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.
BACKGROUND
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 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.


CONCLUSIONS
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.
Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, Patras, Rion, 26504, Greece. jimdaoussis@hotmail.com
Dimitrios
D
Daoussis
Athanassios C
AC
Tsamandas
Stamatis-Nick C
SN
Liossis
Ioannis
I
Antonopoulos
Elli
E
Karatza
Georgios
G
Yiannopoulos
Andrew P
AP
Andonopoulos
D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects; D005260:Female; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D008212:Lymphocyte Depletion / Q000379:methods; D008297:Male; D008875:Middle Aged; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000096:biosynthesis* / Q000187:drug effects; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis* / Q000187:drug effects; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D000069283:Rituximab; D045743:Scleroderma, Diffuse / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D012867:Skin / Q000378:metabolism / Q000473:pathology
D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D000069283:Rituximab; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor