Skip to main content

Advertisement

SpringerLink
Log in

Pathogenesis of systemic sclerosis—current concept and emerging treatments

  • Review
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Systemic sclerosis (SSc) is an intractable multifaceted disease with high mortality. Although its pathogenesis is not fully understood, recent studies have advanced our knowledge on SSc. The cardinal pathological features of SSc are autoimmunity, vasculopathy, and fibrosis. The B cells in SSc are constitutively activated and lead to the production of a plethora of autoantibodies, such as anti-topoisomerase I and anti-centromere antibodies. In addition to these autoantibodies, which are valuable for diagnostic criteria or biomarkers, many other autoantibodies targeting endothelial cells, including endothelin type A receptor and angiotensin II type I receptor, are known to be functional and induce activation or apoptosis of endothelial cells. The autoantibody-mediated endothelial cell perturbation facilitates inflammatory cell infiltration, cytokine production, and myofibroblastic transformation of fibroblasts and endothelial cells. Profibrotic cytokines, such as transforming growth factor β, connective tissue growth factor, interleukin 4/interleukin 13, and interleukin 6, play a pivotal role in collagen production from myofibroblasts. Specific treatments targeting these causative molecules may improve the clinical outcomes of patients with SSc. In this review, we summarize recent topics on the pathogenesis (autoantibodies, vasculopathy, and fibrosis), animal models, and emerging treatments for SSc.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Distler O, Cozzio A. Systemic sclerosis and localized scleroderma—current concepts and novel targets for therapy. Semin Immunopathol. 2016;38(1):87–95.

    Article  CAS  PubMed  Google Scholar 

  2. Furue M, Yamazaki S, Jimbow K, Tsuchida T, Amagai M, Tanaka T, et al. Prevalence of dermatological disorders in Japan: a nationwide, cross-sectional, seasonal, multicenter, hospital-based study. J Dermatol. 2011;38(4):310–20.

    Article  PubMed  Google Scholar 

  3. Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117(3):557–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Desbois AC, Cacoub P. Systemic sclerosis: an update in 2016. Autoimmun Rev. 2016;15(5):417–26.

    Article  PubMed  Google Scholar 

  5. Jimenez SA, Piera-Velazquez S. Endothelial to mesenchymal transition (EndoMT) in the pathogenesis of systemic sclerosis-associated pulmonary fibrosis and pulmonary arterial hypertension. Myth or reality? Matrix Biol. 2016;51:26–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, 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 

  7. Toki S, Motegi S, Yamada K, Uchiyama A, Kanai S, Yamanaka M, et al. Clinical and laboratory features of systemic sclerosis complicated with localized scleroderma. J Dermatol. 2015;42(3):283–7.

    Article  PubMed  Google Scholar 

  8. Yanaba K. Strategy for treatment of fibrosis in systemic sclerosis: present and future. J Dermatol. 2016;43(1):46–55.

    Article  PubMed  Google Scholar 

  9. Feghali-Bostwick C, Medsger TA Jr, 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 

  10. Fuschiotti P. Current perspectives on the immunopathogenesis of systemic sclerosis. Immunotargets Ther. 2016;5:21–35.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Makino T, Jinnin M. Genetic and epigenetic abnormalities in systemic sclerosis. J Dermatol. 2016;43(1):10–8.

    Article  CAS  PubMed  Google Scholar 

  12. Murdaca G, Contatore M, Gulli R, Mandich P, Puppo F. Genetic factors and systemic sclerosis. Autoimmun Rev. 2016;15(5):427–32.

    Article  CAS  PubMed  Google Scholar 

  13. Asano Y. Recent advances in animal models of systemic sclerosis. J Dermatol. 2016;43(1):19–28.

    Article  CAS  PubMed  Google Scholar 

  14. Vettori S, Cuomo G, Iudici M, D’Abrosca V, Giacco V, Barra G, et al. Early systemic sclerosis: serum profiling of factors involved in endothelial, T-cell, and fibroblast interplay is marked by elevated interleukin-33 levels. J Clin Immunol. 2014;34(6):663–8.

