Shrinking the Psoriasis assessment gap: Early gene-expression profiling accurately predicts response to long-term treatment
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE85034 | GEO | 2017/07/01
SECONDARY ACCESSION(S): PRJNA336007
REPOSITORIES: GEO
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Project description:Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease that is characterized by the presence of inflammatory cytokines, including interleukin-6 (IL-6). Here, we investigated the global molecular effects of Tocilizumab, an approved humanized anti-IL6 Receptor antibody, versus Methotrexate therapy, in synovial biopsy samples collected prospectively in early RA before and 12 weeks after administration of the drug. The results were compared with our previous data, generated in prospective cohorts of Adalimumab- and Rituximab-treated (Methotrexate- and anti-TNF-resistant, respectively) RA patients. We found that Tocilizumab induces a significant down-regulation of genes included in specific pathways: cytokines & chemokines (e.g. IL-6, IL-7, IL-22, CCL8, CCL11, CCL13, CCL19, CCL20), and T cell activation. By contrast, Tocilizumab induces a significant up-regulation of genes associated with healing processes. These effects are significantly more pronounced as compared to Methotrexate, Rituximab, or Adalimumab therapies. By opposition to the effects of Adalimumab, Tocilizumab therapy does not induce a decreased expression of genes involved in cell proliferation. Paired synovial biopsy samples were obtained from the affected knee of early RA patients before and 12 weeks after initiation of Tocilizumab (n=12) or Methotrexate (n=8) therapy. SDAI remission criteria were computed prospectively before, 3 months and 6 months after administration of the drugs and patientsM-bM-^@M-^Y responses were defined according to their SDAI remission status at 6 months. Gene expression studies were performed using GeneChip Human Genome U133 Plus 2.0 arrays.
2013-12-30 | E-GEOD-45867 | biostudies-arrayexpress
Project description:Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease that is characterized by the presence of inflammatory cytokines, including interleukin-6 (IL-6). Here, we investigated the global molecular effects of Tocilizumab, an approved humanized anti-IL6 Receptor antibody, versus Methotrexate therapy, in synovial biopsy samples collected prospectively in early RA before and 12 weeks after administration of the drug. The results were compared with our previous data, generated in prospective cohorts of Adalimumab- and Rituximab-treated (Methotrexate- and anti-TNF-resistant, respectively) RA patients. We found that Tocilizumab induces a significant down-regulation of genes included in specific pathways: cytokines & chemokines (e.g. IL-6, IL-7, IL-22, CCL8, CCL11, CCL13, CCL19, CCL20), and T cell activation. By contrast, Tocilizumab induces a significant up-regulation of genes associated with healing processes. These effects are significantly more pronounced as compared to Methotrexate, Rituximab, or Adalimumab therapies. By opposition to the effects of Adalimumab, Tocilizumab therapy does not induce a decreased expression of genes involved in cell proliferation.
2013-12-30 | GSE45867 | GEO
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2021-08-23 | GSE172188 | GEO
Project description:The objective of this study was to identify specific gene expression profiles able to predict the response of rheumatoid arthritis patients treated with methotrexate (MTX)/adalimumab (ADA) or MTX/etanercept (ETA). Twenty RA patients were received subcutaneously Adalimumab (40 mg each other week) and eleven RA patients were received Etanercept (50 mg per week). The drug efficacy was evaluated with the DAS28 score after 3 months of treatment according to the EULAR response criteria. A blood sample was carried out in patients just before the first injection of treatment in order to isolate peripheral blood mononuclear cells (PBMC) and extract total RNA.
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Project description:TNF antagonists are routinely used in severe rheumatoid arthritis (RA) patients who failed conventional DMARD therapy. According to large clinical trials, the three available drugs (adalimumab, infliximab and etanercept) display similar effects in terms of efficacy, tolerability and side effects. These studies also indicate that about 25% of RA patients treated with TNF-antagonists do not display any significant clinical improvement. The aim of this study was to investigate global molecular patterns in synovial biopsies from RA patients obtained 12 weeks after initiation of adalimumab therapy. All patients had rheumatoid arthritis (RA), according to the American College of rheumatology criteria for the diagnosis of RA. They had active disease at the time of initiation of adalimumab therapy and were resistant to conventional therapy. They all had erosive changes imaged on conventional x-rays of the hands and/or feet. All patients were treated with disease-modifying antirheumatic drugs (DMARD’s), 23 with methotrexate (median dose 15 mg/week, range 7.5 – 20 mg/week), and 2 with leflunomide (20 mg/day); 18 of them were treated with low-dose steroids (prednisolone ≤ 7.5 mg/day). Six patients had been included in double-blind clinical trials before inclusion in the present study (1 in a Golimumab versus placebo trial, 3 in a MapKinase inhibitor versus placebo trial and 2 in a TACE-inhibitor versus placebo trial). These trials were stopped at least 3 months prior to initiation of TNF-blocking therapy. All drug dosages were stable from at least 3 months prior to initiation of TNF blocking therapy until completion of the study. No steroid injections were allowed during the duration of the study. Adalimumab therapy was initiated at a dosage of 40 mg subcutaneously every other week. Disease activity at baseline and 12 weeks after initiation of therapy (T12) was evaluated using DAS(28)-CRP (3- and 4-variables) scores, and response to therapy was assessed according to the EULAR response criteria that categorize patients in responders (good- or moderate-) and non- (or poor-) responders based on changes in DAS activity between T0 and T12 and absolute DAS values at T12. Synovial biopsies were obtained by needle-arthroscopy of knee of the patients at T12. The aim of the study was to compare gene expression profiles in synovial tissue of RA patients who responded versus not responded to adalimumab therapy.
