A proportion of patients with certain types of interstitial lung disease (ILD), including chronic hypersensitivity pneumonitis and ILDs associated with autoimmune diseases, develop a progressive fibrosing phenotype that shows similarities in clinical course to idiopathic pulmonary fibrosis. Irrespective of the clinical diagnosis, these progressive fibrosing ILDs show commonalities in the underlying pathogenetic mechanisms that drive a self-sustaining process of pulmonary fibrosis. The natural history of progressive fibrosing ILDs is characterized by decline in lung function, worsening of symptoms and health-related quality of life, and early mortality. Greater impairment in forced vital capacity or diffusion capacity of the lungs for carbon monoxide, and a greater extent of fibrotic changes on a computed tomography scan, are predictors of mortality in patients with fibrosing ILDs. However, the course of these diseases is heterogenous and cannot accurately be predicted for an individual patient. Data from ongoing clinical trials and patient registries will provide a better understanding of the clinical course and impact of progressive fibrosing ILDs.

Department of Respiratory Medicine Thomayer Hospital Videnska 800 14059 Prague Czech Republic

McMaster University and St Joseph's Healthcare 50 Charlton Avenue East Hamilton Ontario L8N 4A6 Canada

Zobrazit více v PubMed

Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, et al. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198(5):e44–e68. PubMed

Wells AU, Brown KK, Flaherty KR, Kolb M, Thannickal VJ; IPF Consensus Working Group. What's in a name? That which we call IPF, by any other name would act the same. Eur Respir J 2018;51(5) pii: 1800692. PubMed

Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med. 2018;378:1811–1823. PubMed

Zamora-Legoff JA, Krause ML, Crowson CS, Ryu JH, Matteson EL. Progressive decline of lung function in rheumatoid arthritis-associated interstitial lung disease. Arthritis Rheumatol. 2017;69(3):542–549. PubMed PMC

Winstone TA, Assayag D, Wilcox PG, Dunne JV, Hague CJ, Leipsic J, et al. Predictors of mortality and progression in scleroderma-associated interstitial lung disease: a systematic review. Chest. 2014;146(2):422–436. PubMed

Marie I, Hatron PY, Dominique S, Cherin P, Mouthon L, Menard JF. Short-term and long-term outcomes of interstitial lung disease in polymyositis and dermatomyositis: a series of 107 patients. Arthritis Rheum. 2011;63(11):3439–3447. PubMed

Spagnolo P, Rossi G, Trisolini R, Sverzellati N, Baughman RP, Wells AU. Pulmonary sarcoidosis. Lancet Respir Med. 2018;6(5):389–402. PubMed

Wang P, Jones KD, Urisman A, Elicker BM, Urbania T, Johannson KA, et al. Pathologic findings and prognosis in a large prospective cohort of chronic hypersensitivity pneumonitis. Chest. 2017;152(3):502–509. PubMed

Belloli EA, Beckford R, Hadley R, Flaherty KR. Idiopathic non-specific interstitial pneumonia. Respirology. 2016;21(2):259–268. PubMed

Hyldgaard C, Hilberg O, Pedersen AB, Ulrichsen SP, Løkke A, Bendstrup E, et al. A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease: comorbidity and mortality. Ann Rheum Dis. 2017;76(10):1700–1706. PubMed

Wijsenbeek M, Kreuter M, Fischer A, Mounir B, Zouad-Lejour L, Wells CD, et al. Non-IPF progressive fibrosing interstitial lung disease (PF-ILD): the patient journey. Am J Respir Crit Care Med. 2018;197:A167.

