Predictors of disease worsening defined by progression of organ damage in diffuse systemic sclerosis: a European Scleroderma Trials and Research (EUSTAR) analysis
Por:
Becker, M, Graf, N, Sauter, R, Curram, J, Denton, C, Khanna, D, Pena, J, Pope, J, Distler, O, Matucci-Cerinic, M, Guiducci, S, Walker, U, Jaeger, V, Bannert, B, Lapadula, G, Becvarare, R, Cutolo, M, Valentini, G, Siegert, E, Rednic, S, Allanore, Y, Montecucco, C, Carreira, P, Novak, S, Czirjak, L, Varju, C, Chizzolini, C, Allai, D, Kucharz, E, Cozzi, F, Rozman, B, Mallia, C, Gabrielli, A, Bancel, D, Airo, P, Hesselstrand, R, Martinovic, D, Balbir-Gurman, A, Braun-Moscovici, Y, Hunzelmann, N, Pellerito, R, Caramaschi, P, Black, C, Damjanov, N, Henes, J, Santamaria, V, Heitmann, S, Seidel, M, Da Silva, J, Stamenkovic, B, Selmi, C, Tikly, M, Denisov, L, Muller-Ladner, U, Engelhart, M, Hachulla, E, Riccieri, V, Ionescu, R, Mihai, C, Sunderkotter, C, Kuhn, A, Schett, G, Distler, J, Meroni, P, Ingegnoli, F, Mouthon, L, De Keyser, F, Smith, V, Cantatore, F, Corrado, A, Ullman, S, Iversen, L, Pozzi, M, Eyerich, K, Hein, R, Knott, E, Wiland, P, Szmyrka-Kaczmarek, M, Sokolik, R, Morgiel, E, Madej, M, Alegre-Sancho, J, Krummel-Lorenz, B, Saar, P, Aringer, M, Gunther, C, Anne, E, Westhovens, R, De Langhe, E, Lenaerts, J, Anic, B, Baresic, M, Mayer, M, Uprus, M, Otsa, K, Yavuz, S, Radominski, S, Muller, C, Azevedo, V, Popa, S, Zenone, T, Stebbings, S, Highton, J, Mathieu, A, Vacca, A, Stamp, L, Chapman, P, O'Donnell, J, Solanki, K, Doube, A, Veale, D, O'Rourke, M, Loyo, E, Li, M, Rosato, E, Amoroso, A, Gigante, A, Oksel, F, Yargucu, F, Tanaseanu, C, Popescu, M, Dumitrascu, A, Tiglea, I, Foti, R, Visalli, E, Benenati, A, Amato, G, Ancuta, C, Chirieac, R, Villiger, P, Adler, S, Dan, D, Lefebvre, P, Rubio, S, Exposito, M, Sibilia, J, Chatelus, E, Gottenberg, J, Chifflot, H, Litinsky, I, Del Galdo, F, Venalis, A, Saketkoo, L, Lasky, J, Kerzberg, E, Montoya, F, Cosentino, V, Limonta, M, Brucato, A, Lupi, E, Spertini, F, Ribi, C, Buss, G, Martin, T, Guffroy, A, Poindron, V, Chung, L, Schmeiser, T, Zebryk, P, Riso, N, Riemekasten, G, Rezus, E, Puttini, P and EUSTAR Collaborators
Publicada:
1 sep 2019
Resumen:
Objectives Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database.
Methods Inclusion criteria were diagnosis of diffuse SSc and follow-up over 12 +/- 3 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression.
Results Of 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model.
Conclusions The use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trials.
