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Transforming growth factor β as a therapeutic target in systemic sclerosis

Nature Reviews Rheumatology volume 5, pages 200–206 (2009)Cite this article

Abstract

Transforming growth factor β (TGF-β) is a pleiotropic cytokine with vital homeostatic functions. Aberrant TGF-β expression is implicated in the pathogenesis of fibrosis in systemic sclerosis (SSc); thus, TGF-β represents a molecular therapeutic target in this disease. Anti-TGF-β monoclonal antibody has been evaluated in a small trial of early SSc, with disappointing results. Antibodies against the αvβ6 integrin that prevent latent TGF-β activation, however, have shown promise in preclinical studies. Small-molecule inhibitors of TGF-β-receptor activity are effective in animal models of fibrosis. Imatinib mesylate and related tyrosine kinase inhibitors also block TGF-β pathways and abrogate fibrotic responses. The blocking of TGF-β activity might lead to spontaneous immune activation, epithelial hyperplasia and impaired wound healing. Loss of immune tolerance is a potential concern in an autoimmune disease such as SSc. Novel insights from microarray-based gene expression analyses and studies of genetic polymorphisms in TGF-β signaling could aid in identifying patients who are most likely to respond to anti-TGF-β treatment. This intervention promises to have a major impact on the treatment of SSc. Concerns regarding efficacy and safety and whether biomarkers can indicate these features, questions regarding appropriate dosing and timing of therapy, and identification of potential responders are critical challenges ahead.

Key Points

  • Systemic sclerosis (SSc) is a highly heterogeneous fibrotic condition that has no effective disease-modifying therapy; arresting disease progression and reversing organ damage will require antifibrotic therapies

  • Fibrosis is associated with fibroblast activation mediated by transforming growth factor β (TGF-β); therefore, blocking TGF-β signaling pathways is a rational approach to antifibrotic therapy

  • Targeting the TGF-β pathway with biologic therapies prevents fibrosis in animal models, but efficacy has not yet been shown in patients with SSc

  • Small-molecule inhibitors of tyrosine kinases block TGF-β signaling and prevent TGF-β-driven fibrotic responses in vitro and in vivo; clinical trials are evaluating two such inhibitors in patients with SSc

  • Blocking the TGF-β pathway could be associated with adverse effects such as loss of immune tolerance and spontaneous autoimmunity, epithelial hyperplasia, and defective tissue repair

  • Key challenges for the development of anti-TGF-β therapies in SSc include determining optimum timing and dosing, and developing biomarkers of biological response and clinical efficacy

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Figure 1: Major components of the TGF-β signaling pathway.
Figure 2: Strategies for blocking TGF-β pathways.

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Acknowledgements

Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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  1. Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

    John Varga

  2. UAB Comprehensive Cancer Center, University of Alabama, Birmingham, AL, USA

    Boris Pasche

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Correspondence to John Varga.

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Both authors have received grants/research support from the NIH. J Varga has also received a grant/research support from Novartis.

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Varga, J., Pasche, B. Transforming growth factor β as a therapeutic target in systemic sclerosis. Nat Rev Rheumatol 5, 200–206 (2009). https://doi.org/10.1038/nrrheum.2009.26

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