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.

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.

Conclusion: 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.