    Article  CAS  PubMed  Google Scholar 

  15. Matucci-Cerinic M, Kahaleh B, Wigley FM. Review: evidence that systemic sclerosis is a vascular disease. Arthritis Rheum. 2013;65(8):1953–62.

    Article  CAS  PubMed  Google Scholar 

  16. Denton CP. Advances in pathogenesis and treatment of systemic sclerosis. Clin Med (Lond). 2016;16(1):55–60.

    Article  Google Scholar 

  17. O’Reilly S. Role of interleukin-13 in fibrosis, particularly systemic sclerosis. Biofactors. 2013;39(6):593–6.

    Article  PubMed  CAS  Google Scholar 

  18. Bergmann C, Distler JH. Canonical Wnt signaling in systemic sclerosis. Lab Investig. 2016;96(2):151–5.

    Article  CAS  PubMed  Google Scholar 

  19. Hasegawa M. Biomarkers in systemic sclerosis: their potential to predict clinical courses. J Dermatol. 2016;43(1):29–38.

    Article  CAS  PubMed  Google Scholar 

  20. Perosa F, Prete M, Di Lernia G, Ostuni C, Favoino E, Valentini G. Anti-centromere protein a antibodies in systemic sclerosis: significance and origin. Autoimmun Rev. 2016;15(1):102–9.

    Article  CAS  PubMed  Google Scholar 

  21. Günther J, Rademacher J, van Laar JM, Siegert E, Riemekasten G. Functional autoantibodies in systemic sclerosis. Semin Immunopathol. 2015;37(5):529–42.

    Article  PubMed  CAS  Google Scholar 

  22. Yoshizaki A. B lymphocytes in systemic sclerosis: abnormalities and therapeutic targets. J Dermatol. 2016;43(1):39–45.

    Article  CAS  PubMed  Google Scholar 

  23. Sakkas LI, Bogdanos DP. Systemic sclerosis: new evidence re-enforces the role of B cells. Autoimmun Rev. 2016;15(2):155–61.

    Article  CAS  PubMed  Google Scholar 

  24. Mavropoulos A, Simopoulou T, Varna A, Liaskos C, Katsiari CG, Bogdanos DP, et al. Breg cells are numerically decreased and functionally impaired in patients with systemic sclerosis. Arthritis Rheumatol. 2016;68(2):494–504.

    Article  CAS  PubMed  Google Scholar 

  25. Odaka M, Hasegawa M, Hamaguchi Y, Ishiura N, Kumada S, Matsushita T, et al. Autoantibody-mediated regulation of B cell responses by functional anti-CD22 autoantibodies in patients with systemic sclerosis. Clin Exp Immunol. 2010;159(2):176–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sato S, Hasegawa M, Fujimoto M, Tedder TF, Takehara K. Quantitative genetic variation in CD19 expression correlates with autoimmunity. J Immunol. 2000;165(11):6635–43.

    Article  CAS  PubMed  Google Scholar 

  27. Saigusa R, Asano Y, Nakamura K, Yamashita T, Ichimura Y, Takahashi T, et al. Association of anti-RNA polymerase III antibody and silicone breast implants in patients with systemic sclerosis. J Dermatol. 2016;43(7):808–10.

    Article  CAS  PubMed  Google Scholar 

  28. Saigusa R, Asano Y, Nakamura K, Miura S, Ichimura Y, Takahashi T, et al. Association of anti-RNA polymerase III antibody and malignancy in Japanese patients with systemic sclerosis. J Dermatol. 2015;42(5):524–7.

    Article  CAS  PubMed  Google Scholar 

  29. Yanaba K, Hayashi M, Yoshihara Y, Nakagawa H. Serum levels of soluble programmed death-1 and programmed death ligand-1 in systemic sclerosis: association with extent of skin sclerosis. J Dermatol. 2016;43(8):954–7.

