Fibrosing interstitial lung diseases: knowns and unknowns

Vincent Cottin, Lutz Wollin, Aryeh Fischer, Manuel Quaresma, Susanne Stowasser, Sergio Harari, Vincent Cottin, Lutz Wollin, Aryeh Fischer, Manuel Quaresma, Susanne Stowasser, Sergio Harari

Abstract

Patients with certain types of fibrosing interstitial lung disease (ILD) are at risk of developing a progressive phenotype characterised by self-sustaining fibrosis, decline in lung function, worsening quality of life, and early mortality. It has been proposed that such progressive fibrosing ILDs, which show commonalities in clinical behaviour and in the pathogenetic mechanisms that drive progressive fibrosis, may be "lumped" together for the purposes of clinical research and, potentially, for treatment. At present, no drugs are approved for the treatment of ILDs other than nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis. For other progressive fibrosing ILDs, the mainstay of drug therapy is immunosuppression. However, it is postulated that, once the response to lung injury in fibrosing ILDs has reached the stage at which fibrosis has become progressive and self-sustaining, targeted antifibrotic therapy would be required to slow disease progression. Nintedanib, an intracellular inhibitor of tyrosine kinases, has shown antifibrotic, anti-inflammatory and vascular remodelling effects in several non-clinical models of fibrosis, irrespective of the trigger for the injury. Ongoing clinical trials will provide insight into the role of antifibrotic treatment with nintedanib or pirfenidone in the management of fibrosing ILDs with a progressive phenotype.

Conflict of interest statement

Conflict of interest: V. Cottin reports personal fees from Actelion (for consultancy, lectures and travel to medical meetings), Boehringer Ingelheim (for development of educational presentations, consultancy, lectures and travel to medical meetings), Bayer (for consultancy), Gilead (as a member of an adjudication committee), MSD (for consultancy and travel to medical meetings), Novartis (for consultancy and lectures), Roche (for consultancy, lectures and travel to medical meetings), Sanofi (for consultancy and lectures), Promedior (as chair of the Data and Safety Monitoring Board (DSMB)), Celgene (for the DSMB) and Galapagos (for consultancy and as chair of the DSMB), as well as grants from Boehringer Ingelheim and Roche to his institution, all outside the submitted work. Conflict of interest: L. Wollin is an employee of Boehringer Ingelheim International GmbH. Conflict of interest: A. Fischer reports grants and consultancy fees from Boehringer Ingelheim, and consultancy fees from F. Hoffman La Roche, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer and Genentech, during the conduct of the study. Conflict of interest: M. Quaresma is an employee of Boehringer Ingelheim International GmbH. Conflict of interest: S. Stowasser is an employee of Boehringer Ingelheim International GmbH. Conflict of interest: S. Harari reports grants and personal fees from Roche, Actelion and Boehringer Ingelheim, outside the submitted work. In addition to being investigator in trials involving these companies, relationships include lectures and membership of scientific advisory boards, and grants for research.

Copyright ©ERS 2019.

Figures

FIGURE 1
FIGURE 1
Types of interstitial lung disease (ILD) that may be associated with a progressive fibrosing phenotype. HP: hypersensitivity pneumonitis; IPF: idiopathic pulmonary fibrosis; IIPs: idiopathic interstitial pneumonias.
FIGURE 2
FIGURE 2
Knowns and unknowns in progressive fibrosing interstitial lung diseases (ILDs).

