A four‐gene biomarker predicts skin disease in patients with diffuse cutaneous systemic sclerosis

Abstract

Objective. Improved outcome measures in systemic sclerosis (SSc) are critical to finding active therapeutics for this disease. The modified Rodnan skin thickness score (MRSS) is the current standard for evaluating skin disease in SSc, but it is not commonly used in the clinical setting, in part because it requires specialized training to perform accurately and consistently. The purpose of this study was to investigate whether skin gene expression might serve as a more objective surrogate outcome measure to supplement skin score evaluations.Methods. Skin RNAs from a group of patients with diffuse cutaneous SSc were studied for expression levels of genes known to be regulated by transforming growth factor ␤ (TGF␤) and interferon (IFN). These levels were correlated with the MRSS, using multiple regression analyses to obtain best-fit models.Results. Skin expression of the TGF␤-regulated genes cartilage oligomeric matrix protein (COMP) and thrombospondin 1 (TSP-1) correlated moderately well with the MRSS, but the addition of other TGF␤-regulated genes failed to significantly improve best-fit models. IFN-regulated genes were also found to correlate with the MRSS, and the addition of interferoninducible 44 (IFI44) and sialoadhesin (Siglec-1) to COMP and TSP-1 in multiple regression analyses significantly improved best-fit models, achieving an R 2 value of 0.89. These results were validated using an independent group of skin biopsy samples. Longitudinal scores using this 4-gene biomarker indicated that it detects change over time that corresponds to changes in the MRSS.Conclusion. We describe a 4-gene predictor of the MRSS and validate its performance. This objective measure of skin disease could provide a strong surrogate outcome measure for patient care and for clinical trials.

Identification and Characterization of Cartilage Oligomeric Matrix Protein as a Novel Pathogenic Factor in Keloids

“…In scleroderma, serum COMP has been reported to be significantly higher than normal controls 30 and correlate to skin involvement as measured by modified Rodnan total skin thickness score. 25,28 Moreover, a pathogenic role of COMP in scleroderma has been reported. [25][26][27][28]30 By the gene expression profiling of cultured skin fibroblasts, COMP mRNA level is elevated in scleroderma fibroblasts and COMP protein accumulates in scleroderma, but not normal skin by immunohistochemistry.…”

“…25,28 Moreover, a pathogenic role of COMP in scleroderma has been reported. [25][26][27][28]30 By the gene expression profiling of cultured skin fibroblasts, COMP mRNA level is elevated in scleroderma fibroblasts and COMP protein accumulates in scleroderma, but not normal skin by immunohistochemistry. 26 Cultured scleroderma fibroblasts express higher amount of COMP than normal controls and further TGF-␤1 induces a large increase of COMP mRNA and protein in vitro.…”

“…22 In addition, the coiled-coil domain stores and delivers hydrophobic ligands, such as retinoid and vitamin D. 23,24 These studies suggest that COMP potentially exerts a wide range of biological functions. Furthermore, recent evidences are accumulating that COMP is both a pathogenic factor and biomarker in scleroderma, [25][26][27][28][29][30] indicating that this molecule can be involved in pathogenesis of other fibrosing diseases. Additionally, existence of COMP in horse scar was previously reported, 31 but the role of COMP in scar or keloid is still unknown.…”

COMP-assisted collagen secretion - a novel intracellular function required for fibrosis

“…These are the key cells depositing the excess amounts of ECM that are characteristic of fibrosis (Hinz et al, 2012;Tomasek et al, 2002). COMP is produced by myofibroblasts in systemic sclerosis and has reached diagnostic relevance as one component of a four-gene signature that is typically seen in individuals with systemic sclerosis (Farina et al, 2010(Farina et al, , 2009. We have also shown that high COMP levels are not restricted to fibrosis occurring in systemic sclerosis but that high levels also occur also in the fibrotic stroma adjacent to epidermal tumors as well as in the fibrosis underlying chronic non-healing ulcers (Agarwal et al, 2013), all characterized by overproduction of collagen.…”

Biological Therapy in Systemic Sclerosis

“…It includes two TFG-β-regulated genes: cartilage oligomeric matrix protein (COMP) and thrombospondin-1 (THS1), and two interferon (IFN)-regulated genes: interferon-induced 44 (IFI44) and sialoadhesin (SIG1). The central hypothesis is that if IL-1 is a key cytokine leading to fibrosis in SSc, its inhibition will downregulate the expression of the 4-gene biomarker in the skin [30,31].…”