A Proteome-Derived Longitudinal Pharmacodynamic Biomarker for Diffuse Systemic Sclerosis Skin Lisa M. Rice, Julio C. Mantero, Giuseppina Stifano, Jessica.

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A Proteome-Derived Longitudinal Pharmacodynamic Biomarker for Diffuse Systemic Sclerosis Skin Lisa M. Rice, Julio C. Mantero, Giuseppina Stifano, Jessica Ziemek, Robert W. Simms, Jessica Gordon, Robyn Domsic, Robert Lafyatis Journal of Investigative Dermatology Volume 137, Issue 1, Pages 62-70 (January 2017) DOI: 10.1016/j.jid.2016.08.027 Copyright © 2016 The Authors Terms and Conditions

Figure 1 Hierarchical clustering of sera protein expression in dcSSc patients. The 43 analytes analyzed by unsupervised clustering that were identified again as differentially regulated in dcSSc patients (n = 14) compared with healthy control subjects (n = 4), as well as correlated with MRSS (FDR < 0.02). Here, red and blue indicate high or low expression; group 2 indicates healthy control subjects, and group 1 indicates dcSSc patients. dcSSc, diffuse cutaneous systemic sclerosis; FDR, false discovery rate; HC, health control subject; MRSS, modified Rodnan skin score. Journal of Investigative Dermatology 2017 137, 62-70DOI: (10.1016/j.jid.2016.08.027) Copyright © 2016 The Authors Terms and Conditions

Figure 2 TGF-β pathway signature in sera of dcSSc patients. Graphical representation of the proteins involved the TGF-β signature pathway of dcSSc patients. Colors indicate predicted activation (orange = activated, blue = inhibited) and regulation status (red = up-regulated, green = down-regulated) of molecules in the dataset. Lines between molecules depict predicted relationships on the basis of what is known in the current literature. dcSSc, diffuse cutaneous systemic sclerosis; TGF, transforming growth factor. Journal of Investigative Dermatology 2017 137, 62-70DOI: (10.1016/j.jid.2016.08.027) Copyright © 2016 The Authors Terms and Conditions

Figure 3 Validation of cross-sectional biomarkers. Graphs show differences in IGFBP-2, FSTL3, spondin-1, and IL-1R4 (ST2) protein concentrations. Top panel shows statistical significance of protein concentration difference (Wilcoxon signed rank test) from healthy control subjects of IGFBP-2, FSTL3, spondin-1, and IL-1R4. Bottom panel shows the relationship (Spearman’s ρ) between protein concentrations and the MRSS. dcSSc, diffuse cutaneous systemic sclerosis; MRSS, modified Rodnan skin score. Journal of Investigative Dermatology 2017 137, 62-70DOI: (10.1016/j.jid.2016.08.027) Copyright © 2016 The Authors Terms and Conditions

Figure 4 Altered mRNA expression in SSc skin biopsy samples and PBMCs. Graphs show differences (Wilcoxon signed rank test) of IGFBP-2, FSTL3, spondin-1, and IL-1R4 (ST2) gene expression compared with healthy control subjects in both skin biopsy samples (top panel) and PBMCs (bottom panel). dcSSc, diffuse cutaneous systemic sclerosis; PBMC, peripheral blood mononuclear cell. Journal of Investigative Dermatology 2017 137, 62-70DOI: (10.1016/j.jid.2016.08.027) Copyright © 2016 The Authors Terms and Conditions

Figure 5 Testing and validation of the proteomic biomarker. Graphs show correlations between biomarker score derived using a mixed model equation. Values used to develop the model and in the third validation cohort are from Boston Medical Center patients. Values used to validate the model (cohorts 1 and 2) are from outside R-values and corresponding P-values are indicated on each panel. Dotted line indicates 95% confidence intervals of the regression line. Journal of Investigative Dermatology 2017 137, 62-70DOI: (10.1016/j.jid.2016.08.027) Copyright © 2016 The Authors Terms and Conditions