Pathophysiology of systemic sclerosis: current understanding and new insights

Expert Rev Clin Immunol. 2019 Jul;15(7):753-764. doi: 10.1080/1744666X.2019.1614915. Epub 2019 May 13.


Introduction: Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease characterized by chronic and progressive tissue and organ fibrosis with broad patient-to-patient variability. Some risk factors are known and include combination of persistent Raynaud's phenomenon, steroid hormone imbalance, selected chemicals, thermal, or other injuries. Endogenous and/or exogenous environmental trigger/risk factors promote epigenetic mechanisms in genetically primed subjects. Disease pathogenesis presents early microvascular changes with endothelial cell dysfunction, followed by the activation of mechanisms promoting their transition into myofibroblasts. A complex autoimmune response, involving innate and adaptive immunity with specific/functional autoantibody production, characterizes the disease. Progressive fibrosis and ischemia involve skin and visceral organs resulting in their irreversible damage/failure. Progenitor circulating cells (monocytes, fibrocytes), together with growth factors and cytokines participate in disease diffusion and evolution. Epigenetic, vascular and immunologic mechanisms implicated in systemic fibrosis, represent major targets for incoming disease modifying therapeutic approaches. Areas covered: This review discusses current understanding and new insights of SSc pathogenesis, through an overview of the most relevant advancements to present aspects and mechanisms involved in disease pathogenesis. Expert opinion: Considering SSc intricacy/heterogeneity, early combination therapy with vasodilators, immunosuppressive and antifibrotic drugs should successfully downregulate the disease progression, especially if started from the beginning.

Keywords: Raynaud’s phenomenon; Systemic sclerosis; autoimmune rheumatic diseases; connective tissue diseases; endothelial cells; epigenetic; fibrocytes myofibroblasts; growth factors; immune response; macrophages; nailfold capillaroscopy.

Publication types

  • Review

MeSH terms

  • Animals
  • Autoantibodies / immunology
  • Autoimmunity*
  • Gonadal Steroid Hormones / immunology
  • Humans
  • Scleroderma, Systemic* / drug therapy
  • Scleroderma, Systemic* / immunology
  • Scleroderma, Systemic* / pathology
  • Scleroderma, Systemic* / physiopathology
  • Stem Cells* / immunology
  • Stem Cells* / pathology


  • Autoantibodies
  • Gonadal Steroid Hormones