Fibrosis in systemic sclerosis: Emerging concepts and implications for targeted therapy

Abstract

Systemic sclerosis (SSc) is a complex and incompletely understood disease associated with fibrosis in multiple organs. Recent findings identify transforming growth factor-ß (TGF-ß), Wnt ligands, toll-like receptor-mediated signaling, hypoxia, type I interferon, type 2 immune responses and mechanical stress as extracellular cues that modulate fibroblast function and differentiation, and as potential targets for therapy. Moreover, fibrillin-1 has a major role in storing and regulating the bioavailability of TGF-ß and other cytokines, and fibrillin-1 mutations are implicated in a congenital form of scleroderma called stiff skin syndrome. Fibrosis is due not only to the activation of tissue-resident fibroblasts and their transdifferentiation into myofibroblasts, but also the differentiation of bone marrow-derived fibrocytes, and transition of endothelial and epithelial cells, pericytes and adipocytes into activated mesenchymal cells. These responses are modulated by signaling mediators and microRNAs that amplify or inhibit TGF-ß and Wnt signaling. Gain-of-function and loss-of-function abnormalities of these mediators may account for the characteristic activated phenotype of SSc fibroblasts. The nuclear orphan receptor PPAR-γ plays a particularly important role in limiting the duration and intensity of fibroblast activation and differentiation, and impaired PPAR-γ expression or function in SSc may underlie the uncontrolled progression of fibrosis.

Identifying the perturbations in signaling pathways, mediators and differentiation programs that are responsible for SSc tissue damage allows their selective targeting. This in turn opens the door for therapies utilizing novel compounds, or drug repurposing by innovative uses of already-approved drugs. In view of the heterogeneous clinical presentation and unpredictable course of SSc, as well as its complex pathogenesis, only robust clinical trials incorporating the judicious application of biomarkers will be able to clarify the clinical utility of these innovative approaches.

Introduction

Systemic sclerosis (SSc) is a progressive autoimmune disease of unknown cause associated with substantial mortality. To date there are no disease-modifying therapies, and immunomodulatory agents that are highly effective in other rheumatic diseases have shown disappointing results in SSc. The explanation may lie in the complex nature of SSc, characterized by a constellation of vascular injury, inflammation and fibrosis. It is not clear which of these perturbations is primary. Every SSc patient manifests some degree of vascular injury, immune activation and tissue fibrosis, but the relative contributions of these distinct processes to individual disease phenotype and natural history varies greatly from patient to patient. This variability accounts for the strikingly heterogeneous clinical picture of SSc. The three seemingly disparate yet interrelated pathophysiologic processes account for the clinical manifestations of SSc. Evidence of vascular injury and endothelial damage are detected at initial evaluation in a majority of patients. Over time, progressive vascular damage and obliteration of small and medium sized arteries cause tissue ischemia and its myriad complications. Vascular injury also plays a role in activation of the innate and adaptive immune systems, and contribute directly and indirectly to tissue fibrosis. The interrelationship of the three cardinal processes in the pathogenesis of SSc is illustrated in Fig. 1. In this review we focus on recent exciting developments in understanding fibrosis, the final common pathway in SSc that accounts for much of its mortality.