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

---

« Back to 2013 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/treatment-with-rituximab-reduces-activation-of-scleroderma-dermal-fibroblasts/