Skip to main content

Abstract

Systemic sclerosis (SSc, also called scleroderma) is an autoimmune connective tissue disease characterized by cutaneous sclerosis. It commonly progresses to involve fibrosis of one or more internal organs, with pulmonary involvement as the leading cause of death. In many ways, SSc is the prototype disease for which optimal management requires streamlined collaboration between multiple subspecialists, including dermatologists, rheumatologists, pulmonologists, nephrologists, gastroenterologists, nursing and support staff. Patients may be best served at academic centers with a focus on SSc patients, such as the Scleroderma Centers of Excellence, which may also offer participation in clinical trials. Rheumatologists often function as the coordinating physicians for these patients, while dermatologists have a role in managing cutaneous sclerosis, pruritus and digital ulcers.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. 2012;24(2):165–70.

    Article  PubMed  Google Scholar 

  2. 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. 2013;65(11):2737–47.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Steen V. Epidemiology and classification of scleroderma. In: Rheumatology. London: Elsevier Ltd; 2008.

    Google Scholar 

  4. D’Amico F, Skarmoutsou E, Mazzarino MC. The sex bias in systemic sclerosis: on the possible mechanisms underlying the female disease preponderance. Clin Rev Allergy Immunol. 2014;47(3):334–43.

    Article  PubMed  Google Scholar 

  5. Tiniakou E, Costenbader KH, Kriegel MA. Sex-specific environmental influences on the development of autoimmune diseases. Clin Immunol. 2013;149(2):182–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mayes MD, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003;48(8):2246–55.

    Article  PubMed  Google Scholar 

  7. Hoffmann-Vold AM, et al. Survival and causes of death in an unselected and complete cohort of Norwegian patients with systemic sclerosis. J Rheumatol. 2013;40(7):1127–33.

    Article  PubMed  Google Scholar 

  8. Sampaio-Barros PD, et al. Survival, causes of death, and prognostic factors in systemic sclerosis: analysis of 947 Brazilian patients. J Rheumatol. 2012;39(10):1971–8.

    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. 2016;75(1):163–9.

    Article  PubMed  Google Scholar 

  10. Reveille JD. Ethnicity and race and systemic sclerosis: how it affects susceptibility, severity, antibody genetics, and clinical manifestations. Curr Rheumatol Rep. 2003;5(2):160–7.

    Article  PubMed  Google Scholar 

  11. Laing TJ, et al. Racial differences in scleroderma among women in Michigan. Arthritis Rheum. 1997;40(4):734–42.

    Article  CAS  PubMed  Google Scholar 

  12. Steen VD, et al. Incidence of systemic sclerosis in Allegheny County, Pennsylvania. A twenty-year study of hospital-diagnosed cases, 1963-1982. Arthritis Rheum. 1997;40(3):441–5.

    Article  CAS  PubMed  Google Scholar 

  13. Gelber AC, 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 (Baltimore). 2013;92(4):191–205.

    Article  Google Scholar 

  14. Steen VD, et al. Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum. 1994;37(9):1283–9.

    Article  CAS  PubMed  Google Scholar 

  15. Reveille JD, et al. Systemic sclerosis in 3 US ethnic groups: a comparison of clinical, sociodemographic, serologic, and immunogenetic determinants. Semin Arthritis Rheum. 2001;30(5):332–46.

    Article  CAS  PubMed  Google Scholar 

  16. Li R, et al. Epidemiology of eight common rheumatic diseases in China: a large-scale cross-sectional survey in Beijing. Rheumatology (Oxford). 2012;51(4):721–9.

    Article  Google Scholar 

  17. Tamaki T, Mori S, Takehara K. Epidemiological study of patients with systemic sclerosis in Tokyo. Arch Dermatol Res. 1991;283(6):366–71.

    Article  CAS  PubMed  Google Scholar 

  18. 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. 1980;23(5):581–90.

    Google Scholar 

  19. LeRoy EC, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15(2):202–5.

    CAS  PubMed  Google Scholar 

  20. Medsger T Jr. Classification, prognosis. In: Systemic sclerosis. Philadelphia: Lippincott Williams & Wilkins; 2004.

    Google Scholar 

  21. 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. 2007;56(8):2740–6.

    Article  PubMed  Google Scholar 

  22. Barnett AJ. The “neck sign” in scleroderma. Arthritis Rheum. 1989;32(2):209–11.

    Article  CAS  PubMed  Google Scholar 

  23. Medsger TA. Natural history of systemic sclerosis and the assessment of disease activity, severity, functional status, and psychologic well-being. Rheum Dis Clin N Am. 2003;29(2):255–73, vi.

