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OP0092 Decreased dickkopf-1 expression in clinically uninvolved skin from patients with systemic sclerosis

Background Evidence suggests that the Wnt pathway is a critical mediator of the fibrotic process. The activity of the pathway is tightly regulated by several soluble inhibitors such as Dickkopf-1 (Dkk-1). We, among others, have previously shown that Dkk-1 is absent from scleroderma skin in sharp contrast to skin from healthy subjects where it is clearly expressed.1 2 Objectives Up until now, Dkk-1 skin expression has only been assessed in established fibrosis, in biopsies obtained from clinically involved areas. We aimed to assess whether the striking lack of Dkk-1 skin expression is also evident in a) clinically uninvolved skin from patients with SSc and b) very early disease at the puffy/edematous phase, prior to skin thickening. Methods Skin biopsies were obtained from a) 12 patients with SSc from lesional skin of the forearm, b) 5 patients with SSc from the upper back which was not affected clinically, c) 2 patients with systemic sclerosis (SSc) with very early disease (<12 months). These patients had puffy hands but no skin thickening; the biopsy was obtained from the distal part of the forearm, in close proximity to the edematous area d) 5 healthy subjects. Dkk-1 expression was immunohistochemically assessed using a mouse anti-human monoclonal antibody (R and D Systems) by a semi-quantitative method (high/moderate/weak/no expression). Results Healthy skin displayed a high Dkk-1 immunoexpression in basal cells of the epidermis as well as in the fibroblasts of the dermis in sharp contrast to clinically involved scleroderma skin that displayed no Dkk-1 immunoexpression. Clinically uninvolved skin was obtained from 5 patients with SSc (4 diffuse-1 limited) with a median age of 5046–72 and disease duration of 62–13 years. In all 5 biopsies Dkk-1 was only moderately expressed in basal cells of the epidermis and dermal fibroblasts. Clinically uninvolved scleroderma skin could by differentiated by immunohistochemical means from both skin from healthy subjects (high Dkk-1 expression) and clinically involved scleroderma skin (no Dkk-1 expression). Skin from very early disease at the edematous phase, prior to skin thickening, displayed only a weak Dkk-1 immunoreactivity in basal cells of the epidermis as well as in the fibroblasts of the dermis. Conclusions The decrease in Dkk-1 expression in clinically uninvolved scleroderma skin substantiates previous evidence that the skin in SSc is universally affected underling the systemic nature of the disease. The downregulation of Dkk-1 at the edematous phase of the disease indicates that the Wnt pathway is involved early in the disease process, prior to establishment of fibrosis a finding with potential pathogenetic implications References [1] Daoussis, et al. ART2008. [2] Akhmetshina, et al. Nat Commun2012. Disclosure of Interest None declared