Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Advances in Therapy
Published in: Advances in Therapy 7/2019

Open Access 01-07-2019 | Idiopathic Pulmonary Fibrosis | Review

Management of Fibrosing Interstitial Lung Diseases

Authors: Toby M. Maher, Wim Wuyts

Published in: Advances in Therapy | Issue 7/2019

Login to get access

Abstract

A proportion of patients with interstitial lung diseases (ILDs), including the ILDs that are commonly associated with autoimmune diseases, develop a progressive fibrosing phenotype characterised by worsening of lung function, dyspnoea and quality of life, and early mortality. No drugs are approved for the treatment of ILDs other than idiopathic pulmonary fibrosis (IPF). At present, immunomodulatory medications are the mainstay of treatment for non-IPF ILDs. However, with the exception of systemic sclerosis-associated ILD, the evidence to suggest that immunosuppression may preserve lung function in patients with these ILDs comes only from retrospective, observational, or uncontrolled studies. In this article, we review the evidence for the treatments currently used to treat ILDs associated with autoimmune diseases and other ILDs and the ongoing trials of immunosuppressant and antifibrotic therapies in patients with these ILDs.
Funding: Boehringer Ingelheim.
Literature
1.
2.
Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198:e44–68.CrossRefPubMed
3.
Raghu G, Chen SY, Yeh WS, et al. Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001–11. Lancet Respir Med. 2014;2:566–72.CrossRefPubMed
4.
Strongman H, Kausar I, Maher TM. Incidence, prevalence, and survival of patients with idiopathic pulmonary fibrosis in the UK. Adv Ther. 2018;35:724–36.CrossRefPubMedPubMedCentral
5.
Zamora-Legoff JA, Krause ML, Crowson CS, et al. Progressive decline of lung function in rheumatoid arthritis-associated interstitial lung disease. Arthritis Rheumatol. 2017;69:542–9.CrossRefPubMedPubMedCentral
6.
Guler SA, Winstone TA, Murphy D, et al. Does systemic sclerosis-associated interstitial lung disease burn out? Specific phenotypes of disease progression. Ann Am Thorac Soc. 2018;15:1427–33.CrossRefPubMed
7.
Marie I, Hatron PY, Dominique S, et al. Short-term and long-term outcomes of interstitial lung disease in polymyositis and dermatomyositis: a series of 107 patients. Arthritis Rheum. 2011;63:3439–47.CrossRefPubMed
8.
Patterson KC, Strek ME. Pulmonary fibrosis in sarcoidosis. Clinical features and outcomes. Ann Am Thorac Soc. 2013;10:362–70.CrossRefPubMed
9.
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;144:1644–51.CrossRefPubMedPubMedCentral
10.
Belloli EA, Beckford R, Hadley R, et al. Idiopathic non-specific interstitial pneumonia. Respirology. 2016;21:259–68.CrossRefPubMed
11.
Guler SA, Ellison K, Algamdi M, et al. Heterogeneity in unclassifiable interstitial lung disease. A systematic review and meta-analysis. Ann Am Thorac Soc. 2018;15:854–63.CrossRefPubMed
12.
Wuyts WA, Agostini C, Antoniou KM, et al. The pathogenesis of pulmonary fibrosis: a moving target. Eur Respir J. 2013;41:1207–18.CrossRefPubMed
13.
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.CrossRefPubMedPubMedCentral
14.
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:e3–19.CrossRefPubMed
15.
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;68:620–8.CrossRefPubMed
16.
Kowal-Bielecka O, Fransen J, Avouac J, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017;76:1327–39.CrossRefPubMed
17.
18.
Fernández-Codina A, Walker KM, Pope JE. Treatment algorithms for systemic sclerosis according to experts. Arthritis Rheumatol. 2018;70:1820–8.CrossRefPubMed
19.
Idiopathic Pulmonary Fibrosis Clinical Research Network, Raghu G, Anstrom KJ, et al. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366:1968–77.CrossRef
20.
Idiopathic Pulmonary Fibrosis Clinical Research Network, Martinez FJ, De Andrade JA, et al. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2093–101.CrossRef
21.
Kreuter M, Olson A, Fischer A, et al. Current treatment of patients with non-IPF progressive fibrosing interstitial lung diseases. In: Poster presented at the American Thoracic Society (ATS) international conference, San Diego, May 2018.
