Abstract
Objectives
To evaluate the clinical characteristics of patients with interstitial lung disease (ILD) in the setting of a large cohort of systemic sclerosis (SSc) patients, and to analyse the differences according to the SSc subtype (following the modification of classification criteria of the American College of Rheumatology for SSc proposed by LeRoy and Medsger), factors are associated with moderate-to-severe impairment of lung function, as well as mortality and causes of death.
Methods
A descriptive study was performed, using the available data from the Spanish Scleroderma Study Group.
Results
Twenty-one referral centers participated in the registry. By April 2014, 1374 patients with SSc had been enrolled, and 595 of whom (43%) had ILD: 316 (53%) with limited cutaneous SSc (lcSSc), 240 (40%) with diffuse cutaneous SSc (dcSSc), and 39 (7%) with SSc sine scleroderma (ssSSc). ILD in the lcSSc and the ssSSc subsets tended to develop later, and showed a less impaired forced vital capacity (FVC) and a ground glass pattern on high-resolution computed tomography (HRCT) less frequently, compared with the dcSSc subset. Factors related to an FVC < 70% of predicted in the multivariate analysis were: dcSSc, positivity to anti-topoisomerase I antibodies, a ground glass pattern on HCRT, an active nailfold capillaroscopy pattern, lower DLco, older age at symptoms onset, and longer time between symptoms onset and ILD diagnosis. Finally, SSc-associated mortality and ILD-related mortality were highest in dcSSc patients, whereas that related to pulmonary arterial hypertension was highest in those with lcSSc-associated ILD.
Conclusions
Our study indicates that ILD constitutes a remarkable complication of SSc with significant morbidity and mortality, which should be borne in mind in all three subgroups (lcSSc, dcSSc, and ssSSc).
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References
Tamby MC, Chanseaud Y, Guillevin L, Mouthon L (2003) New insights into the pathogenesis of systemic sclerosis. Autoimmun Rev 2:152–157
Barsotti S, Bruni C, Orlandi M, Della Rossa A, Marasco E, Codullo V et al. One year in review 2017: systemic sclerosis. vol 35, clinical and experimental rheumatology. 2017. pp S3–S20
Van Den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A et al (2013) 2013 classification criteria for systemic sclerosis: an american college of rheumatology/European league against rheumatism collaborative initiative. Arthritis Rheum 65(11):2737–2747
LeRoy EC, Medsger J (2001) Criteria for the classification of early systemic sclerosis. J Rheumatol 28(7):1573–1576
Steen VD, Medsger TA (2007) Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis 66(7):940–4. https://doi.org/10.1136/ard.2006.066068
Solomon JJ, Olson AL, Fischer A, Bull T, Brown KK, Raghu G et al (2013) Scleroderma lung disease. Eur Respir Rev 22(127):6–19. http://www.ncbi.nlm.nih.gov/pubmed/23457159%5Cn, http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC4103193
McNearney TA, Reveille JD, Fischbach M, Friedman AW, Lisse JR, Goel N et al (2007) Pulmonary involvement in systemic sclerosis: associations with genetic, serologic, sociodemographic, and behavioral factors. Arthritis Care Res 57(2):318–326
Steele R, Hudson M, Lo E, Baron M (2012) Clinical decision rule to predict the presence of interstitial lung disease in systemic sclerosis. Arthritis Care Res (Hoboken) 64(4):519–24. https://doi.org/10.1002/acr.21583
Steen VD, Medsger TA (2000) Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum 43(11):2437–2444
Goh NSL, Desai SR, Veeraraghavan S, Hansell DM, Copley SJ, Maher TM et al (2008) Interstitial lung disease in systemic sclerosis: A simple staging system. Am J Respir Crit Care Med 177(11):1248–54. http://www.ncbi.nlm.nih.gov/pubmed/18369202
Al MASET (1980) Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 23(5):581–90. http://www.ncbi.nlm.nih.gov/pubmed/7378088
Johnson SR (2017) Progress in the clinical classification of systemic sclerosis. Curr Opin Rheumatol. http://insights.ovid.com/crossref?an=00002281-900000000-99200
Galiè N, Hoeper MMM, Humbert M, Torbicki a, Vachiery J-LL, Barbera JA et al (2009) Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 34(6):1219–63. http://raredis.ru/upload/pdf_document/Galie-2009-Guidelines for the d.pdf%5Cnpapers3://publication/doi/10.1183/09031936.00139009%5Cn,http://www.ncbi.nlm.nih.gov/pubmed/19749199