    Article  Google Scholar 

  24. Steen VD, Medsger TA. Improvement in skin thickening in systemic sclerosis associated with improved survival. Arthritis Rheum. 2001;44(12):2828–35.

    Article  CAS  PubMed  Google Scholar 

  25. Shah AA, Wigley FM, Hummers LK. Telangiectases in scleroderma: a potential clinical marker of pulmonary arterial hypertension. J Rheumatol. 2010;37(1):98–104.

    Article  PubMed  Google Scholar 

  26. Caramaschi P, et al. Digital amputation in systemic sclerosis: prevalence and clinical associations. A retrospective longitudinal study. J Rheumatol. 2012;39(8):1648–53.

    Article  PubMed  Google Scholar 

  27. Lonzetti LS, 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. 2001;44(3):735–6.

    Article  CAS  PubMed  Google Scholar 

  28. Hughes M, et al. A study comparing videocapillaroscopy and dermoscopy in the assessment of nailfold capillaries in patients with systemic sclerosis-spectrum disorders. Rheumatology (Oxford). 2015;54(8):1435–42.

    Article  Google Scholar 

  29. Mazzotti NG, et al. Assessment of nailfold capillaroscopy in systemic sclerosis by different optical magnification methods. Clin Exp Dermatol. 2014;39(2):135–41.

    Article  CAS  PubMed  Google Scholar 

  30. Bauersachs RM, Lössner F. The poor man’s capillary microscope. A novel technique for the assessment of capillary morphology. Ann Rheum Dis. 1997;56(7):435–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Forbes A, Marie I. Gastrointestinal complications: the most frequent internal complications of systemic sclerosis. Rheumatology (Oxford). 2009;48 Suppl 3:iii36–9.

    CAS  Google Scholar 

  32. Sjogren RW. Gastrointestinal features of scleroderma. Curr Opin Rheumatol. 1996;8(6):569–75.

    Article  CAS  PubMed  Google Scholar 

  33. Steen VD, Medsger TA. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum. 2000;43(11):2437–44.

    Article  CAS  PubMed  Google Scholar 

  34. Montesi A, et al. Oropharyngeal and esophageal function in scleroderma. Dysphagia. 1991;6(4):219–23.

    Article  CAS  PubMed  Google Scholar 

  35. Savarino E, et al. Gastroesophageal reflux and pulmonary fibrosis in scleroderma: a study using pH-impedance monitoring. Am J Respir Crit Care Med. 2009;179(5):408–13.

    Article  PubMed  Google Scholar 

  36. Wipff J, et al. Outcomes of Barrett’s oesophagus related to systemic sclerosis: a 3-year EULAR Scleroderma Trials and Research prospective follow-up study. Rheumatology (Oxford). 2011;50(8):1440–4.

    Article  Google Scholar 

  37. Watson M, et al. Gastric antral vascular ectasia (watermelon stomach) in patients with systemic sclerosis. Arthritis Rheum. 1996;39(2):341–6.

    Article  CAS  PubMed  Google Scholar 

  38. Assassi S, et al. Primary biliary cirrhosis (PBC), PBC autoantibodies, and hepatic parameter abnormalities in a large population of systemic sclerosis patients. J Rheumatol. 2009;36(10):2250–6.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Rigamonti C, et al. Clinical features and prognosis of primary biliary cirrhosis associated with systemic sclerosis. Gut. 2006;55(3):388–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Meier FM, et al. Update on the profile of the EUSTAR cohort: an analysis of the EULAR Scleroderma Trials and Research group database. Ann Rheum Dis. 2012;71(8):1355–60.

    Article  PubMed  Google Scholar 

  41. D’Angelo WA, et al. Pathologic observations in systemic sclerosis (scleroderma). A study of fifty-eight autopsy cases and fifty-eight matched controls. Am J Med. 1969;46(3):428–40.

    Article  PubMed  Google Scholar 

  42. Gyger G, Baron M. Gastrointestinal manifestations of scleroderma: recent progress in evaluation, pathogenesis, and management. Curr Rheumatol Rep. 2012;14(1):22–9.

    Article  PubMed  Google Scholar 

  43. Wells AU. Interstitial lung disease in systemic sclerosis. Presse Med. 2014;43(10 Pt 2):e329–43.

    Article  PubMed  Google Scholar 

  44. Wells AU, et al. Fibrosing alveolitis in systemic sclerosis: indices of lung function in relation to extent of disease on computed tomography. Arthritis Rheum. 1997;40(7):1229–36.

    CAS  PubMed  Google Scholar 

  45. Man A, et al. Changes in forced vital capacity over time in systemic sclerosis: application of group-based trajectory modelling. Rheumatology (Oxford). 2015;54(8):1464–71.