22.
Adler S, Huscher D, Siegert E, et al. Systemic sclerosis associated interstitial lung disease—individualized immunosuppressive therapy and course of lung function: results of the EUSTAR group. Arthritis Res Ther. 2018;20:17.CrossRefPubMedPubMedCentral
23.
Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2016;68:1–25.CrossRef
24.
Schutt AC, Bullington WM, Judson MA. Pharmacotherapy for pulmonary sarcoidosis: a Delphi consensus study. Respir Med. 2010;104:717–23.CrossRefPubMed
25.
Kokkarinen JI, Tukiainen HO, Terho EO. Effect of corticosteroid treatment on the recovery of pulmonary function in farmer’s lung. Am Rev Respir Dis. 1992;145:3–5.CrossRefPubMed
26.
De Sadeleer LJ, Hermans F, De Dycker E, et al. Effects of corticosteroid treatment and antigen avoidance in a large hypersensitivity pneumonitis cohort: a single-centre cohort study. J Clin Med. 2018;8(1):14.CrossRefPubMedCentral
27.
Lee SH, Park MS, Kim SY, et al. Factors affecting treatment outcome in patients with idiopathic nonspecific interstitial pneumonia: a nationwide cohort study. Respir Res. 2017;18:204.CrossRefPubMedPubMedCentral
28.
Oray M, Abu Samra K, Ebrahimiadib N, et al. Long-term side effects of glucocorticoids. Expert Opin Drug Saf. 2016;15:457–65.CrossRefPubMed
29.
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;54:3962–70.CrossRefPubMed
30.
Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006;354:2655–66.CrossRefPubMed
31.
Kelly C, Palmer E, Gordon J, et al. Pulsed cyclophosphamide in the treatment of rheumatoid arthritis-related interstitial lung disease (RA-ILD). Ann Rheum Dis. 2014;73:74.CrossRef
32.
Saunders P, Sharma S, Kokosi M, et al. Intravenous cyclophosphamide as a treatment for severe interstitial lung disease. Am J Respir Crit Care Med. 2017;195:A1544.CrossRef
33.
Paone C, Chiarolanza I, Cuomo G, et al. Twelve-month azathioprine as maintenance therapy in early diffuse systemic sclerosis patients treated for 1-year with low dose cyclophosphamide pulse therapy. Clin Exp Rheumatol. 2007;25:613–6.PubMed
34.
Bérezné A, Ranque B, Valeyre D, et al. Therapeutic strategy combining intravenous cyclophosphamide followed by oral azathioprine to treat worsening interstitial lung disease associated with systemic sclerosis: a retrospective multicenter open-label study. J Rheumatol. 2008;35:1064–72.PubMed
35.
Müller-Quernheim J, Kienast K, Held M, et al. Treatment of chronic sarcoidosis with an azathioprine/prednisolone regimen. Eur Respir J. 1999;14:1117–22.CrossRefPubMed
36.
Vorselaars ADM, Wuyts WA, Vorselaars VMM, et al. Methotrexate vs azathioprine in second-line therapy of sarcoidosis. Chest. 2013;144:805–12.CrossRefPubMed
37.
Morisset J, Johannson KA, Vittinghoff E, et al. Use of mycophenolate mofetil or azathioprine for the management of chronic hypersensitivity pneumonitis. Chest. 2017;151:619–25.CrossRefPubMed
38.
Oldham JM, Lee C, Valenzi E, et al. Azathioprine response in patients with fibrotic connective tissue disease-associated interstitial lung disease. Respir Med. 2016;121:117–22.CrossRefPubMedPubMedCentral
39.
Arakawa H, Yamasaki M, Kurihara Y, et al. Methotrexate-induced pulmonary injury: serial CT findings. J Thorac Imaging. 2003;18:231–6.CrossRefPubMed
40.
41.
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;4:708–19.CrossRefPubMedPubMedCentral
42.
Rahaghi FF, Strek ME, Southern BD, et al. Expert consensus on the screening, treatment, and management of patients with SSc-ILD, and the potential future role of anti-fibrotics in a treatment paradigm for SSc-ILD: a Delphi consensus study. In: Poster to be presented at the American Thoracic Society (ATS) international conference, May 2019, Dallas, USA.
43.
Fischer A, Brown KK, Du Bois RM, et al. Mycophenolate mofetil improves lung function in connective tissue disease-associated interstitial lung disease. J Rheumatol. 2013;40:640–6.CrossRefPubMedPubMedCentral
44.
Daoussis D, Liossis SN, Tsamandas AC, et al. Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology (Oxford). 2010;49:271–80.CrossRef
45.