    Article  CAS  PubMed  Google Scholar 

  30. Nakamura K, Asano Y, Taniguchi T, Minatsuki S, Inaba T, Maki H, et al. Serum levels of interleukin-18-binding protein isoform a: clinical association with inflammation and pulmonary hypertension in systemic sclerosis. J Dermatol. 2016;43(8):912–8.

    Article  CAS  PubMed  Google Scholar 

  31. Miura S, Asano Y, Saigusa R, Yamashita T, Taniguchi T, Takahashi T, et al. Serum omentin levels: a possible contribution to vascular involvement in patients with systemic sclerosis. J Dermatol. 2015;42(5):461–6.

    Article  CAS  PubMed  Google Scholar 

  32. Miura S, Asano Y, Saigusa R, Yamashita T, Taniguchi T, Takahashi T, et al. Serum vaspin levels: a possible correlation with digital ulcers in patients with systemic sclerosis. J Dermatol. 2015;42(5):528–31.

    Article  CAS  PubMed  Google Scholar 

  33. Wu CY, Asano Y, Taniguchi T, Sato S, Yu HS. Serum level of circulating syndecan-1: a possible association with proliferative vasculopathy in systemic sclerosis. J Dermatol. 2016;43(1):63–6.

    Article  CAS  PubMed  Google Scholar 

  34. Wu CY, Asano Y, Taniguchi T, Sato S, Yu HS. Serum heparanase levels: a protective marker against digital ulcers in patients with systemic sclerosis. J Dermatol. 2015;42(6):625–8.

    Article  CAS  PubMed  Google Scholar 

  35. Campbell PM, LeRoy EC. Pathogenesis of systemic sclerosis: a vascular hypothesis. Semin Arthritis Rheum. 1975;4(4):351–68.

    Article  CAS  PubMed  Google Scholar 

  36. Fleischmajer R, Perlish JS. Capillary alterations in scleroderma. J Am Acad Dermatol. 1980;2:161–70.

    Article  CAS  PubMed  Google Scholar 

  37. Haustein UF, Herrmann K, Böhme HJ. Pathogenesis of progressive systemic sclerosis. Int J Dermatol. 1986;25(5):286–93.

    Article  CAS  PubMed  Google Scholar 

  38. Cabral-Marques O, Riemekasten G. Vascular hypothesis revisited: role of stimulating antibodies against angiotensin and endothelin receptors in the pathogenesis of systemic sclerosis. Autoimmun Rev. 2016;15(7):690–4.

    Article  CAS  PubMed  Google Scholar 

  39. Bordron A, Dueymes M, Levy Y, Jamin C, Leroy JP, Piette JC, et al. The binding of some human antiendothelial cell antibodies induces endothelial cell apoptosis. J Clin Invest. 1998;101(10):2029–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wolf SI, Howat S, Abraham DJ, Pearson JD, Lawson C. Agonistic anti-ICAM-1 antibodies in scleroderma: activation of endothelial pro-inflammatory cascades. Vasc Pharmacol. 2013;59(1–2):19–26.

    Article  CAS  Google Scholar 

  41. Kill A, Tabeling C, Undeutsch R, Kühl AA, Günther J, Radic M, et al. Autoantibodies to angiotensin and endothelin receptors in systemic sclerosis induce cellular and systemic events associated with disease pathogenesis. Arthritis Res Ther. 2014;16(1):R29. doi:10.1186/ar4457.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Xia Y, Kellems RE. Angiotensin receptor agonistic autoantibodies and hypertension: preeclampsia and beyond. Circ Res. 2013;113(1):78–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Becker MO, Kill A, Kutsche M, Guenther J, Rose A, Tabeling C, et al. Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis. Am J Respir Crit Care Med. 2014;190(7):808–17.

    Article  CAS  PubMed  Google Scholar 

  44. Kawaguchi Y, Takagi K, Hara M, Fukasawa C, Sugiura T, Nishimagi E, et al. Angiotensin II in the lesional skin of systemic sclerosis patients contributes to tissue fibrosis via angiotensin II type 1 receptors. Arthritis Rheum. 2004 Jan;50(1):216–26.