Simeón-Aznar CP, Fonollosa-Plá V, Tolosa-Vilella C, Espinosa-Garriga G, Ramos-Casals M, Campillo-Grau M et al (2012) Registry of the Spanish network for systemic sclerosis: clinical pattern according to cutaneous subsets and immunological status. Semin Arthritis Rheum 41(6):789–800
Schurawitzki H, Stiglbauer R, Graninger W, Herold C, Polzleitner D, Burghuber OC et al (1990) Interstitial lung disease in progressive systemic sclerosis: High-resolution CT versus radiography. Radiology 176(3):755–9. http://www.ncbi.nlm.nih.gov/pubmed/2389033
Steen VD, Conte C, Owens GR, Medsger TA (1994) Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum 37(9):1283–1289
Highland KB, Silver RM (2005) New developments in scleroderma interstitial lung disease. Curr Opin Rheumatol 17(6):737–45. http://www.ncbi.nlm.nih.gov/pubmed/16224252
Plastiras SC, Karadimitrakis SP, Ziakas PD, Vlachoyiannopoulos PG, Moutsopoulos HM, Tzelepis GE (2006) Scleroderma lung: initial forced vital capacity as predictor of pulmonary function decline. Arthritis Care Res 55(4):598–602
Steen VD. The Many Faces of Scleroderma. vol 34, Rheumatic Disease Clinics of North America. 2008. pp 1–15
Steen VD (2005) Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 35(1):35–42. http://www.ncbi.nlm.nih.gov/pubmed/16084222
Saketkoo LA, Mittoo S, Huscher D, Khanna D, Dellaripa PF, Distler O et al (2014) Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials. Thorax 69(5):428–36. https://doi.org/10.1136/thoraxjnl-2013-204202
Bouros D, Wells AU, Nicholson AG, Colby TV, Polychronopoulos V, Pantelidis P et al (2002) Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med 165(12):1581–1586
Launay D, Remy-Jardin M, Michon-Pasturel U, Mastora I, Hachulla E, Lambert M et al (2006) High resolution computed tomography in fibrosing alveolitis associated with systemic sclerosis. J Rheumatol 33:1789–1801
Hachulla E, Gressin V, Guillevin L, Carpentier P, Diot E, Sibilia J et al (2005) Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum 52(12):3792–3800
Mukerjee D, St George D, Coleiro B, Knight C, Denton CP, Davar J et al (2003) Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis 62(11):1088–93. http://www.ncbi.nlm.nih.gov/pubmed/14583573%5Cn, http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC1754353
Thakkar V, Stevens W, Prior D, Youssef P, Liew D, Gabbay E et al (2013) The inclusion of N-terminal pro-brain natriuretic peptide in a sensitive screening strategy for systemic sclerosis-related pulmonary arterial hypertension: a cohort study. Arthritis Res Ther 15(6):R193. http://arthritis-research.biomedcentral.com/articles/10.1186/ar4383
Mukerjee D, St George D, Knight C, Davar J, Wells AU, Du Bois RM et al (2004) Echocardiography and pulmonary function as screening tests for pulmonary arterial hypertension in systemic sclerosis. Rheumatology (Oxford) 43(4):461–6. https://academic.oup.com/rheumatology/article-lookup/doi/10.1093/rheumatology/keh067
Demir N, Şahin A, Küçükşahin O, Kayacan O, Dinçer İ, Sayın T et al (2014) Pulmonary arterial hypertension and systemic sclerosis relation: a single centre experience. Heart Lung Circ 23(7):667–73. http://www.sciencedirect.com/science/article/pii/S1443950614000705
Steen V, Medsger TA (2003) Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum 48(2):516–522
Campo A, Mathai SC, Le Pavec J, Zaiman AL, Hummers LK, Boyce D et al (2010) Hemodynamic predictors of survival in scleroderma-related pulmonary arterial hypertension. Am J Respir Crit Care Med 182(2):252–260
Poormoghim H, Lucas M, Fertig N, Medsger TA (2000) Systemic sclerosis sine scleroderma: demographic, clinical, and serologic features and survival in forty-eight patients. Arthritis Rheum 43(2):444–451
Simeón-Aznar CP, Tolosa-Vilella C, Gabarró-Juliá L, Campillo-Grau M, Guillén Del Castillo A, Fonollosa-Plá V et al (2014) Systemic sclerosis sine scleroderma and limited cutaneous systemic sclerosis: similarities and differences. Clin Exp Rheumatol 32(6 Suppl 86):S-33–40. http://www.ncbi.nlm.nih.gov/pubmed/24776173
Christmann RB, Wells AU, Capelozzi VL, Silver RM (2010) Gastroesophageal reflux incites interstitial lung disease in systemic sclerosis: clinical, radiologic, histopathologic, and treatment evidence. vol 40, Seminars in Arthritis and Rheumatism. pp 241–249
Ntoumazios SK, Voulgari PV, Potsis K, Koutis E, Tsifetaki N, Assimakopoulos DA (2006) Esophageal involvement in scleroderma: gastroesophageal reflux, the common problem. Semin Arthritis Rheum 36(3):173–181
