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  • Primer
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Systemic sclerosis

Nature Reviews Disease Primers volume 1, Article number: 15002 (2015) Cite this article

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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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References

  1. Nihtyanova, S. I. et al. Prediction of pulmonary complications and long-term survival in systemic sclerosis. Arthritis Rheumatol. 66, 1625–1635 (2014).

    Article  PubMed  Google Scholar 

  2. Domsic, R. T., Rodriguez-Reyna, T., Lucas, M., Fertig, N. & Medsger, T. A. Skin thickness progression rate: a predictor of mortality and early internal organ involvement in diffuse scleroderma. Ann. Rheum. Dis. 70, 104–109 (2011).

    Article  PubMed  Google Scholar 

  3. LeRoy, E. C. et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J. Rheumatol. 15, 202–205 (1988).

    CAS  PubMed  Google Scholar 

  4. Steen, V. D. Autoantibodies in systemic sclerosis. Semin. Arthritis Rheum. 35, 35–42 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Van den Hoogen, F. et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League Against Rheumatism Collaborative Initiative. Arthritis Rheum. 65, 2737–2747 (2013). This paper describes the revised classification criteria for systemic sclerosis.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Van den Hoogen, F. et al. 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann. Rheum. Dis. 72, 1747–1755 (2013).

    Article  PubMed  Google Scholar 

  7. Barnes, J. & Mayes, M. D. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr. Opin. Rheumatol. 24, 165–170 (2012).

    Article  PubMed  Google Scholar 

  8. Andréasson, K., Saxne, T., Bergknut, C., Hesselstrand, R. & Englund, M. Prevalence and incidence of systemic sclerosis in southern Sweden: population-based data with case ascertainment using the 1980 ARA criteria and the proposed ACR–EULAR classification criteria. Ann. Rheum. Dis. 73, 1788–1792 (2014). This paper describes prevalence and incidence estimations using the EULAR database and the revised classification criteria.

    Article  PubMed  Google Scholar 

  9. Elhai, M. et al. A gender gap in primary and secondary heart dysfunctions in systemic sclerosis: a EUSTAR prospective study. Ann. Rheum. Dis.http://dx.doi.org/10.1136/annrheumdis-2014-206386 (2014). This study highlights the gender gap in disease manifestations associated with systemic sclerosis.

  10. Gelber, A. C. et al. Race and association with disease manifestations and mortality in scleroderma: a 20-year experience at the Johns Hopkins Scleroderma Center and review of the literature. Medicine 92, 191–205 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Elhai, M., Avouac, J., Kahan, A. & Allanore, Y. Systemic sclerosis at the crossroad of polyautoimmunity. Autoimmun. Rev. 12, 1052–1057 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. Katsumoto, T. R., Whitfield, M. L. & Connolly, M. K. The pathogenesis of systemic sclerosis. Annu. Rev. Pathol. 6, 509–537 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Bhattacharyya, S., Wei, J. & Varga, J. Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat. Rev. Rheumatol. 8, 42–54 (2012). This is an up-to-date comprehensive review on fibrotic-complication mechanisms of systemic sclerosis.

    Article  CAS  Google Scholar 

  14. Trojanowska, M. Cellular and molecular aspects of vascular dysfunction in systemic sclerosis. Nat. Rev. Rheumatol. 6, 453–460 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Mayes, M. D. et al. ImmunoChIP analysis identifies multiple susceptibility loci for systemic sclerosis. Am. J. Hum. Genet. 94, 47–61 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Assassi, S. et al. Systemic sclerosis and lupus: points in an interferon-mediated continuum. Arthritis Rheum. 62, 589–598 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kim, D. et al. Induction of interferon-α by scleroderma sera containing autoantibodies to topoisomerase I: association of higher interferon-α activity with lung fibrosis. Arthritis Rheum. 58, 2163–2173 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. York, M. R. et al. A macrophage marker, Siglec-1, is increased on circulating monocytes in patients with systemic sclerosis and induced by type I interferons and Toll-like receptor agonists. Arthritis Rheum. 56, 1010–1020 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Chizzolini, C., Parel, Y., Scheja, A. & Dayer, J.-M. Polarized subsets of human T-helper cells induce distinct patterns of chemokine production by normal and systemic sclerosis dermal fibroblasts. Arthritis Res. Ther. 8, R10 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Brembilla, N. C. et al. TH17 cells favor inflammatory responses while inhibiting type I collagen deposition by dermal fibroblasts: differential effects in healthy and systemic sclerosis fibroblasts. Arthritis Res. Ther. 15, R151 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shimizu, K. et al. Increased serum levels of soluble CD163 in patients with scleroderma. Clin. Rheumatol. 31, 1059–1064 (2012).

    Article  PubMed  Google Scholar 

  22. Christmann, R. B. et al. Association of Interferon- and transforming growth factor β-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis. Arthritis Rheumatol. 66, 714–725 (2014). This paper highlights the role of innate immunity and macrophages in systemic sclerosis-associated interstitial lung disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mathes, A. L. et al. Global chemokine expression in systemic sclerosis (SSc): CCL19 expression correlates with vascular inflammation in SSc skin. Ann. Rheum. Dis. 73, 1864–1872 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Mathai, S. K. et al. Circulating monocytes from systemic sclerosis patients with interstitial lung disease show an enhanced profibrotic phenotype. Lab. Invest. 90, 812–823 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. O'Reilly, S., Hügle, T. & van Laar, J. M. T cells in systemic sclerosis: a reappraisal. Rheumatology 51, 1540–1549 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. O'Reilly, S. Role of interleukin-13 in fibrosis, particularly systemic sclerosis. Biofactors 39, 593–596 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Khan, K. et al. Clinical and pathological significance of interleukin 6 overexpression in systemic sclerosis. Ann. Rheum. Dis. 71, 1235–1242 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. Kitaba, S. et al. Blockade of interleukin-6 receptor alleviates disease in mouse model of scleroderma. Am. J. Pathol. 180, 165–176 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. Yoshizaki, A. et al. Immunization with DNA topoisomerase I and Freund's complete adjuvant induces skin and lung fibrosis and autoimmunity via interleukin-6 signaling. Arthritis Rheum. 63, 3575–3585 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. Bandinelli, F. et al. CCL2, CCL3 and CCL5 chemokines in systemic sclerosis: the correlation with SSc clinical features and the effect of prostaglandin E1 treatment. Clin. Exp. Rheumatol. 30, S44–49 (2012).

