A Proteome-Derived Longitudinal Pharmacodynamic Biomarker for Diffuse Systemic Sclerosis Skin

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• 作者：Lisa M. Rice¹ ; ^{lisarice@bu.edu} ; Julio C. Mantero¹ ; Giuseppina Stifano¹ ; Jessica Ziemek¹ ; Robert W. Simms¹ ; Jessica Gordon² ; Robyn Domsic³ ; Robert Lafyatis³
• 关键词：dcSSC ; diffuse cutaneous systemic sclerosis ; ILD ; interstitial lung disease ; LASSO ; least absolute shrinkage and selection operator ; MRSS ; modified Rodnan skin score ; PBMC ; peripheral blood mononuclear cell ; SSc ; systemic sclerosis ; TGF ; transforming growth factor ; TLR ; toll-like receptor ; TNF ; tumor necrosis factor
• 刊名：Journal of Investigative Dermatology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：137
• 期：1
• 页码：62-70
• 全文大小：2159 K
• 卷排序：137

文摘

In this study we systematically investigated alterations in the serum proteome of patients with diffuse cutaneous systemic sclerosis and identified differentially expressed proteins that correlated with disease severity. Our goal was to identify a combination of serum proteins that would provide a biological measure for the extent of skin disease and that could be combined into a longitudinal pharmacodynamic biomarker. We found that 16% of the sera proteins analyzed by SOMAscan aptamer technology, from two cohorts of patients with diffuse cutaneous systemic sclerosis, were identified as differentially regulated between diffuse cutaneous systemic sclerosis and controls and correlated with modified Rodnan skin score. This dataset showed tumor necrosis factor-α, IFN-γ, transforming growth factor-β, and IL-13 as potential upstream regulators of the serum protein patterns in the sera of patients with diffuse cutaneous systemic sclerosis. By ELISA, two analytes (ST2 and Spondin-1) best described longitudinal change in modified Rodnan skin score, using linear mixed models. This model was then validated in three independent cohorts. In this study we discovered a large array of proteins not previously associated with systemic sclerosis that provide insight into pathogenesis and potential targets for therapeutic intervention. Furthermore, we show that two of these proteins can be combined to form a robust longitudinal biomarker that might be used in clinical trials to assess changes in diffuse cutaneous systemic sclerosis skin disease over time.