title: 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.
authors.affiliation: Boston University School of Medicine, Boston, Massachusetts, USA. Electronic address: lisarice@bu.edu.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Rice
authors.affiliation: Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Mantero
authors.affiliation: Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Stifano
authors.affiliation: Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ziemek
authors.affiliation: Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Simms
authors.affiliation: Hospital for Special Surgery, New York, New York, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Gordon
authors.affiliation: University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
authors.forename: Robyn
authors.initials: R
authors.lastname: Domsic
authors.affiliation: University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D016014:Linear Models; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D000071185:Pharmacogenomic Testing; D020543:Proteome / Q000378:metabolism*; D015203:Reproducibility of Results; D045743:Scleroderma, Diffuse / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D016207:Cytokines; D020543:Proteome