Unknown,Transcriptomics,Genomics,Proteomics

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Effects of tocilizumab versus methotrexate therapy on gene expression profiles in the early rheumatoid arthrtis synovium

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Bernard Lauwerys

PROVIDER: E-GEOD-45867 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

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Effects of tocilizumab versus methotrexate therapy on gene expression profiles in the early rheumatoid arthrtis synovium

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