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Review
. 2021 Feb;80(2):143-150.
doi: 10.1136/annrheumdis-2020-217230. Epub 2020 Oct 9.

Mechanisms of progressive fibrosis in connective tissue disease (CTD)-associated interstitial lung diseases (ILDs)

Paolo Spagnolo  1 , Oliver Distler  2 , Christopher J Ryerson  3 , Argyris Tzouvelekis  4 , Joyce S Lee  5 , Francesco Bonella  6 , Demosthenes Bouros  7 , Anna-Maria Hoffmann-Vold  8 , Bruno Crestani  9   10 , Eric L Matteson  11
Affiliations
Review

Mechanisms of progressive fibrosis in connective tissue disease (CTD)-associated interstitial lung diseases (ILDs)

Paolo Spagnolo et al. Ann Rheum Dis. 2021 Feb.

Abstract

Interstitial lung diseases (ILDs), which can arise from a broad spectrum of distinct aetiologies, can manifest as a pulmonary complication of an underlying autoimmune and connective tissue disease (CTD-ILD), such as rheumatoid arthritis-ILD and systemic sclerosis (SSc-ILD). Patients with clinically distinct ILDs, whether CTD-related or not, can exhibit a pattern of common clinical disease behaviour (declining lung function, worsening respiratory symptoms and higher mortality), attributable to progressive fibrosis in the lungs. In recent years, the tyrosine kinase inhibitor nintedanib has demonstrated efficacy and safety in idiopathic pulmonary fibrosis (IPF), SSc-ILD and a broad range of other fibrosing ILDs with a progressive phenotype, including those associated with CTDs. Data from phase II studies also suggest that pirfenidone, which has a different-yet largely unknown-mechanism of action, may also have activity in other fibrosing ILDs with a progressive phenotype, in addition to its known efficacy in IPF. Collectively, these studies add weight to the hypothesis that, irrespective of the original clinical diagnosis of ILD, a progressive fibrosing phenotype may arise from common, underlying pathophysiological mechanisms of fibrosis involving pathways associated with the targets of nintedanib and, potentially, pirfenidone. However, despite the early proof of concept provided by these clinical studies, very little is known about the mechanistic commonalities and differences between ILDs with a progressive phenotype. In this review, we explore the biological and genetic mechanisms that drive fibrosis, and identify the missing evidence needed to provide the rationale for further studies that use the progressive phenotype as a target population.

Keywords: Sjøgren's syndrome; autoimmune diseases; pulmonary fibrosis; rheumatoid arthritis; systemic sclerosis.

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Conflict of interest statement

Competing interests: PS reports grants, personal fees, non-financial support and other from Boehringer Ingelheim, during the conduct of the study; grants, personal fees and non-financial support from Roche and PPM Services; and personal fees from Red X Pharma, Galapagos and Chiesi outside the submitted work. His wife is an employee of Novartis. OD reports personal fees from Boehringer Ingelheim, during the conduct of the study; grants and personal fees from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi; personal fees and non-financial support from Pfizer; and personal fees from Abbvie, Acceleron Pharma, Anamar, Amgen, Catenion, CSL Behring, ChemomAb, Ergonex, GSK, Inventiva, Italfarmaco, iQone, iQvia, Medac, Medscape, Menarini, Mepha, MSD, Lilly, Novartis, Roche, Sanofi, Target BioScience, UCB, Baecon Discovery, Blade Therapeutics, Curzion Pharmaceuticals and Glenmark Pharmaceuticals, outside the submitted work. In addition, OD has a patent US8247389, EP2331143 issued. CJR reports grants and personal fees from Boehringer Ingelheim and Hoffmann-La Roche, outside the submitted work. AT reports grants, personal fees, non-financial support and other from BI Hellas, during the conduct of the study; and other from Roche, outside the submitted work. In addition, AT has a patent for inhaled or aerosolised delivery of thyroid hormone to the lung as a novel therapeutic agent in fibrotic lung diseases issued. JSL reports grants from NIH and Boehringer Ingelheim, and personal fees from Boehringer Ingelheim, Galapagos, Celgene and Genentech, outside the submitted work. FB reports grants, personal fees and non-financial support from Boehringer Ingelheim, during the conduct of the study; grants, personal fees and non-financial support from Boehringer Ingelheim; personal fees and non-financial support from Savara, Bristol Myers Squibb and Roche; and personal fees from Galapagos, outside the submitted work. DB reports grants, personal fees, non-financial support and other from BI Hellas and other from Roche, outside the submitted work. A-MH-V reports personal fees, grants, non-financial support and other from Boehringer Ingelheim, personal fees and non-financial support from Actelion, personal fees from Bayer and Roche, outside the submitted work. BC reports personal fees and non-financial support from AstraZeneca, Sanofi and BMS; grants, personal fees and non-financial support from Boehringer Ingelheim and Roche; and personal fees from Genzyme, outside the submitted work. ELM reports personal fees from Boehringer Ingelheim, outside the submitted work.

Figures

Figure 1
Figure 1
Known and proposed targets for the antifibrotic actions of nintedanib and pirfenidone. CSF, colony-stimulating factor-1; CXCL, C-X-C ligand; PDGF, platelet-derived growth factor; TGF, transforming growth factor; TNF, tumour necrosis factor; SDF, stromal cell-derived factor; VEGF, vascular endothelial growth factor.
See this image and copyright information in PMC

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