Dermal cellular senescence and EndMT in patients with systemic sclerosis undergoing cyclophosphamide or aHSCT treatment

Objectives: Cellular senescence and endothelial-to-mesenchymal transition (EndMT) are profibrotic cellular processes involved in systemic sclerosis (SSc), but how they respond to treatment is largely unknown. Methods: Skin biopsies from diffuse cutaneous SSc (dcSSc) patients who underwent either autologous haematopoietic stem cell transplantation (aHSCT) or cyclophosphamide pulse (iv CYC) treatment were collected before and 6 months after randomization in the Autologous Stem Cell Transplantation International Scleroderma trial. The extent of fibrosis, inflammation, senescence, EndMT and tissue remodelling were examined in histopathology. Results: Fourteen pairs of skin biopsies were analysed. Decrease in modified Rodnan skin score was more pronounced in aHSCT-treated patients compared with iv CYC at 6 months (median change −14 [IQR −16 to −9] vs -6 [IQR −9 to −4], respectively, P = 0.028). Histologically, expression of urokinase-type plasminogen activator receptor (uPAR) on fibroblasts, P21 on vessels and EndMT decreased after treatment in both groups, yet the reduction was more pronounced in the aHSCT group. Poor skin response was associated with high baseline connective tissue growth factor (CTGF) on fibroblasts and low baseline P21 on vessels, with an odds ratio (OR) of 1.43 and 0.41, respectively. Furthermore, poor response was also seen in patients with a rise in CTGF on fibroblasts (OR 1.29) and P21 on vessels (OR 3.02) after treatment, P < 0.001. Conclusion: Both aHSCT and iv CYC in dcSSc reduced skin thickening clinically and attenuated EndMT, but affected cellular senescence not significantly different. EndMT and uPAR were associated with fibro-remodelling activity, whereas senescence, CTGF, uPAR and vascularity were associated with treatment response.