    Article  CAS  PubMed  Google Scholar 

  45. Akamata K, Asano Y, Aozasa N, Noda S, Taniguchi T, Takahashi T, et al. Bosentan reverses the pro-fibrotic phenotype of systemic sclerosis dermal fibroblasts via increasing DNA binding ability of transcription factor Fli1. Arthritis Res Ther. 2014;16(2):R86. doi:10.1186/ar4529.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Günther J, Kill A, Becker MO, Heidecke H, Rademacher J, Siegert E, et al. Angiotensin receptor type 1 and endothelin receptor type a on immune cells mediate migration and the expression of IL-8 and CCL18 when stimulated by autoantibodies from systemic sclerosis patients. Arthritis Res Ther. 2014;16(2):R65. doi:10.1186/ar4503.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Sgonc R, Gruschwitz MS, Dietrich H, Recheis H, Gershwin ME, Wick G. Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. J Clin Invest. 1996;98(3):785–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lunardi C, Bason C, Navone R, Millo E, Damonte G, Corrocher R, et al. Systemic sclerosis immunoglobulin G autoantibodies bind the human cytomegalovirus late protein UL94 and induce apoptosis in human endothelial cells. Nat Med. 2000;6(10):1183–6.

    Article  CAS  PubMed  Google Scholar 

  49. Lunardi C, Dolcino M, Peterlana D, Bason C, Navone R, Tamassia N, et al. Antibodies against human cytomegalovirus in the pathogenesis of systemic sclerosis: a gene array approach. PLoS Med. 2006;3(1):e2.

    Article  PubMed  CAS  Google Scholar 

  50. Roumm AD, Whiteside TL, Medsger TA Jr, Rodnan GP. Lymphocytes in the skin of patients with progressive systemic sclerosis. Quantification, subtyping, and clinical correlations. Arthritis Rheum. 1984;27(6):645–53.

    Article  CAS  PubMed  Google Scholar 

  51. Gilbane AJ, Denton CP, Holmes AM. Scleroderma pathogenesis: a pivotal role for fibroblasts as effector cells. Arthritis Res Ther. 2013;15(3):215.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Pannu J, Gore-Hyer E, Yamanaka M, Smith EA, Rubinchik S, Dong JY, et al. An increased transforming growth factor beta receptor type I:type II ratio contributes to elevated collagen protein synthesis that is resistant to inhibition via a kinase-deficient transforming growth factor beta receptor type II in scleroderma. Arthritis Rheum. 2004;50(5):1566–77.

    Article  CAS  PubMed  Google Scholar 

  53. Serratì S, Chillà A, Laurenzana A, Margheri F, Giannoni E, Magnelli L, et al. Systemic sclerosis endothelial cells recruit and activate dermal fibroblasts by induction of a connective tissue growth factor (CCN2)/transforming growth factor β-dependent mesenchymal-to-mesenchymal transition. Arthritis Rheum. 2013;65(1):258–69.

    Article  PubMed  CAS  Google Scholar 

  54. Leask A. Towards an anti-fibrotic therapy for scleroderma: targeting myofibroblast differentiation and recruitment. Fibrogenesis Tissue Repair. 2010;3:8. doi:10.1186/1755-1536-3-8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Leask A. Getting out of a sticky situation: targeting the myofibroblast in scleroderma. Open Rheumatol J. 2012;6:163–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Igarashi A, Nashiro K, Kikuchi K, Sato S, Ihn H, Fujimoto M, et al. Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders. J Invest Dermatol. 1996;106(4):729–33.

    Article  CAS  PubMed  Google Scholar 

  57. Lakos G, Takagawa S, Chen SJ, Ferreira AM, Han G, Masuda K, et al. Targeted disruption of TGF-beta/Smad3 signaling modulates skin fibrosis in a mouse model of scleroderma. Am J Pathol. 2004;165(1):203–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Gay S, Jones RE Jr, Huang GQ, Gay RE. Immunohistologic demonstration of platelet-derived growth factor (PDGF) and sis-oncogene expression in scleroderma. J Invest Dermatol. 1989;92(2):301–3.

    Article  CAS  PubMed  Google Scholar 

  59. Baroni SS, Santillo M, Bevilacqua F, Luchetti M, Spadoni T, Mancini M, 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 

  60. Hasegawa M, Hamaguchi Y, Yanaba K, Bouaziz JD, Uchida J, Fujimoto M, et al. B-lymphocyte depletion reduces skin fibrosis and autoimmunity in the tight-skin mouse model for systemic sclerosis. Am J Pathol. 2006;169(3):954–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Castelino FV, Bain G, Pace VA, Black KE, George L, Probst CK, et al. An Autotaxin-LPA-IL-6 amplification loop drives scleroderma fibrosis. Arthritis Rheumatol. 2001;68(12):2964–74.

    Article  CAS  Google Scholar 

  62. O’Reilly S, Ciechomska M, Cant R, van Laar JM. 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  CAS  Google Scholar 

  63. Postlethwaite AE, Holness MA, Katai H, Raghow R. Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin 4. J Clin Invest. 1992;90(4):1479–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Jinnin M, Ihn H, Yamane K, Tamaki K. Interleukin-13 stimulates the transcription of the human alpha2(I) collagen gene in human dermal fibroblasts. J Biol Chem. 2004;279(40):41783–91.

    Article  CAS  PubMed  Google Scholar 

  65. Kaviratne M, Hesse M, Leusink M, Cheever AW, Davies SJ, McKerrow JH, et al. IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta independent. J Immunol. 2004;173(6):4020–9.

    Article  CAS  PubMed  Google Scholar 

  66. Hasegawa M, Fujimoto M, Kikuchi K, Takehara K. Elevated serum levels of interleukin 4 (IL-4), IL-10, and IL-13 in patients with systemic sclerosis. J Rheumatol. 1997;24(2):328–32.

    CAS  PubMed  Google Scholar 

  67. Fallon PG, Richardson EJ, McKenzie GJ, McKenzie AN. Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent. J Immunol. 2000;164(5):2585–91.

    Article  CAS  PubMed  Google Scholar 

  68. Fuschiotti P, Larregina AT, Ho J, Feghali-Bostwick C, Medsger TA Jr. Interleukin-13-producing CD8+ T cells mediate dermal fibrosis in patients with systemic sclerosis. Arthritis Rheum. 2013;65(1):236–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Takagawa S, Lakos G, Mori Y, Yamamoto T, Nishioka K, Varga J. Sustained activation of fibroblast transforming growth factor-beta/Smad signaling in a murine model of scleroderma. J Invest Dermatol. 2003;121(1):41–50.

    Article  CAS  PubMed  Google Scholar 

  70. Jaffee BD, Claman HN. Chronic graft-versus-host disease (GVHD) as a model for scleroderma. I. Description of model systems. Cell Immunol. 1983;77(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  71. Ruzek MC, Jha S, Ledbetter S, Richards SM, Garman RD. A modified model of graft-versus-host-induced systemic sclerosis (scleroderma) exhibits all major aspects of the human disease. Arthritis Rheum. 2004;50(4):1319–31.

    Article  PubMed  Google Scholar 

  72. Servettaz A, Goulvestre C, Kavian N, Nicco C, Guilpain P, Chéreau C, et al. Selective oxidation of DNA topoisomerase 1 induces systemic sclerosis in the mouse. J Immunol. 2009;182(9):5855–64.

    Article  CAS  PubMed  Google Scholar 

  73. Yoshizaki A, Yanaba K, Ogawa A, Asano Y, Kadono T, Sato S. Immunization with DNA topoisomerase I and Freund’s complete adjuvant induces skin and lung fibrosis and autoimmunity via interleukin-6 signaling. Arthritis Rheum. 2011;63(11):3575–85.

