Abstract
IntroductionRecently, several studies assessing the clinical efficacy of rituximab (RTX) in systemic sclerosis (SSc) have reported encouraging results. We aimed at exploring whether RTX exerts its beneficial effects on fibrosis through attenuation of platelet-derived growth factor receptor (PDGFR) pathway activation.MethodsWe immunohistochemically assessed skin biopsies obtained from eight patients with SSc prior to and 6 months following RTX treatment, three control SSc patients (at the same time points) and three healthy subjects. We assessed the expression of platelet-derived growth factor, PDGFR and phosphorylated (activated) PDGFR.ResultsWe found a strong correlation of PDGFRα and PDGFRβ expression on spindle-like cells and collagen deposition in SSc biopsies (r = 0.97 and r = 0.96 for PDGFRα and PDGFRβ, respectively; P < 0.0001 for both), indicating a strong link between PDGFR expression and fibrosis. Expression of PDGFRα and PDGFRβ in the papillary dermis significantly decreased following RTX administration (mean ± standard error of the mean at baseline vs. 6 months, respectively: PDGFRα, 42.05 ± 5.03 vs. 26.85 ± 3.00, P = 0.004; and PDGFRβ, 37.14 ± 4.94 vs. 24.01 ± 3.27, P = 0.012). Similarly, expression of phosphorylated PDGFRα and PDGFRβ in the papillary dermis significantly decreased following RTX administration (P = 0.006 and P = 0.013 for phospho-PDGFRα and phospho-PDGFRβ, respectively). No changes in platelet-derived growth factor tissue expression or serum levels were found following RTX treatment.ConclusionRTX may favorably affect skin fibrosis through attenuation of PDGFR expression and activation, a finding that supports a disease-modifying role of RTX in SSc. Large-scale, multicenter studies are needed to further explore the efficacy of RTX in SSc.
Highlights
Several studies assessing the clinical efficacy of rituximab (RTX) in systemic sclerosis (SSc) have reported encouraging results
platelet-derived growth factor receptor (PDGFR) expression on spindle-like cells in scleroderma skin is strongly associated with collagen deposition and attenuates following rituximab administration We first studied, by immunohistochemistry, the expression of PDGFRa and PDGFRb in scleroderma versus normal skin
We found a strong correlation of PDGFRa and PDGFRb expression on spindle-like cells and collagen deposition in SSc biopsies (r = 0.97 and r = 0.96 for PDGFRa and PDGFRb, respectively; P < 0.0001 for both), indicating a strong link between PDGFR expression and fibrosis
Summary
Several studies assessing the clinical efficacy of rituximab (RTX) in systemic sclerosis (SSc) have reported encouraging results. We aimed at exploring whether RTX exerts its beneficial effects on fibrosis through attenuation of platelet-derived growth factor receptor (PDGFR) pathway activation. Treatment should be considered a positive outcome in this devastating disease where patients tend to gradually worsen over time. In three of those studies where skin biopsies were performed, a significant histologic improvement in terms of reduction of collagen deposition and myofibroblast score was reported [1,3,4], suggesting a potential disease-modifying role of RTX in skin fibrosis. Platelet-derived growth factor (PDGF) is a pivotal mediator of fibrosis; it has stimulatory effects on scleroderma fibroblasts by enhancing their proliferation and increasing collagen production [10]. Agonistic autoantibodies against PDGFR have been found in patients with SSc; these stimulatory autoantibodies have been suggested to participate in disease pathogenesis [13]
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