    Article  Google Scholar 

  46. Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis. 2007;66(7):940–4.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Ong YY, et al. Decreased nailfold capillary density in limited scleroderma with pulmonary hypertension. Asian Pac J Allergy Immunol. 1998;16(2–3):81–6.

    CAS  PubMed  Google Scholar 

  48. Kawut SM, et al. Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest. 2003;123(2):344–50.

    Article  PubMed  Google Scholar 

  49. Steen V, Medsger TA. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum. 2003;48(2):516–22.

    Article  PubMed  Google Scholar 

  50. Koh ET, et al. Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients. Br J Rheumatol. 1996;35(10):989–93.

    Article  CAS  PubMed  Google Scholar 

  51. Tyndall AJ, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis. 2010;69(10):1809–15.

    Article  PubMed  Google Scholar 

  52. Ferri C, et al. Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine (Baltimore). 2002;81(2):139–53.

    Article  Google Scholar 

  53. Champion HC. The heart in scleroderma. Rheum Dis Clin N Am. 2008;34(1):181–90; viii.

    Article  Google Scholar 

  54. de Groote P, et al. Evaluation of cardiac abnormalities by Doppler echocardiography in a large nationwide multicentric cohort of patients with systemic sclerosis. Ann Rheum Dis. 2008;67(1):31–6.

    Article  PubMed  Google Scholar 

  55. Au K, et al. Atherosclerosis in systemic sclerosis: a systematic review and meta-analysis. Arthritis Rheum. 2011;63(7):2078–90.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Man A, et al. The risk of cardiovascular disease in systemic sclerosis: a population-based cohort study. Ann Rheum Dis. 2013;72(7):1188–93.

    Article  PubMed  Google Scholar 

  57. Steen VD, et al. Kidney disease other than renal crisis in patients with diffuse scleroderma. J Rheumatol. 2005;32(4):649–55.

    PubMed  Google Scholar 

  58. Teixeira L, et al. Mortality and risk factors of scleroderma renal crisis: a French retrospective study of 50 patients. Ann Rheum Dis. 2008;67(1):110–6.

    Article  CAS  PubMed  Google Scholar 

  59. 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. 2013;72(7):1217–20.

    Article  CAS  PubMed  Google Scholar 

  60. Avouac J, et al. Characteristics of joint involvement and relationships with systemic inflammation in systemic sclerosis: results from the EULAR Scleroderma Trial and Research Group (EUSTAR) database. J Rheumatol. 2010;37(7):1488–501.

    Article  PubMed  Google Scholar 

  61. Avouac J, et al. Articular involvement in systemic sclerosis. Rheumatology (Oxford). 2012;51(8):1347–56.

    Article  Google Scholar 

  62. Avouac J, et al. Radiological hand involvement in systemic sclerosis. Ann Rheum Dis. 2006;65(8):1088–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Steen VD, Medsger TA. The palpable tendon friction rub: an important physical examination finding in patients with systemic sclerosis. Arthritis Rheum. 1997;40(6):1146–51.

    Article  CAS  PubMed  Google Scholar 

  64. Shulman LE, Kurban AK, Harvey AM. Tendon friction rubs in progressive system sclerosis (scleroderma). Trans Assoc Am Phys. 1961;74:378–88.

    CAS  PubMed  Google Scholar 

  65. Khanna PP, et al. Tendon friction rubs in early diffuse systemic sclerosis: prevalence, characteristics and longitudinal changes in a randomized controlled trial. Rheumatology (Oxford). 2010;49(5):955–9.

    Article  Google Scholar 

  66. Avouac J, et al. Joint and tendon involvement predict disease progression in systemic sclerosis: a EUSTAR prospective study. Ann Rheum Dis. 2016;75(1):103–9.

    Article  PubMed  Google Scholar 

  67. Abraham DJ, et al. Overview of pathogenesis of systemic sclerosis. Rheumatology (Oxford). 2009;48 Suppl 3:iii3–7.

    CAS  Google Scholar 

  68. Abraham D, Distler O. How does endothelial cell injury start? The role of endothelin in systemic sclerosis. Arthritis Res Ther. 2007;9 Suppl 2:S2.

    Article  PubMed  Google Scholar 

  69. Pattanaik D, et al. Pathogenesis of systemic sclerosis. Front Immunol. 2015;6:272.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Altorok N, Wang Y, Kahaleh B. Endothelial dysfunction in systemic sclerosis. Curr Opin Rheumatol. 2014;26(6):615–20.

    Article  CAS  PubMed  Google Scholar 

  71. Dumoitier N, Lofek S, Mouthon L. Pathophysiology of systemic sclerosis: state of the art in 2014. Presse Med. 2014;43(10 Pt 2):e267–78.

