• Hubert Marotte, Béatrice Arnaud, Jennifer Diasparra, Saloua Zrioual, and Pierre Miossec.
• Hôpital Edouard Hérriot, Lyon, France.
• Arthritis Rheum. 2008 May 1; 58 (5): 1258-63.

ObjectiveThe tumor necrosis factor alpha (TNFalpha) -308A polymorphism has been associated with high production of TNFalpha and poor response to anti-TNFalpha therapy, but these associations remain controversial. The aim of this study was to explore the association between circulating TNFalpha bioactivity, the TNFalpha -308 polymorphism, and the clinical response to infliximab in patients with rheumatoid arthritis (RA).MethodsOne 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 TNFalpha -308 polymorphism was performed by enzyme-linked oligosorbent assay. Circulating TNFalpha 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 TNFalpha plus plasma. IL-6 production in 48-hour supernatants and the levels of TNFalpha protein and IL-6 were measured by enzyme-linked immunosorbent assay.ResultsThe TNFalpha -308 polymorphism was not associated with the ACR response to infliximab. The level of circulating TNFalpha bioactivity was higher in patients with the TNFalpha -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 TNFalpha 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 TNFalpha bioactivity was higher in good responders (> or =50% improvement) than in poor responders (< or =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 TNFalpha protein was similar in both groups.ConclusionThe level of functional circulating TNFalpha is partially genetically determined and is predictive of the clinical response to infliximab. Nonresponders to anti-TNFalpha therapy are likely to have a disease that is not primarily driven by TNFalpha.

24 keywords...

hide…