    PubMed  Google Scholar 

  31. Hasegawa, M. et al. Serum chemokine levels as prognostic markers in patients with early systemic sclerosis: a multicenter, prospective, observational study. Mod. Rheumatol. 23, 1076–1084 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Tiev, K. P. et al. Serum CC chemokine ligand-18 predicts lung disease worsening in systemic sclerosis. Eur. Respir. J. 38, 1355–1360 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Van Bon, L. et al. Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N. Engl. J. Med. 370, 433–443 (2014). This paper describes plasmacytoid dendritic cells as important mediators of fibrosis.

    Article  CAS  PubMed  Google Scholar 

  34. Dragun, D., Distler, J. H. W., Riemekasten, G. & Distler, O. Stimulatory autoantibodies to platelet-derived growth factor receptors in systemic sclerosis: what functional autoimmunity could learn from receptor biology. Arthritis Rheum. 60, 907–911 (2009).

    Article  PubMed  Google Scholar 

  35. Baroni, S. S. et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N. Engl. J. Med. 354, 2667–2676 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Kill, A. et al. Autoantibodies to angiotensin and endothelin receptors in systemic sclerosis induce cellular and systemic events associated with disease pathogenesis. Arthritis Res. Ther. 16, R29 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Castelino, F. V. & Varga, J. Emerging cellular and molecular targets in fibrosis: implications for scleroderma pathogenesis and targeted therapy. Curr. Opin. Rheumatol. 26, 607–614 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Hinz, B. et al. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am. J. Pathol. 180, 1340–1355 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Marangoni, R. G. et al. Myofibroblasts in cutaneous fibrosis originate from adiponectin-positive intradermal progenitors. Arthritis Rheumatol.http://dx.doi.org/10.1002/art.38990 (2014). This paper describes the adipogenic progenitor cells as precursors of myofibroblasts in skin lesions associated with systemic sclerosis.

  40. Ho, Y. Y., Lagares, D., Tager, A. M. & Kapoor, M. Fibrosis — a lethal component of systemic sclerosis. Nat. Rev. Rheumatol. 10, 390–402 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Bhattacharyya, S. et al. FibronectinEDA promotes chronic cutaneous fibrosis through Toll-like receptor signaling. Sci. Transl. Med. 6, 232ra50 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Varga, J. & Pasche, B. Transforming growth factor β as a therapeutic target in systemic sclerosis. Nat. Rev. Rheumatol. 5, 200–206 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Asano, Y., Ihn, H., Yamane, K., Kubo, M. & Tamaki, K. Impaired SMAD7–SMURF-mediated negative regulation of TGF-β signaling in scleroderma fibroblasts. J. Clin. Invest. 113, 253–264 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhou, F. et al. Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-β signalling. Nat. Commun. 5, 3388 (2014).

  45. Wong, V. W. et al. Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling. Nature Med. 18, 148–152 (2012).

    Article  CAS  Google Scholar 

  46. Abraham, D. Connective tissue growth factor: growth factor, matricellular organizer, fibrotic biomarker or molecular target for anti-fibrotic therapy in SSc? Rheumatology 47, (Suppl. 5), v8–v9 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Leask, A., Denton, C. P. & Abraham, D. J. Insights into the molecular mechanism of chronic fibrosis: the role of connective tissue growth factor in scleroderma. J. Invest. Dermatol. 122, 1–6 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Trojanowska, M. Role of PDGF in fibrotic diseases and systemic sclerosis. Rheumatology 47, (Suppl. 5), v2–v4 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Olson, L. E. & Soriano, P. Increased PDGFRα activation disrupts connective tissue development and drives systemic fibrosis. Dev. Cell 16, 303–313 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Svegliati, S. et al. Oxidative DNA damage induces the ATM-mediated transcriptional suppression of the WNT inhibitor WIF-1 in systemic sclerosis and fibrosis. Sci. Signal. 7, ra84 (2014). This study implicates oxidative stress and WNT signalling as key drivers in tissue damage and fibrosis.

    Article  CAS  PubMed  Google Scholar 

  51. Beyer, C. et al. Blockade of canonical WNT signalling ameliorates experimental dermal fibrosis. Ann. Rheum. Dis. 72, 1255–1258 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Lam, A. P. et al. WNT coreceptor Lrp5 is a driver of idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 190, 185–195 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wei, J. et al. WNT/β-catenin signaling is hyperactivated in systemic sclerosis and induces Smad-dependent fibrotic responses in mesenchymal cells. Arthritis Rheum. 64, 2734–2745 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Arnett, F. C. et al. Familial occurrence frequencies and relative risks for systemic sclerosis (scleroderma) in three United States cohorts. Arthritis Rheum. 44, 1359–1362 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Frech, T. et al. Heritability of vasculopathy, autoimmune disease, and fibrosis in systemic sclerosis: a population-based study. Arthritis Rheum. 62, 2109–2116 (2010).

    PubMed  PubMed Central  Google Scholar 

  56. Varga, J. & Hinchcliff, M. Connective tissue diseases: systemic sclerosis: beyond limited and diffuse subsets? Nat. Rev. Rheumatol. 10, 200–202 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Altorok, N., Almeshal, N., Wang, Y. & Kahaleh, B. Epigenetics, the holy grail in the pathogenesis of systemic sclerosis. Rheumatologyhttp://dx.doi.org/10.1093/rheumatology/keu155 (2014).

