Systemic Sclerosis: From Pathophysiology to Novel Therapeutic Approaches

Abstract

Systemic sclerosis (SSc) is a systemic, immune-mediated chronic disorder characterized by small vessel alterations and progressive fibrosis of the skin and internal organs. The combination of a predisposing genetic background and triggering factors that causes a persistent activation of immune system at microvascular and tissue level is thought to be the pathogenetic driver of SSc. Endothelial alterations with subsequent myofibroblast activation, excessive extracellular matrix (ECM) deposition, and unrestrained tissue fibrosis are the pathogenetic steps responsible for the clinical manifestations of this disease, which can be highly heterogeneous according to the different entity of each pathogenic step in individual subjects. Although substantial progress has been made in the management of SSc in recent years, disease-modifying therapies are still lacking. Several molecular pathways involved in SSc pathogenesis are currently under evaluation as possible therapeutic targets in clinical trials. These include drugs targeting fibrotic and metabolic pathways (e.g., TGF-β, autotaxin/LPA, melanocortin, and mTOR), as well as molecules and cells involved in the persistent activation of the immune system (e.g., IL4/IL13, IL23, JAK/STAT, B cells, and plasma cells). In this review, we provide an overview of the most promising therapeutic targets that could improve the future clinical management of SSc.

SARA suppresses myofibroblast precursor transdifferentiation in fibrogenesis in a mouse model of scleroderma

“…Most current approaches mainly target immune cells, and only a few target signals in activated ECM-producing myofibroblasts, such as nintedanib, which is an antifibrotic drug ( 4 , 5 ), with limited successes. Instead, the following 2 novel strategies that target earlier pathogenic changes in SSc are novel and promising ( 6 ) to control this devastating disease more effectively. The first is to prevent transdifferentiation of myofibroblast precursors, and the second involves suppressing a specific subset of immune cells that contribute to disease progression.…”

Tissue Resident Foxp3+ Regulatory T Cells: Sentinels and Saboteurs in Health and Disease

“…In vitiligo, a T cell mediated autoimmune condition resulting in the loss of melanocytes, cutaneous Treg cells are greatly reduced, suggesting that autoreactive T cell activation is not adequately controlled ( 72 ). Diffuse systemic scleroderma/sclerosis (SSc) is an autoimmune condition characterized by excessive fibrosis in barrier tissues like skin ( 73 ). Skin Treg cells are similarly reduced in the SSc skin, which seems associated with diminished TGFβ and IL-10 expression ( 74 ).…”

PDGF/PDGFR: A Possible Molecular Target in Scleroderma Fibrosis

“…Numerous post-hoc and subgroup analyses of the SENSCIS study suggest that nintedanib efficacy is consistent across the disease spectrum, regardless of predicted %FVC, disease duration, the extent of fibrotic involvement on HRCT, autoantibody status, or SSc [ 78 ].…”