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Mechanisms and consequences of fibrosis in systemic sclerosis

Nature Clinical Practice Rheumatology volume 2, pages 134–144 (2006)Cite this article

Abstract

Systemic sclerosis (SSc), also known as scleroderma, is a complex connective tissue disease that is associated with a high mortality and is challenging to treat because of its clinical heterogeneity and a lack of effective antifibrotic therapies. SSc has vascular, immunologic and fibrotic components that are pathologically interconnected. A growing understanding of the molecular and cellular mechanisms that underlie SSc pathogenesis provides logical and novel approaches to treatment. At present most therapies are organ-based. Vascular and inflammatory components of the disease can also be treated, but effective antifibrotic therapies are lacking. A number of key molecular mediators have the potential to alter immune-cell, vascular and fibrotic processes and these mediators, which include transforming growth factor-β isoforms, endothelin-1, connective-tissue growth factor, chemokines and members of the interleukin family, are attractive targets for therapeutic modulation. Key mediators can be blocked using antibodies, soluble receptors, endogenous inhibitors or small-molecule antagonists of ligands, receptors or signaling intermediates. Overall, this is an exciting time for new therapies in SSc and advances are being made in synchrony with an improved understanding of the molecular and biochemical basis of the disease.

Key Points

  • The clinical heterogeneity of systemic sclerosis probably reflects differential activity of vascular, immunologic and connective-tissue pathology

  • Immunosuppression with cyclophosphamide might be effective in pulmonary fibrosis associated with systemic sclerosis but needs to be balanced against toxicity

  • Management of organ-based complications is more successful than current disease-modifying treatment and so patients should be actively screened for complications

  • Understanding pathogenesis and identifying pivotal mediators or key signaling pathways might allow logical targeted therapy in the future

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Figure 1: Key features of scleroderma pathogenesis.
Figure 2: Connections—pathogenic links, key cell and molecular players and therapeutic targets.

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Author information

Authors and Affiliations

  1. Senior Lecturer at University College London and a Consultant Rheumatologist at the Royal Free Hospital,

    Christopher P Denton

  2. Professor of Rheumatology at University College London, a Consultant Rheumatologist at the Royal Free Hospital and the President of the Royal College of Physicians,

    Carol M Black

  3. Professor of Cell and Molecular Biology at the Centre for Rheumatology, Royal Free and University College Medical School, London, UK

    David J Abraham

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  1. Christopher P Denton
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  2. Carol M Black
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  3. David J Abraham
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Corresponding author

Correspondence to Christopher P Denton.

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Competing interests

Christopher P Denton has received research funding and acted as an external consultant to Actelion Pharmaceuticals, Genzyme Inc., Aspreva Pharmaceuticals and Encysive Pharmaceuticals. Carol M Black has received research funding, been on advisory boards, and has been an invited lecturer for Actelion Pharmaceuticals, Genzyme Inc., and Serono Pharmaceuticals. David J Abraham has declared no competing interests.

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Denton, C., Black, C. & Abraham, D. Mechanisms and consequences of fibrosis in systemic sclerosis. Nat Rev Rheumatol 2, 134–144 (2006). https://doi.org/10.1038/ncprheum0115

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