  58. Broen, J. C. A., Radstake, T. R. D. J. & Rossato, M. The role of genetics and epigenetics in the pathogenesis of systemic sclerosis. Nat. Rev. Rheumatol. 10, 671–681 (2014).

    Article  CAS  PubMed  Google Scholar 

  59. Altorok, N., Tsou, P.-S., Coit, P., Khanna, D. & Sawalha, A. H. Genome-wide DNA methylation analysis in dermal fibroblasts from patients with diffuse and limited systemic sclerosis reveals common and subset-specific DNA methylation aberrancies. Ann. Rheum. Dis.http://dx.doi.org/10.1136/annrheumdis-2014-205303 (2014).

  60. Noda, S. et al. Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis. Nat. Commun. 5, 5797 (2014).

  61. Dees, C. et al. The WNT antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis. Ann. Rheum. Dis. 73, 1232–1239 (2014).

    Article  CAS  PubMed  Google Scholar 

  62. Wang, Y., Fan, P.-S. & Kahaleh, B. Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. Arthritis Rheum. 54, 2271–2279 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Lei, W. et al. Abnormal DNA methylation in CD4+ T cells from patients with systemic lupus erythematosus, systemic sclerosis, and dermatomyositis. Scand. J. Rheumatol. 38, 369–374 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Wang, Y. Y. et al. DNA hypermethylation of the forkhead box protein 3 (FOXP3) promoter in CD4+ T cells of patients with systemic sclerosis. Br. J. Dermatol. 171, 39–47 (2014).

    Article  CAS  PubMed  Google Scholar 

  65. Ghosh, A. K., Mori, Y., Dowling, E. & Varga, J. Trichostatin A blocks TGF-β-induced collagen gene expression in skin fibroblasts: involvement of Sp1. Biochem. Biophys. Res. Commun. 354, 420–426 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Huber, L. C. et al. Trichostatin A prevents the accumulation of extracellular matrix in a mouse model of bleomycin-induced skin fibrosis. Arthritis Rheum. 56, 2755–2764 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Ghosh, A. K. et al. p300 is elevated in systemic sclerosis and its expression is positively regulated by TGF-β: epigenetic feed-forward amplification of fibrosis. J. Invest. Dermatol. 133, 1302–1310 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Zhu, H. et al. MicroRNA-21 in scleroderma fibrosis and its function in TGF-β-regulated fibrosis-related genes expression. J. Clin. Immunol. 33, 1100–1109 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Bhattacharyya, S. et al. Toll-like receptor 4 signaling augments transforming growth factor-β responses: a novel mechanism for maintaining and amplifying fibrosis in scleroderma. Am. J. Pathol. 182, 192–205 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Maurer, B. et al. MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis Rheum. 62, 1733–1743 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Chaudhary, P. et al. Cigarette smoking is not a risk factor for systemic sclerosis. Arthritis Rheum. 63, 3098–3102 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Hissaria, P. et al. Survival in scleroderma: results from the population-based South Australian Register. Intern. Med. J. 41, 381–390 (2011).

    Article  CAS  PubMed  Google Scholar 

  73. Dospinescu, P., Jones, G. T. & Basu, N. Environmental risk factors in systemic sclerosis. Curr. Opin. Rheumatol. 25, 179–183 (2013).

    Article  PubMed  Google Scholar 

  74. Lunardi, C. et al. Antibodies against human cytomegalovirus in the pathogenesis of systemic sclerosis: a gene array approach. PLoS Med. 3, e2 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Farina, A. et al. Epstein–Barr virus infection induces aberrant TLR activation pathway and fibroblast–myofibroblast conversion in scleroderma. J. Invest. Dermatol. 134, 954–964 (2014). This paper describes the potential pathogenic role of latent virus infection in triggering systemic sclerosis.

    Article  CAS  PubMed  Google Scholar 

  76. [No authors listed]. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum. 23, 581–590 (1980).

  77. Lonzetti, L. S. et al. Updating the American College of Rheumatology preliminary classification criteria for systemic sclerosis: addition of severe nailfold capillaroscopy abnormalities markedly increases the sensitivity for limited scleroderma. Arthritis Rheum. 44, 735–736 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Alhajeri, H. et al. The 2013 ACR/EULAR Classification Criteria for Systemic Sclerosis out-perform the 1980 Criteria. Data from the Canadian Scleroderma Research Group. Arthritis Care Res.http://dx.doi.org/10.1002/acr.22451 (2015).

  79. Jordan, S., Maurer, B., Toniolo, M., Michel, B. & Distler, O. Performance of the new ACR/EULAR classification criteria for systemic sclerosis in clinical practice. Rheumatology (Oxford)http://dx.doi.org/10.1093/rheumatology/keu530 (2015).

  80. Avouac, J. et al. Preliminary criteria for the Very Early Diagnosis of Systemic Sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group. Ann. Rheum. Dis. 70, 476–481 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. Minier, T. et al. Preliminary analysis of the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) EUSTAR multicentre study: evidence for puffy fingers as a pivotal sign for suspicion of systemic sclerosis. Ann. Rheum. Dis. 73, 2087–2093 (2013).

    Article  PubMed  Google Scholar 

  82. Koenig, M. et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosi. Arthritis Rheum. 58, 3902–3912 (2008). This paper reinforces that Raynaud phenomenon precedes and can predict development of systemic sclerosis in some cases.

    Article  PubMed  Google Scholar 

  83. Valentini, G. et al. Early systemic sclerosis: analysis of the disease course in patients with marker autoantibody and/or capillaroscopic positivity. Arthritis Care Res. 66, 1520–1527 (2014).

    Article  Google Scholar 

  84. Bartelink, M. L., Wollersheim, H., van de Lisdonk, E., Spruijt, R. & van Weel, C. Prevalence of Raynaud's phenomenon. Neth. J. Med. 41, 149–152 (1992).

