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  • Review Article
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Emerging targets of disease-modifying therapy for systemic sclerosis

Nature Reviews Rheumatology volume 15, pages 208–224 (2019)Cite this article

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Abstract

Systemic sclerosis (SSc) has the highest cause-specific mortality of all the connective tissue diseases, and the aetiology of this complex and heterogeneous condition remains an enigma. Current disease-modifying therapies for SSc predominantly target inflammatory and vascular pathways but have variable and unpredictable clinical efficacy, and none is curative. Moreover, many of these therapies possess undesirable safety profiles and have no appreciable effect on long-term mortality. This Review describes the most promising of the existing therapeutic targets for SSc and places them in the context of our evolving understanding of the pathophysiology of this disease. As well as taking an in-depth look at the immune, inflammatory, vascular and fibrotic pathways implicated in the pathogenesis of SSc, this Review discusses emerging treatment targets and therapeutic strategies. The article concludes with an overview of important unanswered questions in SSc research that might inform the design of future studies of treatments aimed at modifying the course of this disease.

Key points

  • Systemic sclerosis (SSc) is associated with the highest mortality among the rheumatic diseases and to date lacks approved disease-modifying therapies.

  • The clinical presentation and course of SSc are highly variable, which reflects interpatient genetic and molecular heterogeneity.

  • Advances in our understanding of the immune, vascular and fibrotic mechanisms underlying the pathogenesis of SSc have revealed a growing number of potential therapeutic targets.

  • Clinical trials have shown some efficacy of therapies for SSc that target immune cell types and mediators and cellular pathways that drive fibrosis.

  • Key challenges in the development of effective disease-modifying therapies for SSc include patient heterogeneity and a lack of consensus on optimal trial design and efficacy end points.

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Fig. 1: A model of SSc pathogenesis that highlights potential targets for disease-modifying therapy.
Fig. 2: Pathogenic fibroblast activation triggers pathways in SSc that are potential targets for disease-modifying therapy.

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Acknowledgements

The authors thank D. Legares, S. Bhattacharyya and B. Korman for helpful discussions. The authors’ research is supported by grants from the National Institutes of Health (AR42309 and R56AG054207 to J.V. and E.R.V.) and a grant from the Rheumatology Research Foundation (to E.R.V.).

Review criteria

Articles for inclusion in this narrative review and overview article were selected by searching PubMed to identify relevant articles published in the past 5 years using the following search terms: “systemic sclerosis” OR “scleroderma” and “treatment” OR “therapy”. The abstracts of retrieved articles were reviewed to determine whether they described an inflammatory target, a fibrosis target or a vascular target, and articles that described none of these were eliminated. Additionally, the ClinicalTrials.gov database was searched using the terms “scleroderma” or “systemic sclerosis” to identify relevant clinical trials published within the past 5 years.

Reviewer information

Nature Reviews Rheumatology thanks C. Buckley, M. Matucci-Cerinic, and other anonymous reviewer(s), for their contribution to the peer review of this work.

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  1. Department of Medicine, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA

    Elizabeth R. Volkmann

  2. Scleroderma Program, Departments of Medicine, Dermatology and Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    John Varga

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The authors contributed equally to all aspects of the article.

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Correspondence to John Varga.

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E.R.V. declares that she has acted as a clinical trial investigator for Boehringer-Ingelheim and Genentech/Roche and is an advisory board member for Boehringer-Ingelheim. J.V. declares that he has acted as a clinical trial investigator for Corbus, Cytori, GlaxoSmithKline and Genentech/Roche; has received research grants from Bristol-Myers Squibb, Pfizer and the National Institutes of Health (NIH); and is an advisory board member for Boehringer-Ingelheim, Corbus, Emerald, Inventiva and Mitsubishi.

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Volkmann, E.R., Varga, J. Emerging targets of disease-modifying therapy for systemic sclerosis. Nat Rev Rheumatol 15, 208–224 (2019). https://doi.org/10.1038/s41584-019-0184-z

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