Fibrosing CTD-ILDs with a progressive phenotype

Up to 4 in 10 patients with connective tissue disease-associated interstitial lung diseases (CTD-ILDs) can develop a progressive fibrosing phenotype1⁠–⁠5

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The progressive fibrosing phenotype is defined by the presence of:6–9
Defining characteristics of the progressive fibrosing phenotype

In progressive fibrosing ILD, pulmonary fibrosis continues to develop independent of the originating disease (SSc, RA, primary Sjögren’s syndrome, etc.) or trigger (inflammation, exposure, etc.), along common pathogenic pathways6,9–11


It is estimated that 16%–40% of patients with CTD-ILDs develop a progressive fibrosing phenotype – based on a systematic review of the published literature and a physician survey1–5

Fibrosing ILD

Proportion of patients with a progressive phenotype, %

Reference / source

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD)


Zamora-Legoff 2017

Systemic sclerosis-associated interstitial lung disease (SSc-ILD)


Hoffmann-Vold 2015

Polymyositis- and dermatomyositis-associated interstitial lung disease (PM/DM-ILD)


Marie 2011

Primary Sjögren’s syndrome-associated interstitial lung disease (primary Sjögren’s syndrome-ILD) 24

Wijsensbeek 2019*

Systemic lupus erythematosus-associated interstitial lung disease (SLE-ILD)


Wijsensbeek 2019*

Mixed connective tissue disease-associated interstitial lung disease (MCTD-ILD)


Wijsensbeek 2019*

* Estimates of the percentage of patients with non-IPF ILD that develop progressive fibrosis based on an online survey of total 486 physicians (243 pulmonologists, 203 rhuematologists and 40 internists) from the United States, Japan, France, Germany, Italy, Spain and the United Kingdom. Sourced percentages (24%) for primary Sjögren’s syndrome-ILD, SLE-ILD and MCTD-ILD were from the same ‘Other CTD-ILDs’ group.

It is important to note, SSc-ILD shows heterogeneous rates of progression but is fundamentally progressive over the long term13,14


Cough and dyspnea adversely affect the everyday lives of patients with CTD-ILDs15–17

  • ILD-related cough adversely impacts physical function, social participation, activities of daily living, and sleep quality17

  • Dyspnea impacts the patients’ ability to perform functional activities and life priorities17

How progressive CTD-ILDs can impact patients’ quality of life

Patients with progressive CTD-ILDs suffer from emotional distress that may include feelings of depression, anxiety and loss of independence18,19





Loss of independence

Loss of independence




Patients with progressive CTD-ILDs report almost universal symptoms of anxiety and/or depression18

Progressive fibrosing ILD is characterized by progression of pulmonary fibrosis, worsening of symptoms, decline in lung function and deterioration in health-related quality of life7
Characteristics and potential impacts of the progressive fibrosing phenotype

Factors that reflect progression of ILDs
Adapted from: Kolb M, Vašáková M. Respir Res. 2019;20(1).

Declines in lung function shown by PFTs are associated with increased mortality in patients with CTD-ILDs14,20–22


See the impact of progressive fibrosing ILD across a range of CTD-ILDs 

Patients with interstitial lung diseases face an unpredictable journey. There are over 200 types of ILDs, of which Idiopathic pulmonary fibrosis, or IPF, is the most common fibrosing type.  Around 1 in 5 patients with differing ILD diagnoses may develop a ‘progressive fibrosing phenotype’. Progressive fibrosing ILDs are believed to progress via common pathobiological fibrotic pathways, independent of the original trigger. These progressive fibrosing ILDs are characterised by self-sustaining, diffuse and irreversible fibrosis, worsening respiratory symptoms and declining lung function.   The progressive and permanent fibrotic lung damage can place an overwhelming burden on patient’s quality of life and is associated with high mortality.   No treatments are currently approved for progressive fibrosing ILDs, other than IPF.  Thus, there is a high unmet need for effective treatments that slow the disease progression in these patients.  Boehringer Ingelheim has a strong commitment to scientific research.  The INBUILD® clinical trial is the first and largest phase III global trial to include patients across the broad spectrum of ILDs that develop the ‘progressive fibrosing phenotype’, into a single trial. So together, we hope to help patients with progressive fibrosing ILDs find new ways forward. 

Decline in lung function predicts mortality in patients with CTD-ILDs14,20–22 – slow ILD progression in patients with a progressive fibrosing ILD before the risk of early mortality is increased9

The first step to slowing progressive CTD-ILDs is identification of ILD

CTD, connective tissue disease; CTD-ILD, connective tissue disease-associated interstitial lung disease; DLCO, diffusing capacity of the lung for carbon monoxide; DM-ILD, dermatomyositis-associated interstitial lung disease; FVC, forced vital capacity; HRCT, high-resolution computed tomography; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; MCTD-ILD, mixed connective tissue disease-associated interstitial lung disease; PFT, pulmonary function test; PM-ILD, polymyositis-associated interstitial lung disease; RA-ILD, rheumatoid arthritis-associated interstitial lung disease; SLE-ILD, systemic lupus erythematosus associated interstitial lung disease; SSc-ILD, systemic sclerosis-associated interstitial lung disease.

