B-cell depletion therapy in patients with diffuse systemic sclerosis associates with a significant decrease in PDGFR expression and activation in spindle-like cells in the skin

Introduction: Recently, 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. Methods: We 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. Results: We found a strong correlation of PDGFR alpha and PDGFR beta expression on spindle-like cells and collagen deposition in SSc biopsies (r = 0.97 and r = 0.96 for PDGFR alpha and PDGFR beta, respectively; P < 0.0001 for both), indicating a strong link between PDGFR expression and fibrosis. Expression of PDGFR alpha and PDGFR beta in the papillary dermis significantly decreased following RTX administration (mean +/- standard error of the mean at baseline vs. 6 months, respectively: PDGFR alpha, 42.05 +/- 5.03 vs. 26.85 +/- 3.00, P = 0.004; and PDGFR beta, 37.14 +/- 4.94 vs. 24.01 +/- 3.27, P = 0.012). Similarly, expression of phosphorylated PDGFR alpha and PDGFR beta in the papillary dermis significantly decreased following RTX administration (P = 0.006 and P = 0.013 for phospho-PDGFR alpha and phospho-PDGFR beta, respectively). No changes in platelet-derived growth factor tissue expression or serum levels were found following RTX treatment. Conclusion: RTX 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.