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

Abstract

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.

The ST2/IL-33 Axis in Immune Cells during Inflammatory Diseases

“…In a two cohort study, serum sST2 levels were increased in patients with scleroderma compared to healthy controls, which, when combined with Spondin-1, best described longitudinal change in MRSS, using mixed linear models (187). This was validated using three other independent cohorts (187). …”

“…sST2 usefulness as a clinical biomarker has been studied extensively in both cardiac and allo-HCT patients, showing both prognostic and diagnostic value (11, 12, 17–24, 27, 39, 187, 188). sST2 levels are also increased in patients suffering from intestinal (13–16) and metabolic diseases (27, 28, 197, 198); however, the data from these studies so far are correlative and have not passed the qualification for biomarkers that can be used in clinic (199).…”

Promoting new concepts of skincare via skinomics and systems biology—From traditional skincare and efficacy‐based skincare to precision skincare

“…The development of skinomics will promote the discovery of markers for different skin conditions. For instance, Rice et al screened for markers of systemic sclerosis using proteomics data. In comparison with the noninvasive methods in skin and skin imaging technology, skinomics allows for a comprehensive understanding of skin metabolism.…”

The search for drug-targetable diagnostic, prognostic and predictive biomarkers in chronic graft-versus-host disease

“…A prominent clinical feature of chronic GVHD is a debilitating fibrosing skin disease whose histologic features are similar to scleroderma. Spondin-1 was increased in diffuse cutaneous systemic sclerosis skin disease over time [53]. …”