Objectives To identify overall disease course, progression patterns and risk factors predictive for progressive interstitial lung disease (ILD) in patients with systemic sclerosis-associated ILD (SSc-ILD), using data from the European Scleroderma Trials And Research (EUSTAR) database over long-term follow-up.
Methods Eligible patients with SSc-ILD were registered in the EUSTAR database and had measurements of forced vital capacity (FVC) at baseline and after 12±3 months. Long-term progressive ILD and progression patterns were assessed in patients with multiple FVC measurements. Potential predictors of ILD progression were analysed using multivariable mixed-effect models.
Results 826 patients with SSc-ILD were included. Over 12±3 months, 219 (27%) showed progressive ILD: either moderate (FVC decline 5% to 10%) or significant (FVC decline >10%). A total of 535 (65%) patients had multiple FVC measurements available over mean 5-year follow-up. In each 12-month period, 23% to 27% of SSc-ILD patients showed progressive ILD, but only a minority of patients showed progression in consecutive periods. Most patients with progressive ILD (58%) had a pattern of slow lung function decline, with more periods of stability/improvement than decline, whereas only 8% showed rapid, continuously declining FVC; 178 (33%) experienced no episode of FVC decline. The strongest predictive factors for FVC decline over 5 years were male sex, higher modified Rodnan skin score and reflux/dysphagia symptoms.
Conclusion SSc-ILD shows a heterogeneous and variable disease course, and thus monitoring all patients closely is important. Novel treatment concepts, with treatment initiation before FVC decline occurs, should aim for prevention of progression to avoid irreversible organ damage.
- pulmonary fibrosis
- autoimmune diseases
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Handling editor Josef S Smolen
Correction notice This article has been corrected since it published Online First. The collaborator group, EUSTAR, has been added to the author list and affiliations updated.
Collaborators On behalf of EUSTAR collaborators: Marco Matucci Cerinic (Florence (Italy)); Ulrich Walker (Basel (Switzerland)); Florenzo Iannone (Bari (Italy)); Radim Becvar (Prague (Czech Republic)); Gabriele Valentini (Naples (Italy)); Elise Siegert (Berlin (Germany)); C. Montecucco (Pavia (Italy)); Patricia E. Carreira (Madrid (Spain)); Carlo Chizzolini (Geneva (Switzerland)); Eugene J. Kucharz (Katowice (Poland)); Andrea Doria (Padova (Italy)); Pr Dominique Farge Bancel (Paris (France)); Roger Hesselstrand (Lund (Sweden)); Alexandra Balbir-Gurman (Haifa (Israel)); Raffaele Pellerito (Torino (Italy)); Cristian Caimmi (Verona (Italy)); Christopher Denton (London (United Kingdom)); Nemanja Damjanov (Belgrade (Serbia & Montenegro)); Jörg Henes (Tübingen (Germany)); Vera Ortiz-Santamaria Granollers (Barcelona (Spain)); Stefan Heitmann (Stuttgart (Germany)); Maria João Salvador (Coimbra (Portugal)); Bojana Stamenkovic (Niska Banja (Serbia and Montenegro)); Carlo Francesco Selmi (Rozzano, Milano (Italy)); Ariane Herrick (Salford (United Kingdom)); Ulf Müller-Ladner (Bad Nauheim (Germany)); Merete Engelhart (Hellerup (Denmark)); Valeria Riccieri (Roma (Italy)); Ruxandra Maria Ionescu (Bucharest (Romania)); Ana Maria Gheorghiu (Bucharest (Romania)); Cord Sunderkötter (Münster (Germany)); Jörg Distler (Erlangen (Germany)); Francesca Ingegnoli (Milano (Italy)); Luc Mouthon (Paris (France)); Vanessa Smith (Gent (Belgium)); Francesco Paolo Cantatore (Foggia (Italy)); Susanne Ullman (Copenhagen (Denmark)); Maria Rosa Pozzi (Monza (Italy)); Piotr Wiland (Wroclaw (Poland)); Marie Vanthuyne (Brussels (Belgium)); Brigitte Krummel-Lorenz, Petra Saar (Frankfurt (Germany)); Kristine Herrmann (Dresden (Germany)); Ellen De Langhe (Leuven (Belgium)); Branimir Anic, Marko Baresic, Miroslav Mayer (Zagreb (Croatia)); Sule Yavuz (Altunizade-Istanbul (Turkey)); Carolina de Souza Müller (Curitiba (Brasil)); Thierry Zenone (Valence (France)); Alessandro Mathieu; Alessandra Vacca (Monserrato (CA) (Italy)); Kamal Solanki (Hamilton (New Zealand)); Edoardo Rosato (Roma (Italy)); Fahrettin Oksel Figen Yargucu (Bornova, Izmir (Turkey)); Cristina-Mihaela Tanaseanu (Bucharest (Romania)); Rosario Foti (Catania (Italy)); Daniel E. Furst (Los Angeles (USA)); Peter Villiger Sabine Adler (Bern (Switzerland)); Paloma García de la Peña Lefebvre, Jorge Juan González Martín (Madrid (Spain)); Ira Litinsky (Tel-Aviv (Israel)); Francesco Del Galdo (Leeds (United Kingdom)); Goda Seskute (Vilnius (Lithuania)); Lesley Ann Saketkoo (New Orleans (USA)); Eduardo Kerzberg (Buenos Aires (Argentina)); Ivan Castellví (Barcelona (Spain)); François Spertini (Lausanne (Switzerland)); Vivien M. Hsu (New Brunswick (USA)); Thierry Martin (Strasbourg (France)); Tim Schmeiser (Wuppertal-Elberfeld (Germany)); Dominik Majewski (Poznan (Poland)); Vera Bernardino (Lisboa (Portugal)); Piercarlo Sarzi Puttini (Milano (Italy)).
Contributors The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). Authors maintained full editorial control over the content of the manuscript and were responsible for all final decisions on manuscript content, for final approval of the version for submission and the version for publication.
Funding The study was funded by Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany.
Competing interests A-MH-V received research funding and/or consulting fees or other remuneration from Actelion, Boehringer Ingelheim, Roche, Bayer, Thermo Fisher, MSD, Arxx and Medscape. YA received research funding and/or consulting fees from Actelion, Alpine, Bayer, BMS, Boehringer Ingelheim, Inventiva, Italfarmaco, Genentech Roche, Sanofi and Servier. MA is an employee of Boehringer Ingelheim. LA received consulting fees or other remuneration from Boehringer Ingelheim and Roche. LC received consulting fees from Actelion, Bayer, Boehringer Ingelheim, Medac, Pfizer and Roche. EH received research funding and/or consulting fees or other remuneration from Actelion, Bayer, GSK and Pfizer. CM received consulting fees or other remuneration from Actelion, Geneva, Roche and Rofarm. OK-B received consulting fees or other remuneration from Bayer, Boehringer Ingelheim, Inventiva, Medac, Novartis and Roche. OD received consulting fees and/or research funding from A.Menarini, Acceleron Pharma, Amgen, AnaMar, Bayer, Blade Therapeutics, Boehringer Ingelheim, Catenion, CSL Behring, ChemomAb, Ergonex, Glenmark Pharmaceuticals, GSK, Inventiva, Italfarmaco, iQone, IQVIA, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Target Bioscience and UCB in the area of potential treatments of scleroderma and its complications, and holds Patent mir 29 for the treatment of systemic sclerosis (US8247389, EP2331143). CB, PA, SG, ML, GR, AR and PPS have no competing interests to disclose.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer-reviewed.
Data availability statement Data are available upon reasonable request.
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