References

    1. Travis WD, Costabel U, Hansell DM, et al. . An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013; 188: 733–748.
    1. Raghu G, Collard HR, Egan JJ, et al. . An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183: 788–824.
    1. Belloli EA, Beckford R, Hadley R, et al. . Idiopathic non-specific interstitial pneumonia. Respirology 2016; 21: 259–268.
    1. Hyldgaard C, Bendstrup E, Wells AU, et al. . Unclassifiable interstitial lung diseases: clinical characteristics and survival. Respirology 2017; 22: 494–500.
    1. Fischer A, Chartrand S. Assessment and management of connective tissue disease-associated interstitial lung disease. Sarcoidosis Vasc Diffuse Lung Dis 2015; 32: 2–21.
    1. Patterson KC, Strek ME. Pulmonary fibrosis in sarcoidosis. Clinical features and outcomes. Ann Am Thorac Soc 2013; 10: 362–370.
    1. Fernández Pérez ER, Swigris JJ, Forssén AV, et al. . Identifying an inciting antigen is associated with improved survival in patients with chronic hypersensitivity pneumonitis. Chest 2013; 144: 1644–1651.
    1. Khalil N, Churg A, Muller N, et al. . Environmental, inhaled and ingested causes of pulmonary fibrosis. Toxicol Pathol 2007; 35: 86–96.
    1. Flaherty KR, Brown KK, Wells AU, 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 Respir Res 2017; 4: e000212.
    1. Wells AU, Brown KK, Flaherty KR, et al. . What's in a name? That which we call IPF, by any other name would act the same. Eur Respir J 2018; 51: 1800692.
    1. du Bois RM, Weycker D, Albera C, 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: 1382–1389.
    1. Paterniti MO, Bi Y, Rekić D, et al. . Acute exacerbation and decline in forced vital capacity are associated with increased mortality in idiopathic pulmonary fibrosis. Ann Am Thorac Soc 2017; 14: 1395–1402.
    1. Collard HR, Ryerson CJ, Corte TJ, et al. . Acute exacerbation of idiopathic pulmonary fibrosis. An international working group report. Am J Respir Crit Care Med 2016; 194: 265–275.
    1. Natsuizaka M, Chiba H, Kuronuma K, et al. . Epidemiologic survey of Japanese patients with idiopathic pulmonary fibrosis and investigation of ethnic differences. Am J Respir Crit Care Med 2014; 190: 773–779.
    1. Hook JL, Arcasoy SM, Zemmel D, et al. . Titrated oxygen requirement and prognostication in idiopathic pulmonary fibrosis. Eur Respir J 2012; 39: 359–365.
    1. Sharp C, Adamali HI, Millar AB. A comparison of published multidimensional indices to predict outcome in idiopathic pulmonary fibrosis. ERJ Open Res 2017; 3: 00096-2016.
    1. Schmidt SL, Tayob N, Han MK, et al. . Predicting pulmonary fibrosis disease course from past trends in pulmonary function. Chest 2014; 145: 579–585.
    1. Nathan SD, Albera C, Bradford WZ, et al. . Effect of continued treatment with pirfenidone following clinically meaningful declines in forced vital capacity: analysis of data from three phase 3 trials in patients with idiopathic pulmonary fibrosis. Thorax 2016; 71: 429–435.
    1. Russell AM, Adamali H, Molyneaux PL, et al. . Daily home spirometry: an effective tool for detecting progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2016; 194: 989–997.
    1. Johannson KA, Vittinghoff E, Morisset J, et al. . Home monitoring improves endpoint efficiency in idiopathic pulmonary fibrosis. Eur Respir J 2017; 50: 1602406.
    1. Maher TM. Beyond the diagnosis of idiopathic pulmonary fibrosis; the growing role of systems biology and stratified medicine. Curr Opin Pulm Med 2013; 19: 460–465.
    1. Brownell R, Kaminski N, Woodruff PG, et al. . Precision medicine: the new frontier in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2016; 193: 1213–1218.
    1. Magnini D, Montemurro G, Iovene B, et al. . Idiopathic pulmonary fibrosis: molecular endotypes of fibrosis stratifying existing and emerging therapies. Respiration 2017; 93: 379–395.
    1. Solomon JJ, Olson AL, Fischer A, et al. . Scleroderma lung disease. Eur Respir Rev 2013; 22: 6–19.
    1. Turesson C, O'Fallon WM, Crowson CS, et al. . Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis 2003; 62: 722–727.
    1. Marie I, Hachulla E, Chérin P, et al. . Interstitial lung disease in polymyositis and dermatomyositis. Arthritis Rheum 2002; 47: 614–622.
    1. Lega JC, Reynaud Q, Belot A, et al. . Idiopathic inflammatory myopathies and the lung. Eur Respir Rev 2015; 24: 216–238.
