Publications [#142014] of Geoffrey S Ginsburg

Papers Published

1. A Parker, ES Izmailova, J Narang, S Badola, T Le, R Roubenoff, GS Ginsburg, A Maier, JS Coblyn, NA Shadick, ME Weinblatt, Peripheral blood expression of nuclear factor-kappab-regulated genes is associated with rheumatoid arthritis disease activity and responds differentially to anti-tumor necrosis factor-alpha versus methotrexate., The Journal of rheumatology, vol. 34 no. 9 (September, 2007), pp. 1817-22, ISSN 0315-162X
   (last updated on 2013/05/16)

   Abstract:
   OBJECTIVE: To evaluate peripheral blood expression of genes regulated by nuclear factor-kappaB (NF-kappaB), a key mediator of tumor necrosis factor-alpha (TNF-alpha) signaling, in patients with rheumatoid arthritis (RA) before and during treatment with anti-TNF-alpha or methotrexate (MTX). We analyzed association of gene expression with disease activity, rheumatoid factor (RF), age, sex, disease duration, treatment modality, and clinical response. METHODS: Sixty patients consented for RNA analysis at baseline and after 2 and 6 weeks of treatment. Disease activity was quantified using Disease Activity Score (DAS28) and C-reactive protein (CRP). Expression of 67 TNF-alpha-responsive, NF-kappaB-regulated genes was measured using Affymetrix arrays and RT-PCR. RESULTS: Expression of 34 genes was associated with DAS28-CRP, notably S100A12/calgranulin C, IL7R, and aquaporin 3. No association was observed with age, sex, RF, or disease duration. Expression of 16 genes changed in a manner that differed significantly between treatment groups. Eleven were reduced in anti-TNF-alpha-treated patients relative to MTX, while 5 were increased. The majority of these observations were confirmed using RT-PCR. Gene expression was not associated significantly with change in disease activity. CONCLUSIONS: NF-kappaB-dependent gene expression in peripheral leukocytes is highly correlated with RA activity as measured by DAS28-CRP. Expression of many genes responds differentially to anti-TNF-alpha versus MTX, suggesting fundamentally different effects on the NF-kappaB pathway. This peripheral blood expression signature provides candidate markers that could lead to development of a simple, minimally invasive pharmacodynamic assay for RA treatments directed at the NF-kappaB pathway. Combination of gene expression data with clinical scores and serum markers may provide more sensitive and predictive measures of RA disease activity.

   Keywords:
   Adult • Aged • Antirheumatic Agents • Arthritis, Rheumatoid • Biological Markers • Down-Regulation • Female • Gene Expression Regulation • Humans • Male • Methotrexate • Middle Aged • NF-kappa B p50 Subunit • Receptors, Tumor Necrosis Factor • Severity of Illness Index • Tumor Necrosis Factor-alpha • Up-Regulation • administration & dosage* • antagonists & inhibitors • drug effects • drug effects* • drug therapy* • pharmacology*