The pharmacogenetic relevance of the tumour necrosis factor α (TNFα) gene has just begun to be investigated. There is only preliminary evidence that the –238 GG genotype is associated with unresponsiveness to conventional disease modifying antirheumatic drugs¹ and that a combination of alleles (−308 TNF1/TNF1 and –1087 GG interleukin 10) is associated with good responsiveness to etanercept.² In addition, Mugnier et al recently suggested that patients with rheumatoid arthritis (RA) with a TNFα −308 GG genotype might, in the short term, be better infliximab responders than patients with AA or AG genotypes.³

To evaluate the influence of the polymorphism at position −308 of the TNFα gene in the long term response to infliximab, we performed a prospective study of 22 consecutive patients with RA who were given infliximab treatment. All patients fulfilled the American College of Rheumatology 1987 revised criteria for RA⁴ and had a Disease Activity Score in 28 joints (DAS28)⁵ persistently above 3.2 after treatment with methotrexate 20 mg/week for 3 months, according to the guidelines of the Portuguese Society for Rheumatology.⁶

Patients were given intravenous infusions of 3 mg/kg infliximab at weeks 0, 2, 6, and then each 8 weeks. Before each infusion patients were evaluated with a protocol, which included evaluation of the DAS28 and the Health Assessment Questionnaire (HAQ).⁷ Radiological evaluation (hands and feet) was performed at inclusion and after 1 year of follow up. A blinded observer (JEF) using the Sharp/van der Heijde method analysed radiographs.⁸ DNA was extracted from a blood sample and the TNFα gene polymorphism at position −308 was determined by polymerase chain reaction, according to Grove et al.⁹ Patients who had the AA or AG genotype were compared with those who had the GG genotype. Comparisons of the two groups were evaluated by Student’s two tailed t test. All patients gave informed consent and the Egas Moniz Hospital ethics committee approved the study.

Fifteen of the 22 (68%) patients had the −308 GG genotype and 7/22 (32%) patients the −308 AG genotype. No significant differences were found between the two groups for disease duration (AG: 5.7 (4.9) years and GG: 10.3 (7.1) years; mean (SD)), age of onset (AG: 47.9 (14.2) years and GG: 45.8 (11.1) years), baseline DAS28 (AG: 4.2 (1.3) and GG: 5.0 (1.5)), baseline modified Sharp score (AG: 97.7 (40.3) and GG: 97.8 (67.2)), and baseline HAQ (AG: 1.32 (0.51) and GG: 1.47 (0.68)). Two of the seven (29%) AG patients were DR3 positive, whereas only one of 15 (7%) GG patients was DR3 positive.

After 24.8 (11.5) months of treatment with infliximab, patients with the −308 GG genotype had a significantly better response than the patients with the −308 AG genotype. In fact, they had a decrease in the DAS28 score of −2.4 (0.6), whereas the −308 AG group had a slight increase in the DAS28 score of +0.12 (0.18) (p<0.01). This difference was significant from the second month of treatment (fig 1). There was also a tendency for a better HAQ evolution in the −308 GG group (a decrease of −0.38 (0.74) in the GG group and an increase of 0.32 (0.92) in the AG group; p = 0.064). Curiously, there was no difference in the radiological outcome (both groups had a decrease in the modified Sharp score of, respectively, −1 (13.1) and −1 (15.7); NS).

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Figure 1

 Mean improvement in DAS28 with infliximab treatment between first administration and the evaluation performed before each subsequent treatment in seven patients with RA with the TNFα −308 genotype AG and 15 patients with RA with the TNFα −308 genotype GG. Bars represent standard deviation; *p<0.05.

Our observations show that the TNFα −308 genotype AG is associated with sustained (over 1 year) high disease activity and functional degradation despite treatment with infliximab, in patients with RA refractory to conventional disease modifying antirheumatic drugs.