by replication studies in independent cohorts and meta-analysis between studies. In this regard, CCR6 gene variants have been recently associated with anti-topoisomerase I positive (ATA+) production in SSc patients in a candidate gene study. This gene has been proposed to have a critical role in IL-17-driven autoimmunity in human diseases. Methods. In order to confirm the association between CCR6 and ATA+ SSc patients, we performed an independent replication study in populations of European ancestry. We studied two CCR6 genetic variants (rs968334 and rs3093024) in a total of 901 ATA+ SSc cases, 3,258 ATA- SSc cases and 7,865 healthy controls and compared allelic frequencies for those SNPs in ATA+ SSc with healthy controls and also with ATA- SSc patients. Results. The comparison performed between ATA+ SSc patients and healthy controls showed significant association with SNP rs968334 (p=4.88 x 10(-2), OR= 1.11). When we compared ATA+ SSc cases with ATA- SSc, both SNPs, rs3093024 and rs968334, showed significant associations (p=2.89 x 10(-2), OR-1.13; p=1.69 x 10(-2), OR=1.15). Finally, in order to increase even more sample size and statistical power, we meta-analysed our study with the previous reported and found a significant association between SNP rs3093024 and ATA+ SSc patients (p= 1.00 x 10(-4), OR= 1.16) comparing with healthy controls. Conclusion. Our work confirms the association of CCR6 gene and ATA+ SSc patients.
Published: 2015

33. Confirmation of CCR6 as a risk factor for anti-topoisomerase I antibodies in systemic sclerosis

Author: Ochoa, E., Martin, J.E., Assasi, S., Beretta, L., Carreira, P., Guillen, A., Simeon, C.P., Koumakis, E., Dieude, P., Allanore, Y., Garcia-Hernandez, F.J., Espinosa, G., Castellvi, I., Trapiella, J.L., Rodriguez, L., Gonzalez-Gay, M.A., Egurbide, M.V., Saez, L., Callejas-Rubio, J.L., Vargas-Hitos, J.A., Hunzelmann, N., Riemekasten, G., Witte, T. de, Distler, J.H., Kreuter, A., Lunardi, C., Santaniello, A., Tan, F.K., Shiels, P.G., Herrick, A., Worthington, J., Vonk, M.C., Koeleman, B.P.C., Radstake, T.R., Mayes, M.D., Martin, J., et al., Ochoa, E., Martin, J.E., Assasi, S., Beretta, L., Carreira, P., Guillen, A., Simeon, C.P., Koumakis, E., Dieude, P., Allanore, Y., Garcia-Hernandez, F.J., Espinosa, G., Castellvi, I., Trapiella, J.L., Rodriguez, L., Gonzalez-Gay, M.A., Egurbide, M.V., Saez, L., Callejas-Rubio, J.L., Vargas-Hitos, J.A., Hunzelmann, N., Riemekasten, G., Witte, T. de, Distler, J.H., Kreuter, A., Lunardi, C., Santaniello, A., Tan, F.K., Shiels, P.G., Herrick, A., Worthington, J., Vonk, M.C., Koeleman, B.P.C., Radstake, T.R., Mayes, M.D., Martin, J., and et al.
Abstract: Item does not contain fulltext, OBJECTIVES: The current knowledge of the influence of systemic sclerosis (SSc) risk loci in the clinical sub-phenotypes is still limited. The main limitation lies in the low frequency of some sub-phenotypes which could be solved by replication studies in independent cohorts and meta-analysis between studies. In this regard, CCR6 gene variants have been recently associated with anti-topoisomerase I positive (ATA+) production in SSc patients in a candidate gene study. This gene has been proposed to have a critical role in IL-17-driven autoimmunity in human diseases. METHODS: In order to confirm the association between CCR6 and ATA+ SSc patients, we performed an independent replication study in populations of European ancestry. We studied two CCR6 genetic variants (rs968334 and rs3093024) in a total of 901 ATA+ SSc cases, 3,258 ATA- SSc cases and 7,865 healthy controls and compared allelic frequencies for those SNPs in ATA+ SSc with healthy controls and also with ATA- SSc patients. RESULTS: The comparison performed between ATA+ SSc patients and healthy controls showed significant association with SNP rs968334 (p=4.88 x 10-2, OR=1.11). When we compared ATA+ SSc cases with ATA- SSc, both SNPs, rs3093024 and rs968334, showed significant associations (p=2.89 x 10-2, OR=1.13; p=1.69 x 10-2, OR=1.15). Finally, in order to increase even more sample size and statistical power, we meta-analysed our study with the previous reported and found a significant association between SNP rs3093024 and ATA+ SSc patients (p=1.00 x 10-4, OR=1.16) comparing with healthy controls. CONCLUSIONS: Our work confirms the association of CCR6 gene and ATA+ SSc patients.
Published: 2015

