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Assessment of disease outcome measures in systemic sclerosis

Nature Reviews Rheumatology volume 18, pages 527–541 (2022)Cite this article

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Abstract

The assessment of disease activity in systemic sclerosis (SSc) is challenging owing to its heterogeneous manifestations across multiple organ systems, the variable rate of disease progression and regression, and the relative paucity of patients in early-phase therapeutic trials. Despite some recent successes, most clinical trials have failed to show efficacy, underscoring the need for improved outcome measures linked directly to disease pathogenesis, particularly applicable for biomarker studies focused on skin disease. Current outcome measures in SSc-associated interstitial lung disease and SSc skin disease are largely adequate, although advancing imaging technology and the incorporation of skin mRNA biomarkers might provide opportunities for earlier detection of the therapeutic effect. Biomarkers can further inform pathogenesis, enabling early phase trials to act as reverse translational studies through the incorporation of routine high-throughput sequencing.

Key points

  • The majority of clinical trials for systemic sclerosis (SSc) focus on skin disease, interstitial lung disease (ILD), or pulmonary arterial hypertension, with modified Rodnan skin score (MRSS), forced vital capacity and 6-min walk distance being the primary clinical end points assessed, respectively.

  • Increased variability in the natural history of SSc skin disease impedes the identification of treatment-related effects, and strategies for shorter duration trials might improve the separation of treatment effect from variation in disease natural history.

  • Forced vital capacity is an FDA-accepted surrogate outcome measure for SSc-ILD, whereas novel imaging technologies and serum biomarkers present opportunities for future additional SSc-ILD outcome measures to show significant changes at earlier timepoints.

  • Skin mRNA biomarkers, including THBS1 and COMP, could be considered as surrogate outcome measures in early-phase clinical trials, to more rapidly assess target engagement by therapeutic efficacy.

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Fig. 1: Heterogeneity of SSc skin pathology.
Fig. 2: Skin cell populations expressing biomarkers in SSc skin disease.
Fig. 3: Lung cell populations expressing biomarkers in SSc-ILD.

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Acknowledgements

R.L. is supported by the National Institutes of Health. E.V. is supported by the National Scleroderma Foundation and the Pulmonary Fibrosis Foundation.

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  1. Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA

    Robert Lafyatis

  2. Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Eleanor Valenzi

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Correspondence to Robert Lafyatis.

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R.L. has served as a consultant for Pfizer, Bristol Myers Squibb, Boehringer-Ingelheim, Formation, Sanofi, Boehringer-Mannheim, Merck and Genentech/Roche, and holds or recently had research grants from Corbus, Formation, Moderna, Regeneron, Pfizer, and Kiniksa. E.V. declares no competing interests.

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Lafyatis, R., Valenzi, E. Assessment of disease outcome measures in systemic sclerosis. Nat Rev Rheumatol 18, 527–541 (2022). https://doi.org/10.1038/s41584-022-00803-6

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