Olson AL, Gifford AH, Inase N, Fernández Pérez ER, Suda T. The epidemiology of idiopathic pulmonary fibrosis and interstitial lung diseases at risk of a progressive-fibrosing phenotype. Eur Respir Rev. 2018;27(150). pii: 180077. PubMed PMC

O'Reilly S, Hügle T, van Laar JM. T cells in systemic sclerosis: a reappraisal. Rheumatology. 2012;51(9):1540–1549. PubMed

Vašáková M, Poletti V. Fibrosing interstitial lung diseases involve different pathogenic pathways with similar outcomes. Sarcoidosis Vasc Diffuse Lung Dis. 2015;32(3):246–250. PubMed

Strieter RM, Mehrad B. New mechanisms of pulmonary fibrosis. Chest. 2009;136(5):1364–1370. PubMed PMC

Maher TM, Wells AU, Laurent GJ. Idiopathic pulmonary fibrosis: multiple causes and multiple mechanisms? Eur Respir J. 2007;30(5):835–839. PubMed

Altorok N, Wang Y, Kahaleh B. Endothelial dysfunction in systemic sclerosis. Curr Opin Rheumatol. 2014;26(6):615–620. PubMed

Bagnato G, Harari S. Cellular interactions in the pathogenesis of interstitial lung diseases. Eur Respir Rev. 2015;24(135):102–114. PubMed PMC

Andersson-Sjöland A, de Alba CG, Nihlberg K, Becerril C, Ramírez R, Pardo A, et al. Fibrocytes are a potential source of lung fibroblasts in idiopathic pulmonary fibrosis. Int J Biochem Cell Biol. 2008;40(10):2129–2140. PubMed

Willis BC, du Bois RM, Borok Z. Epithelial origin of myofibroblasts during fibrosis in the lung. Proc Am Thorac Soc. 2006;3(4):377–382. PubMed PMC

Hung C, Linn G, Chow YH, Kobayashi A, Mittelsteadt K, Altemeier WA, et al. Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med. 2013;188(7):820–830. PubMed PMC

Fernandez IE, Eickelberg O. New cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis. Lancet. 2012;380(9842):680–688. PubMed

Huang X, Yang N, Fiore VF, Barker TH, Sun Y, Morris SW, et al. Matrix stiffness-induced myofibroblast differentiation is mediated by intrinsic mechanotransduction. Am J Respir Cell Mol Biol. 2012;47(3):340–348. PubMed PMC

Froese AR, Shimbori C, Bellaye PS, Inman M, Obex S, Fatima S, et al. Stretch-induced activation of transforming growth factor-β1 in pulmonary fibrosis. Am J Respir Crit Care Med. 2016;194(1):84–96. PubMed

Baron M, Sutton E, Hudson M, Thombs B, Markland J, Pope J, et al. The relationship of dyspnoea to function and quality of life in systemic sclerosis. Ann Rheum Dis. 2008;67(5):644–650. PubMed

Kreuter M, Swigris J, Pittrow D, Geier S, Klotsche J, Prasse A, et al. Health related quality of life in patients with idiopathic pulmonary fibrosis in clinical practice: INSIGHTS-IPF registry. Respir Res. 2017;18(1):139. PubMed PMC

Kreuter M, Stansen W, Stowasser S, Schoof N. Impact of lung function decline on health-related quality of life in patients with idiopathic pulmonary fibrosis (IPF). Am J Respir Crit Care Med. 2018;197:A1604. Poster available at: http://ILDPosters2018.com/pdf/ATS_FVCandHRQL_Kreuter.pdf.

Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006;354(25):2655–2666. PubMed

Walker UA, Tyndall A, Czirják L, Denton C, Farge-Bancel D, Kowal-Bielecka O, et al. Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR scleroderma trials and research group database. Ann Rheum Dis. 2007;66(6):754–763. PubMed PMC

Jaeger VK, Wirz EG, Allanore Y, Rossbach P, Riemekasten G, Hachulla E, et al. Incidences and risk factors of organ manifestations in the early course of systemic sclerosis: a longitudinal EUSTAR study. PLoS One. 2016;11(10):e0163894. PubMed PMC

Guler SA, Winstone TA, Murphy D, Hague C, Soon J, Sulaiman N, et al. Does systemic sclerosis-associated interstitial lung disease burn out? Specific phenotypes of disease progression. Ann Am Thorac Soc. 2018;15(12):1427–1433. PubMed

Vašáková M, Morell F, Walsh S, Leslie K, Raghu G. Hypersensitivity pneumonitis: perspectives in diagnosis and management. Am J Respir Crit Care Med. 2017;196(6):680–689. PubMed