Keir JG, Maher TM, Hansell DM, et al. Severe interstitial lung disease in connective tissue disease: rituximab as rescue therapy. Eur Respir J. 2012;40:641–6.CrossRefPubMed
46.
Keir GJ, Maher TM, Ming D, et al. Rituximab in severe, treatment-refractory interstitial lung disease. Respirology. 2014;19:353–9.CrossRefPubMed
47.
Lepri G, Avouac J, Airo P, et al. Effects of rituximab in connective tissue disorders related interstitial lung disease. Clin Exp Rheumatol. 2016;34:181–5.PubMed
48.
Md Yusof MY, Kabia A, Darby M, et al. Effect of rituximab on the progression of rheumatoid arthritis-related interstitial lung disease: 10 years’ experience at a single centre. Rheumatology (Oxford). 2017;56:1348–57.CrossRef
49.
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 (Oxford). 2018;57:2106–13.CrossRef
50.
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;45:841–50.CrossRefPubMedPubMedCentral
51.
52.
Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016;387:2630–40.CrossRefPubMed
53.
Khanna D, Lin CJF, Kuwana M, et al. Efficacy and safety of tocilizumab for the treatment of systemic sclerosis: results from a phase 3 randomized controlled trial. In: Oral presentation at the American College of Rheumatology (ACR)/Association of Rheumatology Professionals (ARHP) annual meeting 2018, Chicago, USA.
54.
Van Laar JM, Farge D, Sont JK, et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis. A randomized trial. JAMA. 2014;311:2490–8.CrossRefPubMed
55.
Sullivan KM, Goldmuntz EA, Keyes-Elstein L, et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N Engl J Med. 2018;378:35–47.CrossRefPubMedPubMedCentral
56.
Sullivan KM, Majhail NS, Bredeson C, et al. Systemic sclerosis as an indication for autologous hematopoietic cell transplantation: position statement from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2018;24(10):1961–4.
57.
Weill D, Benden C, Corris PA, et al. A consensus document for the selection of lung transplant candidates: 2014—an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2015;34:1–15.CrossRefPubMed
58.
Crespo MM, Bermudez CA, Dew MA, et al. Lung transplant in patients with scleroderma compared with pulmonary fibrosis. Short- and long-term outcomes. Ann Am Thorac Soc. 2016;13:84–92.CrossRef
59.
Pradère P, Tudorache I, Magnusson J, et al. Lung transplantation for scleroderma lung disease: an international, multicenter, observational cohort study. J Heart Lung Transplant. 2018;37:903–11.CrossRefPubMed
60.
Yazdani A, Singer LG, Strand V, et al. Survival and quality of life in rheumatoid arthritis-associated interstitial lung disease after lung transplantation. J Heart Lung Transplant. 2014;33:514–20.CrossRefPubMed
61.
Ameye H, Ruttens D, Benveniste O, et al. Is lung transplantation a valuable therapeutic option for patients with pulmonary polymyositis? Experiences from the Leuven transplant cohort. Transplant Proc. 2014;46:3147–53.CrossRefPubMed
62.
Park JE, Kim SY, Song JH, et al. Comparison of short-term outcomes for connective tissue disease-related interstitial lung disease and idiopathic pulmonary fibrosis after lung transplantation. J Thorac Dis. 2018;10:1538–47.CrossRefPubMedPubMedCentral
63.
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(5):1800692.
64.
65.
Herzog EL, Mathur A, Tager AM, et al. Review: interstitial lung disease associated with systemic sclerosis and idiopathic pulmonary fibrosis: how similar and distinct? Arthritis Rheumatol. 2014;66:1967–78.CrossRefPubMedPubMedCentral
66.
Wolters PJ, Blackwell TS, Eickelberg O, et al. Time for a change: is idiopathic pulmonary fibrosis still idiopathic and only fibrotic? Lancet Respir Med. 2018;6:154–60.CrossRefPubMedPubMedCentral
67.
68.
Bagnato G, Harari S. Cellular interactions in the pathogenesis of interstitial lung diseases. Eur Respir Rev. 2015;24:102–14.CrossRefPubMed
69.
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;370:2083–92.CrossRefPubMed
70.
Khanna D, Albera C, Fischer A, et al. An open-label, phase II study of the safety and tolerability of pirfenidone in patients with scleroderma-associated interstitial lung disease: the LOTUSS trial. J Rheumatol. 2016;43:1672–9.CrossRefPubMed
