A Longitudinal Biomarker for the Extent of Skin Disease in Patients With Diffuse Cutaneous Systemic Sclerosis

作者：Lisa Rice, Jessica Ziemek, Eric A. Stratton, Sarah McLaughlin, Cristina M. Padilla, Allison L. Mathes, Romy Christmann, Giuseppina Stifano, Jeffrey L. Browning, Michael L. Whitfield, Robert Spiera, Jessica Gordon, Robert W. Simms, Yuqing Zhang, Robert Lafyatis · 发表于：Arthritis & Rheumatology · 年份：2015 · DOI：10.1002/art.39287 · 被引用次数：111 · 研究领域：Systemic Sclerosis and Related Diseases、Connective Tissue Growth Factor Research、Dermatological and Skeletal Disorders

OBJECTIVE: To define a pharmacodynamic biomarker based on gene expression in skin that would provide a biologic measure of the extent of disease in patients with diffuse cutaneous systemic sclerosis (dcSSc) and could be used to monitor skin disease longitudinally. METHODS: Skin biopsy specimens obtained from a cohort of patients with dcSSc (including longitudinal specimens) were analyzed by microarray. Expression of genes correlating with the modified Rodnan skin thickness score (MRSS) were examined for change over time using a NanoString platform, and a generalized estimating equation (GEE) was used to define and validate longitudinally measured pharmacodynamic biomarkers composed of multiple genes. RESULTS: Microarray analysis of genes parsed to include only those correlating with the MRSS revealed prominent clusters of profibrotic/transforming growth factor β-regulated, interferon-regulated/proteasome, macrophage, and vascular marker genes. Using genes changing longitudinally with the MRSS, we defined 2 multigene pharmacodynamic biomarkers. The first was defined mathematically by applying a GEE to longitudinal samples. This modeling method selected cross-sectional THBS1 and longitudinal THBS1 and MS4A4A. The second model was based on a weighted selection of genes, including additional genes that changed statistically significantly over time: CTGF, CD163, CCL2, and WIF1. In an independent validation data set, biomarker levels calculated using both models correlated highly w...