Biological hallmarks of systemic sclerosis are present in the skin and serum of patients with Very Early Diagnosis of Systemic Sclerosis (VEDOSS)

Abstract

Objective: The Very Early Diagnosis of Systemic Sclerosis (VEDOSS) EUSTAR study showed that, despite not showing any clinical sign of disease, patients with Raynaud's and ANA and/or capillaroscopy abnormalities often progress to SSc within 5 years. We aimed to determine whether VEDOSS biosamples show biological SSc activity pre-clinically.

Methods: Skin biopsies were histologically analysed. Dermal fibroblasts analysed by RT-qPCR and gel contraction assays. Sera were assayed by Luminex (CXCL10) or ELISA (ELF score). Healthy controls (HC) and SSc biosamples were used for controls.

Results: Overall, 114 consecutive VEDOSS patients were enrolled, of which 36 consented to have skin biopsies. Skin biopsies showed a variable but overall increased collagen staining and skin thickness, increased perivascular infiltrate of CD45-positive cells and CXCL10 expression. In vitro, VEDOSS dermal fibroblasts showed increased profibrotic gene expression and contractibility compared with HC. Increased serological CXCL10 [mean (s.d.) 75.90 (107.80) vs HC 39.90 (26.27) pg/ml, P = 0.02] and ELF score was evident in VEDOSS compared with HC [8.19 (0.78) vs 8.55 (0.79), P = 0.04]. In longitudinal analysis of a median of 27.5 (interquartile range 44.5) months, 14.9% of VEDOSS patients progressed to SSc. Baseline CXCL10 serum concentration was significantly higher in the VEDOSS patients that progressed (2-fold increase, P = 0.0071) and correlated with ELF score (R = 0.3096, P = 0.0065).

Conclusions: Despite not fulfilling classification criteria, VEDOSS patients show SSc-linked fibrosis and immunity dysregulation both within the tissue and sera, supporting a biological diagnosis of disease and a window of opportunity to detect the biological pathways amenable for preventive intervention.

Keywords: CXCL10; VEDOSS; autoimmune diseases; collagen; connective tissue diseases; dermal fibroblasts; extracellular matrix; fibrosis; interferon; systemic sclerosis.