Salisbury ML, Gu T, Murray S, Gross BH, Chughtai A, Sayyouh M, et al. Hypersensitivity pneumonitis: radiologic phenotypes are associated with distinct survival time and pulmonary function trajectory. Chest. 2018. 10.1016/j.chest.2018.08.1076 epub ahead of print. PubMed PMC

Adegunsoye A, Oldham JM, Chung JH, Montner SM, Lee C, Witt LJ, et al. Phenotypic clusters predict outcomes in a longitudinal interstitial lung disease cohort. Chest. 2018;153(2):349–360. PubMed PMC

Nardi A, Brillet PY, Letoumelin P, Girard F, Brauner M, Uzunhan Y, et al. Stage IV sarcoidosis: comparison of survival with the general population and causes of death. Eur Respir J. 2011;38(6):1368–1373. PubMed

Travis WD, Hunninghake G, King TE, Jr, Lynch DA, Colby TV, Galvin JR, et al. Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project. Am J Respir Crit Care Med. 2008;177(12):1338–1347. PubMed

Collard HR, Ryerson CJ, Corte TJ, Jenkins G, Kondoh Y, Lederer DJ, et al. Acute exacerbation of idiopathic pulmonary fibrosis. An international working group report. Am J Respir Crit Care Med. 2016;194(3):265–275. PubMed

Song JW, Lee HK, Lee CK, Chae EJ, Jang SJ, Colby TV, et al. Clinical course and outcome of rheumatoid arthritis-related usual interstitial pneumonia. Sarcoidosis Vasc Diffuse Lung Dis. 2013;30(2):103–112. PubMed

Hozumi H, Nakamura Y, Johkoh T, Sumikawa H, Colby TV, Kono M, et al. Acute exacerbation in rheumatoid arthritis-associated interstitial lung disease: a retrospective case control study. BMJ Open. 2013;3(9):e003132. PubMed PMC

Tomiyama F, Watanabe R, Ishii T, Kamogawa Y, Fujita Y, Shirota Y, et al. High prevalence of acute exacerbation of interstitial lung disease in Japanese patients with systemic sclerosis. Tohoku J Exp Med. 2016;239(4):297–230. PubMed

Okamoto M, Fujimoto K, Sadohara J, Furuya K, Kaieda S, Miyamura T, et al. A retrospective cohort study of outcome in systemic sclerosis-associated interstitial lung disease. Respir Investig. 2016;54(6):445–453. PubMed

Miyazaki Y, Tateishi T, Akashi T, Ohtani Y, Inase N, Yoshizawa Y. Clinical predictors and histologic appearance of acute exacerbations in chronic hypersensitivity pneumonitis. Chest. 2008;134(6):1265–1270. PubMed

Raghu G, Chen SY, Yeh WS, Maroni B, Li Q, Lee YC, et al. Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001-11. Lancet Respir Med. 2014;2(7):566–572. PubMed

Strongman H, Kausar I, Maher TM. Incidence, prevalence, and survival of patients with idiopathic pulmonary fibrosis in the UK. Adv Ther. 2018;35(5):724–736. PubMed PMC

Ryerson CJ, Kolb M. The increasing mortality of idiopathic pulmonary fibrosis: fact or fallacy? Eur Respir J 2018;51(1). pii: 1702420. PubMed

Elhai M, Meune C, Boubaya M, Avouac J, Hachulla E, Balbir-Gurman A, et al. Mapping and predicting mortality from systemic sclerosis. Ann Rheum Dis. 2017;76(11):1897–1905. PubMed

Bongartz T, Nannini C, Medina-Velasquez YF, Achenbach SJ, Crowson CS, Ryu JH, et al. Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study. Arthritis Rheum. 2010;62(6):1583–1591. PubMed PMC

Kim EJ, Elicker BM, Maldonado F, Webb WR, Ryu JH, Van Uden JH, et al. Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J. 2010;35(6):1322–1328. PubMed

Solomon JJ, Chung JH, Cosgrove GP, Demoruelle MK, Fernandez-Perez ER, Fischer A, et al. Predictors of mortality in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J. 2016;47(2):588–596. PubMed

Fischer A, Antoniou KM, Brown KK, Cadranel J, Corte TJ, du Bois RM, et al. An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur Respir J. 2015;46(4):976–987. PubMed

