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Progression and self-sustaining fibrosis in CTD-ILDs

Connective tissue disease-associated interstitial lung diseases (CTD-ILDs) can share self-sustaining mechanisms of progressive pulmonary fibrosis1,2

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SELF-SUSTAINING NATURE OF PROGRESSIVE FIBROSIS

SHARED PATHOGENIC MECHANISMS OF PULMONARY FIBROSIS IN CTD-ILDs

Learn about the pathophysiological mechanisms applicable to a broad range of fibrotic CTD-ILDs that can develop a progressive fibrosing phenotype

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The pathogenesis of fibrotic interstitial lung disease in connective tissue diseases involves a complex interplay of inflammatory and fibrotic processes. Patients with connective tissue diseases (CTDs), such as rheumatoid arthritis, systemic sclerosis and primary Sjogren’s syndrome, develop fibrotic interstitial lung disease (ILD) via common pathogenic processes, irrespective of the underlying diagnosis or trigger. Fibrotic ILD often develops early in the course of a CTD. For example, in a study of systemic sclerosis patients, approximately 24% of systemic sclerosis-associated ILD patients showed an extent of more than 10% pulmonary fibrosis on high-resolution computed tomography at their baseline systemic sclerosis diagnosis. At the cellular level, ILD in CTDs is triggered by repeated tissue injury which induces an inflammatory response, and releases probiotic mediators, including VEGF, PDGF and FGF. These contribute to the recruitment and activation of leukocytes and fibroblasts. Resulting in a complex interplay of inflammatory and fibrotic processes. Activation of leukocytes also produces profibrotic mediators leading to further activation of the fibrotic process with excessive secretion of extracellular matrix. Excess extracellular matrix increases lung tissue stiffness, further activating fibroblasts in a feed-forward loop of self-sustaining progressive pulmonary fibrosis. Pulmonary fibrosis causes irreversible destruction and architectural disruption of the lung tissue. Based on the pathogenesis of fibrotic interstitial lung disease in connective tissue diseases, a new treatment paradigm of CTD-ILDs suggests to not only target inflammation but also fibrosis.

Self-sustaining progression of fibrosis3⁠–⁠5

Progression

 

Irrespective of the clinical diagnosis, there are commonalities in the underlying pathogenetic mechanisms that drive a self-sustaining process of pulmonary fibrosis.2

Excessive secretion of extracellular matrix can lead to a self-sustaining process of progressive fibrosis, where increased tissue stiffness and release of profibrotic cytokines further activates fibroblasts1

In a feed-forward loop, increased lung tissue stiffness further activates and stimulates fibroblasts to drive a self-sustaining process of fibrosis6,7

Once pulmonary fibrosis has become self-sustaining, fibroblasts can become partially independent of external stimulation and the initiating inflammatory response8-10

Self-sustaining progressive fibrosis mechanisms of CTD-ILDs

Adapted from: Wollin L, et al. Eur Respir J. 2019;54:1900161.4

Mechanisms behind self-sustaining fibrosis in pathogenesis of CTD-ILDs1,5,11-18
Mechanisms behind inflammation and fibrosis in pathogenesis of CTD-ILDs

Pulmonary fibrosis in CTDs can become self-sustaining, independent of the original trigger1,2,17,19-21 – ensure you are targeting the main pathways

How can you identify and manage self-sustaining fibrosis in CTD-ILDs?

Self-sustaining mechanisms behind progressive fibrosis require treatment that aims to slow ILD progression in chronic fibrosing CTD-ILDs1,2

How can you target progressive fibrosis in your patients with:  
 

RA-ILD
Primary Sjögren’s syndrome-ILD

How can you monitor and treat progression of fibrosis in patients with CTD-ILDs?

Footnote

bFGF, basic fibroblast growth factor; CTD, connective tissue disease; CTD-ILD, connective tissue disease-associated interstitial lung disease; CTGF, connective tissue growth factor; EMT, epithelial-mesenchymal transition; HRCT, high-resolution computed tomography; ILD, interstitial lung disease; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; PFT, pulmonary function test; RA-ILD, rheumatoid arthritis-associated interstitial lung disease; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; TNF-β, tumor necrosis factor-β; VEGF, vascular endothelial growth factor. 

  1. Fischer A and Distler J. Progressive fibrosing interstitial lung disease associated with systemic autoimmune diseases. Clin Rheumatol. 2019;38(10):2673–2681. 

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

  3. 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.

  4. Wollin L, Distler JHW, Redente EF, et al. Potential of nintedanib in treatment of progressive fibrosing interstitial lung diseases. Eur Respir J. 2019;54(3):1900161. doi: 10.1183/13993003.00161-2019.

  5. Wells AU, Denton CP. Interstitial lung disease in connective tissue disease— mechanisms and management. Nat Rev Rheumatol. 2014;10:728–739.

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

  7. Froese AR, Shimbori C, Ballaye PS, et al. Stretch-induced Activation of Transforming Growth Factor-β1 in Pulmonary Fibrosis. Am J Respir Crit Care Med. 2016;194(1):84–96.

  8. Distler J, et al. Shared and distinct mechanisms of fibrosis. Nat Rev Rheumatol 2019(b):15:705–30.

  9. Kolb M, Flaherty KR. The justification for the progressive fibrotic phenotype. Curr Opin Pulm Med 2021; online ahead of print.

  10. Leask A. The hard problem: Mechanotransduction perpetuates the myofibroblast phenotype in scleroderma fibrosis. Wound Rep Reg. 2021;29:582–587.

  11. Cutolo M, Soldano S, Smith V. Pathophysiology of systemic sclerosis: current understanding and new insights. Exp Rev Clin Immunol. 2019;15:753–764.

  12. Khanna D, Tashkin DP, Denton CP, et al. Etiology, Risk Factors, and Biomarkers in Systemic Sclerosis with Interstitial Lung Disease. Am J Respir Crit Care Med. 2019; doi: 10.1164/rccm.201903-0563CI.

  13. Shaw M, Collins BF, Ho LA, Raghu G. Rheumatoid arthritis-associated lung disease. Eur Respir Rev. 2015;24(135):1–16.

  14. Cavagna L, Monti S, Grosso V, et al. The multifaceted aspects of interstitial lung disease in rheumatoid arthritis. Biomed Res Int. 2013;2013:759760. doi: 10.1155/2013/759760.

  15. Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117:557-567.

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

  17. Nicolosi P A, Tombetti E, Maugeri N, et al. Vascular Remodelling and Mesenchymal Transition in Systemic Sclerosis. Stem Cell Int. 2016; doi: 10.1155/2016/4636859.

  18. Flaherty KR, Brown KK, Wells AU, et al. Design of the PF-ILD trial: a doubleblind, randomised, placebo-controlled phase III trial of nintedanib in patients with progressive fibrosing interstitial lung disease. BMJ Open Respir Res. 2017;4(1):e000212. doi: 10.1136/bmjresp-2017-000212.

  19. 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. 

  20. 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.

  21. 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.

  22. 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.

  23. Chowaniec M, Skoczyńska M, Sokolik R, Wiland P. Interstitial lung disease in systemic sclerosis: challenges in early diagnosis and management. Reumatologia. 2018;56(4):249–254.

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

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