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Abstract Number: 705

Treatment With Rituximab Reduces Activation Of Scleroderma Dermal Fibroblasts

Paolo Fraticelli1, Salvatore De Vita2, Nicoletta Franzolini3, Silvia Svegliati4, Cecilia Tonnini4, Barbara Gabrielli5, Cathryn Anne Scott6, Giovanni Pomponio7, Gianluca Moroncini4 and Armando Gabrielli4, 1Istituto di Clinica Medica, Università Politecnica delle Marche, Ancona, Italy, 2Rheumatology, DSMB, University Hospital Santa Maria della Misericordia, Udine, Italy, 3Presidio Ospedaliero di San Daniele del Friuli, ASS 4 “Medio Friuli, Udine, Italy, 4Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy, 5Università Politecnica delle Marche, Ancona, Italy, 6Department of Medical and Biological Sciences, Università degli studi di Udine ·, Udine, Italy, 7Medicina Interna, Ospedali Riuniti, Ancona, Italy

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Autoantibodies and systemic sclerosis, B cells

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Session Information

Session Title: Systemic Sclerosis, Fibrosing Syndromes, and Raynaud’s - Clinical Aspects and Therapeutics I

Session Type: Abstract Submissions (ACR)

Background/Purpose:  There is evidence that B lymphocytes play a role in the pathogenesis  of systemic sclerosis (scleroderma). Stimulatory autoantibodies targeting PDGF receptor and activating normal human fibroblasts in vitrohave been demonstrated in sera from scleroderma patients(1-3). Rituximab is a monoclonal antibody which selectively targets and depletes CD20+ B lymphocytes. We investigated the biological effects of rituximab in six patients with scleroderma and severe skin involvement.

Methods: Six patients with severe skin fibrosis documented by rapidly increasing skin score not responsive to immunosuppressive treatment were treated with 375 mg/m2 per week of intravenous rituximab for a total of four doses. Primary outcomes were the reduction of the levels of anti-PDGF receptor autoantibodies in patients sera and down-regulation of skin fibroblast activation in vitro.  Stimulatory autoantibodies to the PDGF receptor  were detected with a biological assay using IgG immunopurified from patients serum samples at baseline and 3 and 6 months after treatment. Secondary outcomes included the modified Rodnan’s skin score, heath assessment of quality of life (HAQ) and visual analogic scale (VAS) for global wellness. CD19+ lymphocyte count was performed monthly to  assess B cell depletion.

Results: Significant reduction of the serum levels of anti-PDGF receptor autoantibodies was observed in all patients 3 months after treatment. However, a slight increase was again detected six months after rituximab infusion. Fibroblasts grown from skin biopsies taken 6 months after treatment showed a significant reduction of type I collagen gene expression and down-regulation of the intracellular signalling triggered by anti PDGFR autoantibodies. A decrease of skin score and improvement of disability indexes paralleled  biological results. No infusion reaction or adverse effects were recorded.

Conclusion: A single course of rituximab reduced scleroderma fibroblast activation in vitro and the serum levels of anti PDGFR stimulatory autoantibodies. The data provide further evidence of B-cell involvement in the pathophysiology of scleroderma. Targeting B cells may be a promising treatment for scleroderma patients and large, controlled clinical trials are warranted.

REFERENCES

 1. Svegliati Baroni S, Santillo MR Bevilacqua F, Luchetti M, Spadoni T, Mancini M , Fraticelli P, Sambo P, Funaro A , Kazlauskas A, Avvedimento EV, Gabrielli A Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis  N Engl J Med 354; 2667-76, 2006

 2. Moroncini G, Grieco A, Nacci G, Paolini C, Tonnini C, Pozniak K, Cuccioloni M, Mozzicafreddo M, Giuliano P, Sveglaiti S, Angeletti M, Avvedimento EV, Funaro A, Gabrielli A. B cell receptor editing in scleroderma patients generates pathogenic conformational anti-PDGF receptor autoantibodies that cause oxidative stress and fibrosis. EMBO Mol Med In Press

3. Cuccioloni M, Moroncini G, Mozzicafreddo M , Pozniak KN, Nacci G, Grieco A, Paolini C, Tonnini C, Funaro A, Angeletti M, Gabrielli A. Biosensor-based Binding Assay for Platelet-Derived Growth Factor Receptor-α Autoantibodies in Human Serum. J Anal Bioanal Tech 2013, In Press


Disclosure:

P. Fraticelli,
None;

S. De Vita,
None;

N. Franzolini,
None;

S. Svegliati,
None;

C. Tonnini,
None;

B. Gabrielli,
None;

C. A. Scott,
None;

G. Pomponio,
None;

G. Moroncini,
None;

A. Gabrielli,
None.

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