    Article  CAS  PubMed  Google Scholar 

  74. Stawski L, Han R, Bujor AM, Trojanowska M. Angiotensin II induces skin fibrosis: a novel mouse model of dermal fibrosis. Arthritis Res Ther. 2012;14(4):R194. doi:10.1186/ar4028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Siracusa LD, McGrath R, Ma Q, Moskow JJ, Manne J, Christner PJ, et al. A tandem duplication within the fibrillin 1 gene is associated with the mouse tight skin mutation. Genome Res. 1996;6(4):300–13.

    Article  CAS  PubMed  Google Scholar 

  76. Sonnylal S, Denton CP, Zheng B, Keene DR, He R, Adams HP, et al. Postnatal induction of transforming growth factor beta signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma. Arthritis Rheum. 2007;56(1):334–44.

    Article  CAS  PubMed  Google Scholar 

  77. Sonnylal S, Shi-Wen X, Leoni P, Naff K, Van Pelt CS, Nakamura H, et al. Selective expression of connective tissue growth factor in fibroblasts in vivo promotes systemic tissue fibrosis. Arthritis Rheum. 2010;62(5):1523–32.

    Article  PubMed  CAS  Google Scholar 

  78. Wei J, Melichian D, Komura K, Hinchcliff M, Lam AP, Lafyatis R, et al. Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: a novel mouse model for scleroderma? Arthritis Rheum. 2011;63(6):1707–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Eferl R, Hasselblatt P, Rath M, Popper H, Zenz R, Komnenovic V, et al. Development of pulmonary fibrosis through a pathway involving the transcription factor Fra-2/AP-1. Proc Natl Acad Sci U S A. 2008;105(30):10525–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Maurer B, Busch N, Jüngel A, Pileckyte M, Gay RE, Michel BA, et al. Transcription factor fos-related antigen-2 induces progressive peripheral vasculopathy in mice closely resembling human systemic sclerosis. Circulation. 2009;120(23):2367–76.

    Article  CAS  PubMed  Google Scholar 

  81. Kanno Y, Kaneiwa A, Minamida M, Kanno M, Tomogane K, Takeuchi K, et al. The absence of uPAR is associated with the progression of dermal fibrosis. J Invest Dermatol. 2008;128(12):2792–7.

    Article  CAS  PubMed  Google Scholar 

  82. Bernstein AM, Twining SS, Warejcka DJ, Tall E, Masur SK. Urokinase receptor cleavage: a crucial step in fibroblast-to-myofibroblast differentiation. Mol Biol Cell. 2007;18(7):2716–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. D’Alessio S, Fibbi G, Cinelli M, Guiducci S, Del Rosso A, Margheri F, et al. Matrix metalloproteinase 12-dependent cleavage of urokinase receptor in systemic sclerosis microvascular endothelial cells results in impaired angiogenesis. Arthritis Rheum. 2004;50(10):3275–85.

    Article  PubMed  CAS  Google Scholar 

  84. Margheri F, Manetti M, Serratì S, Nosi D, Pucci M, Matucci-Cerinic M, et al. Domain 1 of the urokinase-type plasminogen activator receptor is required for its morphologic and functional, beta2 integrin-mediated connection with actin cytoskeleton in human microvascular endothelial cells: failure of association in systemic sclerosis endothelial cells. Arthritis Rheum. 2006;54(12):3926–38.

    Article  CAS  PubMed  Google Scholar 

  85. Manetti M, Rosa I, Milia AF, Guiducci S, Carmeliet P, Ibba-Manneschi L, et al. Inactivation of urokinase-type plasminogen activator receptor (uPAR) gene induces dermal and pulmonary fibrosis and peripheral microvasculopathy in mice: a new model of experimental scleroderma? Ann Rheum Dis. 2014;73(9):1700–9.

    Article  PubMed  Google Scholar 

  86. Noda S, Asano Y, Nishimura S, Taniguchi T, Fujiu K, Manabe I, et al. Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis. Nat Commun. 2014;5:5797. doi:10.1038/ncomms6797.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Czuwara-Ladykowska J, Shirasaki F, Jackers P, Watson DK, Trojanowska M. Fli-1 inhibits collagen type I production in dermal fibroblasts via an Sp1-dependent pathway. J Biol Chem. 2001;276(24):20839–48.