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  2. Wijsenbeek MS, Kreuter M, Olson A, et al. Progressive fibrosing interstitial lung diseases: current practice in diagnosis and management. Curr Med Res Opin. 2019:1–10. 

  3. 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(3):542–549. 

  4. Hoffmann-Vold A, Aaløkken TM, Lund MB, et al. Predictive Value of Serial High-Resolution Computed Tomography Analyses and Concurrent Lung Function Tests in Systemic Sclerosis. Arthritis Rheumatol. 2015;67:2205–2212.

  5. Marie I, Hatron PY, Dominique S, et al. Short-Term and Long-Term Outcomes of Interstitial Lung Disease in Polymyositis and Dermatomyositis. Arthritis Rheum. 2011;63:3439–3447.

  6. Cottin V, Hirani N, Hotchkin D, et al. Presentation, diagnosis and clinical course of the spectrum of progressive-fibrosing interstitial lung diseases. Eur Respir Rev. 2018;27(150):180076. 

  7. Kolb M, Vašáková M. The natural history of progressive fibrosing interstitial lung diseases. Respir Res. 2019;20(1).

  8. Cottin V, Wollin L, Fischer A, et al. Fibrosing interstitial lung diseases: knowns and unknowns. Eur Respir Rev. 2019;28(151):180100. doi: 10.1183/16000617.0100-2018.

  9. 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 Resp Res. 2017;4(1):e000212.

  10. Selman M, King TE, Pardo A; American Thoracic Society; European Respiratory Society; American College of Chest Physicians. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001;134(2):136–151.

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

  12. Wijsenbeek M, Kreuter M, Fischer A, et al. Non-IPF Progressive Fibrosing Interstitial Lung Disease (PF-ILD): The Patient Journey. Am J Respir Crit Care Med. 2018;197:A1678.

  13. Hoffmann-Vold AM, Maher TM, Philpot EE, et al. The identification and management of interstitial lung disease in systemic sclerosis: evidence-based European consensus statements. Lancet Rheum. 2020;2 e71–e83.

  14. Guler, S.A., Winstone, T.A., Murphy, D., et al. Does systemic sclerosis–associated interstitial lung disease burn out? Specific phenotypes of disease progression. Annals ATS. 2018;15;1427–1433.

  15. Saketkoo LA, MMittoo S, Huscher D, et al. Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials. Thorax. 2014;69(5):428–436.

  16. Saketkoo LA, Scholand MB, Lammi MR, et al. Patient-reported outcome measures in systemic sclerosis–related interstitial lung disease for clinical practice and clinical trials. Scleroderma Relat Disord. 2020;5(2 Suppl):48–60. 

  17. Mittoo S, Frankel S, LeSage D, et al. Patient perspectives in OMERACT provide an anchor for future metric development and improved approaches to healthcare delivery in connective tissue disease related interstitial lung disease (CTD-ILD). Curr Respir Med Rev. 2015;11:175–183.

  18. Morisset J, Dubé B, Garvey C, et al. The Unmet Educational Needs of Patients with Interstitial Lung Disease: Setting the Stage for Tailored Pulmonary Rehabilitation. Ann Am Thorac Soc. 2016;13:1026–1033.

  19. Swigris JJ, Brown KK, Abdulqawi R, et al. Patients’ perceptions and patient-reported outcomes in progressive-fibrosing interstitial lung diseases. Eur Respir Rev. 2018;27(150):pii:180075.

  20. Hoffmann-Vold AM, Fretheim H, Halse AK, et al. Tracking impact of interstitial lung disease in systemic sclerosis in a complete nationwide cohort. Am J Respir Crit Care Med. 2019;200;1258–1266.

  21. Goh NS, Hoyles RK, Denton CP, et al. Short-term pulmonary function trends are predictive of mortality in interstitial lung disease associated with systemic sclerosis. Arthritis Rheumatol. 2017;69;1670–1678.

  22. Walsh SLF, Sverzellati N, Devaraj A, et al. Connective tissue disease related fibrotic lung disease: high resolution computed tomographic and pulmonary function indices as prognostic determinants. Thorax. 2014;69(3):216–222.

  23. Chowaniec M, Skoczyńska M, Sokolik R, et al. Interstitial lung disease in systemic sclerosis: challenges in early diagnosis and management. Reumatologia. 2018;56;249–254.

  24. Cottin V, Brown KK. Interstitial lung disease associated with systemic sclerosis (SSc–ILD). Respir Res. 2019a;20(1):13.

  25. Maher TM, Wuyts W. Management of fibrosing interstitial lung diseases. Adv Ther. 2019;36(7);1518–1531.

  26. Wuyts WA, Agostini C, Antoniou KM, et al. The pathogenesis of pulmonary fibrosis: a moving target. Eur Respir J. 2013;41(5):1207–1218.

  27. Geerts S, Wuyts W, De Langhe E, et al. Connective tissue disease associated interstitial pneumonia: a challenge for both rheumatologists and pulmonologists. Sarcoidosis Vasc Diffuse Lung Dis. 2017;34(4):326–335.

  28. Wallace B, Vummidi D, Khanna D. Management of connective tissue diseases associated interstitial lung disease: a review of the published literature. Curr Opin Rheumatol. 2016;28(3):236–245.

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