Filiaciones:
Becker, M:
Univ Hosp Zurich, Dept Rheumatol, CH-8091 Zurich, Switzerland
Univ Hosp Zurich, Ctr Expt Rheumatol, Zurich, Switzerland
Graf, N:
Graf Biostat, Winterthur, Switzerland
Sauter, R:
Univ Oxford, Nuffield Dept Med, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford, England
Curram, J:
Bayer PLC, Data Sci & Analyt, Reading, Berks, England
Denton, C:
UCL Div Med, Royal Free Campus, London, England
Khanna, D:
Univ Michigan, Dept Internal Med, Div Rheumatol, Scleroderma Program, Ann Arbor, MI 48109 USA
Pena, J:
Bayer US LLC, Whippany, NJ USA
Pope, J:
Univ Western Ontario, St Josephs Hlth Care, Dept Med, Div Rheumatol, London, ON, Canada
Distler, O:
Univ Hosp Zurich, Dept Rheumatol, CH-8091 Zurich, Switzerland
Univ Hosp Zurich, Ctr Expt Rheumatol, Zurich, Switzerland
Matucci-Cerinic, M:
Univ Florence, Dept Expt & Clin Med, Florence, Italy
Univ Florence, Florence, Italy
Guiducci, S:
Univ Florence, Florence, Italy
Walker, U:
Univ Hosp Basel, Basel, Switzerland
Jaeger, V:
Univ Hosp Basel, Basel, Switzerland
Bannert, B:
Univ Hosp Basel, Basel, Switzerland
Lapadula, G:
Univ Bari, Sch Med, Bari, Italy
Becvarare, R:
Charles Univ Prague, Med Sch 1, Prague, Czech Republic
Cutolo, M:
Univ Genoa, Genoa, Italy
Valentini, G:
Policlin UO Reumatol, Naples, Italy
Siegert, E:
Charite, Berlin, Germany
Rednic, S:
Univ Med & Pharm Iuliu Hatieganu Cluj, Cluj Napoca, Romania
Allanore, Y:
Paris Descartes Univ, Cochin Hosp, Sorbonne Paris Cite, Rheumatol Dept A, Paris, France
Univ Cochin Hosp, Paris, France
Montecucco, C:
IRCCS Policlin S Matteo, Pavia, Italy
Carreira, P:
Hosp 12 Octubre, Madrid, Spain
Novak, S:
KBC Rijeka, Rijeka, Croatia
Czirjak, L:
Univ Pecs, Pecs, Hungary
Varju, C:
Univ Pecs, Pecs, Hungary
Chizzolini, C:
Univ Hosp Geneva, Geneva, Switzerland
Allai, D:
Univ Hosp Geneva, Geneva, Switzerland
Kucharz, E:
Med Univ Silesia, Katowice, Poland
Cozzi, F:
Univ Padua, Padua, Italy
Rozman, B:
Univ Med Ctr Ljubljana, Ljubljana, Slovenia
Mallia, C:
Stella Maris, Balzan, Malta
Gabrielli, A:
Univ Ancona, Univ Politecn Marche Polo Didatt, Ist Clin Med Gen Ematol & Immunol Clin, Ancona, Italy
Bancel, D:
Hop St Louis, Paris, France
Airo, P:
Spedali Civili Brescia, Serv Reumatol Allergol & Immunol Clin, Brescia, Italy
Hesselstrand, R:
Lund Univ Hosp, Lund, Sweden
Martinovic, D:
Clin Hosp Split, Split, Croatia
Balbir-Gurman, A:
Rambam Hlth Care Campus, B Shine Rheumatol Inst, Haifa, Israel
Braun-Moscovici, Y:
Rambam Hlth Care Campus, B Shine Rheumatol Inst, Haifa, Israel
Hunzelmann, N:
Univ Haut Klin Koln, Cologne, Germany
Pellerito, R:
Osped Mauriziano Umberto 1, Turin, Italy
Caramaschi, P:
Univ Verona, Verona, Italy