34. Confirmation of CCR6 as a risk factor for anti-topoisomerase I antibodies in systemic sclerosis

Author: Ochoa, E., Martin, J.E., Assasi, S., Beretta, L., Carreira, P., Guillen, A., Simeon, C.P., Koumakis, E., Dieude, P., Allanore, Y., Garcia-Hernandez, F.J., Espinosa, G., Castellvi, I., Trapiella, J.L., Rodriguez, L., Gonzalez-Gay, M.A., Egurbide, M.V., Saez, L., Callejas-Rubio, J.L., Vargas-Hitos, J.A., Hunzelmann, N., Riemekasten, G., Witte, T. de, Distler, J.H., Kreuter, A., Lunardi, C., Santaniello, A., Tan, F.K., Shiels, P.G., Herrick, A., Worthington, J., Vonk, M.C., Koeleman, B.P.C., Radstake, T.R., Mayes, M.D., Martin, J., et al., Ochoa, E., Martin, J.E., Assasi, S., Beretta, L., Carreira, P., Guillen, A., Simeon, C.P., Koumakis, E., Dieude, P., Allanore, Y., Garcia-Hernandez, F.J., Espinosa, G., Castellvi, I., Trapiella, J.L., Rodriguez, L., Gonzalez-Gay, M.A., Egurbide, M.V., Saez, L., Callejas-Rubio, J.L., Vargas-Hitos, J.A., Hunzelmann, N., Riemekasten, G., Witte, T. de, Distler, J.H., Kreuter, A., Lunardi, C., Santaniello, A., Tan, F.K., Shiels, P.G., Herrick, A., Worthington, J., Vonk, M.C., Koeleman, B.P.C., Radstake, T.R., Mayes, M.D., Martin, J., and et al.
Abstract: Item does not contain fulltext, OBJECTIVES: The current knowledge of the influence of systemic sclerosis (SSc) risk loci in the clinical sub-phenotypes is still limited. The main limitation lies in the low frequency of some sub-phenotypes which could be solved by replication studies in independent cohorts and meta-analysis between studies. In this regard, CCR6 gene variants have been recently associated with anti-topoisomerase I positive (ATA+) production in SSc patients in a candidate gene study. This gene has been proposed to have a critical role in IL-17-driven autoimmunity in human diseases. METHODS: In order to confirm the association between CCR6 and ATA+ SSc patients, we performed an independent replication study in populations of European ancestry. We studied two CCR6 genetic variants (rs968334 and rs3093024) in a total of 901 ATA+ SSc cases, 3,258 ATA- SSc cases and 7,865 healthy controls and compared allelic frequencies for those SNPs in ATA+ SSc with healthy controls and also with ATA- SSc patients. RESULTS: The comparison performed between ATA+ SSc patients and healthy controls showed significant association with SNP rs968334 (p=4.88 x 10-2, OR=1.11). When we compared ATA+ SSc cases with ATA- SSc, both SNPs, rs3093024 and rs968334, showed significant associations (p=2.89 x 10-2, OR=1.13; p=1.69 x 10-2, OR=1.15). Finally, in order to increase even more sample size and statistical power, we meta-analysed our study with the previous reported and found a significant association between SNP rs3093024 and ATA+ SSc patients (p=1.00 x 10-4, OR=1.16) comparing with healthy controls. CONCLUSIONS: Our work confirms the association of CCR6 gene and ATA+ SSc patients.
Published: 2015

35. Confirmation of CCR6 as a risk factor for anti-topoisomerase I antibodies in systemic sclerosis

Author: Ochoa, E., Martin, J. -E., Assassi, S., Beretta, L., Carreira, P., Guillen, A., Simeon, C. P., Koumakis, E., Dieude, P., Allanore, Y., Garcia-Hernandez, F. J., Espinosa, G., Castellvi, I., Trapiella, J. L., Rodriguez, L., Gonzalez-Gay, M. A., Egurbide, M. V., Saez, L., Callejas-Rubio, J. L., Vargas-Hitos, J. A., Hunzelmann, N., Riemekasten, G., Witte, T., Distler, J. H. W., Kreuter, A., Lunardi, C., Santaniello, A., Tan, F. K., Shiels, P. G., Herrick, A., Worthington, J., Vonk, M. C., Koeleman, B. P., Radstake, T. R. D. J., Mayes, M. D., Martin, J., Ochoa, E., Martin, J. -E., Assassi, S., Beretta, L., Carreira, P., Guillen, A., Simeon, C. P., Koumakis, E., Dieude, P., Allanore, Y., Garcia-Hernandez, F. J., Espinosa, G., Castellvi, I., Trapiella, J. L., Rodriguez, L., Gonzalez-Gay, M. A., Egurbide, M. V., Saez, L., Callejas-Rubio, J. L., Vargas-Hitos, J. A., Hunzelmann, N., Riemekasten, G., Witte, T., Distler, J. H. W., Kreuter, A., Lunardi, C., Santaniello, A., Tan, F. K., Shiels, P. G., Herrick, A., Worthington, J., Vonk, M. C., Koeleman, B. P., Radstake, T. R. D. J., Mayes, M. D., and Martin, J.
Abstract: Objective. The current knowledge of the influence of systemic sclerosis (SSc) risk loci in the clinical sub-phenotypes is still limited. The main limitation lies in the low frequency of some sub-phenotypes which could be solved by replication studies in independent cohorts and meta-analysis between studies. In this regard, CCR6 gene variants have been recently associated with anti-topoisomerase I positive (ATA+) production in SSc patients in a candidate gene study. This gene has been proposed to have a critical role in IL-17-driven autoimmunity in human diseases. Methods. In order to confirm the association between CCR6 and ATA+ SSc patients, we performed an independent replication study in populations of European ancestry. We studied two CCR6 genetic variants (rs968334 and rs3093024) in a total of 901 ATA+ SSc cases, 3,258 ATA- SSc cases and 7,865 healthy controls and compared allelic frequencies for those SNPs in ATA+ SSc with healthy controls and also with ATA- SSc patients. Results. The comparison performed between ATA+ SSc patients and healthy controls showed significant association with SNP rs968334 (p=4.88 x 10(-2), OR= 1.11). When we compared ATA+ SSc cases with ATA- SSc, both SNPs, rs3093024 and rs968334, showed significant associations (p=2.89 x 10(-2), OR-1.13; p=1.69 x 10(-2), OR=1.15). Finally, in order to increase even more sample size and statistical power, we meta-analysed our study with the previous reported and found a significant association between SNP rs3093024 and ATA+ SSc patients (p= 1.00 x 10(-4), OR= 1.16) comparing with healthy controls. Conclusion. Our work confirms the association of CCR6 gene and ATA+ SSc patients.
Published: 2015

36. A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility

Author: Lopez-Isac, E., Bossini-Castillo, L., Simeon, C.P., Egurbide, M.V., Alegre-Sancho, J.J., Callejas, J.L., Roman-Ivorra, J.A., Freire, M., Beretta, L., Santaniello, A., Airo, P., Lunardi, C., Hunzelmann, N., Riemekasten, G., Witte, T. de, Kreuter, A., Distler, J.H., Schuerwegh, A.J., Vonk, M.C., Voskuyl, A.E., Shiels, P.G., Laar, J.M. van, Fonseca, C., Denton, C., Herrick, A., Worthington, J., Assassi, S., Koeleman, B.P., Mayes, M.D., Radstake, T.R.D.J., Martin, J., et al., Lopez-Isac, E., Bossini-Castillo, L., Simeon, C.P., Egurbide, M.V., Alegre-Sancho, J.J., Callejas, J.L., Roman-Ivorra, J.A., Freire, M., Beretta, L., Santaniello, A., Airo, P., Lunardi, C., Hunzelmann, N., Riemekasten, G., Witte, T. de, Kreuter, A., Distler, J.H., Schuerwegh, A.J., Vonk, M.C., Voskuyl, A.E., Shiels, P.G., Laar, J.M. van, Fonseca, C., Denton, C., Herrick, A., Worthington, J., Assassi, S., Koeleman, B.P., Mayes, M.D., Radstake, T.R.D.J., Martin, J., and et al.
Abstract: Contains fulltext : 137741.pdf (publisher's version ) (Open Access), INTRODUCTION: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy. METHODS: Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. RESULTS: We observed nominal associations for both PPARG rs310746 (PMH = 1.90 x 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 x 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 x 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis. CONCLUSION: Our results suggest a role of PPARG gene in the development of SSc.
Published: 2014

37. Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis

Author: Bon, L. van, Affandi, A.J., Broen, J.C.A., Christmann, R.B., Marijnissen, R.J., Stawski, L., Farina, G.A., Stifano, G., Mathes, A.L., Cossu, M., York, M., Collins, C., Wenink, M., Huijbens, R., Hesselstrand, R., Saxne, T., DiMarzio, M., Wuttge, D., Agarwal, S.K., Reveille, J.D., Assassi, S., Mayes, M., Deng, Y., Drenth, J.P.H., Graaf, J. de, Heijer, M. den, Kallenberg, C.G.M., Bijl, M. van der, Loof, A., Berg, W.B. van den, Joosten, L.A.B., Smith, V., Keyser, F. de, Scorza, R., Lunardi, C., Riel, P.L.C.M. van, Vonk, M.C., Heerde, W.L. van, Meller, S., Homey, B., Beretta, L., Roest, M., Trojanowska, M., Lafyatis, R., Radstake, T.R.D.J., Bon, L. van, Affandi, A.J., Broen, J.C.A., Christmann, R.B., Marijnissen, R.J., Stawski, L., Farina, G.A., Stifano, G., Mathes, A.L., Cossu, M., York, M., Collins, C., Wenink, M., Huijbens, R., Hesselstrand, R., Saxne, T., DiMarzio, M., Wuttge, D., Agarwal, S.K., Reveille, J.D., Assassi, S., Mayes, M., Deng, Y., Drenth, J.P.H., Graaf, J. de, Heijer, M. den, Kallenberg, C.G.M., Bijl, M. van der, Loof, A., Berg, W.B. van den, Joosten, L.A.B., Smith, V., Keyser, F. de, Scorza, R., Lunardi, C., Riel, P.L.C.M. van, Vonk, M.C., Heerde, W.L. van, Meller, S., Homey, B., Beretta, L., Roest, M., Trojanowska, M., Lafyatis, R., and Radstake, T.R.D.J.
Abstract: Contains fulltext : 136617.pdf (publisher's version ) (Open Access), BACKGROUND: Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon. METHODS: We isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then performed proteome-wide analysis and validated these observations in five large cohorts of patients with systemic sclerosis. Next, we compared the results with those in patients with systemic lupus erythematosus, ankylosing spondylitis, and hepatic fibrosis. We correlated plasma levels of CXCL4 protein with features of systemic sclerosis and studied the direct effects of CXCL4 in vitro and in vivo. RESULTS: Proteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. The mean (+/-SD) level of CXCL4 in patients with systemic sclerosis was 25,624+/-2652 pg per milliliter, which was significantly higher than the level in controls (92.5+/-77.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346+/-1011 pg per milliliter), ankylosing spondylitis (1368+/-1162 pg per milliliter), or liver fibrosis (1668+/-1263 pg per milliliter). CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro, CXCL4 down-regulated expression of transcription factor FLI1, induced markers of endothelial-cell activation, and potentiated responses of toll-like receptors. In vivo, CXCL4 induced the influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis. CONCLUSIONS: Levels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypert
Published: 2014

38. Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis.

Author: Soft Condensed Matter and Biophysics, Sub Soft Condensed Matter, van Bon, L., Affandi, A.J., dr. Broen, J.C.A., Christmann, R.B., Marijnissen, R.J., Stawski, L., Farina, G.A., Stifano, G., Mathes, A.L., Cossu, M., York, M., Collins, C., Wenink, M.H., Huijbens, R., Hesselstrand, R., Saxne, T., Dimarzio, M, Wuttge, D., Agarwal, S.K., Reveille, J.D., Assassi, S., Mayes, M.D., Deng, Y., Drenth, J.P., de Graaf, J., den Heijer, M., Kallenberg, C.G., Bijl, M., de Loof, A., van der Berg, W.B., Joosten, L.A., Smith, V., de Keyser, F., Scorza, R., Lunardi, C., van Riel, P.L.C.M., Vonk, M., van Heerde, W.L., Meller, S., Homey, B., Beretta, L., Roest, M., Trojanowska, M., Lafyatis, R., Radstake, T.R.D.J., Soft Condensed Matter and Biophysics, Sub Soft Condensed Matter, van Bon, L., Affandi, A.J., dr. Broen, J.C.A., Christmann, R.B., Marijnissen, R.J., Stawski, L., Farina, G.A., Stifano, G., Mathes, A.L., Cossu, M., York, M., Collins, C., Wenink, M.H., Huijbens, R., Hesselstrand, R., Saxne, T., Dimarzio, M, Wuttge, D., Agarwal, S.K., Reveille, J.D., Assassi, S., Mayes, M.D., Deng, Y., Drenth, J.P., de Graaf, J., den Heijer, M., Kallenberg, C.G., Bijl, M., de Loof, A., van der Berg, W.B., Joosten, L.A., Smith, V., de Keyser, F., Scorza, R., Lunardi, C., van Riel, P.L.C.M., Vonk, M., van Heerde, W.L., Meller, S., Homey, B., Beretta, L., Roest, M., Trojanowska, M., Lafyatis, R., and Radstake, T.R.D.J.
Published: 2014

