Interplay of inflammation and fibrosis in CTD-ILDs
Irrespective of the trigger for the lung injury, fibrosing connective tissue disease-associated interstitial lung diseases (CTD-ILDs) show commonalities in the pathogenic mechanisms driving fibrosis1-3
THE PATHOGENESIS OF CTD-ILDs INVOLVES THE INTERPLAY OF INFLAMMATION AND FIBROSIS EARLY IN THE COURSE OF THE DISEASE4–6
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
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.
While CTDs differ, common pathogenic pathways to fibrogenesis are shared irrespective of the trigger for the lung injury1–3,7
Autoimmunity, and/or repetitive injury to the alveolar epithelium and/or vascular endothelium, can cause persistent fibroblast activation and progressive injury through vicious cycles of profibrotic events4,5,8,9
A complex interplay of inflammatory, fibrotic and vascular processes leads to the activation and proliferation of fibroblasts, their differentiation into myofibroblasts, and the excessive secretion of extracellular matrix4,5,10
Mechanisms behind inflammation and fibrosis in pathogenesis of CTD-ILDs4,8–16
How can you identify fibrotic ILD early in your patients with CTDs?
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; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; TNF-β, tumor necrosis factor-β; VEGF, vascular endothelial growth factor.
- Maher TM, Wuyts W. Management of fibrosing interstitial lung diseases. Adv Ther. 2019;36(7):1518–1531.
- Wuyts WA, Agostini C, Antoniou KM, et al. The pathogenesis of pulmonary fibrosis: a moving target. Eur Respir J. 2013;41(5):1207–1218.
- Kolb M, Vašáková M. The natural history of progressive fibrosing interstitial lung diseases. Respir Res. 2019;20(1).
- Wells AU, Denton CP. Interstitial lung disease in connective tissue disease— mechanisms and management. Nat Rev Rheumatol. 2014;10:728–739.
- Castelino FV and Varga J. Interstitial lung disease in connective tissue diseases: evolving concepts of pathogenesis and management. Arthritis Res Ther. 2010;12(4):213. doi: 10.1186/ar3097.
- Dellaripa PF. Interstitial lung disease in the connective tissue diseases; a paradigm shift in diagnosis and treatment. Clin Immunol. 2018;186:71–73.
- 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.
- Shaw M, Collins BF, Ho LA, Raghu G. Rheumatoid arthritis-associated lung disease. Eur Respir Rev. 2015;24(135):1–16.
- 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.
- Fischer A and Distler J. Progressive fibrosing interstitial lung disease associated with systemic autoimmune diseases. Clin Rheumatol. 2019;38(10):2673–2681.
- Cutolo M, Soldano S, Smith V. Pathophysiology of systemic sclerosis: current understanding and new insights. Exp Rev Clin Immunol. 2019;15:753–764.
- 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. 2020;201:650–660.
- Volkmann E, Varga J. Emerging targets of disease-modifying therapy for systemic sclerosis. Nat Rev Rheumatol. 2019;15:208–224.
- Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117:557-567.
- Bagnato G and Harari S. Cellular interactions in the pathogenesis of interstitial lung diseases. Eur Respir Rev. 2015;24(135):102–114.Fischer A and Distler J. Progressive fibrosing interstitial lung disease associated with systemic autoimmune diseases. Clin Rheumatol. 2019;38(10):2673–2681.
- 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.
- 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.
- Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381(18):1718-1727. doi:10.1056/NEJMoa1908681.
- 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.
- 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.