    Article  CAS  PubMed  Google Scholar 

  88. Kubo M, Czuwara-Ladykowska J, Moussa O, Markiewicz M, Smith E, Silver RM, et al. Persistent down-regulation of Fli1, a suppressor of collagen transcription, in fibrotic scleroderma skin. Am J Pathol. 2003;163(2):571–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Whitfield ML, Finlay DR, Murray JI, Troyanskaya OG, Chi JT, Pergamenschikov A, et al. Systemic and cell type-specific gene expression patterns in scleroderma skin. Proc Natl Acad Sci U S A. 2003;100(21):12319–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. van den Hoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ, van Lier HJ, van de Putte LB. Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week observational trial. Br J Rheumatol. 1996;35(4):364–72.

    Article  PubMed  Google Scholar 

  91. Pope JE, Bellamy N, Seibold JR, Baron M, Ellman M, Carette S, 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 

  92. Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006;354(25):2655–66.

    Article  CAS  PubMed  Google Scholar 

  93. Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS, 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 

  94. Koutroumpas A, Ziogas A, Alexiou I, Barouta G, Sakkas LI. Mycophenolate mofetil in systemic sclerosis-associated interstitial lung disease. Clin Rheumatol. 2010;29(10):1167–8.

    Article  PubMed  Google Scholar 

  95. Gerbino AJ, Goss CH, Molitor JA. Effect of mycophenolate mofetil on pulmonary function in scleroderma-associated interstitial lung disease. Chest. 2008;133(2):455–60.

    Article  CAS  PubMed  Google Scholar 

  96. Poelman CL, Hummers LK, Wigley FM, Anderson C, Boin F, Shah AA. Intravenous immunoglobulin may be an effective therapy for refractory, active diffuse cutaneous systemic sclerosis. J Rheumatol. 2015;42(2):236–42.

    Article  CAS  PubMed  Google Scholar 

  97. Takehara K, Ihn H, Sato S. A randomized, double-blind, placebo-controlled trial: intravenous immunoglobulin treatment in patients with diffuse cutaneous systemic sclerosis. Clin Exp Rheumatol. 2013;31(2 Suppl 76):151–6.

    PubMed  Google Scholar 

  98. Kowal-Bielecka O, Landewé R, Avouac J, Chwiesko S, Miniati I, Czirjak L, et al. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR scleroderma trials and research group (EUSTAR). Ann Rheum Dis. 2009;68(5):620–8.

    Article  CAS  PubMed  Google Scholar 

  99. Denton CP, Pope JE, Peter HH, Gabrielli A, Boonstra A, van den Hoogen FH, et al. Long-term effects of bosentan on quality of life, survival, safety and tolerability in pulmonary arterial hypertension related to connective tissue diseases. Ann Rheum Dis. 2008;67(9):1222–8.

    Article  CAS  PubMed  Google Scholar 

  100. Lopez-Ovejero JA, Saal SD, D’Angelo WA, Cheigh JS, Stenzel KH, Laragh JH. Reversal of vascular and renal crises of scleroderma by oral angiotensin-converting-enzyme blockade. N Engl J Med. 1979;300(25):1417–9.

    Article  CAS  PubMed  Google Scholar 

  101. Motegi S, Yamada K, Toki S, Uchiyama A, Kubota Y, Nakamura T, et al. Beneficial effect of botulinum toxin a on Raynaud’s phenomenon in Japanese patients with systemic sclerosis: a prospective, case series study. J Dermatol. 2016;43(1):56–62.

    Article  CAS  PubMed  Google Scholar 

  102. Daoussis D, Melissaropoulos K, Sakellaropoulos G, Antonopoulos I, Markatseli TE, Simopoulou T, et al. A multicenter, open-label, comparative study of B-cell depletion therapy with rituximab for systemic sclerosis-associated interstitial lung disease. Semin Arthritis Rheum. 2016; doi:10.1016/j.semarthrit.2016.10.003.