    CAS  PubMed  Google Scholar 

  85. Valentini, G. et al. Early systemic sclerosis: assessment of clinical and pre-clinical organ involvement in patients with different disease features. Rheumatology 50, 317–323 (2011).

    Article  PubMed  Google Scholar 

  86. Lepri, G. et al. Evidence for oesophageal and anorectal involvement in very early systemic sclerosis (VEDOSS): report from a single VEDOSS/EUSTAR centre. Ann. Rheum. Dis. 74, 124–128 (2015).

    Article  PubMed  Google Scholar 

  87. Steen, V. D. & Medsger, T. A. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum. 43, 2437–2444 (2000). This paper describes predictors of severe organ damage in systemic sclerosis.

    Article  CAS  PubMed  Google Scholar 

  88. Humbert, M. et al. Screening for pulmonary arterial hypertension in patients with systemic sclerosis: clinical characteristics at diagnosis and long-term survival. Arthritis Rheum. 63, 3522–3530 (2011).

    Article  PubMed  Google Scholar 

  89. Galiè, N. et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 371, 2093–2100 (2008).

    Article  PubMed  Google Scholar 

  90. Furst, D. E. et al. The modified Rodnan skin score is an accurate reflection of skin biopsy thickness in systemic sclerosis. J. Rheumatol. 25, 84–88 (1998).

    CAS  PubMed  Google Scholar 

  91. Clements, P. et al. Inter and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis. J. Rheumatol. 22, 1281–1285 (1995).

    CAS  PubMed  Google Scholar 

  92. Merkel, P. A. et al. Patterns and predictors of change in outcome measures in clinical trials in scleroderma: an individual patient meta-analysis of 629 subjects with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 64, 3420–3429 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Maurer, B. et al. Prediction of worsening of skin fibrosis in patients with diffuse cutaneous systemic sclerosis using the EUSTAR database. Ann. Rheum. Dis.http://dx.doi.org/10.1136/annrheumdis-2014-205226 (2014).

  94. Lefèvre, G. et al. Survival and prognostic factors in systemic sclerosis-associated pulmonary hypertension: a systematic review and meta-analysis. Arthritis Rheum. 65, 2412–2423 (2013).

    Article  PubMed  Google Scholar 

  95. Shahane, A. Pulmonary hypertension in rheumatic diseases: epidemiology and pathogenesis. Rheumatol. Int. 33, 1655–1667 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Shah, A. A., Wigley, F. M. & Hummers, L. K. Telangiectases in scleroderma: a potential clinical marker of pulmonary arterial hypertension. J. Rheumatol. 37, 98–104 (2010).

    Article  PubMed  Google Scholar 

  97. Galiè, N. et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the Internat. Eur. Heart J. 30, 2493–2537 (2009).

    Article  PubMed  Google Scholar 

  98. McLaughlin, V. V. et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College. Circulation 119, 2250–2294 (2009).

    Article  PubMed  Google Scholar 

  99. Avouac, J. et al. Expert consensus for performing right heart catheterisation for suspected pulmonary arterial hypertension in systemic sclerosis: a Delphi consensus study with cluster analysis. Ann. Rheum. Dis. 73, 191–197 (2014).

    Article  PubMed  Google Scholar 

  100. Khanna, D. et al. Recommendations for screening and detection of connective tissue disease-associated pulmonary arterial hypertension. Arthritis Rheum. 65, 3194–3201 (2013).

    Article  PubMed  Google Scholar 

  101. Meune, C. et al. Prediction of pulmonary hypertension related to systemic sclerosis by an index based on simple clinical observations. Arthritis Rheum. 63, 2790–2796 (2011).

    Article  PubMed  Google Scholar 

  102. Coghlan, J. G. et al. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann. Rheum. Dis. 73, 1340–1349 (2014).

    Article  PubMed  Google Scholar 

  103. Winstone, T. A. et al. Predictors of mortality and progression in scleroderma-associated interstitial lung disease: a systematic review. Chest 146, 422–436 (2014).

    Article  PubMed  Google Scholar 

  104. Suliman, Y. A. et al. FRI0377 High rate of false negatives in the early detection of interstitial lung disease associated with systemic sclerosis by pulmonary function tests. Ann. Rheum. Dis. 72, A500–A501 (2014).

    Google Scholar 

  105. Goldin, J. G. et al. High-resolution CT scan findings in patients with symptomatic scleroderma-related interstitial lung disease. Chest 134, 358–367 (2008).

    Article  PubMed  Google Scholar 

  106. Herzog, E. L. et al. Review: interstitial lung disease associated with systemic sclerosis and idiopathic pulmonary fibrosis: how similar and distinct?. Arthritis Rheumatol. 66, 1967–1978 (2014). This review highlights similarities and differences among systemic sclerosis-associated interstitial lung disease and idiopathic pulmonary fibrosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Barskova, T. et al. Lung ultrasound for the screening of interstitial lung disease in very early systemic sclerosis. Ann. Rheum. Dis. 72, 390–395 (2013).

    Article  PubMed  Google Scholar 

  108. Frauenfelder, T. et al. Screening for interstitial lung disease in systemic sclerosis: performance of high-resolution CT with limited number of slices: a prospective study. Ann. Rheum. Dis. 73, 2069–2073 (2014).

    Article  PubMed  Google Scholar 

  109. Winklehner, A. et al. Screening for interstitial lung disease in systemic sclerosis: the diagnostic accuracy of HRCT image series with high increment and reduced number of slices. Ann. Rheum. Dis. 71, 549–552 (2012).

    Article  PubMed  Google Scholar 

  110. Moore, O. A. et al. Extent of disease on high-resolution computed tomography lung is a predictor of decline and mortality in systemic sclerosis-related interstitial lung disease. Rheumatol. (Oxford). 52, 155–160 (2013).

