Therapeutic Options for Systemic Sclerosis: Current and Future Perspectives in Tackling Immune-Mediated Fibrosis

Abstract

Systemic sclerosis (SSc) is a severe auto-immune, rheumatic disease, characterized by excessive fibrosis of the skin and visceral organs. SSc is accompanied by high morbidity and mortality rates, and unfortunately, few disease-modifying therapies are currently available. Inflammation, vasculopathy, and fibrosis are the key hallmarks of SSc pathology. In this narrative review, we examine the relationship between inflammation and fibrosis and provide an overview of the efficacy of current and novel treatment options in diminishing SSc-related fibrosis based on selected clinical trials. To do this, we first discuss inflammatory pathways of both the innate and acquired immune systems that are associated with SSc pathophysiology. Secondly, we review evidence supporting the use of first-line therapies in SSc patients. In addition, T cell-, B cell-, and cytokine-specific treatments that have been utilized in SSc are explored. Finally, the potential effectiveness of tyrosine kinase inhibitors and other novel therapeutic approaches in reducing fibrosis is highlighted.

Keywords: anti-inflammatory; fibrosis; immune cells; systemic sclerosis; therapy.

Figure 1

Simplified schematic representation of the complex interplay between inflammation, vasculopathy, and fibrosis in SSc. Abbreviations: Th1 = T helper type 1 cells; DAMPs = damage-associated molecular patterns; T = T lymphocyte; B = B lymphocyte; MΦ = macrophage.

Figure 2

An overview of the main pathogenic mechanisms by which T cells, B cells, macrophages, mast cells, and plasmacytoid dendritic cells may contribute to (pro-)fibrotic manifestations in SSc immunopathology. Abbreviations: MΦ = macrophages; B = B lymphocyte; CD8 = cytotoxic T cell; CD4 = T helper cell; pDC = plasmacytoid dendritic cell; TGF-β = transforming growth factor-β; BAFF = B cell activating factor; APRIL = a proliferation-inducing ligand; PDGF = platelet-derived growth factor; ECM = extracellular matrix.

Figure 3

A simplified schematic illustration of the pathogenic mechanisms by which T cells, B cells, and macrophages may be involved in the vascular abnormalities that characterize SSc immunopathology. ICAM-1 = intercellular adhesion molecule 1; VCAM-1 = vascular cell adhesion molecule 1; EndoMT = endothelial-to-mesenchymal transition; GZMB = granzyme B; NOS = nitric oxide synthase; DAMPs = damage-associated molecular patterns; MΦ = macrophages; B = B lymphocyte; CD4 = T helper cell; CD8 = cytotoxic T cell; TGF-β = transforming growth factor-β.

Figure 4

Schematic representation of the mechanism of action of synthetic corticosteroids (CS), mycophenolate mofetil, cyclophosphamide, inebilizumab, rituximab, belimumab, abatacept, nintedanib, tocilizumab, tofacitinib, fresolimumab, metelimumab, and pirfenidone in reducing fibrosis in SSc. Abbreviations: ECM = extracellular matrix; TGF-β = transforming growth factor-β.