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Polymorphism at position –308 of the tumour necrosis factor α gene and rheumatoid arthritis pharmacogenetics
  1. J E Fonseca1,2,
  2. T Carvalho2,
  3. M Cruz1,
  4. P Nero1,
  5. M Sobral2,
  6. A F Mourão2,
  7. J Cavaleiro2,
  8. D Ligeiro3,
  9. I Abreu4,
  10. M Carmo-Fonseca2,
  11. J C Branco1
  1. 1Rheumatology Unit, Egas Moniz Hospital, Lisbon, Portugal
  2. 2Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal
  3. 3Centro de Histocompatibilidade do Sul, Lisbon, Portugal
  4. 4Departamento de Imunologia da Faculdade de Ciências Médicas, Lisbon, Portugal
  1. Correspondence to:
    Professor J E Fonseca
    Rheumatoid Arthritis Unit, Institute of Molecular Medicine, University of Lisbon, Faculdade de Medicina, Avenue Professor Egas Moniz, 1649-028 Lisbon, Portugal; jefonsecanetcabo.pt

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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).

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.

Acknowledgments

Work supported by Programa Operacional Ciência Tecnologia Inovação (POCTI), financed by the EU and by national funds of the MCES.

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