Background Experimental and clinical data indicate that B cells may actively participate in the fibrotic process in the context of systemic sclerosis (SSc). Recently the Wnt pathway has emerged as a crucial regulator of fibrosis. In scleroderma skin, the Wnt pathway is highly activated; this is linked to the fact that Dickkopf-1 (Dkk-1), an inhibitor of the Wnt pathway, is virtually absent from scleroderma skin1
Objectives To assess the effect of B cell depletion therapy on Dkk-1 skin expression
Methods Skin biopsies were obtained from 8 patients with SSc, prior to and 6 months following RTX administration. Skin biopsies were also obtained from 3 additional patients with SSc at baseline and at 6 months for control purposes (2 patients receiving cyclophosphamide and 1 no treatment). These patients were enrolled in a clinical study assessing the efficacy of RTX in SSc2. All biopsies were taken from lesional skin of the forearm. Skin involvement was assessed both clinically by applying the MRSS tool and histologically. Collagen accumulation was assessed by Masson's thrichrome and computerized image analysis was used to quantify the results. Dkk-1 skin expression was assessed by immunohistochemistry. Circulating Dkk-1 levels were measured using an established solid phase immunoassay
Results In all baseline biopsies Dkk-1 had no expression in spindle like cells in the dermis; a single patient showed a weak staining at the epidermis. However, following RTX administration, 4 patients exhibited a significant upregulation of Dkk-1 expression in spindle like cells. In sharp contrast, in the control biopsies Dkk-1 was undetectable in spindle like cells at 6 months. In the subgroup of patients which exhibited upregulation of Dkk-1 skin expression, an enhanced clinical response, in terms of resolution of skin fibrosis, was found. In these patients, histologic analysis revealed that Dkk-1 upregulation associated with a significant decrease in collagen accumulation in the upper dermis by a mean ± SEM 49.47±10.63% compared to 18.18±6.67% in patients which did not exhibit Dkk-1 upregulation (p=0.04). Histologic data matched the clinical data; MRSS at 1 year (following 2 cycles of RTX treatment; at baseline and at 6 months) decreased by mean ± SEM 57.31±10.37% compared to 29.59±7.71% decrease in the subgroup with undetectable Dkk-1 (p=0.07). PFT's improved following RTX treatment, irrespective of Dkk-1 skin expression. Circulating levels of Dkk-1 did not change following RTX treatment (mean ± SEM of OD: 0.17±0.04 vs 0.19±0.03 for patients with SSc and healthy subjects, respectively, p=ns).
Conclusions Upregulation of Dkk-1 skin expression associates with an enhanced resolution of skin fibrosis following B cell depletion therapy. RTX may mediate its beneficial effects on fibrosis by increasing Dkk-1 skin expression. This could potentially downregulate the Wnt pathway, a well known driver of fibrosis
Akhmetshina et al. Nat Commun 2012.
Daoussis et al. Rheumatol (Oxford) 2010.
Disclosure of Interest None declared
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