Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs and widespread vasculopathy. Current therapies for SSc focus on treating specific symptoms, but disease-modifying agents targeting the underlying pathogenesis are lacking.
The pathogenesis of SSc involves activation of profibrotic pathways, with over-expression of the cytokines transforming growth factor (TGF)-β and platelet derived growth factor (PDGF). A recent report showed that SSc patients have autoantibodies against the PDGF receptor, which stimulate the production of reactive oxygen species and type I collagen expression(1
). PDGF receptors are upregulated in the skin and bronchoalveolar lavage fluid of patients with SSc, and when activated, lead to fibroblast and myofibroblast proliferation(2
). PDGF participates in smooth muscle cell recruitment and mitogenic signaling that underlie the vasculopathy associated with pulmonary arterial hypertension (PAH), a complication of SSc associated with high mortality(4
). In addition, stimulation of the TGF-β profibrotic pathway involves activation of c-Abl(2
). Thus, the PDGF and TGF-β pathways are thought to contribute to the fibrotic and vascular complications in SSc.
Imatinib mesylate (Gleevec, Novartis, East Hanover, New Jersey) is a small molecule that antagonizes specific tyrosine kinases that mediate fibrotic pathways, including c-Abl, a downstream mediator of TGF-β(2
) and PDGF receptors(5
). Imatinib has been shown to inhibit lung and dermal fibrosis in bleomycin-induced mouse models(6
), and the proliferation of synovial fibroblasts derived from patients with rheumatoid arthritis(8
). Imatinib has also been reported to provide benefit in the treatment of refractory idiopathic PAH through its effects on vascular remodeling(9
). We now describe two patients with early diffuse SSc who experienced clinical improvement in response to imatinib therapy and provide evidence that both c-Abl and PDGFR are targets of imatinib in scleroderma skin. Finally, we show that an imatinib-responsive gene signature is present in most cases of diffuse SSc.