Oldham JM, Adegunsoye A, Valenzi E, Lee C, Witt L, Chen L, et al. Characterisation of patients with interstitial pneumonia with autoimmune features. Eur Respir J. 2016;47(6):1767–1775. PubMed PMC

Fernández Pérez ER, Kong AM, Raimundo K, Koelsch TL, Kulkarni R, Cole AL. Epidemiology of hypersensitivity pneumonitis among an insured population in the United States: a claims-based cohort analysis. Ann Am Thorac Soc. 2018;15(4):460–469. PubMed

Park IN, Jegal Y, Kim DS, Do KH, Yoo B, Shim TS, et al. Clinical course and lung function change of idiopathic nonspecific interstitial pneumonia. Eur Respir J. 2009;33(1):68–76. PubMed

Guler SA, Ellison K, Algamdi M, Collard HR, Ryerson CJ. Heterogeneity in unclassifiable interstitial lung disease. A systematic review and meta-analysis. Ann Am Thorac Soc. 2018;15(7):854–863. PubMed

Paterniti MO, Bi Y, Rekić D, Wang Y, Karimi-Shah BA, Chowdhury BA. Acute exacerbation and decline in forced vital capacity are associated with increased mortality in idiopathic pulmonary fibrosis. Ann Am Thorac Soc. 2017;14(9):1395–1402. PubMed

Jo HE, Glaspole I, Grainge C, Goh N, Hopkins PMA, Moodley Y, et al. Baseline characteristics of idiopathic pulmonary fibrosis: analysis from the Australian Idiopathic Pulmonary Fibrosis Registry. Eur Respir J 2017;49. pii: 1601592. PubMed

Snyder L, Neely ML, Hellkamp AS, O’Brien E, de Andrade J, Conoscenti CS, et al. Predictors of death or lung transplant after a diagnosis of idiopathic pulmonary fibrosis: insights from the IPF-PRO registry. Respir Res. in press. PubMed PMC

Goh NS, Desai SR, Veeraraghavan S, Hansell DM, Copley SJ, Maher TM, et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med. 2008;177(11):1248–1254. PubMed

Sánchez-Cano D, Ortego-Centeno N, Callejas JL, Fonollosa Plá V, Ríos-Fernández R, Tolosa-Vilella C, et al. Interstitial lung disease in systemic sclerosis: data from the Spanish scleroderma study group. Rheumatol Int. 2018;38(3):363–374. PubMed

Doubková M, Švancara J, Svoboda M, Šterclová M, Bartoš V, Plačková M, et al. EMPIRE registry, Czech part: impact of demographics, pulmonary function and HRCT on survival and clinical course in idiopathic pulmonary fibrosis. Clin Respir J. 2018;12(4):1526–1535. PubMed

Mooney JJ, Elicker BM, Urbania TH, Agarwal MR, Ryerson CJ, Nguyen MLT, et al. Radiographic fibrosis score predicts survival in hypersensitivity pneumonitis. Chest. 2013;144(2):586–592. PubMed

Gimenez A, Storrer K, Kuranishi L, Soares MR, Ferreira RG, Pereira CAC. Change in FVC and survival in chronic fibrotic hypersensitivity pneumonitis. Thorax. 2017;73(4):391–392. PubMed

Ryerson CJ, Urbania TH, Richeldi L, Mooney JJ, Lee JS, Jones KD, et al. Prevalence and prognosis of unclassifiable interstitial lung disease. Eur Respir J. 2013;42(3):750–757. PubMed

Tyndall AJ, Bannert B, Vonk M, Airò P, Cozzi F, Carreira PE, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR scleroderma trials and research (EUSTAR) database. Ann Rheum Dis. 2010;69(10):1809–1815. PubMed

Goh NS, Hoyles RK, Denton CP, Hansell DM, Renzoni EA, Maher TM, et al. Short-term pulmonary function trends are predictive of mortality in interstitial lung disease associated with systemic sclerosis. Arthritis Rheumatol. 2017;69(8):1670–1678. PubMed

