You are here

Article Text

Article menu

Download PDFPDF

XML
Review
Mechanisms of progressive fibrosis in connective tissue disease (CTD)-associated interstitial lung diseases (ILDs)
  1. Paolo Spagnolo1,
  2. Oliver Distler2,
  3. Christopher J Ryerson3,
  4. Argyris Tzouvelekis4,
  5. Joyce S Lee5,
  6. Francesco Bonella6,
  7. Demosthenes Bouros7,
  8. Anna-Maria Hoffmann-Vold8,
  9. Bruno Crestani9,10,
  10. Eric L Matteson11
  1. 1 Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova School of Medicine and Surgery, Padova, Italy
  2. 2 Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
  3. 3 Department of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada
  4. 4 Department of Respiratory and Internal Medicine, University of Patras Faculty of Medicine, Patras, Greece
  5. 5 School of Medicine, University of Colorado Denver - Anschutz Medical Campus, Aurora, Colorado, USA
  6. 6 Center for Interstitial and Rare Lung Disease Unit, University of Duisburg-Essen, Ruhrlandklinik, Essen, Germany
  7. 7 Department of Pneumonology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
  8. 8 Department of Rheumatology, Oslo University Hospital, Oslo, Norway
  9. 9 Inserm U1152, Université de Paris, F-75018, Paris, France
  10. 10 Department of Pneumonology, Hôpital Bichat, Assistance Publique – Hôpitaux de Paris, F-75018, Paris, France
  11. 11 Division of Rheumatology and Department of Health Sciences Research, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
  1. Correspondence to Professor Paolo Spagnolo, Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova School of Medicine and Surgery, Padova 35128, Italy; paolo.spagnolo{at}unipd.it

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.

  • autoimmune diseases
  • Sjøgren's syndrome
  • pulmonary fibrosis
  • rheumatoid arthritis
  • systemic sclerosis
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/annrheumdis-2020-217230

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    View Full Text

    Footnotes

    • Handling editor Josef S Smolen

    • Contributors All authors contributed equally to the conception and development of the manuscript, including literature review. The final version was approved by all authors.

    • Funding The authors received no direct compensation related to the development of this manuscript. Medical writing support was funded by Boehringer Ingelheim International GmbH.

    • 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.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.