Progressive skin fibrosis is associated with a decline in lung function and worse survival in patients with diffuse cutaneous systemic sclerosis in the european scleroderma trials and research (eustar) cohort

Wu, W.; Jordan, S.; Graf, N.; de Oliveira Pena, J.; Curram, J.; Allanore, Y.; Matucci-Cerinic, M.; Pope, J. E.; Denton, C. P.; Khanna, D.; Distler, O.; Guiducci, S.; Walker, U.; Jaeger, V.; Bannert, B.; Lapadula, G.; Becvarare, R.; Cutolo, M.; Valentini, G.; Siegert, E.; Rednic, S.; Montecucco, C.; Carreira, P. E.; Novak, S.; Czirjak, L.; Varju, C.; Chizzolini, C.; Allai, D.; Kucharz, E. J.; Cozzi, F.; Rozman, B.; Mallia, C.; Gabrielli, A.; Bancel, D. F.; 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. O.; Heitmann, S.; Seidel, M.; Pereira Da Silva, J. A.; Stamenkovic, B.; Selmi, C. F.; Tikly, M.; Denisov, L. N.; Muller-Ladner, U.; Engelhart, M.; Hachulla, E.; Riccieri, V.; Ionescu, R. M.; Mihai, C.; Sunderkotter, C.; Kuhn, A.; Schett, G.; Distler, J.; Meroni, P.; Ingegnoli, F.; Mouthon, L.; De Keyser, F.; Smith, V.; Cantatore, F. P.; Corrado, A.; Ullman, S.; Iversen, L.; Pozzi, M. R.; Eyerich, K.; Hein, R.; Knott, E.; Wiland, P.; Szmyrka-Kaczmarek, M.; Sokolik, R.; Morgiel, E.; Madej, M.; Alegre-Sancho, J. 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. C.; de Souza Muller, C.; Azevedo, V. F.; 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. -M.; Popescu, M.; Dumitrascu, A.; Tiglea, I.; Foti, R.; Visalli, E.; Benenati, A.; Amato, G.; Ancuta, C.; Chirieac, R.; Villiger, P.; Adler, S.; Dan, D.; de la Pena Lefebvre, P. G.; Rubio, S. R.; Exposito, M. V.; Sibilia, J.; Chatelus, E.; Gottenberg, J. E.; Chifflot, H.; Litinsky, I.; Del Galdo, F.; Venalis, A.; Saketkoo, L. A.; Lasky, J. A.; Kerzberg, E.; Montoya, F.; Cosentino, V.; Limonta, M.; Brucato, A. L.; 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.; Sarzi Puttini, P.

doi:10.1136/annrheumdis-2018-213455

Objectives To determine whether progressive skin fibrosis is associated with visceral organ progression and mortality during follow-up in patients with diffuse cutaneous systemic sclerosis (dcSSc). Methods We evaluated patients from the European Scleroderma Trials and Research database with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, valid mRSS at 12±3 months after baseline and ≥1 annual follow-up visit. Progressive skin fibrosis was defined as an increase in mRSS >5 and ≥25% from baseline to 12±3 months. Outcomes were pulmonary, cardiovascular and renal progression, and all-cause death. Associations between skin progression and outcomes were evaluated by Kaplan-Meier survival analysis and multivariable Cox regression. Results Of 1021 included patients, 78 (7.6%) had progressive skin fibrosis (skin progressors). Median follow-up was 3.4 years. Survival analyses indicated that skin progressors had a significantly higher probability of FVC decline ≥10% (53.6% vs 34.4%; p<0.001) and all-cause death (15.4% vs 7.3%; p=0.003) than non-progressors. These significant associations were also found in subgroup analyses of patients with either low baseline mRSS (≤22/51) or short disease duration (≤15 months). In multivariable analyses, skin progression within 1 year was independently associated with FVC decline ≥10% (HR 1.79, 95% CI 1.20 to 2.65) and all-cause death (HR 2.58, 95% CI 1.31 to 5.09). Conclusions Progressive skin fibrosis within 1 year is associated with decline in lung function and worse survival in dcSSc during follow-up. These results confirm mRSS as a surrogate marker in dcSSc, which will be helpful for cohort enrichment in future trials and risk stratification in clinical practice.

Progressive skin fibrosis is associated with a decline in lung function and worse survival in patients with diffuse cutaneous systemic sclerosis in the european scleroderma trials and research (eustar) cohort / Wu, W.; Jordan, S.; Graf, N.; de Oliveira Pena, J.; Curram, J.; Allanore, Y.; Matucci-Cerinic, M.; Pope, J. E.; Denton, C. P.; Khanna, D.; Distler, O.; Guiducci, S.; Walker, U.; Jaeger, V.; Bannert, B.; Lapadula, G.; Becvarare, R.; Cutolo, M.; Valentini, G.; Siegert, E.; Rednic, S.; Montecucco, C.; Carreira, P. E.; Novak, S.; Czirjak, L.; Varju, C.; Chizzolini, C.; Allai, D.; Kucharz, E. J.; Cozzi, F.; Rozman, B.; Mallia, C.; Gabrielli, A.; Bancel, D. F.; 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. O.; Heitmann, S.; Seidel, M.; Pereira Da Silva, J. A.; Stamenkovic, B.; Selmi, C. F.; Tikly, M.; Denisov, L. N.; Muller-Ladner, U.; Engelhart, M.; Hachulla, E.; Riccieri, V.; Ionescu, R. M.; Mihai, C.; Sunderkotter, C.; Kuhn, A.; Schett, G.; Distler, J.; Meroni, P.; Ingegnoli, F.; Mouthon, L.; De Keyser, F.; Smith, V.; Cantatore, F. P.; Corrado, A.; Ullman, S.; Iversen, L.; Pozzi, M. R.; Eyerich, K.; Hein, R.; Knott, E.; Wiland, P.; Szmyrka-Kaczmarek, M.; Sokolik, R.; Morgiel, E.; Madej, M.; Alegre-Sancho, J. 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. C.; de Souza Muller, C.; Azevedo, V. F.; 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. -M.; Popescu, M.; Dumitrascu, A.; Tiglea, I.; Foti, R.; Visalli, E.; Benenati, A.; Amato, G.; Ancuta, C.; Chirieac, R.; Villiger, P.; Adler, S.; Dan, D.; de la Pena Lefebvre, P. G.; Rubio, S. R.; Exposito, M. V.; Sibilia, J.; Chatelus, E.; Gottenberg, J. E.; Chifflot, H.; Litinsky, I.; Del Galdo, F.; Venalis, A.; Saketkoo, L. A.; Lasky, J. A.; Kerzberg, E.; Montoya, F.; Cosentino, V.; Limonta, M.; Brucato, A. L.; 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.; Sarzi Puttini, P.. - In: ANNALS OF THE RHEUMATIC DISEASES. - ISSN 0003-4967. - 78:5(2019), pp. 648-656. [10.1136/annrheumdis-2018-213455]