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THU0008 Tnf-alpha gene polymorphism in severe and mild rheumatoid arthritis
  1. M Fabris1,
  2. L Sinigaglia2,
  3. S Sacco1,
  4. E Di Poi1,
  5. G Favret1,
  6. GF Ferraccioli1
  1. 1Division of Rheumatology-DPMSC, University of Udine, Udine, Italy
  2. 2Division of Rheumatology, University of Milan, Milan, Italy

Abstract

Background TNF-α is thought to be the key driving cytokine in Rheumatoid Arthritis (RA) and recently became a therapeutic target for treatment of patients particularly resistant to conventional therapy. In our study we looked for a genetic background that should indicate some criteria to address RA patients towards more aggressive treatments with anti-TNF-α agents.

Objectives We assessed the role of the -238 and +489 TNF-α gene polymorphisms in a series of patients with severe aggressive disease who were treated with anti-TNF-α therapy because of their poor response to a DMARDs combination strategy. The phenotypes of these patients were compared to those of a cohort of patients who had a good response to Methotrexate (MTX), thus revealing a mild/moderate disease.

Methods One hundred and thirty-eight (138) RA patients and sixty-four (64) controls (Healthy Blood Donors, HBD) entered the study. RA patients were divided into 2 subgroups. Group A: 72 rheumatoids, called MTX-responders (MTX-R), who were in stable partial remission since at least six months after MTX treatment (15 mg/w weekly, range 10–25 mg/w). Stable partial remission was defined when patients had less than 3 swollen joints and a morning stiffness of less than 20’. Group B: 68 rheumatoids with still active disease (more than 6 swollen joints and a morning stiffness of at least 60’) despite 6 months of combination therapy (MTX + Sulphasalazine + Hydroxychloroquine or MTX + Cyclosporine, including low doses of prednisone, 5 mg/day). This group subsequently received anti-TNF-α therapy and was labelled as anti-TNF-treated, (TNF-T). Genotyping for -238 and +489 TNF-α polymorphisms was made according to Weiss et al.1 Statistical analyses (Odds Ratio, 95% Confidence Interval) were performed using Prism Software (Graph-Pad, S. Diego, CA 92121-USA).

Results MTX-R had an overall frequency of GG homozygousity for the -238 polymorphism of 91.6% vs 92.2% in HBD, while in TNF-T subgroup the GG genotype had a frequency of 100% (OR = 13, CI = 0.7–240, p = 0.008 vs MTX-R). The comparison between TNF-T and HBD is similarly striking (POR = 12, CI = 0.7–230, p = 0.01). The major finding concerning the +489 polymorphism is the lower frequency of the AA genotype in RA in general (OR = 4.2, CI = 1–18, p = 0.01) and in TNF-T in particular.

Conclusion The GG genotype for the -238 TNF-α polymorphism marks all patients who received anti-TNF-α therapy. This group of patients also showed a significant reduction of the AA genotype of the +489 polymorphism. This latter finding supports the hypothesis that the A allele of the +489 TNF-α intronic polymorphism is linked to a genetic setting that offers a less aggressive phenotype in RA.

Reference

  1. Weiss, et al. N Engl J Med. 1996;334:1090–94

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