39. A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility

Author: Lopez-Isac, E., Bossini-Castillo, L., Simeon, C.P., Egurbide, M.V., Alegre-Sancho, J.J., Callejas, J.L., Roman-Ivorra, J.A., Freire, M., Beretta, L., Santaniello, A., Airo, P., Lunardi, C., Hunzelmann, N., Riemekasten, G., Witte, T. de, Kreuter, A., Distler, J.H., Schuerwegh, A.J., Vonk, M.C., Voskuyl, A.E., Shiels, P.G., Laar, J.M. van, Fonseca, C., Denton, C., Herrick, A., Worthington, J., Assassi, S., Koeleman, B.P., Mayes, M.D., Radstake, T.R.D.J., Martin, J., et al., Lopez-Isac, E., Bossini-Castillo, L., Simeon, C.P., Egurbide, M.V., Alegre-Sancho, J.J., Callejas, J.L., Roman-Ivorra, J.A., Freire, M., Beretta, L., Santaniello, A., Airo, P., Lunardi, C., Hunzelmann, N., Riemekasten, G., Witte, T. de, Kreuter, A., Distler, J.H., Schuerwegh, A.J., Vonk, M.C., Voskuyl, A.E., Shiels, P.G., Laar, J.M. van, Fonseca, C., Denton, C., Herrick, A., Worthington, J., Assassi, S., Koeleman, B.P., Mayes, M.D., Radstake, T.R.D.J., Martin, J., and et al.
Abstract: Contains fulltext : 137741.pdf (publisher's version ) (Open Access), INTRODUCTION: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy. METHODS: Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. RESULTS: We observed nominal associations for both PPARG rs310746 (PMH = 1.90 x 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 x 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 x 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis. CONCLUSION: Our results suggest a role of PPARG gene in the development of SSc.
Published: 2014

40. Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis

Author: Bon, L. van, Affandi, A.J., Broen, J.C.A., Christmann, R.B., Marijnissen, R.J., Stawski, L., Farina, G.A., Stifano, G., Mathes, A.L., Cossu, M., York, M., Collins, C., Wenink, M., Huijbens, R., Hesselstrand, R., Saxne, T., DiMarzio, M., Wuttge, D., Agarwal, S.K., Reveille, J.D., Assassi, S., Mayes, M., Deng, Y., Drenth, J.P.H., Graaf, J. de, Heijer, M. den, Kallenberg, C.G.M., Bijl, M. van der, Loof, A., Berg, W.B. van den, Joosten, L.A.B., Smith, V., Keyser, F. de, Scorza, R., Lunardi, C., Riel, P.L.C.M. van, Vonk, M.C., Heerde, W.L. van, Meller, S., Homey, B., Beretta, L., Roest, M., Trojanowska, M., Lafyatis, R., Radstake, T.R.D.J., Bon, L. van, Affandi, A.J., Broen, J.C.A., Christmann, R.B., Marijnissen, R.J., Stawski, L., Farina, G.A., Stifano, G., Mathes, A.L., Cossu, M., York, M., Collins, C., Wenink, M., Huijbens, R., Hesselstrand, R., Saxne, T., DiMarzio, M., Wuttge, D., Agarwal, S.K., Reveille, J.D., Assassi, S., Mayes, M., Deng, Y., Drenth, J.P.H., Graaf, J. de, Heijer, M. den, Kallenberg, C.G.M., Bijl, M. van der, Loof, A., Berg, W.B. van den, Joosten, L.A.B., Smith, V., Keyser, F. de, Scorza, R., Lunardi, C., Riel, P.L.C.M. van, Vonk, M.C., Heerde, W.L. van, Meller, S., Homey, B., Beretta, L., Roest, M., Trojanowska, M., Lafyatis, R., and Radstake, T.R.D.J.
Abstract: Contains fulltext : 136617.pdf (publisher's version ) (Open Access), BACKGROUND: Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon. METHODS: We isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then performed proteome-wide analysis and validated these observations in five large cohorts of patients with systemic sclerosis. Next, we compared the results with those in patients with systemic lupus erythematosus, ankylosing spondylitis, and hepatic fibrosis. We correlated plasma levels of CXCL4 protein with features of systemic sclerosis and studied the direct effects of CXCL4 in vitro and in vivo. RESULTS: Proteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. The mean (+/-SD) level of CXCL4 in patients with systemic sclerosis was 25,624+/-2652 pg per milliliter, which was significantly higher than the level in controls (92.5+/-77.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346+/-1011 pg per milliliter), ankylosing spondylitis (1368+/-1162 pg per milliliter), or liver fibrosis (1668+/-1263 pg per milliliter). CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro, CXCL4 down-regulated expression of transcription factor FLI1, induced markers of endothelial-cell activation, and potentiated responses of toll-like receptors. In vivo, CXCL4 induced the influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis. CONCLUSIONS: Levels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypert
Published: 2014

41. Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis

Author: Bon, L. van, Affandi, A.J., Broen, J.C.A., Christmann, R.B., Marijnissen, R.J., Stawski, L., Farina, G.A., Stifano, G., Mathes, A.L., Cossu, M., York, M., Collins, C., Wenink, M., Huijbens, R., Hesselstrand, R., Saxne, T., DiMarzio, M., Wuttge, D., Agarwal, S.K., Reveille, J.D., Assassi, S., Mayes, M., Deng, Y., Drenth, J.P.H., Graaf, J. de, Heijer, M. den, Kallenberg, C.G.M., Bijl, M. van der, Loof, A., Berg, W.B. van den, Joosten, L.A.B., Smith, V., Keyser, F. de, Scorza, R., Lunardi, C., Riel, P.L.C.M. van, Vonk, M.C., Heerde, W.L. van, Meller, S., Homey, B., Beretta, L., Roest, M., Trojanowska, M., Lafyatis, R., Radstake, T.R.D.J., Bon, L. van, Affandi, A.J., Broen, J.C.A., Christmann, R.B., Marijnissen, R.J., Stawski, L., Farina, G.A., Stifano, G., Mathes, A.L., Cossu, M., York, M., Collins, C., Wenink, M., Huijbens, R., Hesselstrand, R., Saxne, T., DiMarzio, M., Wuttge, D., Agarwal, S.K., Reveille, J.D., Assassi, S., Mayes, M., Deng, Y., Drenth, J.P.H., Graaf, J. de, Heijer, M. den, Kallenberg, C.G.M., Bijl, M. van der, Loof, A., Berg, W.B. van den, Joosten, L.A.B., Smith, V., Keyser, F. de, Scorza, R., Lunardi, C., Riel, P.L.C.M. van, Vonk, M.C., Heerde, W.L. van, Meller, S., Homey, B., Beretta, L., Roest, M., Trojanowska, M., Lafyatis, R., and Radstake, T.R.D.J.
Abstract: Contains fulltext : 136617.pdf (publisher's version ) (Open Access), BACKGROUND: Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon. METHODS: We isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then performed proteome-wide analysis and validated these observations in five large cohorts of patients with systemic sclerosis. Next, we compared the results with those in patients with systemic lupus erythematosus, ankylosing spondylitis, and hepatic fibrosis. We correlated plasma levels of CXCL4 protein with features of systemic sclerosis and studied the direct effects of CXCL4 in vitro and in vivo. RESULTS: Proteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. The mean (+/-SD) level of CXCL4 in patients with systemic sclerosis was 25,624+/-2652 pg per milliliter, which was significantly higher than the level in controls (92.5+/-77.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346+/-1011 pg per milliliter), ankylosing spondylitis (1368+/-1162 pg per milliliter), or liver fibrosis (1668+/-1263 pg per milliliter). CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro, CXCL4 down-regulated expression of transcription factor FLI1, induced markers of endothelial-cell activation, and potentiated responses of toll-like receptors. In vivo, CXCL4 induced the influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis. CONCLUSIONS: Levels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypert
Published: 2014

