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An international perspective on the future of systemic sclerosis research

Nature Reviews Rheumatology volume 21, pages 174–187 (2025)Cite this article

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A Publisher Correction to this article was published on 03 March 2025

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Abstract

Systemic sclerosis (SSc) remains a challenging and enigmatic systemic autoimmune disease, owing to its complex pathogenesis, clinical and molecular heterogeneity, and the lack of effective disease-modifying treatments. Despite a century of research in SSc, the interconnections among microvascular dysfunction, autoimmune phenomena and tissue fibrosis in SSc remain unclear. The absence of validated biomarkers and reliable animal models complicates diagnosis and treatment, contributing to high morbidity and mortality. Advances in the past 5 years, such as single-cell RNA sequencing, next-generation sequencing, spatial biology, transcriptomics, genomics, proteomics, metabolomics, microbiome profiling and artificial intelligence, offer new avenues for identifying the early pathogenetic events that, once treated, could change the clinical history of SSc. Collaborative global efforts to integrate these approaches are crucial to developing a comprehensive, mechanistic understanding and enabling personalized therapies. Challenges include disease classification, clinical heterogeneity and the establishment of robust biomarkers for disease activity and progression. Innovative clinical trial designs and patient-centred approaches are essential for developing effective treatments. Emerging therapies, including cell-based and fibroblast-targeting treatments, show promise. Global cooperation, standardized protocols and interdisciplinary research are vital for advancing SSc research and improving patient outcomes. The integration of advanced research techniques holds the potential for important breakthroughs in the diagnosis, treatment and care of individuals with SSc.

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Fig. 1: Steps in the pathogenesis of systemic sclerosis phenotypes.
Fig. 2: The future of research in systemic sclerosis.
Fig. 3: Overview of the pathogenesis of systemic sclerosis.
Fig. 4: Omics for disease differentiation and precision medicine in systemic sclerosis.

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Acknowledgements

The authors thank K. Brennan for administrative support and meeting summary. Workshop support provided by The Edith Busch Foundation and The Fondazione di Medicina Molecolare e Terapia Cellulare, Università Politecnica delle Marche-Ancona, Italy.

Author information

Authors and Affiliations

  1. Department of Inflammation and Rare Diseases, UCL Centre for Rheumatology, UCL Division of Medicine, Royal Free Hospital Campus, London, UK

    David J. Abraham, Carol M. Black & Christopher P. Denton

  2. Department of Rheumatology, University Hospital Düsseldorf, Medical Faculty of the Heinrich-Heine University, Düsseldorf, Germany

    Jörg H. W. Distler

  3. Hiller Research Center, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University, Düsseldorf, Germany

    Jörg H. W. Distler & Armando Gabrielli

  4. Division of Rheumatology, Department of Internal Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Robyn Domsic

  5. Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, USA

    Carol Feghali-Bostwick

  6. Scleroderma Genomics and Health Disparities Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA

    Pravitt Gourh

  7. Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA

    Monique Hinchcliff

  8. Geisel School of Medicine at Dartmouth, Hanover, NH, USA

    Fred Kolling IV

  9. Department of Allergy and Rheumatology. Nippon Medical School Graduate School of Medicine, Tokyo, Japan

    Masataka Kuwana

  10. Division of Rheumatology and Clinical Immunology. University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Robert Lafyatis

  11. Department of Immunology, Genetics and Pathology, Research programme: Molecular Tools and Functional Genomics, Uppsala University, Uppsala, Sweden

    Ulf Landegren

  12. The Jackson Laboratory, Bar Harbour, ME, USA

    J. Matthew Mahoney

  13. Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain

    Javier Martin

  14. Unit of Immunology, Rheumatology, Allergy and Rare Diseases and Inflammation, fibrosis and aging Initiative, IRCCS Ospedle San Raffaele and Vita Salute University San Raffaele, Milan, Italy

    Marco Matucci-Cerinic

  15. Department of Internal Medicine, Division of Rheumatology, UTHealth Houston, Houston, TX, USA

    Zsuzsanna H. McMahan

  16. Division of Pulmonary, Critical Care and Sleep Medicine, Davis Heart and Lung research Institute, The Ohio State University College of Medicine, Columbus, OH, USA

    Ana L. Mora & Mauricio Rojas

  17. Department of Internal Medicine, Reference Center for Rare Systemic Autoimmune and Auto-Inflammatory diseases in Île-de-France, East and West, Cochin Hospital, Public Assistance-Hospitals of Paris, Paris-Centre, Paris Cité University, Paris, France

    Luc Mouthon

  18. Department of Paediatrics, Stanford University School of Medicine, Stanford, CA, USA

    Marlene Rabinovitch

  19. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA

    Marlene Rabinovitch

  20. Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University School of Medicine, Stanford, CA, USA

    Marlene Rabinovitch

  21. Basic Science and Engineering (BASE) Initiative, Betty Irene Moore Children’s Heart Center, Lucile Packard Children’s Hospital, Stanford University School of Medicine, Stanford, CA, USA

    Marlene Rabinovitch

  22. Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden

    Kristofer Rubin

  23. Boston University, Department of Medicine, Arthritis & Autoimmune Diseases Research Center, Boston, MA, USA

    Maria Trojanowska

  24. Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, USA

    John Varga

  25. Department of Biomedical Data Science, Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA

    Michael L. Whitfield

  26. Foundation of Molecular Medicine and Cellular Therapy Polytechnic University of Marche, Via Tronto, Ancona, Italy

    Armando Gabrielli

  27. Translational Matrix Biology, Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Center for Molecular Medicine (CMMC) University of Cologne, Cologne, Germany

    Thomas Krieg

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  1. David J. Abraham
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  2. Carol M. Black
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Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to David J. Abraham, Armando Gabrielli or Thomas Krieg.

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Competing interests

J.H.W.D. has consultancy relationships with AbbVie, Active Biotech, Anamar, ARXX, AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, Genentech, GSK, Inventiva, Janssen, Novartis, Pfizer, Roche and UCB, and has received research funding from AbbVie, Anamar, Argenx, ARXX, BMS, Bayer Pharma, Boehringer Ingelheim, Cantargia, Celgene, CSL Behring, ExoTherapeutics, Galapagos, GSK, Inventiva, Kiniksa, Lassen, Novartis, Sanofi-Aventis, RedX, UCB and Zenasbio. J.H.W.D. is CEO of 4D Science and Scientific Lead of FibroCure. R.D. has received funding from and is a consultant for Aisa Pharma Inc and AstraZeneca. M.K. has received funding from and is a consultant for Boehringer Ingelheim, Mochida, Kissei, GSK, AstraZeneca, Mitsubishi Tanabe, Janssen, Biogen, Novartis, Chugai and Asahi Kasei Pharma. U.L. is the founder of Olink Proteomics and has stocks in Navinci and SampleFacts.

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Nature Reviews Rheumatology thanks Lorinda Chung, who co-reviewed with Brian Lee, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Abraham, D.J., Black, C.M., Denton, C.P. et al. An international perspective on the future of systemic sclerosis research. Nat Rev Rheumatol 21, 174–187 (2025). https://doi.org/10.1038/s41584-024-01217-2

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