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Systemic sclerosis

Abstract

Systemic sclerosis is a complex autoimmune disease characterized by a chronic and frequently progressive course and by extensive patient-to-patient variability. Like other autoimmune diseases, systemic sclerosis occurs more frequently in women, with a peak of onset in the fifth decade of life. The exact cause of systemic sclerosis remains elusive but is likely to involve environmental factors in a genetically primed individual. Pathogenesis is dominated by vascular changes; evidence of autoimmunity with distinct autoantibodies and activation of both innate and adaptive immunity; and fibrosis of the skin and visceral organs that results in irreversible scarring and organ failure. Intractable progression of vascular and fibrotic organ damage accounts for the chronic morbidity and high mortality. Early and accurate diagnosis and classification might improve patient outcomes. Screening strategies facilitate timely recognition of life-threatening complications and initiation of targeted therapies to halt their progression. Effective treatments of organ-based complications are now within reach. Discovery of biomarkers — including autoantibodies that identify patient subsets at high risk for particular disease complications or rapid progression — is a research priority. Understanding the key pathogenetic pathways, cell types and mediators underlying disease manifestations opens the door for the development of targeted therapies with true disease-modifying potential. For an illustrated summary of this Primer, visit: http://go.nature.com/lchkcA

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Figure 1: Characteristics of the EUSTAR cohort.
Figure 2: The disease process in systemic sclerosis.
Figure 3: Molecular mechanisms of fibroblast activation in systemic sclerosis.
Figure 4: Organ complications associated with systemic sclerosis.
Figure 5: Early systemic sclerosis-associated interstitial lung disease.
Figure 6: Future of clinical trial design in systemic sclerosis.
Figure 7: Putative therapeutic targets in systemic sclerosis.

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Acknowledgements

R.S. is supported in part by a grant from the US National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), 1P50AR060780‒01. O.D. is supported by funding from the European League Against Rheumatism orphan disease programme, Swiss National Science Foundation Sinergia, European Union FP‒7 DeSScipher and Rare Disease Initiative Zurich (RADIZ). M.T. is supported by grants NIAMS RO1 AR042334 and P50 AR060780. J.V. is supported by grants NIAMS AR042309 and AR064925.

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Introduction (J.V.); Epidemiology (Y.A.); Mechanisms/pathophysiology (J.V., M.T.); Diagnosis, screening and prevention (O.D.); Management (R.S.); Quality of life (J.P.); Outlook (C.P.D.); overview of Primer (J.V.).

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Correspondence to John Varga.

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Competing interests

Y.A. has/had consultancy relationships and/or has received research funding in the area of systemic sclerosis and related conditions from Actelion, Bayer, Biogen, Bristol–Meyers Squibb, Inventiva, Medac, Pfizer, Roche/Genentech, Sanofi-Aventis and Servier. R.S. has/had consultancy relationships and/or has received research funding in the area of systemic sclerosis and related conditions from Actelion, Gilead, Hoffman–La Roche, Intermune, MedImmune, Novartis, Regeneron and United Therapeutics. O.D. has/had consultancy relationships and/or has received research funding in the area of systemic sclerosis and related conditions from 4D Science, Actelion, Active Biotec, Bayer, Biogen, Biovitrium, Bristol–Meyers Squibb, Boehringer, EpiPharm, Ergonex, GlaxoSmithKline, Inventiva, Medac, Novartis, Pfizer, Pharmacyclics, Roche/Genentech, Sanofi-Aventis, Serodapharm, Sinoxa and United BioSource. J.P. has/had consultancy relationships and/or has received research funding in the area of systemic sclerosis and related conditions from Actelion, Bayer, Biogen, and Roche/Genentech. C.P.D. has/had consultancy relationships and/or has received research funding in the area of systemic sclerosis and related conditions from Actelion, Biogen, Biovitrum, Boehringer Ingelheim, CSL Behring, GlaxoSmithKline, Inventiva, Novartis, Pfizer, Roche/Genetech and Sanofi-Aventis. J.V. has acted as a consultant or received research funding from Biogen/Idec, Takeda, the US National Institutes of Health, US Department of Defense. M.T. declares no competing interests.

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Allanore, Y., Simms, R., Distler, O. et al. Systemic sclerosis. Nat Rev Dis Primers 1, 15002 (2015). https://doi.org/10.1038/nrdp.2015.2

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