42. A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility

Author: Lopez-Isac, E., Bossini-Castillo, L., Simeon, C.P., Egurbide, M.V., Alegre-Sancho, J.J., Callejas, J.L., Roman-Ivorra, J.A., Freire, M., Beretta, L., Santaniello, A., Airo, P., Lunardi, C., Hunzelmann, N., Riemekasten, G., Witte, T. de, Kreuter, A., Distler, J.H., Schuerwegh, A.J., Vonk, M.C., Voskuyl, A.E., Shiels, P.G., Laar, J.M. van, Fonseca, C., Denton, C., Herrick, A., Worthington, J., Assassi, S., Koeleman, B.P., Mayes, M.D., Radstake, T.R.D.J., Martin, J., et al., Lopez-Isac, E., Bossini-Castillo, L., Simeon, C.P., Egurbide, M.V., Alegre-Sancho, J.J., Callejas, J.L., Roman-Ivorra, J.A., Freire, M., Beretta, L., Santaniello, A., Airo, P., Lunardi, C., Hunzelmann, N., Riemekasten, G., Witte, T. de, Kreuter, A., Distler, J.H., Schuerwegh, A.J., Vonk, M.C., Voskuyl, A.E., Shiels, P.G., Laar, J.M. van, Fonseca, C., Denton, C., Herrick, A., Worthington, J., Assassi, S., Koeleman, B.P., Mayes, M.D., Radstake, T.R.D.J., Martin, J., and et al.
Abstract: Contains fulltext : 137741.pdf (publisher's version ) (Open Access), INTRODUCTION: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy. METHODS: Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. RESULTS: We observed nominal associations for both PPARG rs310746 (PMH = 1.90 x 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 x 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 x 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis. CONCLUSION: Our results suggest a role of PPARG gene in the development of SSc.
Published: 2014

43. Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis.

Author: Soft Condensed Matter and Biophysics, Sub Soft Condensed Matter, van Bon, L., Affandi, A.J., dr. Broen, J.C.A., Christmann, R.B., Marijnissen, R.J., Stawski, L., Farina, G.A., Stifano, G., Mathes, A.L., Cossu, M., York, M., Collins, C., Wenink, M.H., Huijbens, R., Hesselstrand, R., Saxne, T., Dimarzio, M, Wuttge, D., Agarwal, S.K., Reveille, J.D., Assassi, S., Mayes, M.D., Deng, Y., Drenth, J.P., de Graaf, J., den Heijer, M., Kallenberg, C.G., Bijl, M., de Loof, A., van der Berg, W.B., Joosten, L.A., Smith, V., de Keyser, F., Scorza, R., Lunardi, C., van Riel, P.L.C.M., Vonk, M., van Heerde, W.L., Meller, S., Homey, B., Beretta, L., Roest, M., Trojanowska, M., Lafyatis, R., Radstake, T.R.D.J., Soft Condensed Matter and Biophysics, Sub Soft Condensed Matter, van Bon, L., Affandi, A.J., dr. Broen, J.C.A., Christmann, R.B., Marijnissen, R.J., Stawski, L., Farina, G.A., Stifano, G., Mathes, A.L., Cossu, M., York, M., Collins, C., Wenink, M.H., Huijbens, R., Hesselstrand, R., Saxne, T., Dimarzio, M, Wuttge, D., Agarwal, S.K., Reveille, J.D., Assassi, S., Mayes, M.D., Deng, Y., Drenth, J.P., de Graaf, J., den Heijer, M., Kallenberg, C.G., Bijl, M., de Loof, A., van der Berg, W.B., Joosten, L.A., Smith, V., de Keyser, F., Scorza, R., Lunardi, C., van Riel, P.L.C.M., Vonk, M., van Heerde, W.L., Meller, S., Homey, B., Beretta, L., Roest, M., Trojanowska, M., Lafyatis, R., and Radstake, T.R.D.J.
Published: 2014

44. Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis.

Author: Soft Condensed Matter and Biophysics, Sub Soft Condensed Matter, van Bon, L., Affandi, A.J., dr. Broen, J.C.A., Christmann, R.B., Marijnissen, R.J., Stawski, L., Farina, G.A., Stifano, G., Mathes, A.L., Cossu, M., York, M., Collins, C., Wenink, M.H., Huijbens, R., Hesselstrand, R., Saxne, T., Dimarzio, M, Wuttge, D., Agarwal, S.K., Reveille, J.D., Assassi, S., Mayes, M.D., Deng, Y., Drenth, J.P., de Graaf, J., den Heijer, M., Kallenberg, C.G., Bijl, M., de Loof, A., van der Berg, W.B., Joosten, L.A., Smith, V., de Keyser, F., Scorza, R., Lunardi, C., van Riel, P.L.C.M., Vonk, M., van Heerde, W.L., Meller, S., Homey, B., Beretta, L., Roest, M., Trojanowska, M., Lafyatis, R., Radstake, T.R.D.J., Soft Condensed Matter and Biophysics, Sub Soft Condensed Matter, van Bon, L., Affandi, A.J., dr. Broen, J.C.A., Christmann, R.B., Marijnissen, R.J., Stawski, L., Farina, G.A., Stifano, G., Mathes, A.L., Cossu, M., York, M., Collins, C., Wenink, M.H., Huijbens, R., Hesselstrand, R., Saxne, T., Dimarzio, M, Wuttge, D., Agarwal, S.K., Reveille, J.D., Assassi, S., Mayes, M.D., Deng, Y., Drenth, J.P., de Graaf, J., den Heijer, M., Kallenberg, C.G., Bijl, M., de Loof, A., van der Berg, W.B., Joosten, L.A., Smith, V., de Keyser, F., Scorza, R., Lunardi, C., van Riel, P.L.C.M., Vonk, M., van Heerde, W.L., Meller, S., Homey, B., Beretta, L., Roest, M., Trojanowska, M., Lafyatis, R., and Radstake, T.R.D.J.
Published: 2014