    Article  PubMed  Google Scholar 

  72. Silver RM. Endothelin and scleroderma lung disease. Rheumatology (Oxford). 2008;47 Suppl 5:v25–6.

    Article  CAS  Google Scholar 

  73. Tuder RM, et al. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D4–12.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Morrell NW, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S20–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hassoun PM, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol. 2009;54(1 Suppl):S10–9.

    Article  CAS  PubMed  Google Scholar 

  76. Stenmark KR, Tuder RM, El Kasmi KC. Metabolic reprogramming and inflammation act in concert to control vascular remodeling in hypoxic pulmonary hypertension. J Appl Physiol (1985). 2015;119(10):1164–72.

    Article  CAS  Google Scholar 

  77. Rossi D, et al. The role of nail-videocapillaroscopy in early diagnosis of scleroderma. Autoimmun Rev. 2013;12(8):821–5.

    Article  PubMed  Google Scholar 

  78. Manetti M, et al. Differential expression of junctional adhesion molecules in different stages of systemic sclerosis. Arthritis Rheum. 2013;65(1):247–57.

    Article  CAS  PubMed  Google Scholar 

  79. Jiang N, Li M, Zeng X. Correlation of Th17 cells and CD4+CD25+ regulatory T cells with clinical parameters in patients with systemic sclerosis. Chin Med J. 2014;127(20):3557–61.

    PubMed  Google Scholar 

  80. Asano Y, Bujor AM, Trojanowska M. The impact of Fli1 deficiency on the pathogenesis of systemic sclerosis. J Dermatol Sci. 2010;59(3):153–62.

    Article  CAS  PubMed  Google Scholar 

  81. Manetti M. Fli1 deficiency and beyond: a unique pathway linking peripheral vasculopathy and dermal fibrosis in systemic sclerosis. Exp Dermatol. 2015;24(4):256–7.

    Article  CAS  PubMed  Google Scholar 

  82. Saigusa R, et al. A possible contribution of endothelial CCN1 downregulation due to Fli1 deficiency to the development of digital ulcers in systemic sclerosis. Exp Dermatol. 2015;24(2):127–32.

    Article  CAS  PubMed  Google Scholar 

  83. Brembilla NC, Chizzolini C. T cell abnormalities in systemic sclerosis with a focus on Th17 cells. Eur Cytokine Netw. 2012;23(4):128–39.

    Article  CAS  PubMed  Google Scholar 

  84. MacDonald KG, et al. Regulatory T cells produce profibrotic cytokines in the skin of patients with systemic sclerosis. J Allergy Clin Immunol. 2015;135(4):946–e9.

    Article  CAS  PubMed  Google Scholar 

  85. Zhou Y, et al. The elevated expression of Th17-related cytokines and receptors is associated with skin lesion severity in early systemic sclerosis. Hum Immunol. 2015;76(1):22–9.

    Article  CAS  PubMed  Google Scholar 

  86. Elhai M, et al. Systemic sclerosis: recent insights. Joint Bone Spine. 2015;82(3):148–53.

    Article  PubMed  Google Scholar 

  87. Assassi S, et al. Genetics of scleroderma: implications for personalized medicine? BMC Med. 2013;11:9.

    Article  PubMed  PubMed Central  Google Scholar 

  88. 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. 2014;16(1):R6.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Hamaguchi Y. Autoantibody profiles in systemic sclerosis: predictive value for clinical evaluation and prognosis. J Dermatol. 2010;37(1):42–53.

    Article  CAS  PubMed  Google Scholar 

  90. Grassegger A, et al. Autoantibodies in systemic sclerosis (scleroderma): clues for clinical evaluation, prognosis and pathogenesis. Wien Med Wochenschr. 2008;158(1–2):19–28.

    Article  PubMed  Google Scholar 

  91. Mehra S, et al. Autoantibodies in systemic sclerosis. Autoimmun Rev. 2013;12(3):340–54.

    Article  CAS  PubMed  Google Scholar 

  92. Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum. 2005;35(1):35–42.

    Article  CAS  PubMed  Google Scholar 

  93. Steen VD, Powell DL, Medsger TA. Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis. Arthritis Rheum. 1988;31(2):196–203.

    Article  CAS  PubMed  Google Scholar 

  94. Greenblatt MB, Aliprantis AO. The immune pathogenesis of scleroderma: context is everything. Curr Rheumatol Rep. 2013;15(1):297.

    Article  PubMed  PubMed Central  Google Scholar 

  95. O’Reilly S, et al. Interleukin-6 (IL-6) trans signaling drives a STAT3-dependent pathway that leads to hyperactive transforming growth factor-β (TGF-β) signaling promoting SMAD3 activation and fibrosis via Gremlin protein. J Biol Chem. 2014;289(14):9952–60.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Needleman BW, Wigley FM, Stair RW. Interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor alpha, and interferon-gamma levels in sera from patients with scleroderma. Arthritis Rheum. 1992;35(1):67–72.

