Reduced type I collagen gene expression by skin fibroblasts of patients with systemic sclerosis after one treatment course with rituximab.
OBJECTIVE
There is evidence that B lymphocytes play a role in the pathogenesis of systemic sclerosis (scleroderma). Stimulatory autoantibodies targeting and activating normal human fibroblasts in vitro have been demonstrated in sera from scleroderma patients. Rituximab is a monoclonal antibody which selectively targets and depletes CD20+ B lymphocytes. We investigated the biological effects of rituximab in six patients affected by scleroderma with severe skin involvement.


METHODS
Six patients with severe skin fibrosis, unresponsive to immunosuppressive treatment, were treated with 375 mg/m2 per week of intravenous rituximab for a total of four doses. Serum stimulatory autoantibodies to the PDGF receptor were detected. Fibroblast activation was evaluated in fibroblasts grown from skin biopsies performed at baseline and at months 3 and 6 post-treatment. The modified Rodnan's skin score, health assessment questionnaire (HAQ) and visual analogic scale (VAS) for global wellness and B lymphocyte count were performed monthly.


RESULTS
A significant reduction of anti-PDGF receptor autoantibodies was observed in the serum of all patients 3 months after treatment. Fibroblasts showed a significant downregulation of type I collagen gene expression and of the intracellular signalling triggered by anti-PDGFR autoantibodies. A decrease of the skin score and an improvement of disability indexes matched with the in vitro results. A single course of rituximab reduced scleroderma fibroblast activation in vitro and the serum levels of anti-PDGFR stimulatory autoantibodies.


CONCLUSIONS
These data provide further evidence of B-cell involvement in the pathogenesis of scleroderma. Targeting B cells may be a promising treatment for scleroderma patients, and controlled clinical trials are warranted.
Clinica Medica, Dipartimento di Medicina Interna, Ospedali Riuniti, Ancona, Italy.
Paolo
P
Fraticelli
Clinica di Reumatologia, Dipartimento di Patologia e Medicina Sperimentale e Clinica, Università di Udine, Udine, Italy.
Salvatore
S
De Vita
Clinica di Reumatologia, Dipartimento di Patologia e Medicina Sperimentale e Clinica, Università di Udine, Udine, Italy.
Nicoletta
N
Franzolini
Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy.
Silvia
S
Svegliati
Istituto di Anatomia Patologica, Dipartimento di Ricerche Mediche e Morfologiche Università di Udine, Udine, Italy.
Caterina A
CA
Scott
Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy.
Cecilia
C
Tonnini
Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy.
Tatiana
T
Spadoni
Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy.
Barbara
B
Gabrielli
Clinica Medica, Dipartimento di Medicina Interna, Ospedali Riuniti, Ancona, Italy.
Giovanni
G
Pomponio
Clinica Medica, Dipartimento di Medicina Interna, Ospedali Riuniti, Ancona; and Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy.
Gianluca
G
Moroncini
Clinica Medica, Dipartimento di Medicina Interna, Ospedali Riuniti, Ancona; and Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy. a.gabrielli@univpm.it.
Armando
A
Gabrielli
D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage*; D001323:Autoantibodies / Q000097:blood; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004334:Drug Administration Schedule; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D006785:Hospitals, University; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage*; D007262:Infusions, Intravenous; D007558:Italy; D008297:Male; D008875:Middle Aged; D017479:Receptors, Platelet-Derived Growth Factor / Q000276:immunology; D000069283:Rituximab; D012595:Scleroderma, Systemic / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D012720:Severity of Illness Index; D012867:Skin / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D058846:Antibodies, Monoclonal, Murine-Derived; D001323:Autoantibodies; D024042:Collagen Type I; D007155:Immunologic Factors; D000069283:Rituximab; D017479:Receptors, Platelet-Derived Growth Factor