    Article  Google Scholar 

  111. Khanna, D. et al. Clinical course of lung physiology in patients with scleroderma and interstitial lung disease: analysis of the Scleroderma Lung Study Placebo Group. Arthritis Rheum. 63, 3078–3085 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Goh, N. S. L. et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am. J. Respir. Crit. Care Med. 177, 1248–1254 (2008). This paper describes a simple and validated approach for assessing lung fibrosis and predicting progression of lung disease in systemic sclerosis.

    Article  PubMed  Google Scholar 

  113. Perera, A. et al. Clinical subsets, skin thickness progression rate, and serum antibody levels in systemic sclerosis patients with anti-topoisomerase I antibody. Arthritis Rheum. 56, 2740–2746 (2007).

    Article  PubMed  Google Scholar 

  114. Steen, V., Domsic, R. T., Lucas, M., Fertig, N. & Medsger, T. A. A clinical and serologic comparison of African American and caucasian patients with systemic sclerosis. Arthritis Rheum. 64, 2986–2994 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Sebastiani, M. et al. Capillaroscopic skin ulcer risk index: a new prognostic tool for digital skin ulcer development in systemic sclerosis patients. Arthritis Rheum. 61, 688–694 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Sebastiani, M. et al. Predictive role of capillaroscopic skin ulcer risk index in systemic sclerosis: a multicentre validation study. Ann. Rheum. Dis. 71, 67–70 (2012).

    Article  CAS  PubMed  Google Scholar 

  117. Shah, A. A. & Wigley, F. M. My approach to the treatment of scleroderma. Mayo Clin. Proc. 88, 377–393 (2013).

    Article  PubMed  Google Scholar 

  118. Simms, R. W. & Korn, J. H. in Rheumatology and the Kidney (eds Adu, D., Emery, P. & Madaio, M. ) 275–293 (Oxford Univ. Press, 2001).

    Google Scholar 

  119. Ostojić, P. Damjanov N. Pavlov-Dolijanovic S. & Radunović, G. Peripheral vasculopathy in patients with systemic sclerosis: difference in limited and diffuse subset of disease. Clin. Hemorheol. Microcirc. 31, 281–285 (2004).

    PubMed  Google Scholar 

  120. Burt, R. K. et al. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised Phase 2 trial. Lancet 378, 498–506 (2011). This randomized clinical trial shows positive effects of treating systemic sclerosis with HSC transplantation.

    Article  CAS  PubMed  Google Scholar 

  121. Van Laar, J. M. et al. Autologous hematopoietic stem cell transplantation versus intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA 311, 2490–2498 (2014).

    Article  CAS  PubMed  Google Scholar 

  122. Schachna, L. et al. Lung transplantation in scleroderma compared with idiopathic pulmonary fibrosis and idiopathic pulmonary arterial hypertension. Arthritis Rheum. 54, 3954–3961 (2006).

    Article  PubMed  Google Scholar 

  123. Tashkin, D. P. et al. Cyclophosphamide versus placebo in scleroderma lung disease. N. Engl. J. Med. 354, 2655–2666 (2006). This paper describes results from a randomized clinical trial of cyclophosphamide.

    Article  CAS  PubMed  Google Scholar 

  124. Tashkin, D. P. et al. Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am. J. Respir. Crit. Care Med. 176, 1026–1034 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Hoyles, R. K. et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum. 54, 3962–3970 (2006).

    Article  CAS  PubMed  Google Scholar 

  126. Badesch, D. B. et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann. Intern. Med. 132, 425–434 (2000).

    Article  CAS  PubMed  Google Scholar 

  127. Chaisson, N. F. & Hassoun, P. M. Systemic sclerosis-associated pulmonary arterial hypertension. Chest 144, 1346–1356 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Pulido, T. et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N. Engl. J. Med. 369, 809–818 (2013).

    Article  CAS  PubMed  Google Scholar 

  129. Buckley, M. S., Staib, R. L. & Wicks, L. M. Combination therapy in the management of pulmonary arterial hypertension. Int. J. Clin. Pract. 67, (Suppl. S179), 13–23 (2013).

    Article  Google Scholar 

  130. Badesch, D. B. et al. Longterm survival among patients with scleroderma-associated pulmonary arterial hypertension treated with intravenous epoprostenol. J. Rheumatol. 36, 2244–2249 (2009).

    Article  CAS  PubMed  Google Scholar 

  131. Amjadi, S. et al. Course of the modified Rodnan skin thickness score in systemic sclerosis clinical trials: analysis of three large multicenter, double-blind, randomized controlled trials. Arthritis Rheum. 60, 2490–2498 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Pope, J. E. et al. A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum. 44, 1351–1358 (2001).

    Article  CAS  PubMed  Google Scholar 

  133. Penn, H. & Denton, C. P. Diagnosis, management and prevention of scleroderma renal disease. Curr. Opin. Rheumatol. 20, 692–696 (2008).

    Article  PubMed  Google Scholar 

  134. Steen, V. D. Scleroderma renal crisis. Rheum. Dis. Clin. North Am. 22, 861–878 (1996).

    Article  CAS  PubMed  Google Scholar 

  135. Mouthon, L., Bussone, G., Berezné, A., Noël, L.-H. & Guillevin, L. Scleroderma renal crisis. J. Rheumatol. 41, 1040–1048 (2014).

    Article  CAS  PubMed  Google Scholar 

  136. Steen, V. D. Scleroderma renal crisis. Rheum. Dis. Clin. North Am. 29, 315–333 (2003).

    Article  PubMed  Google Scholar 

  137. Hudson, M., Baron, M., Tatibouet, S., Furst, D. E. & Khanna, D. Exposure to ACE inhibitors prior to the onset of scleroderma renal crisis — results from the International Scleroderma Renal Crisis Survey. Semin. Arthritis Rheum. 43, 666–672 (2014).

    Article  CAS  PubMed  Google Scholar 

  138. Hachulla, E. et al. Natural history of ischemic digital ulcers in systemic sclerosis: single-center retrospective longitudinal study. J. Rheumatol. 34, 2423–2430 (2007).