Marie I, Dominique S, Levesque H, Ducrotté P, Denis P, Hellot MF et al (2001) Esophageal involvement and pulmonary manifestations in systemic sclerosis. Arthritis Rheum 45(4):346–54. http://www.ncbi.nlm.nih.gov/pubmed/11501722
Savarino E, Bazzica M, Zentilin P, Pohl D, Parodi A, Cittadini G et al (2009) Gastroesophageal reflux and pulmonary fibrosis in Scleroderma: a study using pH-impedance monitoring. Am J Respir Crit Care Med 179(5):408–413
Cantu E, Appel JZ, Hartwig MG, Woreta H, Green C, Messier R et al (2004) J. Maxwell Chamberlain Memorial Paper. Early fundoplication prevents chronic allograft dysfunction in patients with gastroesophageal reflux disease. Ann Thorac Surg 78(4):1142–1151. http://www.ncbi.nlm.nih.gov/pubmed/15464462
Walsh SJ, Fenster JR (1997) Geographical clustering of mortality from systemic sclerosis in the Southeastern United States, 1981–90. J Rheumatol 24(12):2348–2352
Ioannidis JP, Vlachoyiannopoulos PG, Haidich AB, Medsger TA Jr, Lucas M, Michet CJ et al (2005) Mortality in systemic sclerosis: an international meta-analysis of individual patient data. Am J Med 118(1):2–10. http://www.ncbi.nlm.nih.gov/pubmed/15639201
Rubio-Rivas M, Royo C, Simeon CP, Corbella X, Fonollosa V (2014) Mortality and survival in systemic sclerosis: systematic review and meta-analysis. Semin Arthritis Rheum 44(2):208–19. http://ac.els-cdn.com/S0049017214000808/1-s2.0-S0049017214000808-main.pdf?_tid=fd33cd0a-fcf9-11e5-b222-00000aab0f27&acdnat=1460058813_23657634f72f8dd66903c114e50239b7
Rubio-Rivas M, Simeón-Aznar CP, Velasco C, Marí-Alfonso B, Espinosa G, Corbella X et al (2017) Changes in the pattern of death of 987 patients with systemic sclerosis from 1990 to 2009 from the nationwide Spanish Scleroderma Registry (RESCLE). Clin Exp Rheumatol. http://www.ncbi.nlm.nih.gov/pubmed/28229826
Rubio-Rivas M, Simeón-Aznar CP, Velasco C, Marí-Alfonso B, Espinosa G, Corbella X et al (2017) Changes in the pattern of death of 987 patients with systemic sclerosis from 1990 to 2009 from the nationwide Spanish Scleroderma Registry (RESCLE). Clin Exp Rheumatol 5–12. http://www.ncbi.nlm.nih.gov/pubmed/28229826
Zuhur F, Zuhur SS, Zuhur C, Musellim B, Ongen G (2012) Survival in progressive systemic sclerosis with pulmonary involvement: a single-center experience in Istanbul, Turkey. Rheumatol Int 32(6):1655–1661
Strickland G, Pauling J, Cavill C, Shaddick G, McHugh N (2013) Mortality in systemic sclerosis-a single centre study from the UK. Clin Rheumatol 32(10):1533–9. https://doi.org/10.1007/s10067-013-2289-0
Winstone TA, Assayag D, Wilcox PG, Dunne JV, Hague CJ, Leipsic J et al (2014) Predictors of mortality and progression in scleroderma-associated interstitial lung disease: a systematic review. Chest 146:422–436
Mihai C, Landewé R, van der Heijde D, Walker UA, Constantin PI, Gherghe AM et al. Digital ulcers predict a worse disease course in patients with systemic sclerosis. Ann Rheum Dis [Internet]. 2015;annrheumdis-2014–205897. http://ard.bmj.com/content/early/2015/02/16/annrheumdis-2014-205897.long
Vettori S, Cuomo G, Abignano G, Iudici M, Valentini G (2011) Survival and death causes in 251 systemic sclerosis patients from a single Italian center. Reumatismo 62(3):202–9. http://www.reumatismo.org/index.php/reuma/article/view/482
Morisset J, Vittinghoff E, Elicker BM, Hu X, Le S, Ryu JH et al (2017) Mortality risk prediction in scleroderma-related interstitial lung disease: the SADL model. Chest. http://linkinghub.elsevier.com/retrieve/pii/S0012369217310784
Acknowledgements
We gratefully acknowledge all investigators who form part of the RESCLE Registry. This project was possible thanks to an educational unrestricted scholarship granted by Laboratorios Actelion. We also thank the RESCLE Registry Coordinating Center, S & H Medical Science Service, for their quality control data, logistic and administrative support and Prof. Salvador Ortiz, Universidad Autónoma de Madrid and Statistical Advisor S& H Medical Science Service for the statistical analysis of the data presented in this paper
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DSC, CPSA: Substantial contributions to study conception and design. DSC, CPSA, NOC, JLC, VFP, RRF, CTV, GEG, DCA, MVEA, MRR, MF, JJRB, LTM, MRC, AMB, XPS: Substantial contributions to acquisition of data. DSC, CPSA: Substantial contributions to analysis and interpretation of data. DSC, CPSA, NOC: Drafting the article or revising it critically for important intellectual content. DSC, CPSA, VFP, CTV: Final approval of the version of the article to be published. Other critical study activities (specify).
