Pathophysiology of systemic sclerosis: current understanding and new insights

ABSTRACT

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:

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

Article highlights

• Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease characterized by a chronic and progressive tissue and organ fibrosis.

• The pathophysiology of SSc is a progressive self-amplifying process, that first implicates the microvascular/endothelial damage, followed by the autoimmune response and inflammation, and finally characterized by diffuse fibrosis.

• The progressive microvascular pathophysiology in SSc is associated with the clinical disease progression: from the Raynaud’s phenomenon to the microvessel leak with hemorrhages, capillary collapses/loss (both visible on capillaroscopy) and tissue ischemia.

• New insights on the microvascular SSc pathophysiology include VEGF isoforms (antiangiogenic) and impaired functioning of the endothelial progenitor cells (EPC) that are involved in the angiogenesis.

• Epigenetic studies have identified intrinsic alterations in SSc fibroblasts resulting from epigenetic changes, as well as altered microRNA expression (in particular miR-29, miR-155) that might underlie the persistent activation phenotype of these cells.

• The immune response in SSc is complex and involves both the innate and adaptive immunity with prevalence of Th2 cytokines.

• The macrophage (M) polarization versus a prevalence of hybrid M1/M2 circulating progenitor cells and versus the M2 phenotype in the fibrotic tissues, it is particularly evident in presence of SSc lung involvement.

• The production of specific autoantibodies in SSc seems associated with different clinical aspects, in addition several functional autoantibodies seem implicated in the pathophysiology of the disease.

• The fibrotic process in SSc is characterized by progressive tissue accumulation of extracellular matrix (ECM) protein like collagens, elastin, glycosaminoglycans, tenascin and fibronectin isoforms in skin and multiple organs.

• The endothelial(epitelial)-to-mesenchymal cell transition (EndoMT) process is a source of myofibroblasts in SSc and can be induced by TGF-β together with endothelin-1 (ET-1): both seem to be pivotal soluble players in the development of fibrosis.

• In SSc, myofibroblasts seem to originate also from adiponectin-positive intradermal progenitor cells: the process was confirmed by adipocyte phenotype investigations and is termed adipocyte-myofibroblast transition (AMT).

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This article was not funded.