    Google Scholar 

  103. Smith V, Pizzorni C, Riccieri V, Decuman S, Brusselle G, DE Pauw M, et al. Stabilization of microcirculation in patients with early systemic sclerosis with diffuse skin involvement following rituximab treatment: an open-label study. J Rheumatol. 2016;43(5):995–6.

    Article  PubMed  CAS  Google Scholar 

  104. Bosello S, De Santis M, Lama G, Spanò C, Angelucci C, Tolusso B, et al. B cell depletion in diffuse progressive systemic sclerosis: safety, skin score modification and IL-6 modulation in an up to thirty-six months follow-up open-label trial. Arthritis Res Ther. 2010;12(2):R54. doi:10.1186/ar2965.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Rice LM, Padilla CM, McLaughlin SR, Mathes A, Ziemek J, Goummih S, et al. Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. J Clin Invest. 2015;125(7):2795–807.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Khanna D, Denton CP, Jahreis A, van Laar JM, Frech TM, Anderson ME, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016;387(10038):2630–40.

    Article  CAS  PubMed  Google Scholar 

  107. Shima Y, Hosen N, Hirano T, Arimitsu J, Nishida S, Hagihara K, et al. Expansion of range of joint motion following treatment of systemic sclerosis with tocilizumab. Mod Rheumatol. 2015;25(1):134–7.

    Article  PubMed  Google Scholar 

  108. Yoshizaki A, Yanaba K, Yoshizaki A, Iwata Y, Komura K, Ogawa F, et al. Treatment with rapamycin prevents fibrosis in tight-skin and bleomycin-induced mouse models of systemic sclerosis. Arthritis Rheum. 2010;62(8):2476–87.

    Article  CAS  PubMed  Google Scholar 

  109. Su TI, Khanna D, Furst DE, Danovitch G, Burger C, Maranian P, et al. Rapamycin versus methotrexate in early diffuse systemic sclerosis: results from a randomized, single-blind pilot study. Arthritis Rheum. 2009;60(12):3821–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Albera C, Costabel U, Fagan EA, Glassberg MK, Gorina E, Lancaster L, et al. Efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis with more preserved lung function. Eur Respir J. 2016;48(3):843–51.

    Article  PubMed  Google Scholar 

  111. Lopez-de la Mora DA, Sanchez-Roque C, Montoya-Buelna M, Sanchez-Enriquez S, Lucano-Landeros S, Macias-Barragan J, et al. Role and new insights of Pirfenidone in fibrotic diseases. Int J Med Sci. 2015;12(11):840–7.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Distler JH, Feghali-Bostwick C, Soare A, Asano Y, Distler O, Abraham DJ. Frontiers of antifibrotic therapy in systemic sclerosis. Arthritis Rheumatol. 2017;69(2):257–67.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Dermatology, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka, 812-8582, Japan

    Masutaka Furue, Chikage Mitoma, Gaku Tsuji, Takahito Chiba, Takeshi Nakahara & Hiroshi Uchi

  2. Research and Clinical Center for Yusho and Dioxin, Kyushu University, Fukuoka, Japan

    Masutaka Furue, Chikage Mitoma & Gaku Tsuji

  3. Division of Skin Surface Sensing, Department of Dermatology, Kyushu University, Fukuoka, Japan

    Masutaka Furue & Takeshi Nakahara

  4. Department of Clinical Immunology and Rheumatology/Infectious Disease, Kyushu University, Fukuoka, Japan

    Hiroki Mitoma

  5. Department of Dermatology, St. Marianna University School of Medicine, Kawasaki, Japan

    Takafumi Kadono

Authors
  1. Masutaka Furue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chikage Mitoma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroki Mitoma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gaku Tsuji
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takahito Chiba
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takeshi Nakahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hiroshi Uchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takafumi Kadono
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masutaka Furue.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Furue, M., Mitoma, C., Mitoma, H. et al. Pathogenesis of systemic sclerosis—current concept and emerging treatments. Immunol Res 65, 790–797 (2017). https://doi.org/10.1007/s12026-017-8926-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-017-8926-y

Keywords

Search

Navigation