Targeted therapies for systemic sclerosis

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Pathogenic processes that underlie the development and progression of systemic sclerosis (SSc) are being defined in preclinical, clinical and genetic studies. Important evidence of interplay between the vasculature, connective tissue and specialized epithelial structures is emerging, and abnormalities of both the innate and adaptive immune systems have been identified. In this context, information regarding pivotal mediators, pathways or cell types that could be targets for therapeutic intervention, and that might offer potential for true disease modification, is accruing. Precedent for the regression of some aspects of the pathology has been set in clinical studies showing that potential exists to improve tissue structure and function as well as to prevent disease progression. This article reviews the concept of targeted therapies and considers potential pathways and processes that might be attenuated by therapeutic intervention in SSc. As well as improving outcomes, such approaches will undoubtedly provide information about pathogenesis. The concept of translational medicine is especially relevant in SSc, and we anticipate that the elusive goal of an effective antifibrotic treatment will emerge from one of the several clinical trials currently underway or planned in this disease. Therapeutic advances in SSc would have implications and potential beyond autoimmune rheumatic diseases.

Key Points

  • Therapeutic goals in systemic sclerosis (SSc) include minimization of damage from early inflammation and autoimmunity, restoration of vascular homeostasis, promotion of repair of structural connective tissue and resolution of scarring

  • Cardinal pathogenic processes in SSc—autoimmunity, vascular dysfunction and extracellular matrix overproduction—are interdependent; therapeutic targeting of any of them individually is likely to be of broader benefit

  • Current treatments for SSc, such as broad-spectrum immunosuppression, are adopted from the management of other rheumatic diseases; biologic agents and intracellular signalling inhibitors might also be translated into SSc

  • Increasing understanding of the pathobiology of SSc has identified other relevant biological processes and their signalling pathways, such as stem cell biology and epithelial regeneration, as potential targets for therapy

  • New candidate therapies and advances in clinical trial methodology have made targeted therapy a realistic goal that can be tested robustly, underpinning future progress in SSc management

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Figure 1: Targeting pathogenic processes in SSc.
Figure 2: Targeting multiple pathways of fibroblast activation in SSc.


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C. P. Denton selected the content of the article. Both authors made substantial contributions to researching data for the article, writing the article, and review and editing of the article before submission.

Correspondence to Christopher P. Denton.

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C. P. Denton declares that he has received consultancy fees, honoraria and research funding from Actelion Pharmaceuticals, and consultancy fees and honoraria from GSK, Pfizer, Novartis, Sanofi-Aventis and Merck-Serono. V. H. Ong declares that he has received consultancy fees and honoraria from Actelion Pharmaceuticals.

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Denton, C., Ong, V. Targeted therapies for systemic sclerosis. Nat Rev Rheumatol 9, 451–464 (2013) doi:10.1038/nrrheum.2013.46

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