    1. Nannini C, Jebakumar AJ, Crowson CS, et al. . Primary Sjögren's syndrome 1976–2005 and associated interstitial lung disease: a population-based study of incidence and mortality. BMJ Open 2013; 3: e003569.
    1. Fischer A, Antoniou KM, Brown KK, et al. . An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur Respir J 2015; 46: 976–987.
    1. Sambataro G, Sambataro D, Torrisi SE, et al. . State of the art in interstitial pneumonia with autoimmune features: a systematic review on retrospective studies and suggestions for further advances. Eur Respir Rev 2018; 27: 170139.
    1. Cavagna L, Gonzalez Gay MA, Allanore Y, et al. . Interstitial pneumonia with autoimmune features: a new classification still on the move. Eur Respir Rev 2018; 27: 180047.
    1. Jaeger VK, Wirz EG, Allanore Y, et al. . Incidences and risk factors of organ manifestations in the early course of systemic sclerosis: a longitudinal EUSTAR study. PLoS One 2016; 11: e0163894.
    1. Tyndall AJ, Bannert B, Vonk M, 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: 1809–1815.
    1. Elhai M, Meune C, Boubaya M, et al. . Mapping and predicting mortality from systemic sclerosis. Ann Rheum Dis 2017; 76: 1897–1905.
    1. Goh NS, Desai SR, Veeraraghavan S, et al. . Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med 2008; 177: 1248–1254.
    1. Olson AL, Swigris JJ, Sprunger DB, et al. . Rheumatoid arthritis-interstitial lung disease-associated mortality. Am J Respir Crit Care Med 2011; 183: 372–378.
    1. Juge PA, Lee JS, Ebstein E, et al. . MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease. N Engl J Med 2018; 379: 2209–2219.
    1. Spagnolo P, Lee JS, Sverzellati N, et al. . The lung in rheumatoid arthritis: focus on interstitial lung disease. Arthritis Rheumatol 2018; 70: 1544–1554.
    1. Zamora-Legoff JA, Krause ML, Crowson CS, et al. . Progressive decline of lung function in rheumatoid arthritis-associated interstitial lung disease. Arthritis Rheumatol 2017; 69: 542–549.
    1. Song JW, Lee HK, Lee CK, et al. . Clinical course and outcome of rheumatoid arthritis-related usual interstitial pneumonia. Sarcoidosis Vasc Diffuse Lung Dis 2013; 30: 103–112.
    1. Oldham JM, Adegunsoye A, Valenzi E, et al. . Characterisation of patients with interstitial pneumonia with autoimmune features. Eur Respir J 2016; 47: 1767–1775.
    1. Ryerson CJ, Urbania TH, Richeldi L, et al. . Prevalence and prognosis of unclassifiable interstitial lung disease. Eur Respir J 2013; 42: 750–757.
    1. Assayag D, Lubin M, Lee JS, et al. . Predictors of mortality in rheumatoid arthritis-related interstitial lung disease. Respirology 2014; 19: 493–500.
    1. Solomon JJ, Chung JH, Cosgrove GP, et al. . Predictors of mortality in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J 2016; 47: 588–596.
    1. Kowal-Bielecka O, Landewé R, Avouac J, et al. . EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis 2009; 68: 620–628.
    1. Kowal-Bielecka O, Fransen J, Avouac J, et al. . Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis 2017; 76: 1327–1339.
    1. Hoyles RK, Ellis RW, Wellsbury J, et al. . A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum 2006; 54: 3962–3970.
    1. Tashkin DP, Elashoff R, Clements PJ, et al. . Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006; 354: 2655–2666.
    1. Tashkin DP, Roth MD, Clements PJ, et al. . Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med 2016; 4: 708–719.
    1. Sircar G, Goswami RP, Sircar D, et al. . Intravenous cyclophosphamide vs rituximab for the treatment of early diffuse scleroderma lung disease: open label, randomized, controlled trial. Rheumatology 2018; 57: 2106–2113.
    1. Doyle TJ, Dhillon N, Madan R, et al. . Rituximab in the treatment of interstitial lung disease associated with antisynthetase syndrome: a multicenter retrospective case review. J Rheumatol 2018; 45: 841–850.
    1. Richeldi L, du Bois RM, Raghu G, et al. . Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: 2071–2082.
    1. King TE Jr, Bradford WZ, Castro-Bernardini S, et al. . A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: 2083–2092.
    1. Maher TM, Corte TJ, Fischer A, 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 Respir Res 2018; 5: e000289.
    1. Selman M, Pardo A, King TE Jr. Hypersensitivity pneumonitis: insights in diagnosis and pathobiology. Am J Respir Crit Care Med 2012; 186: 314–324.
    1. Walsh SLF, Wells AU, Desai SR, et al. . Multicentre evaluation of multidisciplinary team meeting agreement on diagnosis in diffuse parenchymal lung disease: a case-cohort study. Lancet Respir Med 2016; 4: 557–565.
