Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression data of whole blood of systemic juvenile idiopathic arthritis (SJIA) patients treated with canakinumab or placebo and age matched healthy controls

ABSTRACT: Canakinumab is a human anti-interleukin-1 beta (IL-1 beta) monoclonal antibody neutralizing IL-1 beta. Systemic juvenile idiopathic arthritis (SJIA) is a rare, multigenic, autoinflammatory disease of unknown etiology characterized by chronic arthritis; intermittent high-spiking fever, rash, and elevated levels of acute-phase reactants. Blood samples of SJIA patients were obtained from two phase 3 clinical trials conducted by the members of the Pediatric Rheumatology International Trials Organization (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG) (Clinicaltrials.gov: NCT00886769 and NCT00889863). For patients, baseline and day 3 samples were analyzed for either placebo or canakinumab (Ilaris) treatment. Clinical response was assessed at day 15 using adapted JIA American College of Rheumatology (ACR) response criteria. Overall, 206 samples were used in this study including 22 samples from healthy controls, 33 samples of placebo treated patients and 151 samples of canakinumab treated patients.

ORGANISM(S): Homo sapiens

SUBMITTER: Arndt Brachat

PROVIDER: E-GEOD-80060 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) is a rare disease associated with dysregulated interleukin (IL)-1 activity. Objectives: To assess the efficacy and safety of Anakinra, an IL-1 receptor antagonist in SJIA and its effects on gene expression profiling. Methods: We conducted a multicenter, randomized, double-blind placebo-controlled trial. The primary objective was to compare the efficacy of a one-month treatment with anakinra (2 mg/kg subcutaneoulsy daily, maximum 100 mg) to a placebo between 2 groups of 12 SJIA patients each. Response was defined by a 30% improvement of the pediatric American College of Rheumatology criteria for JIA, resolution of systemic symptoms and a decrease of at least 50% of both C-reactive protein and erythrocyte sedimentation rate compared to baseline. An intention-to-treat analyze was performed. After Month 1 (M1), patients taking placebo were switched to Anakinra. Secondary objectives included tolerance and efficacy assessment for 12 months. Results: At M1, concluding the randomized trial, there was a significant difference in the response rate between patients treated with Anakinra (8/12 responders) and placebo (1/12) (p=0.003). The number of adverse events, mainly pain to injections, was similar between both groups. Ten patients from the placebo group switched to Anakinra at M1; nine were responders at M2. Between M1 and M12, six patients stopped treatment for an adverse event (Crohn’s disease, hepatitis), a lack of efficacy or a disease flare (2 cases each). Blood gene expression profiling at enrollment and upon follow-up allowed us to identify one set of dysregulated genes that reverted to normal values in the clinical responders and a second set, including interferon-inducible genes, that was induced by Anakinra. Conclusion: Anakinra is an effective treatment of SJIA. Its effect is associated with normalization of blood gene expression profiles in clinical responders and de novo induction of an interferon signature. (Clinical trials registration number: NCT00339157)

Project description:Objective. Follistatin-like protein 1 (FSTL-1) is a secreted glycoprotein that is over-expressed in certain inflammatory diseases. Our objective in this study was to correlate FSTL-1 levels with measures of clinical disease activity in systemic juvenile idiopathic arthritis (sJIA), including macrophage activation syndrome (MAS). Methods. FSTL-1 serum levels were measured by ELISA in 28 patients with sJIA, including 7 patients who developed MAS, as well as in 30 normal controls. Levels were correlated with erythrocyte sedimentation rate (ESR), ferritin and sIL-2Rα expression. Differential gene expression based on FSTL-1 levels was analyzed in peripheral blood mononuclear cells (PBMCs). Results. FSTL-1 serum levels were elevated at time of presentation (pre-treatment) of sJIA (mean 200.7 ng/ml) and decreased to normal (mean 133.7 ng/ml) over 24 months (p<0.01). FSTL-1 levels were markedly elevated during acute MAS (mean 279.8 ng/ml) and decreased to normal (mean 120.3 ng/ml) following treatment (p<0.001). FSTL-1 levels correlated with serum markers of inflammation, including sIL-2Rα and ferritin, in patients with MAS. PBMCs from patients with FSTL-1 levels >200 ng/ml showed an increase in expression of genes related to innate immunity and erythropoiesis, and decrease in NK cell function. Patients with the highest FSTL-1 levels at disease onset (>300 ng/ml) ultimately required cyclosporine treatment. Conclusion. In patients with sJIA, serum FSTL-1 is a biomarker for MAS and FSTL-1 levels at presentation may predict subsequent disease course. Patients with FSTL-1 levels >200 ng/ml had altered gene expression patterns suggestive of subclinical MAS and may represent a subgroup of sJIA with more severe disease. FSTL-1 serum levels were measured by ELISA in 28 patients with sJIA, including 7 patients who developed MAS, as well as in 30 normal controls. Levels were correlated with erythrocyte sedimentation rate (ESR), ferritin and sIL-2Rα expression. Differential gene expression based on FSTL-1 levels was analyzed in peripheral blood mononuclear cells (PBMCs). Only 11 patients were run on microarray.

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Gene expression data of whole blood of systemic juvenile idiopathic arthritis (SJIA) patients treated with canakinumab or placebo and age matched healthy controls

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