Zappala CJ, Latsi PI, Nicholson AG, Colby TV, Cramer D, Renzoni EA, et al. Marginal decline in forced vital capacity is associated with a poor outcome in idiopathic pulmonary fibrosis. Eur Respir J. 2010;35(4):830–836. PubMed

du Bois RM, Weycker D, Albera C, Bradford WZ, Costabel U, Kartashov A, et al. Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and minimal clinically important difference. Am J Respir Crit Care Med. 2011;184(12):1382–1389. PubMed

Reichmann WM, Yu YF, Macaulay D, Wu EQ, Nathan SD. Change in forced vital capacity and associated subsequent outcomes in patients with newly diagnosed idiopathic pulmonary fibrosis. BMC Pulm Med. 2015;15:167. PubMed PMC

Ley B, Ryerson CJ, Vittinghoff E, Ryu JH, Tomassetti S, Lee JS, et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med. 2012;156(10):684–691. PubMed

Morisset J, Vittinghoff E, Lee BY, Tonelli R, Hu X, Elicker BM, et al. The performance of the GAP model in patients with rheumatoid arthritis associated interstitial lung disease. Respir Med. 2017;127:51–56. PubMed PMC

Mango RL, Matteson EL, Crowson CS, Ryu JH, Makol A. Assessing mortality models in systemic sclerosis-related interstitial lung disease. Lung. 2018;196(4):409–416. PubMed

Hyldgaard C, Bendstrup E, Wells AU, Hilberg O. Unclassifiable interstitial lung diseases: clinical characteristics and survival. Respirology. 2017;22(3):494–500. PubMed

Ryerson CJ, Vittinghoff E, Ley B, Lee JS, Mooney JJ, Jones KD, et al. Predicting survival across chronic interstitial lung disease: the ILD-GAP model. Chest. 2014;145(4):723–728. PubMed

Morisset J, Vittinghoff E, Elicker BM, Hu X, Le S, Ryu JH, et al. Mortality risk prediction in scleroderma-related interstitial lung disease: the SADL model. Chest. 2017;152(5):999–1007. PubMed PMC

Wu W, Jordan S, Becker MO, Dobrota R, Maurer B, Fretheim H, et al. Prediction of progression of interstitial lung disease in patients with systemic sclerosis: the SPAR model. Ann Rheum Dis. 2018;77(9):1326–1332. PubMed

Lynch DA, Godwin JD, Safrin S, Starko KM, Hormel P, Brown KK, et al. High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care Med. 2005;172(4):488–493. PubMed

Kelly CA, Saravanan V, Nisar M, Arthanari S, Woodhead FA, Price-Forbes AN, et al. Rheumatoid arthritis-related interstitial lung disease: associations, prognostic factors and physiological and radiological characteristics--a large multicentre UK study. Rheumatology (Oxford) 2014;53(9):1676–1682. PubMed

Walsh SL, Sverzellati N, Devaraj A, Wells AU, Hansell DM. Chronic hypersensitivity pneumonitis: high resolution computed tomography patterns and pulmonary function indices as prognostic determinants. Eur Radiol. 2012;22(8):1672–1679. PubMed

Walsh SL, Wells AU, Sverzellati N, Keir GJ, Calandriello L, Antoniou KM, et al. An integrated clinicoradiological staging system for pulmonary sarcoidosis: a case-cohort study. Lancet Respir Med. 2014;2(2):123–130. PubMed

Lee SM, Seo JB, Oh SY, Kim TH, Song JW, Lee SM, et al. Prediction of survival by texture-based automated quantitative assessment of regional disease patterns on CT in idiopathic pulmonary fibrosis. Eur Radiol. 2018;28(3):1293–1300. PubMed

Walsh SLF. Imaging biomarkers and staging in IPF. Curr Opin Pulm Med. 2018;24(5):445–452. PubMed

Yokoyama A, Kondo K, Nakajima M, Matsushima T, Takahashi T, Nishimura M, et al. Prognostic value of circulating KL-6 in idiopathic pulmonary fibrosis. Respirology. 2006;11(2):164–168. PubMed