Black, C:
Royal Free & Univ Coll London Med Sch, London, England
Damjanov, N:
Inst Rheumatol, Belgrade, Serbia
Inst Rheumatol, Podgorica, Montenegro
Henes, J:
Med Univ Klin Abt II, Tubingen, Germany
Santamaria, V:
Rheumatol Granollers Gen Hosp, Barcelona, Spain
Heitmann, S:
Marienhosp Stuttgart, Stuttgart, Germany
Seidel, M:
Med Univ Poliklin, Bonn, Germany
Da Silva, J:
Univ Coimbra, Coimbra, Portugal
Stamenkovic, B:
Inst Prevent Treatment & Rehabil Rheumat & Cardio, Nish, Serbia
Inst Prevent Treatment & Rehabil Rheumat & Cardio, Podgorica, Montenegro
Selmi, C:
Univ Milan, Milan, Italy
Tikly, M:
Chris Hani Baragwanath Hosp, Johannesburg, South Africa
Univ Witwatersrand, Johannesburg, South Africa
Denisov, L:
VA Nasonova Inst Rheumatol, Moscow, Russia
Muller-Ladner, U:
Kerckhoff Clin Bad Nauheim, Bad Nauheim, Germany
Engelhart, M:
Univ Hosp Gentofte, Hellerup, Denmark
Hachulla, E:
Hop Claude Huriez, Lille, France
Riccieri, V:
Sapienza Univ Roma, Rome, Italy
Ionescu, R:
Carol Davila Univ Med & Pharm, St Maria Hosp, Bucharest, Romania
Mihai, C:
Ion Cantacuzino Clin Hosp, Bucharest, Romania
Sunderkotter, C:
Univ Munster, Munster, Germany
Kuhn, A:
Univ Munster, Munster, Germany
Schett, G:
Univ Klinikum Erlangen, Erlangen, Germany
Distler, J:
Univ Klinikum Erlangen, Erlangen, Germany
Meroni, P:
Univ Milan, Ist Gaetano Pini, Milan, Italy
Ingegnoli, F:
Univ Milan, Ist Gaetano Pini, Milan, Italy
Mouthon, L:
Hop Cochin, Paris, France
De Keyser, F:
Univ Ghent, Ghent, Belgium
Smith, V:
Univ Ghent, Ghent, Belgium
Cantatore, F:
Univ Foggia, UO Reumatol, Osped Col DAvanzo, Foggia, Italy
Corrado, A:
Univ Foggia, UO Reumatol, Osped Col DAvanzo, Foggia, Italy
Ullman, S:
Univ Hosp Copenhagen, Copenhagen, Denmark
Iversen, L:
Univ Hosp Copenhagen, Copenhagen, Denmark
Pozzi, M:
Osped San Gerardo, Monza, Italy
Eyerich, K:
Tech Univ Munich, Munich, Germany
Hein, R:
Tech Univ Munich, Munich, Germany
Knott, E:
Tech Univ Munich, Munich, Germany
Wiland, P:
Wroclaw Univ Med, Wroclaw, Poland
Szmyrka-Kaczmarek, M:
Wroclaw Univ Med, Wroclaw, Poland
Sokolik, R:
Wroclaw Univ Med, Wroclaw, Poland
Morgiel, E:
Wroclaw Univ Med, Wroclaw, Poland
Madej, M:
Wroclaw Univ Med, Wroclaw, Poland
:
Hosp Univ Dr Peset, Valencia, Spain
Krummel-Lorenz, B:
Endokrinol Frankfurt, Frankfurt, Germany
Saar, P:
Endokrinol Frankfurt, Frankfurt, Germany
Aringer, M:
Carl Gustav Carus Tech Univ Dresden, Univ Med Ctr, Dresden, Germany
Gunther, C:
Carl Gustav Carus Tech Univ Dresden, Univ Med Ctr, Dresden, Germany
Anne, E:
Carl Gustav Carus Tech Univ Dresden, Univ Med Ctr, Dresden, Germany
Westhovens, R:
Univ Hosp Leuven, Skeletal Biol & Engn Res Ctr, Leuven, Belgium