45. A candidate gene approach identifies an IL33 genetic variant as a novel genetic risk factor for GCA

Author: Márquez, Ana, Solans, Roser, Hernández-Rodríguez, José, Cid, María C., Castañeda, Santos, Ramentol, Marc, Rodríguez-Rodríguez, Luis, Narváez, Javier, Blanco, Ricardo, Ortego-Centeno, N., Palm, Øyvind, Diamantopoulos, Andreas P., Braun, N., Moosig, Frank, Witte, Torsten, Beretta, Lorenzo, Lunardi, C., Cimmino, Augusto Vaglio, Salvarani, Carlo, González-Gay, M. A., Martín, J., Márquez, Ana, Solans, Roser, Hernández-Rodríguez, José, Cid, María C., Castañeda, Santos, Ramentol, Marc, Rodríguez-Rodríguez, Luis, Narváez, Javier, Blanco, Ricardo, Ortego-Centeno, N., Palm, Øyvind, Diamantopoulos, Andreas P., Braun, N., Moosig, Frank, Witte, Torsten, Beretta, Lorenzo, Lunardi, C., Cimmino, Augusto Vaglio, Salvarani, Carlo, González-Gay, M. A., and Martín, J.
Abstract: © 2014 Márquez et al. Introduction: Increased expression of IL-33 and its receptor ST2, encoded by the IL1RL1 gene, has been detected in the inflamed arteries of giant cell arteritis (GCA) patients. The aim of the present study was to investigate for the first time the potential influence of the IL33 and IL1RL1 loci on GCA predisposition. Methods: A total of 1,363 biopsy-proven GCA patients and 3,908 healthy controls from four European cohorts (Spain, Italy, Germany and Norway) were combined in a meta-analysis. Six genetic variants: rs3939286, rs7025417 and rs7044343, within the IL33 gene, and rs2058660, rs2310173 and rs13015714, within the IL1RL1 gene, previously associated with immunerelated diseases, were genotyped using predesigned TaqMan assays. Results: A consistent association between the rs7025417 polymorphism and GCA was evident in the overall meta-analysis, under both allele (PMH = 0.041, OR = 0.88, CI 95% 0.78-0.99) and recessive (PMH = 3.40E-03, OR = 0.53, CI 95% 0.35-0.80) models. No statistically significant differences between allele or genotype frequencies for the other IL33 and IL1RL1 genetic variants were detected in this pooled analysis. Conclusions: Our results clearly evidenced the implication of the IL33 rs7025417 polymorphism in the genetic network underlying GCA.
Published: 2014

46. A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci

Author: Martin, J.E., Assassi, S., Diaz-Gallo, L.M., Broen, J.C.A., Simeon, C.P., Castellvi, I., Vicente-Rabaneda, E., Fonollosa, V., Ortego-Centeno, N., Gonzalez-Gay, M.A., Espinosa, G., Carreira, P., Scleroderma, G. Spanish, consortium, S., group, U.S.S.G., Biolupus, ., Camps, M., Sabio, J.M., D'Alfonso, S., Vonk, M.C., Voskuyl, A.E., Schuerwegh, A.J., Kreuter, A., Witte, T. de, Riemekasten, G., Hunzelmann, N., Airo, P., Beretta, L., Scorza, R., Lunardi, C., Laar, J. van, Chee, M.M., Worthington, J., Herrick, A., Denton, C., Fonseca, C., Tan, F.K., Arnett, F., Zhou, X., Reveille, J.D., Gorlova, O., Koeleman, B.P., Radstake, T.R.D.J., Vyse, T., Mayes, M.D., Alarcon-Riquelme, M.E., Martin, J.E., Assassi, S., Diaz-Gallo, L.M., Broen, J.C.A., Simeon, C.P., Castellvi, I., Vicente-Rabaneda, E., Fonollosa, V., Ortego-Centeno, N., Gonzalez-Gay, M.A., Espinosa, G., Carreira, P., Scleroderma, G. Spanish, consortium, S., group, U.S.S.G., Biolupus, ., Camps, M., Sabio, J.M., D'Alfonso, S., Vonk, M.C., Voskuyl, A.E., Schuerwegh, A.J., Kreuter, A., Witte, T. de, Riemekasten, G., Hunzelmann, N., Airo, P., Beretta, L., Scorza, R., Lunardi, C., Laar, J. van, Chee, M.M., Worthington, J., Herrick, A., Denton, C., Fonseca, C., Tan, F.K., Arnett, F., Zhou, X., Reveille, J.D., Gorlova, O., Koeleman, B.P., Radstake, T.R.D.J., Vyse, T., Mayes, M.D., and Alarcon-Riquelme, M.E.
Abstract: Item does not contain fulltext, Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are two archetypal systemic autoimmune diseases which have been shown to share multiple genetic susceptibility loci. In order to gain insight into the genetic basis of these diseases, we performed a pan-meta-analysis of two genome-wide association studies (GWASs) together with a replication stage including additional SSc and SLE cohorts. This increased the sample size to a total of 21 109 (6835 cases and 14 274 controls). We selected for replication 19 SNPs from the GWAS data. We were able to validate KIAA0319L (P = 3.31 x 10(-11), OR = 1.49) as novel susceptibility loci for SSc and SLE. Furthermore, we also determined that the previously described SLE susceptibility loci PXK (P = 3.27 x 10(-11), OR = 1.20) and JAZF1 (P = 1.11 x 10(-8), OR = 1.13) are shared with SSc. Supporting these new discoveries, we observed that KIAA0319L was overexpressed in peripheral blood cells of SSc and SLE patients compared with healthy controls. With these, we add three (KIAA0319L, PXK and JAZF1) and one (KIAA0319L) new susceptibility loci for SSc and SLE, respectively, increasing significantly the knowledge of the genetic basis of autoimmunity.
Published: 2013