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Hospital | Reference, file number or approval date |
---|---|
Hospital Universitario Vall d´Hebron (Barcelona) | 30/11/2010 |
Corporación Sanitaria Universitaria Parc Taulí (Barcelona) | 2011518 |
Hospital Universitario Cruces (Bizkaia) | 3/11 |
Hospital Universitario San Cecilio (Granada) | 21/01/2011 |
Hospital Universitario Virgen del Rocio (Sevilla) | 3/11 |
Hospital Universitario Miguel Servet (Zaragoza) | 19/2011 |
Hospital Universitario Clínic (Barcelona) | 2011/6413 |
Hospital Universitario Central de Asturias | 09/2011 |
Hospital Universitario La Paz (Madrid) | 3/2011 |
Hospital Campus de la Salud. Complejo Universitario de Granada | 01/10/2012 |
Hospital Universitario y Politécnico La Fe (Valencia) | 2013/0152 |
Hospital Universitario de Bellvitge (Barcelona) | 09/13 |
Hospital Mutua Terrassa (Barcelona) | 28/03/2012 |
Hospital Universitario Nuestra Señora de la Candelaria (Santa Cruz de Tenerife) | 02/02/2012 |
Complejo Hospitalario Universitario de Vigo (Pontevedra) | 2012/046 |
Hospital de Manises (Valencia) | 25/05/2011 |
Hospital de Cabueñes (Asturias) | 24/2013 |
Hospital Vega Baja de Orihuela (Alicante) | 20/12/2011 |
Hospital Monte San Isidro (León) | 24/01/2012 |
Hospital Clínico Universitario “Lozano Blesa” (Zaragoza) | CP15/2013 |
Hospital d’Igualada (Barcelona) | 13/14 |
Hospital Universitari Sant Joan de Reus (Tarragona) | 13-11-28/11proj2 |
Complexo Hospitalario Universitario de Ferrol (A Coruña) | 01/12/2014 |
Hospital Universitario Fundación Alcorcón (Madrid) | 02/12/2014 |
Hospital Universitario Reina Sofía (Córdoba) | 235/2691 |
Consorci Hospitalari de Vic (Barcelona) | 2014869 |
Hospital General San Jorge (Huesca) | 06/2015 |
Complejo Asistencial Universitario de Salamanca | 01/12/2015 |
Hospital Universitario Rey Juan Carlos (Madrid) | 17/15 |
Hospital Universitario Ramón y Cajal (Madrid) | 25/09/2017 |
Hospital de Sagunto (Valencia) | 26/04/2017 |
Hospital Universitario Virgen de Valme (Sevilla) | 0572-N-17 |
Appendix: RESCLE Registry members
Appendix: RESCLE Registry members
Callejas JL, Castillo MJ, Colunga D, Egurbide MV, de Escalante B, Espinosa G, Fonollosa V, Freire M, Guillén A, Iniesta N, Marí B, Marín A, Márquez-Fernández V, Ortego-Centeno N, Pla X, Ríos-Blanco JJ, Ríos-Fernández R, Rivera A, Robles A, Rodero MM, Rodríguez-Carballeira M, Rubio M, Sánchez-Cano D, Simeón CP, Soto A, Todolí JA, Tolosa C, Trapiella L, Vargas JA.
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Sánchez-Cano, D., Ortego-Centeno, N., Callejas, J.L. et al. Interstitial lung disease in systemic sclerosis: data from the spanish scleroderma study group. Rheumatol Int 38, 363–374 (2018). https://doi.org/10.1007/s00296-017-3916-x
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DOI: https://doi.org/10.1007/s00296-017-3916-x