Lee YS, Kim HC, Lee BY, Lee CK, Kim MY, Jang SJ, et al. The value of biomarkers as predictors of outcome in patients with rheumatoid arthritis-associated usual interstitial pneumonia. Sarcoidosis Vasc Diffuse Lung Dis. 2016;33(3):216–223. PubMed

Yamakawa H, Hagiwara E, Kitamura H, Yamanaka Y, Ikeda S, Sekine A, et al. Serum KL-6 and surfactant protein-D as monitoring and predictive markers of interstitial lung disease in patients with systemic sclerosis and mixed connective tissue disease. J Thorac Dis. 2017;9(2):362–371. PubMed PMC

Jiang Y, Luo Q, Han Q, Huang J, Ou Y, Chen M, et al. Sequential changes of serum KL-6 predict the progression of interstitial lung disease. J Thorac Dis. 2018;10(8):4705–4714. PubMed PMC

Kennedy B, Branagan P, Moloney F, Haroon M, O'Connell OJ, O'Connor TM, et al. Biomarkers to identify ILD and predict lung function decline in scleroderma lung disease or idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis. 2015;32(3):228–236. PubMed

Maher TM, Oballa E, Simpson JK, Porte J, Habgood A, Fahy WA, et al. An epithelial biomarker signature for idiopathic pulmonary fibrosis: an analysis from the multicentre PROFILE cohort study. Lancet Respir Med. 2017;5(12):946–955. PubMed

Rosas IO, Richards TJ, Konishi K, Zhang Y, Gibson K, Lokshin AE, et al. MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS Med. 2008;5(4):e93. PubMed PMC

Richards TJ, Kaminski N, Baribaud F, Flavin S, Brodmerkel C, Horowitz D, et al. Peripheral blood proteins predict mortality in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012;185(1):67–76. PubMed PMC

Bauer Y, White ES, de Bernard S, Cornelisse P, Leconte I, Morganti A, et al. MMP-7 is a predictive biomarker of disease progression in patients with idiopathic pulmonary fibrosis. ERJ Open Res 2017;3(1). pii: 00074–2016. PubMed PMC

Todd J, Vinisko R, Neely ML, Overton R, Flaherty KR, Noth I, et al. Peripheral blood matrix metalloproteinase profiling in the multicenter IPF-PRO Registry cohort. Poster presented at the 10th International Colloquium on Lung and Airway Fibrosis (ICLAF), September 2018. Available at http://uspubs-posters.com/iclaf2018/todd.

Jenkins RG, Simpson JK, Saini G, Bentley JH, Russell AM, Braybrooke R, et al. Longitudinal change in collagen degradation biomarkers in idiopathic pulmonary fibrosis: an analysis from the prospective, multicentre PROFILE study. Lancet Respir Med. 2015;3(6):462–472. PubMed

Maher TM, Stowasser S, Nishioka Y, White ES, Cottin V, Noth I, et al. Investigating the effects of nintedanib on biomarkers of extracellular matrix turnover in patients with IPF: design of the randomised placebo-controlled INMARK trial. BMJ Open Resp Res. 2018;5(1):e000325. PubMed PMC

Peljto AL, Zhang Y, Fingerlin TE, Ma SF, Garcia JG, Richards TJ, et al. Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis. JAMA. 2013;309(21):2232–2239. PubMed PMC

Noth I, Zhang Y, Ma SF, Flores C, Barber M, Huang Y, et al. Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study. Lancet Respir Med. 2013;1(4):309–317. PubMed PMC

Ley B, Newton CA, Arnould I, Elicker BM, Henry TS, Vittinghoff E, et al. The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study. Lancet Respir Med. 2017;5(8):639–647. PubMed PMC

Newton CA, Oldham JM, Ley B, Anand V, Adegunsoye A, Liu G, et al. Telomere length and genetic variant associations with interstitial lung disease progression and survival. Eur Respir J 2019. pii: 1801641 doi: 10.1183/13993003.01641-2018 [Epub ahead of print]. PubMed PMC

Juge PA, Lee JS, Ebstein E, Furukawa H, Dobrinskikh E, Gazal S, et al. MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease. N Engl J Med. 2018;379(23):2209–2219. PubMed PMC

Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356(13):1317–1326. PubMed

Stuart BD, Lee JS, Kozlitina J, Noth I, Devine MS, Glazer CS, et al. Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis: an observational cohort study with independent validation. Lancet Respir Med. 2014;2(7):557–565. PubMed PMC

Dai J, Cai H, Li H, Zhuang Y, Min H, Wen Y, et al. Association between telomere length and survival in patients with idiopathic pulmonary fibrosis. Respirology. 2015;20(6):947–52. PubMed

Juge PA, Borie R, Kannengiesser C, Gazal S, Revy P, Wemeau-Stervinou L, et al. Shared genetic predisposition in rheumatoid arthritis-interstitial lung disease and familial pulmonary fibrosis. Eur Respir J. 2017:49(5). 10.1183/13993003.02314-2016. PubMed

Mak AC, Tang PL, Cleveland C, Smith MH, Kari Connolly M, Katsumoto TR, et al. Brief report: whole-exome sequencing for identification of potential causal variants for diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 2016;68(9):2257–2262. PubMed PMC

Raghu G. Idiopathic pulmonary fibrosis: lessons from clinical trials over the past 25 years. Eur Respir J. 2017;50(4). 10.1183/13993003.01209-2017. PubMed

Flaherty KR, Brown KK, Well AU, Clerisme-Beaty E, Collard HR, Cottin V, et al. Design of the PF-ILD trial: a double-blind, randomised, placebo-controlled phase III trial of nintedanib in patients with progressive fibrosing interstitial lung disease. BMJ Open Resp Res. 2017;4:e000212. PubMed PMC

Distler O, Brown KK, Distler JHW, Assassi S, Maher TM, Cottin V, et al. Design of a randomised, placebo-controlled clinical trial of nintedanib in patients with systemic sclerosis-associated interstitial lung disease (SENSCIS). Clin Exp Rheumatol. 2017;35 Suppl 106(4):75–81. PubMed

Saunders P, Tsipouri V, Keir GJ, Ashby D, Flather MD, Parfrey H, et al. Rituximab versus cyclophosphamide for the treatment of connective tissue disease-associated interstitial lung disease (RECITAL): study protocol for a randomised controlled trial. Trials. 2017;18(1):275. PubMed PMC

Maher TM, Corte TJ, Fischer A, Kreuter M, Lederer DJ, Molina-Molina M, et al. Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: design of a double-blind, randomised, placebo-controlled phase II trial. BMJ Open Resp Res. 2018;5(1):e000289. PubMed PMC

Pulmonary Fibrosis Foundation: PFF Patient Registry. https://www.pulmonaryfibrosis.org/medical-community/pff-patient-registry (2016). Accessed 24 October 2018.

O'Brien EC, Durheim MT, Gamerman V, Garfinkel S, Anstrom KJ, Palmer SM, et al. Rationale for and design of the Idiopathic Pulmonary Fibrosis-PRospective Outcomes (IPF-PRO) Registry. BMJ Open Resp Res. 2016;3(1):e000108. PubMed PMC

Ryerson CJ, Tan B, Fell CD, Manganas H, Shapera S, Mittoo S, et al. The Canadian Registry for Pulmonary Fibrosis: design and rationale of a national pulmonary fibrosis registry. Can Respir J. 2016;2016:3562923. PubMed PMC

Behr J, Hoeper MM, Kreuter M, Klotsche J, Wirtz H, Pittrow D. Investigating significant health trends in idiopathic pulmonary fibrosis (INSIGHTS-IPF): rationale, aims and design of a nationwide prospective registry. BMJ Open Respir Res. 2014;1(1):e000010. PubMed PMC

Kreuter M, Herth FJF, Wacker M, Leidl R, Hellmann A, Pfeifer M, et al. Exploring clinical and epidemiological characteristics of interstitial lung diseases: rationale, aims, and design of a nationwide prospective registry—the EXCITING-ILD registry. Biomed Res Int. 2015;2015:123876. PubMed PMC

Schwarzkopf L, Witt S, Waelscher J, Polke M, Kreuter M. Associations between comorbidities, their treatment and survival in patients with interstitial lung diseases - a claims data analysis. Respir Res. 2018;19(1):73. PubMed PMC