2009-04-15 | E-GEOD-15602 | biostudies-arrayexpress
Project description:In the phase 3 VOYAGE-1 trial (ClinicalTrials.gov identifier: NCT02207231), guselkumab demonstrated superior efficacy versus placebo and the tumor necrosis factor (TNF)-α antagonist, adalimumab, in patients with moderate-to-severe plaque psoriasis (Blauvelt et al., 2017). Here, skin samples were collected from patients in VOYAGE-1 and pharmacodynamic (PD) responses to guselkumab (vs adalimumab) treatment were assessed over 48 weeks.
2024-07-31 | GSE252029 | GEO
Project description:Background:Gap junction protein beta 2 (GJB2) upregulation in psoriasis transcriptome analysis as well as connexin 26 (Cx26, encoded by GJB2) expression upregulation in psoriatic plaques has already been substantiated. GJB2 rs72474224 and rs3751385 have been correlated with psoriasis vulgaris incidence in Chinese populations. Here we study the effect of rs3751385 in patients suffering from psoriasis vulgaris in a Caucasian Greek population at the prefecture of Thrace in Northern Greece. Methods:One hundred and seventy-three (111 males and 62 females) psoriatic patients (108 were of early-onset psoriasis) and 171 matched controls were included in the study. Genomic DNA was extracted from peripheral blood leukocytes and genotyping was carried out by polymerase chain reaction-restriction-fragment length polymorphism (PCR-RFLP). Results:A statistically significant lower frequency of C/T genotype in late-onset male psoriasis vulgaris (P = 0.029) as well as of T allele in female early-onset psoriasis vulgaris (P = 0.049) were ascertained. Conclusions:On condition that all other genetic or environmental factors remain stable, the existence and possible interaction between GJB2 rs3751385 C and T alleles in male psoriatic patients may be considered as protective gene component against late-onset psoriasis appearance, while presence of the T allele in female might block the histogenetic mechanisms of early-onset psoriasis lesions.
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Project description:We investigated whether circulating microRNAs (miRNAs) are associated with residual insulin secretion at diagnosis and predict the severity of its future decline. We studied 53 newly diagnosed subjects enrolled in placebo groups of TrialNet clinical trials. We measured serum levels of 2,083 miRNAs using RNAseq technology, in fasting samples from the baseline visit (<100 days from diagnosis), during which residual insulin secretion was measured with a mixed meal tolerance test (MMTT). Area under the curve (AUC) C-peptide and peak C-peptide were stratified by quartiles of expression of 31 miRNAs. After adjustment for baseline C-peptide, age, BMI and sex, baseline levels of miR-3187-3p, miR-4302, and the miRNA combination of miR-3187-3p/miR-103a-3p predicted differences in MMTT C-peptide AUC/peak levels at the 12-month visit; the combination miR-3187-3p/miR-4723-5p predicted proportions of subjects above/below the 200 pmol/L clinical trial eligibility threshold at the 12-month visit. Thus, miRNA assessment at baseline identifies associations with C-peptide and stratifies subjects for future severity of C-peptide loss after 1 year. We suggest that miRNAs may be useful in predicting future C-peptide decline for improved subject stratification in clinical trials.
2020-09-01 | GSE157177 | GEO
Project description:Factors predicting body weight gain and associated disturbed glucose metabolism remain to be established. Here we assessed the role of subcutaneous adipocyte lipid mobilization (lipolysis) in spontaneous long-term (>10 years) body weight changes. In two independent clinical cohorts we found that low stimulated lipolysis at baseline correlated inversely with body mass index changes over time. Disturbed lipolysis gave odds ratios of ≥4.6 for weight gain and ≥3.2 for development of insulin resistance and impaired fasting glucose/type 2 diabetes. Baseline adipose mRNA expression of a set of established lipolysis-regulating genes was lower in weight gainers.
2018-04-13 | GSE113080 | GEO
Project description:Objectives: To predict response prior to anti-TNF treatment and comprehensively understand the mechanism how patients respond differently to anti-TNF treatment in rheumatoid arthritis (RA). Methods: Gene expression and/or DNA methylation profiling on PBMC, monocytes, and CD4+ T cells, from 80 RA patients before initiating either adalimumab (ADA) or etanercept (ETN) therapy was studied. After 6-month treatment response was evaluated according to the EULAR criteria of disease response. Differential expression and methylation analyses were performed to identify the response-associated transcriptional and epigenetic signatures. Machine learning models were built using these signatures by random forest algorithm to predict response prior to anti-TNF treatment and were further validated by a follow-up study. Results: Transcriptional signatures in ADA and ETN responders are divergent in PBMCs, and this phenomenon was reproduced in monocytes and CD4+ T cells. The genes upregulated in CD4+ T cells of ADA responders were enriched in the TNF signaling pathway, while very few pathways were differential in monocytes. Differential methylation positions (DMPs) of responders to ETN but not to ADA are majorly hypermethylated. The machine learning models to predict the response to ADA and ETN using differential genes reached overall accuracy of 85.9% and 79%, respectively. The models using DMPs reached overall accuracy of 84.7% and 88% for ADA and ETN, respectively. A follow-up study validated the high performance of these models. Conclusions: Machine learning models based on these molecular signatures could accurately predict response before ADA and ETN treatment, paving the path towards personalized anti-TNF treatment.
2020-08-24 | GSE138653 | GEO