    Article  CAS  PubMed  Google Scholar 

  97. Fernandes das Neves M, et al. Treatment of systemic sclerosis with tocilizumab. Rheumatology (Oxford). 2015;54(2):371–2.

    Article  CAS  Google Scholar 

  98. Rockey DC, Bell PD, Hill JA. Fibrosis – a common pathway to organ injury and failure. N Engl J Med. 2015;373(1):96.

    PubMed  Google Scholar 

  99. Eaglstein WH. Wound healing and aging. Clin Geriatr Med. 1989;5(1):183–8.

    Article  CAS  PubMed  Google Scholar 

  100. Brown GL, et al. Enhancement of wound healing by topical treatment with epidermal growth factor. N Engl J Med. 1989;321(2):76–9.

    Article  CAS  PubMed  Google Scholar 

  101. Babu M, Diegelmann R, Oliver N. Fibronectin is overproduced by keloid fibroblasts during abnormal wound healing. Mol Cell Biol. 1989;9(4):1642–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Zhang K, et al. Myofibroblasts and their role in lung collagen gene expression during pulmonary fibrosis. A combined immunohistochemical and in situ hybridization study. Am J Pathol. 1994;145:114–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Masur SK, et al. Myofibroblasts differentiate from fibroblasts when plated at low density. Proc Natl Acad Sci U S A. 1996;93:4219–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kissin EY, Merkel PA, Lafyatis R. Myofibroblasts and hyalinized collagen as markers of skin disease in systemic sclerosis. Arthritis Rheum. 2006;54(11):3655–60.

    Article  PubMed  Google Scholar 

  105. Kirk TZ, et al. Myofibroblasts from scleroderma skin synthesize elevated levels of collagen and tissue inhibitor of metalloproteinase (TIMP-1) with two forms of TIMP-1. J Biol Chem. 1995;270(7):3423–8.

    Article  CAS  PubMed  Google Scholar 

  106. Desmouliere A, et al. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol. 1993;122(1):103–11.

    Article  CAS  PubMed  Google Scholar 

  107. Marangoni RG, et al. Myofibroblasts in murine cutaneous fibrosis originate from adiponectin-positive intradermal progenitors. Arthritis Rheumatol. 2015;67(4):1062–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Liu F, et al. Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am J Physiol Lung Cell Mol Physiol. 2015;308(4):L344–57.

    Article  CAS  PubMed  Google Scholar 

  109. Christmann RB, et al. Association of Interferon- and transforming growth factor β-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis. Arthritis Rheumatol. 2014;66(3):714–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Leask A. Scar wars: is TGFbeta the phantom menace in scleroderma? Arthritis Res Ther. 2006;8(4):213.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Robertson IB, et al. Latent TGF-β-binding proteins. Matrix Biol. 2015;47:44–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Brand OJ, et al. Transforming growth factor-β and interleukin-1β signaling pathways converge on the chemokine CCL20 promoter. J Biol Chem. 2015;290(23):14717–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Dees C, Distler JH. Canonical Wnt signalling as a key regulator of fibrogenesis - implications for targeted therapies? Exp Dermatol. 2013;22(11):710–3.

    Article  PubMed  Google Scholar 

  114. Iwayama T, Olson LE. Involvement of PDGF in fibrosis and scleroderma: recent insights from animal models and potential therapeutic opportunities. Curr Rheumatol Rep. 2013;15(2):304.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Baroni SS, et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med. 2006;354(25):2667–76.

    Article  CAS  PubMed  Google Scholar 

  116. Loizos N, et al. Lack of detection of agonist activity by antibodies to platelet-derived growth factor receptor alpha in a subset of normal and systemic sclerosis patient sera. Arthritis Rheum. 2009;60(4):1145–51.

    Article  CAS  PubMed  Google Scholar 

  117. Balada E, et al. Anti-PDGFR-alpha antibodies measured by non-bioactivity assays are not specific for systemic sclerosis. Ann Rheum Dis. 2008;67(7):1027–9.

    Article  CAS  PubMed  Google Scholar 

  118. Kurasawa K, et al. Autoantibodies against platelet-derived growth factor receptor alpha in patients with systemic lupus erythematosus. Mod Rheumatol. 2010;20(5):458–65.