    1. Morell F, Villar A, Montero MA, et al. . Chronic hypersensitivity pneumonitis in patients diagnosed with idiopathic pulmonary fibrosis: a prospective case-cohort study. Lancet Respir Med 2013; 1: 685–694.
    1. Vašáková M, Morell F, Walsh S, et al. . Hypersensitivity pneumonitis: perspectives in diagnosis and management. Am J Respir Crit Care Med 2017; 196: 680–689.
    1. Salisbury ML, Myers JL, Belloli EA, et al. . Diagnosis and treatment of fibrotic hypersensitivity pneumonia. Where we stand and where we need to go. Am J Respir Crit Care Med 2017; 196: 690–699.
    1. Vourlekis JS, Schwarz MI, Cherniack RM, et al. . The effect of pulmonary fibrosis on survival in patients with hypersensitivity pneumonitis. Am J Med 2004; 116: 662–668.
    1. Sahin H, Brown KK, Curran-Everett D, et al. . Chronic hypersensitivity pneumonitis: CT features comparison with pathologic evidence of fibrosis and survival. Radiology 2007; 244: 591–598.
    1. Wang P, Jones KD, Urisman A, et al. . Pathologic findings and prognosis in a large prospective cohort of chronic hypersensitivity pneumonitis. Chest 2017; 152: 502–509.
    1. Ley B, Newton CA, Arnould I, 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: 639–647.
    1. Morisset J, Johannson KA, Vittinghoff E, et al. . Use of mycophenolate mofetil or azathioprine for the management of chronic hypersensitivity pneumonitis. Chest 2017; 151: 619–625.
    1. Hilberg F, Roth GJ, Krssak M, et al. . BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 2008; 68: 4774–4782.
    1. Hilberg F, Tontsch-Grunt U, Baum A, et al. . Triple angiokinase inhibitor nintedanib directly inhibits tumor cell growth and induces tumor shrinkage via blocking oncogenic receptor tyrosine kinases. J Pharmacol Exp Ther 2018; 364: 494–503.
    1. Wollin L, Ostermann A, Williams C. Nintedanib inhibits pro-fibrotic mediators from T cells with relevance to connective tissue disease-associated interstitial lung disease. Eur Respir J 2017; 50: Suppl. 61, PA903.
    1. Tandon K, Herrmann FE, Ayaub E, et al. . Nintedanib attenuates the polarization of profibrotic macrophages through the inhibition of tyrosine phosphorylation on CSF1 receptor. Am J Respir Crit Care Med 2017; 195: A2397.
    1. Huang J, Maier C, Zhang Y, et al. . Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis. Ann Rheum Dis 2017; 76: 1941–1948.
    1. Sato S, Shinohara S, Hayashi S, et al. . Anti-fibrotic efficacy of nintedanib in pulmonary fibrosis via the inhibition of fibrocyte activity. Respir Res 2017; 18: 172.
    1. Hostettler KE, Zhong J, Papakonstantinou E, et al. . Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis. Respir Res 2014; 5: 157.
    1. Wollin L, Ostermann A, Wex E, et al. . Nintedanib attenuates motility of lung fibroblasts from patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2014; 189: A2008.
    1. Wollin L, Wex E, Pautsch A, et al. . Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J 2015; 45: 1434–1445.
    1. Huang J, Beyer C, Palumbo-Zerr K, et al. . Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis. Ann Rheum Dis 2016; 75: 883–890.
    1. Wollin L, Maillet I, Quesniaux V, et al. . Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J Pharmacol Exp Ther 2014; 349: 209–220.
    1. Ackermann M, Kim YO, Wagner WL, et al. . Effects of nintedanib on the microvascular architecture in a lung fibrosis model. Angiogenesis 2017; 20: 359–372.
    1. Lee HY, Hur J, Kim IK, et al. . Effect of nintedanib on airway inflammation and remodeling in a murine chronic asthma model. Exp Lung Res 2017; 43: 187–196.
    1. Redente EF, Aguilar MA, Black BP, et al. . Nintedanib reduces pulmonary fibrosis in a model of rheumatoid arthritis-associated interstitial lung disease. Am J Physiol Lung Cell Mol Physiol 2018; 314: L998–L1009.
    1. Richeldi L, Costabel U, Selman M, et al. . Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011; 365: 1079–1087.
    1. Richeldi L, Cottin V, du Bois RM, et al. . Nintedanib in patients with idiopathic pulmonary fibrosis: combined evidence from the TOMORROW and INPULSIS trials. Respir Med 2016; 113: 74–79.
    1. Raghu G, Rochwerg B, Zhang Y, et al. . An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med 2015; 192: e3–e19.
    1. Distler O, Brown KK, Distler JHW, 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, 75–81.

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