    PubMed  Google Scholar 

  139. Pope, J. Measures of systemic sclerosis (scleroderma): Health Assessment Questionnaire (HAQ) and Scleroderma HAQ (SHAQ), physician- and patient-rated global assessments, Symptom Burden Index (SBI), University of California, Los Angeles, Scleroderma Clinical Trials. Arthritis Care Res. 63, (Suppl. 1), S98–S111 (2011).

    Article  Google Scholar 

  140. Chung, L. Therapeutic options for digital ulcers in patients with systemic sclerosis. J. Dtsch. Dermatol. Ges. 5, 460–465 (2007).

    Article  PubMed  Google Scholar 

  141. Tingey, T., Shu, J., Smuczek, J. & Pope, J. Meta-analysis of healing and prevention of digital ulcers in systemic sclerosis. Arthritis Care Res. 65, 1460–1471 (2013).

    Article  CAS  Google Scholar 

  142. Korn, J. H. et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum. 50, 3985–3993 (2004).

    Article  CAS  PubMed  Google Scholar 

  143. Matucci-Cerinic, M. et al. Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann. Rheum. Dis. 70, 32–38 (2011).

    Article  CAS  PubMed  Google Scholar 

  144. Asano, Y. & Trojanowska, M. Phosphorylation of Fli1 at threonine 312 by protein kinase C delta promotes its interaction with p300/CREB-binding protein-associated factor and subsequent acetylation in response to transforming growth factor beta. Mol. Cell. Biol. 29, 1882–1894 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Steen, V. D. & Medsger, T. A. Case–control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum. 41, 1613–1619 (1998). This study shows that glucocorticoids are a risk factor for the development of renal crisis.

    Article  CAS  PubMed  Google Scholar 

  146. Elhai, M. et al. Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: a EUSTAR observational study. Ann. Rheum. Dis. 72, 1217–1220 (2013).

    Article  CAS  PubMed  Google Scholar 

  147. Domsic, R., Fasanella, K. & Bielefeldt, K. Gastrointestinal manifestations of systemic sclerosis. Dig. Dis. Sci. 53, 1163–1174 (2008).

    Article  PubMed  Google Scholar 

  148. Jaovisidha, K., Csuka, M. E., Almagro, U. A. & Soergel, K. H. Severe gastrointestinal involvement in systemic sclerosis: report of five cases and review of the literature. Semin. Arthritis Rheum. 34, 689–702 (2005).

    Article  PubMed  Google Scholar 

  149. Watson, M., Hally, R. J., McCue, P. A., Varga, J. & Jiménez, S. A. Gastric antral vascular ectasia (watermelon stomach) in patients with systemic sclerosis. Arthritis Rheum. 39, 341–346 (1996).

    Article  CAS  PubMed  Google Scholar 

  150. Marie, I., Duparc, F., Janvresse, A., Levesque, H. & Courtois, H. Tumoral calcinosis in systemic sclerosis. Clin. Exp. Rheumatol. 22, 269 (2004).

  151. Taki, H. & Tobe, K. Tumoral calcinosis in systemic sclerosis. Joint. Bone. Spine 80, 99 (2013).

  152. Gutierrez, A. & Wetter, D. A. Calcinosis cutis in autoimmune connective tissue diseases. Dermatol. Ther. 25, 195–206 (2012).

    Article  PubMed  Google Scholar 

  153. Chung, L. et al. Validation of a novel radiographic scoring system for calcinosis affecting the hands of patients with systemic sclerosis. Arthritis Care Res. 67, 425–430 (2015).

    Article  Google Scholar 

  154. Al-Dhaher, F. F., Pope, J. E. & Ouimet, J. M. Determinants of morbidity and mortality of systemic sclerosis in Canada. Semin. Arthritis Rheum. 39, 269–277 (2010).

    Article  PubMed  Google Scholar 

  155. Hudson, M. et al. Health-related quality of life in systemic sclerosis: a systematic review. Arthritis Rheum. 61, 1112–1120 (2009).

    Article  PubMed  Google Scholar 

  156. Cole, J. C. et al. Single-factor scoring validation for the Health Assessment Questionnaire- Disability Index (HAQ-DI) in patients with systemic sclerosis and comparison with early rheumatoid arthritis patients. Qual. Life Res. 15, 1383–1394 (2006).

    Article  PubMed  Google Scholar 

  157. Sekhon, S., Pope, J. & Baron, M. The minimally important difference in clinical practice for patient-centered outcomes including health assessment questionnaire, fatigue, pain, sleep, global visual analog scale, and SF-36 in scleroderma. J. Rheumatol. 37, 591–598 (2010). This study defines the minimally important differences in patient-reported outcomes.

    Article  PubMed  Google Scholar 

  158. El-Baalbaki, G., Lober, J., Hudson, M., Baron, M. & Thombs, B. D. Measuring pain in systemic sclerosis: comparison of the short-form McGill Pain Questionnaire versus a single-item measure of pain. J. Rheumatol. 38, 2581–2587 (2011).

    Article  PubMed  Google Scholar 

  159. Milette, K. et al. Clinical correlates of sleep problems in systemic sclerosis: the prominent role of pain. Rheumatology 50, 921–925 (2011).

    Article  PubMed  Google Scholar 

  160. Schnitzer, M., Hudson, M., Baron, M. & Steele, R. Disability in systemic sclerosis — a longitudinal observational study. J. Rheumatol. 38, 685–692 (2011).

    Article  PubMed  Google Scholar 

  161. Schieir, O. et al. Prevalence, severity, and clinical correlates of pain in patients with systemic sclerosis. Arthritis Care Res. 62, 409–417 (2010).

    Article  Google Scholar 

  162. El-Baalbaki, G. et al. Association of pruritus with quality of life and disability in systemic sclerosis. Arthritis Care Res. 62, 1489–1495 (2010).