    Article  CAS  PubMed  Google Scholar 

  119. Bogatkevich GS, et al. Proteomic analysis of CTGF-activated lung fibroblasts: identification of IQGAP1 as a key player in lung fibroblast migration. Am J Physiol Lung Cell Mol Physiol. 2008;295(4):L603–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Abraham D. Connective tissue growth factor: growth factor, matricellular organizer, fibrotic biomarker or molecular target for anti-fibrotic therapy in SSc? Rheumatology (Oxford). 2008;47 Suppl 5:v8–9.

    Article  CAS  Google Scholar 

  121. Sakai N, et al. LPA1-induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation. FASEB J. 2013;27(5):1830–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Feghali-Bostwick C, Medsger TA, Wright TM. Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum. 2003;48(7):1956–63.

    Article  PubMed  Google Scholar 

  123. Arnett FC, et al. Familial occurrence frequencies and relative risks for systemic sclerosis (scleroderma) in three United States cohorts. Arthritis Rheum. 2001;44(6):1359–62.

    Article  CAS  PubMed  Google Scholar 

  124. Roberts-Thomson PJ, Walker JG. Stochastic processes in the aetiopathogenesis of scleroderma. Intern Med J. 2012;42(3):235–42.

    Article  CAS  PubMed  Google Scholar 

  125. Arnett FC, et al. Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma. Association with an Amerindian HLA haplotype. Arthritis Rheum. 1996;39(8):1362–70.

    Article  CAS  PubMed  Google Scholar 

  126. Zhou X, et al. Genome-wide association study for regions of systemic sclerosis susceptibility in a Choctaw Indian population with high disease prevalence. Arthritis Rheum. 2003;48(9):2585–92.

    Article  CAS  PubMed  Google Scholar 

  127. Tan FK, et al. Association of microsatellite markers near the fibrillin 1 gene on human chromosome 15q with scleroderma in a Native American population. Arthritis Rheum. 1998;41(10):1729–37.

    Article  CAS  PubMed  Google Scholar 

  128. Valesini G, et al. Geographical clustering of scleroderma in a rural area in the province of Rome. Clin Exp Rheumatol. 1993;11(1):41–7.

    CAS  PubMed  Google Scholar 

  129. Silman AJ, et al. Geographical clustering of scleroderma in south and west London. Br J Rheumatol. 1990;29(2):93–6.

    Article  CAS  PubMed  Google Scholar 

  130. Thompson AE, Pope JE. Increased prevalence of scleroderma in southwestern Ontario: a cluster analysis. J Rheumatol. 2002;29(9):1867–73.

    PubMed  Google Scholar 

  131. Englert H, et al. Systemic scleroderma: a spatiotemporal clustering. Intern Med J. 2005;35(4):228–33.

    Article  CAS  PubMed  Google Scholar 

  132. Archer C, Gordon DA. Silica and progressive systemic sclerosis (scleroderma): evidence for workers’ compensation policy. Am J Ind Med. 1996;29(5):533–8.

    Article  CAS  PubMed  Google Scholar 

  133. Bramwell B. Diffuse scleroderma: its frequency; its occurrence in stonemasons, its treatment by fibrinolysis: elevations of temperature due to fibrinolysis injections. Edinb Med J. 1914;12:387–401.

    PubMed Central  Google Scholar 

  134. Erasmus LD. Scleroderma in goldminers on the Witwatersrand with particular reference to pulmonary manifestations. S Afr J Lab Clin Med. 1957;3(3):209–31.

    CAS  PubMed  Google Scholar 

  135. Rodnan GP, et al. The association of progressive systemic sclerosis (scleroderma) with coal miners’ pneumoconiosis and other forms of silicosis. Ann Intern Med. 1967;66(2):323–34.

    Article  CAS  PubMed  Google Scholar 

  136. Moisan S, et al. Silica-associated limited systemic sclerosis after occupational exposure to calcined diatomaceous earth. Joint Bone Spine. 2010;77(5):472–3.

    Article  CAS  PubMed  Google Scholar 

  137. McCormic ZD, et al. Occupational silica exposure as a risk factor for scleroderma: a meta-analysis. Int Arch Occup Environ Health. 2010;83(7):763–9.

    Article  CAS  PubMed  Google Scholar 

  138. Kettaneh A, et al. Occupational exposure to solvents and gender-related risk of systemic sclerosis: a metaanalysis of case-control studies. J Rheumatol. 2007;34(1):97–103.

    CAS  PubMed  Google Scholar 

  139. Garabrant DH, et al. Scleroderma and solvent exposure among women. Am J Epidemiol. 2003;157(6):493–500.

    Article  PubMed  Google Scholar 

  140. Domsic RT. Scleroderma: the role of serum autoantibodies in defining specific clinical phenotypes and organ system involvement. Curr Opin Rheumatol. 2014;26(6):646–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Joseph CG, et al. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science. 2014;343(6167):152–7.

