Reduced type I collagen gene expression by skin fibroblasts of patients with systemic sclerosis after one treatment course with rituximab

Clin Exp Rheumatol. Jul-Aug 2015;33(4 Suppl 91):S160-7. Epub 2015 Sep 1.

Abstract

Objectives: 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.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antibodies, Monoclonal, Murine-Derived / administration & dosage*
  • Autoantibodies / blood
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Cells, Cultured
  • Collagen Type I / genetics
  • Collagen Type I / metabolism*
  • Down-Regulation
  • Drug Administration Schedule
  • Female
  • Fibroblasts / drug effects*
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibrosis
  • Hospitals, University
  • Humans
  • Immunologic Factors / administration & dosage*
  • Infusions, Intravenous
  • Italy
  • Male
  • Middle Aged
  • Receptors, Platelet-Derived Growth Factor / immunology
  • Rituximab
  • Scleroderma, Systemic / blood
  • Scleroderma, Systemic / diagnosis
  • Scleroderma, Systemic / drug therapy*
  • Scleroderma, Systemic / genetics
  • Scleroderma, Systemic / immunology
  • Severity of Illness Index
  • Skin / drug effects*
  • Skin / immunology
  • Skin / metabolism
  • Skin / pathology
  • Time Factors
  • Treatment Outcome
  • Young Adult

Substances

  • Antibodies, Monoclonal, Murine-Derived
  • Autoantibodies
  • Collagen Type I
  • Immunologic Factors
  • Rituximab
  • Receptors, Platelet-Derived Growth Factor