71.
Richeldi L, Du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2071–82.CrossRefPubMed
72.
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;113:74–9.CrossRefPubMed
73.
74.
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:PA903.
75.
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;75:883–90.CrossRefPubMed
76.
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;76:1941–8.CrossRefPubMed
77.
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;43:187–96.CrossRefPubMed
78.
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:L998–1009.CrossRefPubMedPubMedCentral
79.
80.
Walsh SLF. Multidisciplinary evaluation of interstitial lung diseases: current insights: number 1 in the series “Radiology” edited by Nicola Sverzellati and Sujal Desai. Eur Respir Rev. 2017;26(144):170002.
81.
Kreuter M, Bendstrup E, Russell AM, et al. Palliative care in interstitial lung disease: living well. Lancet Respir Med. 2017;5:968–80.CrossRefPubMed
82.
Dowman LM, McDonald CF, Hill CJ, et al. The evidence of benefits of exercise training in interstitial lung disease: a randomised controlled trial. Thorax. 2017;72:610–9.CrossRefPubMed
83.
Perez-Bogerd S, Wuyts W, Barbier V, et al. Short and long-term effects of pulmonary rehabilitation in interstitial lung diseases: a randomised controlled trial. Respir Res. 2018;19:182.CrossRefPubMedPubMedCentral
84.
Visca D, Mori L, Tsipouri V, et al. Effect of ambulatory oxygen on quality of life for patients with fibrotic lung disease (AmbOx): a prospective, open-label, mixed-method, crossover randomised controlled trial. Lancet Respir Med. 2018;6:759–70.CrossRefPubMed
85.
Macaluso C, Furcada JM, Alzaher O, et al. The potential impact of azithromycin in idiopathic pulmonary fibrosis. Eur Respir J. 2019;53(2):1800628.
86.
Vasakova M, Morell F, Walsh S, et al. Hypersensitivity pneumonitis: perspectives in diagnosis and management. Am J Respir Crit Care Med. 2017;196:680–9.CrossRefPubMed
87.
Loza E, Lajas C, Andreu JL, et al. Consensus statement on a framework for the management of comorbidity and extra-articular manifestations in rheumatoid arthritis. Rheumatol Int. 2015;35:445–58.CrossRefPubMed
88.
89.
Schwarzkopf L, Witt S, Waelscher J, et al. Associations between comorbidities, their treatment and survival in patients with interstitial lung diseases—a claims data analysis. Respir Res. 2018;19:73.CrossRefPubMedPubMedCentral
90.
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;35:75–81.PubMed
91.
Flaherty KR, Brown KK, Well 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.CrossRefPubMedPubMedCentral
92.
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.CrossRefPubMedPubMedCentral
93.
Saunders P, Tsipouri V, Keir GJ, 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;18:275.CrossRefPubMedPubMedCentral
Metadata
Title
Management of Fibrosing Interstitial Lung Diseases
Authors
Toby M. Maher
Wim Wuyts
Publication date
01-07-2019
Publisher
Springer Healthcare
Published in
Advances in Therapy / Issue 7/2019
Print ISSN: 0741-238X
Electronic ISSN: 1865-8652
DOI
https://doi.org/10.1007/s12325-019-00992-9

Other articles of this Issue 7/2019

Advances in Therapy 7/2019 Go to the issue

Review

How Successful is Switching from Bevacizumab or Ranibizumab to Aflibercept in Age-Related Macular Degeneration? A Systematic Overview

Correction

Correction to: A Multicenter, Observational, Prospective Study of the Effectiveness of Switching from Budesonide/Formoterol Turbuhaler® to Budesonide/Formoterol Easyhaler®

Original Research

Risk of Developing Additional Immune-Mediated Manifestations: A Retrospective Matched Cohort Study

Case Series

Different Solutions for Damaged Nasotracheal Tube during Maxillofacial Surgery: A Case Series

Original Research

YINGLONG: A Multicenter, Prospective, Non-Interventional Study Evaluating the Safety and Tolerability of Ticagrelor in Chinese Patients with Acute Coronary Syndrome

Review

A Structured Literature Review of the Epidemiology and Disease Burden of Non-Alcoholic Steatohepatitis (NASH)
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits