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  • Review Article
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Skin involvement in early diffuse cutaneous systemic sclerosis: an unmet clinical need

Nature Reviews Rheumatology volume 18, pages 276–285 (2022)Cite this article

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Abstract

Diffuse cutaneous systemic sclerosis (dcSSc) is associated with high mortality resulting from early internal-organ involvement. Clinicians therefore tend to focus on early diagnosis and treatment of potentially life-threatening cardiorespiratory and renal disease. However, the rapidly progressive painful, itchy skin tightening that characterizes dcSSc is the symptom that has the greatest effect on patients’ quality of life, and there is currently no effective disease-modifying treatment for it. Considerable advances have been made in predicting the extent and rate of skin-disease progression (which vary between patients), including the development of techniques such as molecular analysis of skin biopsy samples. Risk stratification for progressive skin disease is especially relevant now that haematopoietic stem-cell transplantation is a treatment option, because stratification will inform the balance of risk versus benefit for each patient. Measurement of skin disease is a major challenge. Results from clinical trials have highlighted limitations of the modified Rodnan skin score (the current gold standard). Alternative patient-reported and other potential outcome measures have been and are being developed. Patients with early dcSSc should be referred to specialist centres to ensure best-practice management, including the management of their skin disease, and to maximize opportunities for inclusion in clinical trials.

Key points

  • Much of the pain and disability of early diffuse cutaneous systemic sclerosis (dcSSc) results from skin thickening (scleroderma), which can be rapidly progressive, commencing distally then extending proximally.

  • ‘Progressors’ in terms of skin disease can now be identified by considering disease duration, extent of skin disease, autoantibody status and (potentially) gene-expression profiling of skin biopsy specimens.

  • Improvement in the ability to predict progressive skin disease will inform the selection of patients for haematopoietic stem-cell transplantation, as well as more targeted inclusion of patients in clinical trials.

  • Limitations of the modified Rodnan skin score are stimulating development of other outcome measures of skin disease, including patient-reported outcome measures, non-invasive imaging methods and composite scores.

  • Best-practice management of early dcSSc includes early referral to a specialist centre, pain management, multidisciplinary input, immunosuppressive therapy and, when at all possible, inclusion in a clinical trial.

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Fig. 1: Skin involvement in diffuse cutaneous systemic sclerosis.
Fig. 2: Conceptual framework for skin-score trajectory and clinical diversity in diffuse cutaneous systemic sclerosis.
Fig. 3: Management of skin disease in patients with early diffuse cutaneous systemic sclerosis.

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Acknowledgements

This work was supported by the NIHR Manchester Biomedical Research Centre and NIH/NIAMS (R61AR078078).

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Authors and Affiliations

  1. Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK

    Ariane L. Herrick

  2. McGovern Medical School, The University of Texas, Houston, TX, USA

    Shervin Assassi

  3. UCL Division of Medicine, Royal Free London NHS Foundation Trust, London, UK

    Christopher P. Denton

Authors
  1. Ariane L. Herrick
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  2. Shervin Assassi
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  3. Christopher P. Denton
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Contributions

All authors contributed equally to all aspects of the Review.

Corresponding author

Correspondence to Ariane L. Herrick.

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Competing interests

A.H. has received consultancy fees from Boehringer-Ingelheim, Camurus, CSL Behring and Gesynta, research funding from Gesynta and speaker’s fees from Janssen. S.A. has received grant support from Boehringer-Ingelheim, Janssen and Momenta Pharmaceuticals, and has received personal fees for participation in advisory board meetings from AstraZeneca, Boehringer-Ingelheim, Corbus Pharmaceuticals, CSL Behring and Novartis. C.D. has received grants and personal fees from CSL Behring and GlaxoSmithKline, grants from Arxx Therapeutics, Inventiva and Servier, and personal fees from Acceleron, Bayer, Boehringer-Ingelheim, BristolMyersSquibb, Corbus, Horizon, Roche and Sanofi.

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Nature Reviews Rheumatology thanks L. Chung, who co-reviewed with S. Davuluri; M. Matucci-Cerinic; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Contractures

Deformities resulting from tissue shortening or hardening; in patients with SSc contracture is caused by tightening of the skin.

Ulcers

Skin lesions with discernible depth and loss of the epithelium.

Scleroderma renal crisis

A complication of SSc that involves sudden onset of hypertension accompanied by renal failure.

Tendon friction rubs

Palpable rubs that are found, for example, over wrists, ankles and knees, and are thought to result from inflammatory change in the tenosynovium.

Elastography

Assessment of the elasticity and stiffness of soft tissues, usually by ultrasonography.

Raynaud phenomenon

Colour change of the fingers on exposure to cold or to emotional stress: the classic triphasic change is white to blue to red.

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Herrick, A.L., Assassi, S. & Denton, C.P. Skin involvement in early diffuse cutaneous systemic sclerosis: an unmet clinical need. Nat Rev Rheumatol 18, 276–285 (2022). https://doi.org/10.1038/s41584-022-00765-9

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