    Article  Google Scholar 

  163. Hudson, M., Steele, R., Lu, Y., Thombs, B. D. & Baron, M. Work disability in systemic sclerosis. J. Rheumatol. 36, 2481–2486 (2009).

    Article  PubMed  Google Scholar 

  164. Hong, P., Pope, J. E., Ouimet, J. M., Rullan, E. & Seibold, J. R. Erectile dysfunction associated with scleroderma: a case–control study of men with scleroderma and rheumatoid arthritis. J. Rheumatol. 31, 508–513 (2004).

    PubMed  Google Scholar 

  165. Ouimet, J. M., Pope, J. E., Gutmanis, I. & Koval, J. Work disability in scleroderma is greater than in rheumatoid arthritis and is predicted by high HAQ scores. Open Rheumatol. J. 2, 44–52 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Bassel, M. et al. Frequency and impact of symptoms experienced by patients with systemic sclerosis: results from a Canadian National Survey. Rheumatology 50, 762–767 (2011).

    Article  PubMed  Google Scholar 

  167. Khanna, D. et al. Reliability and validity of the University of California, Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument. Arthritis Rheum. 61, 1257–1263 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Baron, M., Hudson, M., Steele, R. & Lo, E. Validation of the UCLA Scleroderma Clinica Trial Gastrointestinal Tract Instrument version 2.0 for systemic sclerosis. J. Rheumatol. 38, 1925–1930 (2011).

    Article  PubMed  Google Scholar 

  169. Muangchan, C., Baron, M. & Pope, J. The 15% rule in scleroderma: the frequency of severe organ complications in systemic sclerosis. A systematic review. J. Rheumatol. 40, 1545–1556 (2013).

    Article  PubMed  Google Scholar 

  170. Onishi, A., Sugiyama, D., Kumagai, S. & Morinobu, A. Cancer incidence in systemic sclerosis: meta-analysis of population-based cohort studies. Arthritis Rheum. 65, 1913–1921 (2013).

    Article  PubMed  Google Scholar 

  171. Shah, A. A., Rosen, A., Hummers, L., Wigley, F. & Casciola-Rosen, L. Close temporal relationship between onset of cancer and scleroderma in patients with RNA polymerase I/III antibodies. Arthritis Rheum. 62, 2787–2795 (2010). This seminal study provides potential mechanistic links between cancer and systemic sclerosis. Its clinical and biological relevance might provide future insights into aetiopathogenesis of dsSSc.

    Article  PubMed  PubMed Central  Google Scholar 

  172. Moinzadeh, P. et al. Association of anti-RNA polymerase III autoantibodies and cancer in scleroderma. Arthritis Res. Ther. 16, R53 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Joseph, C. G. et al. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science 343, 152–157 (2014).

    Article  CAS  PubMed  Google Scholar 

  174. Malcarne, V. L., Fox, R. S., Mills, S. D. & Gholizadeh, S. Psychosocial aspects of systemic sclerosis. Curr. Opin. Rheumatol. 25, 707–713 (2013).

    Article  PubMed  Google Scholar 

  175. Thombs, B. D. et al. Psychological health and well-being in systemic sclerosis: State of the science and consensus research agenda. Arthritis Care Res. 62, 1181–1189 (2010). This is a review of quality-of-life studies in systemic sclerosis.

    Article  Google Scholar 

  176. Jewett, L. R., Razykov, I., Hudson, M., Baron, M. & Thombs, B. D. Prevalence of current, 12-month and lifetime major depressive disorder among patients with systemic sclerosis. Rheumatology 52, 669–675 (2013).

    Article  PubMed  Google Scholar 

  177. Thombs, B. D., Jewett, L. R., Kwakkenbos, L., Hudson, M. & Baron, M. Major depression diagnoses are often transient among patients with systemic sclerosis: baseline and 1-month follow-up. Arthritis Care Res. 67, 411–416 (2015).

    Article  Google Scholar 

  178. Jewett, L. R. et al. Development and validation of the brief-satisfaction with appearance scale for systemic sclerosis. Arthritis Care Res. 62, 1779–1786 (2010).

    Article  Google Scholar 

  179. Kwakkenbos, L. et al. The Scleroderma Patient-centered Intervention Network (SPIN) Cohort: protocol for a cohort multiple randomised controlled trial (cmRCT) design to support trials of psychosocial and rehabilitation interventions in a rare disease context. BMJ Open 3, e003563 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Khanna, D. et al. Twenty-two points to consider for clinical trials in systemic sclerosis, based on EULAR standards. Rheumatology 54, 144–151 (2015). This paper provides detailed expert guidance for clinical trial design in systemic sclerosis, which will underpin the validation of emerging candidate therapies and accelerate therapeutic progress.

    Article  PubMed  Google Scholar 

  181. Domsic, R. T. et al. Derivation and validation of a prediction rule for two-year mortality in early diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 66, 1616–1624 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  182. Wells, A. U. & Denton, C. P. Interstitial lung disease in connective tissue disease-mechanisms and management. Nat. Rev. Rheumatol. 10, 728–739 (2014).

    Article  CAS  PubMed  Google Scholar 

  183. Nihtyanova, S. I. et al. Improved survival in systemic sclerosis is associated with better ascertainment of internal organ disease: a retrospective cohort study. QJM 103, 109–115 (2010).

    Article  CAS  PubMed  Google Scholar 

  184. Beyer, C., Schett, G., Distler, O. & Distler, J. H. W. Animal models of systemic sclerosis: prospects and limitations. Arthritis Rheum. 62, 2831–2844 (2010).

    Article  CAS  PubMed  Google Scholar 

  185. Derrett-Smith, E. C. et al. Endothelial injury in a transforming growth factor β-dependent mouse model of scleroderma induces pulmonary arterial hypertension. Arthritis Rheum. 65, 2928–2939 (2013).

    Article  CAS  PubMed  Google Scholar 

  186. Quillinan, N. P., McIntosh, D., Vernes, J., Haq, S. & Denton, C. P. Treatment of diffuse systemic sclerosis with hyperimmune caprine serum (AIMSPRO): a phase II double-blind placebo-controlled trial. Ann. Rheum. Dis. 73, 56–61 (2014). This study is the first in recent years to test a novel biological therapy and to be able to differentiate between active treatment and placebo. This underscores the critical importance of having a placebo arm even in very small Phase I/II studies and will help in the design of future trials.

    Article  CAS  PubMed  Google Scholar 

  187. Steen, V. D. & Medsger, T. A. Changes in causes of death in systemic sclerosis, 1972–2002. Ann. Rheum. Dis. 66, 940–944 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Denton, C. P. & Ong, V. H. Targeted therapies for systemic sclerosis. Nat. Rev. Rheumatol. 9, 451–464 (2013). This is a review of current and emerging therapies and their rationale.

    Article  CAS  PubMed  Google Scholar 

  189. Asano, Y. & Trojanowska, M. Fli1 represses transcription of the human α2(I) collagen gene by recruitment of the HDAC1/p300 complex. PLoS ONE 8, e74930 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Koinuma, D. et al. Chromatin immunoprecipitation on microarray analysis of Smad2/3 binding sites reveals roles of ETS1 and TFAP2A in transforming growth factor β signaling. Mol. Cell. Biol. 29, 172–186 (2009).

    Article  CAS  PubMed  Google Scholar 

  191. Van Beek, J. P., Kennedy, L., Rockel, J. S., Bernier, S. M. & Leask, A. The induction of CCN2 by TGFβ1 involves Ets-1. Arthritis Res. Ther. 8, R36 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Ghosh, A. K. et al. Disruption of transforming growth factor β signaling and profibrotic responses in normal skin fibroblasts by peroxisome proliferator-activated receptor γ. Arthritis Rheum. 50, 1305–1318 (2004).

    Article  CAS  PubMed  Google Scholar 

  193. Nakerakanti, S. & Trojanowska, M. The role of TGF-β receptors in fibrosis. Open Rheumatol. J. 6, 156–162 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Bhattacharyya, S., Fang, F., Tourtellotte, W. & Varga, J. Egr-1: new conductor for the tissue repair orchestra directs harmony (regeneration) or cacophony (fibrosis). J. Pathol. 229, 286–297 (2013).

    Article  CAS  PubMed  Google Scholar 

  195. Leask, A. Integrin β1: a mechanosignaling sensor essential for connective tissue deposition by fibroblasts. Adv. Wound Care 2, 160–166 (2013).

    Article  Google Scholar 

  196. Nakerakanti, S. S., Bujor, A. M. & Trojanowska, M. CCN2 is required for the TGF-β induced activation of Smad1-Erk1/2 signaling network. PLoS ONE 6, e21911 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Janmey, P. A., Wells, R. G., Assoian, R. K. & McCulloch, C. A. From tissue mechanics to transcription factors. Differentiation. 86, 112–120 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Duncan, M. R. & Berman, B. Stimulation of collagen and glycosaminoglycan production in cultured human adult dermal fibroblasts by recombinant human interleukin 6. J. Invest. Dermatol. 97, 686–692 (1991).

    Article  CAS  PubMed  Google Scholar 

  199. Jinnin, M., Ihn, H., Yamane, K. & Tamaki, K. Interleukin-13 stimulates the transcription of the human α2(I) collagen gene in human dermal fibroblasts. J. Biol. Chem. 279, 41783–41791 (2004).

    Article  CAS  PubMed  Google Scholar 

  200. Dieudé, P. et al. STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5on disease susceptibility and related pulmonary fibrosis. Arthritis Rheum. 60, 2472–2479 (2009).

    Article  CAS  PubMed  Google Scholar 

  201. Radstake, T. R. D. J. et al. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nature Genet. 42, 426–429 (2010). This is the first GWAS reporting risk alleles for systemic sclerosis.

    Article  CAS  PubMed  Google Scholar 

  202. Dieudé, P. et al. BANK1 is a genetic risk factor for diffuse cutaneous systemic sclerosis and has additive effects with IRF5 and STAT4. Arthritis Rheum. 60, 3447–3454 (2009).

    Article  CAS  PubMed  Google Scholar 

  203. Allanore, Y. et al. Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. PLoS Genet. 7, e1002091 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Koumakis, E. et al. Brief report: candidate gene study in systemic sclerosis identifies a rare and functional variant of the TNFAIP3 locus as a risk factor for polyautoimmunity. Arthritis Rheum. 64, 2746–2752 (2012).

    Article  CAS  PubMed  Google Scholar 

  205. Diaz-Gallo, L. M. et al. Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis. Ann. Rheum. Dis. 70, 454–462 (2011).

    Article  CAS  PubMed  Google Scholar 

  206. López-Isac, E. et al. A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility. Arthritis Res. Ther. 16, R6 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  207. Carmona, F. D. et al. New insight on the Xq28 association with systemic sclerosis. Ann. Rheum. Dis. 72, 2032–2038 (2013).

    Article  CAS  PubMed  Google Scholar 

  208. Dieudé, P. et al. Evidence of the contribution of the X chromosome to systemic sclerosis susceptibility: association with the functional IRAK1 196Phe/532Ser haplotype. Arthritis Rheum. 63, 3979–3987 (2011).

    Article  CAS  PubMed  Google Scholar 

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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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Authors and Affiliations

  1. Rheumatology A Department, Cochin Hospital, Paris, France

    Yannick Allanore

  2. Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA

    Robert Simms & Maria Trojanowska

  3. Division of Rheumatology, University Hospital Zurich, Zurich, Switzerland

    Oliver Distler

  4. Department of Medicine, St. Joseph's Health Centre, London, Ontario, Canada

    Janet Pope

  5. University College London Division of Medicine and Royal Free Hospital, London, UK

    Christopher P. Denton

  6. Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

    John Varga

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Contributions

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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