A TGFβ-Responsive Gene Signature Is Associated with a Subset of Diffuse Scleroderma with Increased Disease Severity

Abstract

Systemic sclerosis is a complex disease with widespread skin fibrosis and variable visceral organ involvement. Since transforming growth factor-β (TGFβ) has been implicated in driving fibrosis in systemic sclerosis, a mechanism-derived gene expression signature was used to assay TGFβ-responsive gene expression in the skin of patients with systemic sclerosis (SSc). Primary dermal fibroblasts from patients with diffuse SSc (dSSc) and healthy controls were treated with TGFβ, and the genome-wide gene expression was measured on DNA microarrays over a time course of 24 hours. Eight hundred and ninety-four probes representing 674 uniquely annotated genes were identified as TGFβ responsive. Expression of the TGFβ-responsive signature was examined in skin biopsies from 17 dSSc, seven limited SSc (lSSc), three morphea patients, and six healthy controls. The TGFβ-responsive signature was expressed in 10 out of 17 dSSc skin biopsies, but was not found in lSSc, morphea, or healthy control biopsies. Expression of dSSC the TGFβ-responsive signature stratifies patients into two major groups, one of which corresponds to the “diffuse-proliferation” intrinsic subset that showed higher modified Rodnan skin score and a higher likelihood of scleroderma lung disease. The TGFβ-responsive signature is found in only a subset of dSSc patients who could be targeted by specific therapies.

Biological Therapy in Systemic Sclerosis

“…This TGF-β responsive signature was found only in patients with the diffuse subset and correlated with higher mRSS and with a higher prevalence of interstitial lung disease. There was no association between disease duration, specific autoantibodies or any other clinical manifestation and TGF-β-expression gene signature [43].…”

“…Transforming growth factor-β (TGF-β) has been recognised as the central mediator of fibrosis in SSc and the persistence of TBG-β signalling is a key feature in SSc pathogenesis [43]. TGF-β is secreted from monocytes, lymphocytes and fibroblasts in the latent form and sequestered in the extracellular matrix.…”

Biomarkers in Systemic Sclerosis

“…Indeed, recent microarray studies of intact skin, peripheral blood mononuclear cells or cultured dermal fibroblasts disclosed distinct patterns of gene expression capable of distinguishing patients with limited SSc from those with diffuse SSc, and allowed the identification of separate subsets within these two groups that correlate with various clinical parameters and internal organ involvement [113][114][115][116][117][118]. Microarray studies have also been employed to identify specific patterns of gene expression in SSc-associated pulmonary fibrosis [119] and pulmonary hypertension [120], and have identified a subset of SSc patients who display a TGF-b signature in their skin [121]. Thus, global gene-expression studies promise to provide mole cular signatures that will be useful as molecular biomarkers for the diagnosis of SSc, identification of its clinical subsets, evaluation of effectiveness of disease-modifying therapies, and stratification of patients who may respond and benefit from specific therapies, as recently shown for imatinib mesylate [121,122].…”

“…Microarray studies have also been employed to identify specific patterns of gene expression in SSc-associated pulmonary fibrosis [119] and pulmonary hypertension [120], and have identified a subset of SSc patients who display a TGF-b signature in their skin [121]. Thus, global gene-expression studies promise to provide mole cular signatures that will be useful as molecular biomarkers for the diagnosis of SSc, identification of its clinical subsets, evaluation of effectiveness of disease-modifying therapies, and stratification of patients who may respond and benefit from specific therapies, as recently shown for imatinib mesylate [121,122].…”

Dermal Melanocortin Receptor Rebound in Diffuse Systemic Sclerosis after Anti‐TGFβ1 Antibody Therapy

“…Likewise, increased TGFb mRNa and protein is present in affected areas in ILD in SSc [5]. A TGFb responsive gene signature may also be found in the skin of dSSc patients with severe disease [6]. These findings prompted the CAT-192 study, which comprised treatment of dSSc with infusions of a recombinant human anti-TGFb1 antibody [7].…”