De Langhe, E:
Univ Hosp Leuven, Skeletal Biol & Engn Res Ctr, Leuven, Belgium
Lenaerts, J:
Univ Hosp Leuven, Skeletal Biol & Engn Res Ctr, Leuven, Belgium
Anic, B:
Univ Zagreb, Sch Med, Univ Hosp Ctr Zagreb, Zagreb, Croatia
Baresic, M:
Univ Zagreb, Sch Med, Univ Hosp Ctr Zagreb, Zagreb, Croatia
Mayer, M:
Univ Zagreb, Sch Med, Univ Hosp Ctr Zagreb, Zagreb, Croatia
Uprus, M:
East Tallin Cent Hosp, Tallinn, Estonia
Otsa, K:
East Tallin Cent Hosp, Tallinn, Estonia
Yavuz, S:
Univ Marmara, Istanbul, Turkey
Radominski, S:
Univ Fed Parana, Hosp Clin, Curitiba, Parana, Brazil
Muller, C:
Univ Fed Parana, Hosp Clin, Curitiba, Parana, Brazil
Azevedo, V:
Univ Fed Parana, Hosp Clin, Curitiba, Parana, Brazil
Popa, S:
Republican Clin Hosp, Kishinev, Moldova
Zenone, T:
Unit Internal Med, Valence, France
Stebbings, S:
Dunedin Sch Med, Dunedin, New Zealand
Highton, J:
Dunedin Sch Med, Dunedin, New Zealand
Mathieu, A:
Univ Cagliari, Policlin Univ, Chair Rheumatol 2, Cagliari, Italy
Vacca, A:
Univ Cagliari, Policlin Univ, Chair Rheumatol 2, Cagliari, Italy
Stamp, L:
Univ Otago, Christchurch, New Zealand
Chapman, P:
Univ Otago, Christchurch, New Zealand
O'Donnell, J:
Univ Otago, Christchurch, New Zealand
Solanki, K:
Waikato Univ Hosp, Hamilton, New Zealand
Doube, A:
Waikato Univ Hosp, Hamilton, New Zealand
Veale, D:
St Vincents Univ Hosp, Dublin, Ireland
O'Rourke, M:
St Vincents Univ Hosp, Dublin, Ireland
Loyo, E:
Hosp Reg Univ Jose Ma Cabral & Baez, Clin Corominas, Santiago, Dominican Rep
Li, M:
Peking Union Med Coll Hosp, West Campus, Beijing, Peoples R China
Rosato, E:
Sapienza Univ Roma, Univ La Sapienza, Policlin Umberto 1, Rome, Italy
Amoroso, A:
Sapienza Univ Roma, Univ La Sapienza, Policlin Umberto 1, Rome, Italy
Gigante, A:
Sapienza Univ Roma, Univ La Sapienza, Policlin Umberto 1, Rome, Italy
Oksel, F:
Ege Univ, Izmir, Turkey
Yargucu, F:
Ege Univ, Izmir, Turkey
Tanaseanu, C:
Clin Emergency Hosp St Pantelimon, Bucharest, Romania
Popescu, M:
Clin Emergency Hosp St Pantelimon, Bucharest, Romania
Dumitrascu, A:
Clin Emergency Hosp St Pantelimon, Bucharest, Romania
Tiglea, I:
Clin Emergency Hosp St Pantelimon, Bucharest, Romania
Foti, R:
AOU Policlin VE Catania Ctr Riferimento Reg Malat, AOU Policlin Vittorio Emanuele UO Reumatol, Catania, Italy
Visalli, E:
AOU Policlin VE Catania Ctr Riferimento Reg Malat, AOU Policlin Vittorio Emanuele UO Reumatol, Catania, Italy
Benenati, A:
AOU Policlin VE Catania Ctr Riferimento Reg Malat, AOU Policlin Vittorio Emanuele UO Reumatol, Catania, Italy
Amato, G:
AOU Policlin VE Catania Ctr Riferimento Reg Malat, AOU Policlin Vittorio Emanuele UO Reumatol, Catania, Italy
Ancuta, C:
Univ Med & Pharm, Rehabil Hosp, European Ctr Translat Res, GR T Popa Ctr Biomed Res, Iasi, Romania
Chirieac, R:
Univ Med & Pharm, Rehabil Hosp, European Ctr Translat Res, GR T Popa Ctr Biomed Res, Iasi, Romania
Villiger, P:
Univ Bern, Bern, Switzerland
Adler, S:
Univ Bern, Bern, Switzerland
Dan, D:
Univ Bern, Bern, Switzerland
Lefebvre, P:
Hosp Univ Sanchinarro, Madrid, Spain
Rubio, S:
Hosp Univ Sanchinarro, Madrid, Spain
Exposito, M:
Hosp Univ Sanchinarro, Madrid, Spain
Sibilia, J:
Univ Hosp Strasbourg, Hop Hautepierre, Strasbourg, France
Chatelus, E:
Univ Hosp Strasbourg, Hop Hautepierre, Strasbourg, France
Gottenberg, J:
Univ Hosp Strasbourg, Hop Hautepierre, Strasbourg, France
Chifflot, H:
Univ Hosp Strasbourg, Hop Hautepierre, Strasbourg, France
Litinsky, I:
Tel Aviv Sourasky Med Ctr, Tel Aviv, Israel
Del Galdo, F:
Univ Leeds, Chapel Allerton Hosp, Leeds, W Yorkshire, England
Venalis, A:
Vilnius Univ, State Res Inst Innovat Med, Vilnius, Lithuania
Saketkoo, L:
Tulane Univ, Med Ctr, Scleroderma & Sarcoidosis Patient Care & Res Ctr, New Orleans, LA 70118 USA
Lasky, J:
Tulane Univ, Med Ctr, Scleroderma & Sarcoidosis Patient Care & Res Ctr, New Orleans, LA 70118 USA
Kerzberg, E:
Univ Buenos Aires, Ramos Mejia Hosp, Sch Med, Osteoarticular Dis & Osteoporosis Ctr,Pharmacol &, Buenos Aires, DF, Argentina
Montoya, F:
Univ Buenos Aires, Ramos Mejia Hosp, Sch Med, Osteoarticular Dis & Osteoporosis Ctr,Pharmacol &, Buenos Aires, DF, Argentina
Cosentino, V:
Univ Buenos Aires, Ramos Mejia Hosp, Sch Med, Osteoarticular Dis & Osteoporosis Ctr,Pharmacol &, Buenos Aires, DF, Argentina
Limonta, M:
Osped Riuniti Bergamo, USSD Reumatol, Bergamo, Italy
Brucato, A:
Osped Riuniti Bergamo, USSD Reumatol, Bergamo, Italy
Lupi, E:
Osped Riuniti Bergamo, USSD Reumatol, Bergamo, Italy
Spertini, F:
Dept Rheumatol Clin Immunol & Allergy, Lausanne, Switzerland
Ribi, C:
Dept Rheumatol Clin Immunol & Allergy, Lausanne, Switzerland
Buss, G:
Dept Rheumatol Clin Immunol & Allergy, Lausanne, Switzerland
Martin, T:
Nouvel Hop Civil, Strasbourg, France
Guffroy, A:
Nouvel Hop Civil, Strasbourg, France
Poindron, V:
Nouvel Hop Civil, Strasbourg, France
Chung, L:
Stanford Univ, Sch Med, Stanford, CA 94305 USA
Schmeiser, T:
Krankenhaus St Josef, Wuppertal, Germany
Zebryk, P:
Poznan Univ Med Sci, Poznan, Poland
Riso, N:
Ctr Hosp Lisboa Cent, Hosp Curry Cabral, Unidade Doencas Autoimunes, Lisbon, Portugal
Riemekasten, G:
Univ Klin Lubeck, Lubeck, Germany
Rezus, E:
Univ Med & Pharm GR T Popa Iasi, Rehabil Hosp, Iasi, Romania
Puttini, P:
Univ Hosp Luigi Sacco, Milan, Italy
Green Published, hybrid
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