47. Confirmation of TNIP1 but not RHOB and PSORS1C1 as systemic sclerosis risk factors in a large independent replication study

Author: Bossini-Castillo, L., Martin, J.E., Broen, J., Simeon, C.P., Beretta, L., Gorlova, O.Y., Vonk, M.C., Ortego-Centeno, N., Espinosa, G., Carreira, P., Garcia de la Pena, P., Oreiro, N., Roman-Ivorra, J.A., Castillo, M.J., Gonzalez-Gay, M.A., Saez-Comet, L., Castellvi, I., Schuerwegh, A.J., Voskuyl, A.E., Hoffmann-Vold, A.M., Hesselstrand, R., Nordin, A., Lunardi, C., Scorza, R., Laar, J.M. van, Shiels, P.G., Herrick, A., Worthington, J., Fonseca, C., Denton, C., Tan, F.K., Arnett, F.C., Assassi, S., Koeleman, B.P., Mayes, M.D., Radstake, T.R.D.J., Martin, J., et al., Bossini-Castillo, L., Martin, J.E., Broen, J., Simeon, C.P., Beretta, L., Gorlova, O.Y., Vonk, M.C., Ortego-Centeno, N., Espinosa, G., Carreira, P., Garcia de la Pena, P., Oreiro, N., Roman-Ivorra, J.A., Castillo, M.J., Gonzalez-Gay, M.A., Saez-Comet, L., Castellvi, I., Schuerwegh, A.J., Voskuyl, A.E., Hoffmann-Vold, A.M., Hesselstrand, R., Nordin, A., Lunardi, C., Scorza, R., Laar, J.M. van, Shiels, P.G., Herrick, A., Worthington, J., Fonseca, C., Denton, C., Tan, F.K., Arnett, F.C., Assassi, S., Koeleman, B.P., Mayes, M.D., Radstake, T.R.D.J., Martin, J., and et al.
Abstract: Item does not contain fulltext, INTRODUCTION: A recent genome-wide association study in European systemic sclerosis (SSc) patients identified three loci (PSORS1C1, TNIP1 and RHOB) as novel genetic risk factors for the disease. The aim of this study was to replicate the previously mentioned findings in a large multicentre independent SSc cohort of Caucasian ancestry. METHODS: 4389 SSc patients and 7611 healthy controls from different European countries and the USA were included in the study. Six single nucleotide polymorphisms (SNP): rs342070, rs13021401 (RHOB), rs2233287, rs4958881, rs3792783 (TNIP1) and rs3130573 (PSORS1C1) were analysed. Overall significance was calculated by pooled analysis of all the cohorts. Haplotype analyses and conditional logistic regression analyses were carried out to explore further the genetic structure of the tested loci. RESULTS: Pooled analyses of all the analysed SNPs in TNIP1 revealed significant association with the whole disease (rs2233287 p(MH)=1.94x10(-4), OR 1.19; rs4958881 p(MH)=3.26x10(-5), OR 1.19; rs3792783 p(MH)=2.16x10(-4), OR 1.19). These associations were maintained in all the subgroups considered. PSORS1C1 comparison showed association with the complete set of patients and all the subsets except for the anti-centromere-positive patients. However, the association was dependent on different HLA class II alleles. The variants in the RHOB gene were not associated with SSc or any of its subsets. CONCLUSIONS: These data confirmed the influence of TNIP1 on an increased susceptibility to SSc and reinforced this locus as a common autoimmunity risk factor.
Published: 2013

48. The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis

Author: Carmona, F.D., Martin, J.E., Beretta, L., Simeon, C.P., Carreira, P.E., Callejas, J.L., Fernandez-Castro, M., Saez-Comet, L., Beltran, E., Camps, M.T., Egurbide, M.V., Airo, P., Scorza, R., Lunardi, C., Hunzelmann, N., Riemekasten, G., Witte, T. de, Kreuter, A., Distler, J.H., Madhok, R., Shiels, P., Laar, J.M. van, Fonseca, C., Denton, C., Herrick, A., Worthington, J., Schuerwegh, A.J., Vonk, M.C., Voskuyl, A.E., Radstake, T.R.D.J., Martin, J., et al., Carmona, F.D., Martin, J.E., Beretta, L., Simeon, C.P., Carreira, P.E., Callejas, J.L., Fernandez-Castro, M., Saez-Comet, L., Beltran, E., Camps, M.T., Egurbide, M.V., Airo, P., Scorza, R., Lunardi, C., Hunzelmann, N., Riemekasten, G., Witte, T. de, Kreuter, A., Distler, J.H., Madhok, R., Shiels, P., Laar, J.M. van, Fonseca, C., Denton, C., Herrick, A., Worthington, J., Schuerwegh, A.J., Vonk, M.C., Voskuyl, A.E., Radstake, T.R.D.J., Martin, J., and et al.
Abstract: Contains fulltext : 117843.pdf (publisher's version ) (Open Access), Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P = 1.34x10(-8), OR = 1.22, CI 95% = 1.14-1.30; rs2004640: P = 4.60x10(-7), OR = 0.84, CI 95% = 0.78-0.90; rs10488631: P = 7.53x10(-20), OR = 1.63, CI 95% = 1.47-1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P = 0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P = 9.04x10(-22), OR = 1.75, CI 95% = 1.56-1.97) better explained the observed association (likelihood P-value = 1.48x10(-4)), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific.
Published: 2013

49. Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility

Author: Diaz-Gallo, L.M., Simeon, C.P., Broen, J.C.A., Ortego-Centeno, N., Beretta, L., Vonk, M.C., Carreira, P.E., Vargas, S., Roman-Ivorra, J.A., Gonzalez-Gay, M.A., Tolosa, C., Lopez-Longo, F.J., Espinosa, G., Vicente, E.F., Hesselstrand, R., Riemekasten, G., Witte, T. de, Distler, J.H., Voskuyl, A.E., Schuerwegh, A.J., Shiels, P.G., Nordin, A., Padyukov, L., Hoffmann-Vold, A.M., Scorza, R., Lunardi, C., Airo, P., Laar, J.M. van, Hunzelmann, N., Gathof, B.S., Kreuter, A., Herrick, A., Worthington, J., Denton, C.P., Zhou, X., Arnett, F.C., Fonseca, C., Koeleman, B.P., Assasi, S., Radstake, T.R.D.J., Mayes, M.D., Martin, J., et al., Diaz-Gallo, L.M., Simeon, C.P., Broen, J.C.A., Ortego-Centeno, N., Beretta, L., Vonk, M.C., Carreira, P.E., Vargas, S., Roman-Ivorra, J.A., Gonzalez-Gay, M.A., Tolosa, C., Lopez-Longo, F.J., Espinosa, G., Vicente, E.F., Hesselstrand, R., Riemekasten, G., Witte, T. de, Distler, J.H., Voskuyl, A.E., Schuerwegh, A.J., Shiels, P.G., Nordin, A., Padyukov, L., Hoffmann-Vold, A.M., Scorza, R., Lunardi, C., Airo, P., Laar, J.M. van, Hunzelmann, N., Gathof, B.S., Kreuter, A., Herrick, A., Worthington, J., Denton, C.P., Zhou, X., Arnett, F.C., Fonseca, C., Koeleman, B.P., Assasi, S., Radstake, T.R.D.J., Mayes, M.D., Martin, J., and et al.
Abstract: Item does not contain fulltext, OBJECTIVE: The interleukin 2 (IL-2) and interleukin 21 (IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions. The aim of this study was to evaluate the role of the IL-2/IL-21 locus in systemic sclerosis (SSc). PATIENTS AND METHODS: The case control study included 4493 SSc Caucasian patients and 5856 healthy controls from eight Caucasian populations (Spain, Germany, The Netherlands, USA, Italy, Sweden, UK and Norway). Four single nucleotide polymorphisms (rs2069762, rs6822844, rs6835457 and rs907715) were genotyped using TaqMan allelic discrimination assays. RESULTS: We observed evidence of association of the rs6822844 and rs907715 variants with global SSc (pc=6.6E-4 and pc=7.2E-3, respectively). Similar statistically significant associations were observed for the limited cutaneous form of the disease. The conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs6822844 polymorphism. Consistently, the rs2069762A-rs6822844T-rs6835457G-rs907715T allelic combination showed evidence of association with SSc and limited cutaneous SSc subtype (pc=1.7E-03 and pc=8E-4, respectively). CONCLUSIONS: These results suggested that the IL-2/IL-21 locus influences the genetic susceptibility to SSc. Moreover, this study provided further support for the IL-2/IL-21 locus as a common genetic factor in autoimmune diseases.
Published: 2013

50. Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility

Author: Diaz-Gallo, L.M., Simeon, C.P., Broen, J.C.A., Ortego-Centeno, N., Beretta, L., Vonk, M.C., Carreira, P.E., Vargas, S., Roman-Ivorra, J.A., Gonzalez-Gay, M.A., Tolosa, C., Lopez-Longo, F.J., Espinosa, G., Vicente, E.F., Hesselstrand, R., Riemekasten, G., Witte, T. de, Distler, J.H., Voskuyl, A.E., Schuerwegh, A.J., Shiels, P.G., Nordin, A., Padyukov, L., Hoffmann-Vold, A.M., Scorza, R., Lunardi, C., Airo, P., Laar, J.M. van, Hunzelmann, N., Gathof, B.S., Kreuter, A., Herrick, A., Worthington, J., Denton, C.P., Zhou, X., Arnett, F.C., Fonseca, C., Koeleman, B.P., Assasi, S., Radstake, T.R.D.J., Mayes, M.D., Martin, J., et al., Diaz-Gallo, L.M., Simeon, C.P., Broen, J.C.A., Ortego-Centeno, N., Beretta, L., Vonk, M.C., Carreira, P.E., Vargas, S., Roman-Ivorra, J.A., Gonzalez-Gay, M.A., Tolosa, C., Lopez-Longo, F.J., Espinosa, G., Vicente, E.F., Hesselstrand, R., Riemekasten, G., Witte, T. de, Distler, J.H., Voskuyl, A.E., Schuerwegh, A.J., Shiels, P.G., Nordin, A., Padyukov, L., Hoffmann-Vold, A.M., Scorza, R., Lunardi, C., Airo, P., Laar, J.M. van, Hunzelmann, N., Gathof, B.S., Kreuter, A., Herrick, A., Worthington, J., Denton, C.P., Zhou, X., Arnett, F.C., Fonseca, C., Koeleman, B.P., Assasi, S., Radstake, T.R.D.J., Mayes, M.D., Martin, J., and et al.
Abstract: Item does not contain fulltext, OBJECTIVE: The interleukin 2 (IL-2) and interleukin 21 (IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions. The aim of this study was to evaluate the role of the IL-2/IL-21 locus in systemic sclerosis (SSc). PATIENTS AND METHODS: The case control study included 4493 SSc Caucasian patients and 5856 healthy controls from eight Caucasian populations (Spain, Germany, The Netherlands, USA, Italy, Sweden, UK and Norway). Four single nucleotide polymorphisms (rs2069762, rs6822844, rs6835457 and rs907715) were genotyped using TaqMan allelic discrimination assays. RESULTS: We observed evidence of association of the rs6822844 and rs907715 variants with global SSc (pc=6.6E-4 and pc=7.2E-3, respectively). Similar statistically significant associations were observed for the limited cutaneous form of the disease. The conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs6822844 polymorphism. Consistently, the rs2069762A-rs6822844T-rs6835457G-rs907715T allelic combination showed evidence of association with SSc and limited cutaneous SSc subtype (pc=1.7E-03 and pc=8E-4, respectively). CONCLUSIONS: These results suggested that the IL-2/IL-21 locus influences the genetic susceptibility to SSc. Moreover, this study provided further support for the IL-2/IL-21 locus as a common genetic factor in autoimmune diseases.
Published: 2013

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