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.

Zoledronic Acid Targeting of the Mevalonate Pathway Causes Reduced Cell Recruitment and Attenuates Pulmonary Fibrosis

“…Previous studies have implicated M2 macrophages in IPF pathogenesis, with pro-fibrotic M2 macrophages characterized by expression of CD206 as well as increased metabolism of arginine into ornithine and urea by arginase ( Ruaro et al, 2019 ; Papadimitriou et al, 2022 ). Stimulation of macrophages with profibrotic cytokines IL-4 and IL-13 lead to an increased number of M2 macrophages and fewer M1 macrophages indicative of a pro-fibrotic polarization.…”

Comparative single-cell multiplex immunophenotyping of therapy-naive patients with rheumatoid arthritis, systemic sclerosis, and systemic lupus erythematosus shed light on disease-specific composition of the peripheral immune system

“…Papadimitriou et al. summarized the link between the innate and adaptive arms of the immune system in the pathological mechanisms of SSc in the context of the currently available treatment regimen ( 16 ). Nagafuchi et al.…”

CD7 activation regulates cytotoxicity-driven pathology in systemic sclerosis, yielding a target for selective cell depletion

“…This is exemplified by the development of a dysregulated Raynaud’s phenomenon as the first and principal disease manifestation. T lymphocytes have been detected in SSc-affected tissues and multiple studies have suggested their potential involvement in the observed fibrosis and vasculopathy through the production of cytokines such as interleukin (IL)-4, IL-13 and IL-17 3. Unexpectedly, a recent study showed a prominent role for cytotoxic T cells in mediating SSc skin pathology 4.…”