Project description:Systemic sclerosis is associated with skin fibrosis thought mediated by TGFb. This open label clinical trial examines the effect of TGFb inhibition on skin gene expression. Patients 1-9 received two doses 1 mg/kg dose of fresolimumab at baseline and 3 weeks; patients 10-19 received a single 5 mg/kg dose Patients with diffuse cutaneous systemic sclerosis within 2 years of first raynauds had skin biopsies before treatment and the 3-4 weeks, 7 weeks and 24 weeks after treatment with fresolimumab
Project description:Systemic sclerosis (SSc) is an autoimmune disease characterized by inflammation and fibrosis of the skin and internal organs. We sought to assess the clinical and molecular effects associated with response to intravenous abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc).
Project description:Pathway expression analysis in systemic sclerosis revealed key mediators driving pathology within each of the intrinsic gene expression subsets. Genome-wide expression profiling in systemic sclerosis (SSc) has identified four 'intrinsic' subsets of disease (fibroproliferative, inflammatory, limited, and normal-like), each of which appear to be driven by distinct signaling pathways. Here we examine experimentally derived gene expression signatures for thirteen agonists to better understand the molecular mechanisms underlying each intrinsic subsets. Pathway-specific gene signatures were compared against skin biopsy microarray data consisting of 329 microarray hybridizations from 287 unique biopsies representing 111 patients. Hierarchical clustering recapitulated the four SSc 'intrinsic' gene expression subsets, along with an intermediate subset exhibiting both inflammatory and fibroproliferative gene expression signatures. The fibroproliferative subset is most strongly associated with the PDGF gene signature, while the inflammatory subset demonstrated strong activation of NF-kappaB, characterized by early induction of TH2 signals, which transitions to a more TH17-like immune response over time. The limited subset was associated with IFNalpha signaling, combined with strong downregulation of PDGF signaling. The inflammatory-proliferative subset shows downregulation of NF-kappaB-associated pathways in conjunction with increased PDGF signaling, suggestive of a transitional state linking the inflammatory and fibroproliferative subsets. IL-13 signaling was strongly associated with early disease, while TGFbeta signaling was associated with more severe disease. Together these data suggest a multi-step, progressive model of disease pathogenesis driven by distinct pathways. Targeting these pathways based upon a patient's underlying disease subset should improve therapeutic outcomes. In vitro treatment of human dermal fibroblasts was performed to identify pathway-specific gene signatures. These gene signatures were then compared against systemic sclerosis skin biopsy microarrays to determine the overall contribution of each pathway to disease. This study includes re-analysis of 247 skin biopsy samples from GSE9285, GSE32413, and GSE45485. Links to these Samples are provided below. The re-processed normalized data for these Samples are included in the supplementary file 'GSE56308_247_Skin_Biopsy_Reanalysis_Samples.txt'.
Project description:We used DNA microarrays to characterize gene expression patterns in skin biopsies from individuals with a diagnosis of systemic sclerosis with diffuse scleroderma and compared those to the patterns of gene expression seen in biopsies from normal, unaffected individuals.
Project description:RNA expression profiling was carried out for systemic sclerosis (scleroderma) on skin biopsies obtained from both diffuse scleroderma (dcSSc) and limited scleroderma (lcSSc) subjects patients and compared to normal subjects. The patient group comprised of 4 dcSSc and 2 lcSSc subjects, all of whom were Caucasian and belonged to the age range of 42-73 (Mean age = 61.6). Patient sample set consisted of 3 females and 3 males. Race matched female volunteers from the same geographical area were recruited as controls (n = 4) and belonged to the age range of 41-62 (Mean age = 52).
Project description:We identified fibro-inflammatory and keratin gene expression signatures in systemic sclerosis skin. Skin biopsy samples from 61 patients enrolled in the GENISOS cohort or an open label imatinib study (baseline sample) and 36 controls were examined by global gene expression studies. 5 patients were sampled at two time points (early-late). There is overlap between this data set and GSE47162.
Project description:To assess the safety, efficacy, and molecular change associated with treatment of patients with early, diffuse cutaneous systemic sclerosis (dcSSc) with nilotinib (Tasigna™). In this open-label pilot trial 6 adult patients with early dcSSc received nilotinib. Primary endpoints were safety and change in modified Rodnan Skin Score (MRSS) after 6 months. Lesional skin biopsies at baseline, 6 and 12 months of treatment were assessed by histopathology, immunohistochemistry, and DNA microarray.
Project description:Systemic sclerosis (SSc) is confounded by considerable disease heterogeneity. Animal models of SSc that recapitulate distinct subsets of disease at the molecular level have not delineated. We applied interspecies comparative analysis of genomic data from multiple mouse models of SSc and patients with SSc to determine which animal models best reflect the SSc intrinsic gene expression subsets. Gene expression measured in skin from mice with sclerodermatous graft-versus-host disease, bleomycin-induced fibrosis, or Tsk1/+ and Tsk2/+ mice was mapped to human orthologs and compared to SSc skin biopsy-derived gene expression.
