Association between the level of circulating bioactive tumor necrosis factor α and the tumor necrosis factor α gene polymorphism at −308 in patients with rheumatoid arthritis treated with a tumor necrosis factor α inhibitor

Objective The tumor necrosis factor α (TNFα) −308A polymorphism has been associated with high production of TNFα and poor response to anti‐TNFα therapy, but these associations remain controversial. The aim of this study was to explore the association between circulating TNFα bioactivity, the TNFα −3...

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Published in:Arthritis and rheumatism 2008-05, Vol.58 (5), p.1258-1263
Main Authors: Marotte, Hubert, Arnaud, Béatrice, Diasparra, Jennifer, Zrioual, Saloua, Miossec, Pierre
Format: Article
Language:English
Subjects:
Antibodies, Monoclonal - therapeutic use
Arthritis, Rheumatoid - blood
Arthritis, Rheumatoid - drug therapy
Arthritis, Rheumatoid - genetics
Female
Humans
Infliximab
Interleukin-6 - biosynthesis
Male
Middle Aged
Polymorphism, Genetic
Synovial Membrane - cytology
Synovial Membrane - drug effects
Synovial Membrane - metabolism
Tumor Necrosis Factor-alpha - antagonists & inhibitors
Tumor Necrosis Factor-alpha - blood
Tumor Necrosis Factor-alpha - genetics
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Summary:Objective The tumor necrosis factor α (TNFα) −308A polymorphism has been associated with high production of TNFα and poor response to anti‐TNFα therapy, but these associations remain controversial. The aim of this study was to explore the association between circulating TNFα bioactivity, the TNFα −308 polymorphism, and the clinical response to infliximab in patients with rheumatoid arthritis (RA). Methods One hundred ninety‐eight patients with RA were treated with infliximab and methotrexate. Responses at 6 months according to the American College of Rheumatology (ACR) preliminary criteria for improvement in RA were recorded. Genotyping for the TNFα −308 polymorphism was performed by enzyme‐linked oligosorbent assay. Circulating TNFα bioactivity was evaluated in 50 patients with RA by assessing the production of interleukin‐6 (IL‐6) in synoviocytes induced by a small amount of TNFα plus plasma. IL‐6 production in 48‐hour supernatants and the levels of TNFα protein and IL‐6 were measured by enzyme‐linked immunosorbent assay. Results The TNFα −308 polymorphism was not associated with the ACR response to infliximab. The level of circulating TNFα bioactivity was higher in patients with the TNFα −308 A/A or A/G genotype than that in patients with the G/G genotype (median 50.0 ng/ml [interquartile range (IQR) 31.5–62.0] versus 33.0 ng/ml [IQR 16.5–47.5]; P < 0.02). However, no difference was observed for the TNFα protein level according to genotype (median 0.62 pg/ml [IQR 0.00–8.85] for G/G versus 3.35 pg/ml [IQR 1.55–4.63] for A/A or A/G; P not significant). The level of circulating TNFα bioactivity was higher in good responders (≥50% improvement) than in poor responders (≤20% improvement) (median 45.0 ng/ml [IQR 21.0–59.0] versus 28.0 ng/ml [IQR 14.0–39.0]; P = 0.05). However, the level of TNFα protein was similar in both groups. Conclusion The level of functional circulating TNFα is partially genetically determined and is predictive of the clinical response to infliximab. Nonresponders to anti‐TNFα therapy are likely to have a disease that is not primarily driven by TNFα.
ISSN:0004-3591
1529-0131
DOI:10.1002/art.23430