    Article  CAS  PubMed  Google Scholar 

  142. Nikpour M, et al. Prevalence, correlates and clinical usefulness of antibodies to RNA polymerase III in systemic sclerosis: a cross-sectional analysis of data from an Australian cohort. Arthritis Res Ther. 2011;13(6):R211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Kaji K, et al. Autoantibodies to RuvBL1 and RuvBL2: a novel systemic sclerosis-related antibody associated with diffuse cutaneous and skeletal muscle involvement. Arthritis Care Res (Hoboken). 2014;66(4):575–84.

    Article  CAS  Google Scholar 

  144. Kayser C, Fritzler MJ. Autoantibodies in systemic sclerosis: unanswered questions. Front Immunol. 2015;6:167.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Nihtyanova SI, Denton CP. Autoantibodies as predictive tools in systemic sclerosis. Nat Rev Rheumatol. 2010;6(2):112–6.

    Article  CAS  PubMed  Google Scholar 

  146. Fertig N, et al. Anti-U11/U12 RNP antibodies in systemic sclerosis: a new serologic marker associated with pulmonary fibrosis. Arthritis Rheum. 2009;61(7):958–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Coghlan JG, et al. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis. 2014;73(7):1340–9.

    Article  PubMed  Google Scholar 

  148. Baron M, et al. Malnutrition is common in systemic sclerosis: results from the Canadian scleroderma research group database. J Rheumatol. 2009;36(12):2737–43.

    Article  PubMed  Google Scholar 

  149. Clements P, et al. Inter and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis. J Rheumatol. 1995;22(7):1281–5.

    CAS  PubMed  Google Scholar 

  150. Domsic RT, et al. Skin thickness progression rate: a predictor of mortality and early internal organ involvement in diffuse scleroderma. Ann Rheum Dis. 2011;70(1):104–9.

    Article  PubMed  Google Scholar 

  151. Merkel PA, et al. Validity, reliability, and feasibility of durometer measurements of scleroderma skin disease in a multicenter treatment trial. Arthritis Rheum. 2008;59(5):699–705.

    Article  PubMed  Google Scholar 

  152. Kissin EY, et al. Durometry for the assessment of skin disease in systemic sclerosis. Arthritis Rheum. 2006;55(4):603–9.

    Article  PubMed  Google Scholar 

  153. Steen VD, Medsger TA. The value of the Health Assessment Questionnaire and special patient-generated scales to demonstrate change in systemic sclerosis patients over time. Arthritis Rheum. 1997;40(11):1984–91.

    Article  CAS  PubMed  Google Scholar 

  154. Khanna D, et al. Reliability and validity of the University of California, Los Angeles scleroderma clinical trial consortium gastrointestinal tract instrument. Arthritis Rheum. 2009;61(9):1257–63.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Merkel PA, et al. Measuring disease activity and functional status in patients with scleroderma and Raynaud’s phenomenon. Arthritis Rheum. 2002;46(9):2410–20.

    Article  PubMed  Google Scholar 

  156. Valentini G, et al. European multicentre study to define disease activity criteria for systemic sclerosis. II. Identification of disease activity variables and development of preliminary activity indexes. Ann Rheum Dis. 2001;60(6):592–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Medsger TA, et al. A disease severity scale for systemic sclerosis: development and testing. J Rheumatol. 1999;26(10):2159–67.

    PubMed  Google Scholar 

  158. Geirsson AJ, Wollheim FA, Akesson A. Disease severity of 100 patients with systemic sclerosis over a period of 14 years: using a modified Medsger scale. Ann Rheum Dis. 2001;60(12):1117–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Chu SY, et al. Increased risk of acute myocardial infarction in systemic sclerosis: a nationwide population-based study. Am J Med. 2013;126(11):982–8.

    Article  PubMed  Google Scholar 

  160. Chung WS, et al. Systemic sclerosis increases the risks of deep vein thrombosis and pulmonary thromboembolism: a nationwide cohort study. Rheumatology (Oxford). 2014;53(9):1639–45.

    Article  Google Scholar 

  161. Bonifazi M, et al. Systemic sclerosis (scleroderma) and cancer risk: systematic review and meta-analysis of observational studies. Rheumatology (Oxford). 2013;52(1):143–54.

    Article  Google Scholar 

  162. Robinson D, et al. Systemic sclerosis prevalence and comorbidities in the US, 2001-2002. Curr Med Res Opin. 2008;24(4):1157–66.

    Article  PubMed  Google Scholar 

  163. 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. 2009;60(8):2490–8.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Chora I, et al. Vascular biomarkers and correlation with peripheral vasculopathy in systemic sclerosis. Autoimmun Rev. 2015;14(4):314–22.

    Article  CAS  PubMed  Google Scholar 

  165. Castelino FV, Varga J. Current status of systemic sclerosis biomarkers: applications for diagnosis, management and drug development. Expert Rev Clin Immunol. 2013;9(11):1077–90.

    Article  CAS  PubMed  Google Scholar 

  166. Avouac J, et al. Cardiac biomarkers in systemic sclerosis: contribution of high-sensitivity cardiac troponin in addition to N-terminal pro-brain natriuretic peptide. Arthritis Care Res (Hoboken). 2015;67(7):1022–30.

    Article  CAS  Google Scholar 

  167. Shah AA, Wigley FM. My approach to the treatment of scleroderma. Mayo Clin Proc. 2013;88(4):377–93.

    Article  PubMed  Google Scholar 

  168. Pope JE, et al. A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum. 2001;44(6):1351–8.

    Article  CAS  PubMed  Google Scholar 

  169. Tashkin DP, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006;354(25):2655–66.

    Article  CAS  PubMed  Google Scholar 

  170. Tingey T, et al. Meta-analysis of healing and prevention of digital ulcers in systemic sclerosis. Arthritis Care Res (Hoboken). 2013;65(9):1460–71.

    Article  CAS  Google Scholar 

  171. Chung L. Therapeutic options for digital ulcers in patients with systemic sclerosis. J Dtsch Dermatol Ges. 2007;5(6):460–5.

    Article  PubMed  Google Scholar 

  172. 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. 2011;70(1):32–8.

    Article  CAS  PubMed  Google Scholar 

  173. Korn JH, et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum. 2004;50(12):3985–93.

    Article  CAS  PubMed  Google Scholar 

  174. Domsic R, Fasanella K, Bielefeldt K. Gastrointestinal manifestations of systemic sclerosis. Dig Dis Sci. 2008;53(5):1163–74.

    Article  PubMed  Google Scholar 

  175. Tashkin DP, et al. Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am J Respir Crit Care Med. 2007;176(10):1026–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Hoyles RK, 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. 2006;54(12):3962–70.

    Article  CAS  PubMed  Google Scholar 

  177. Tashkin DP, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 2016;4(9):708–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Schachna L, et al. Lung transplantation in scleroderma compared with idiopathic pulmonary fibrosis and idiopathic pulmonary arterial hypertension. Arthritis Rheum. 2006;54(12):3954–61.

    Article  PubMed  Google Scholar 

  179. Badesch DB, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med. 2000;132(6):425–34.

    Article  CAS  PubMed  Google Scholar 

  180. Pulido T, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809–18.

    Article  CAS  PubMed  Google Scholar 

  181. Pugh ME, Hemnes AR, Robbins IM. Combination therapy in pulmonary arterial hypertension. Clin Chest Med. 2013;34(4):841–55.

    Article  PubMed  Google Scholar 

  182. Buckley MS, Staib RL, Wicks LM. Combination therapy in the management of pulmonary arterial hypertension. Int J Clin Pract Suppl. 2013;179:13–23.

    Article  Google Scholar 

  183. Badesch DB, et al. Longterm survival among patients with scleroderma-associated pulmonary arterial hypertension treated with intravenous epoprostenol. J Rheumatol. 2009;36(10):2244–9.

    Article  CAS  PubMed  Google Scholar 

  184. Penn H, Denton CP. Diagnosis, management and prevention of scleroderma renal disease. Curr Opin Rheumatol. 2008;20(6):692–6.

    Article  PubMed  Google Scholar 

  185. Mouthon L, et al. Scleroderma renal crisis. J Rheumatol. 2014;41(6):1040–8.

    Article  CAS  PubMed  Google Scholar 

  186. Steen VD. Scleroderma renal crisis. Rheum Dis Clin N Am. 2003;29(2):315–33.

    Article  Google Scholar 

  187. Steen VD, Medsger TA. Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum. 1998;41(9):1613–9.

    Article  CAS  PubMed  Google Scholar 

  188. van Laar JM, et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. 2014;311(24):2490–8.

    Article  PubMed  Google Scholar 

  189. Elhai M, et al. Trends in mortality in patients with systemic sclerosis over 40 years: a systematic review and meta-analysis of cohort studies. Rheumatology (Oxford). 2012;51(6):1017–26.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M. Kari Connolly .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Man, A., Connolly, M.K., Simms, R.W. (2022). Systemic Sclerosis. In: Garg, A., Merola, J.F., Fitzpatrick, L. (eds) Interdisciplinary Approaches to Overlap Disorders in Dermatology & Rheumatology. Springer, Cham. https://doi.org/10.1007/978-3-319-18446-3_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-18446-3_6

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-18445-6

  • Online ISBN: 978-3-319-18446-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics