Objective: To determine whether tumor necrosis factor (TNF) gene polymorphisms and/or the shared epitope are genetic predictors of response to adalimumab (ADA) in rheumatoid arthritis (RA).
Methods: This ancillary study to the Research in Active Rheumatoid Arthritis (ReAct) Phase IIIb study included a large cohort of Caucasian patients with RA from France (N=388) treated with ADA plus methotrexate (MTX) (n=182), ADA plus any other DMARD (N=98) or ADA alone (N=108). The primary outcome was ACR50 at 12 weeks. Patients underwent genotyping for HLA-DRB1 and 3 TNF gene polymorphisms (-238A/G, -308A/G and -857C/T). Extended haplotypes involving HLA-DRB1 and TNF loci were reconstructed by use of the PHASE program.
Results: A total of 151 patients (40%) had an ACR50 response at week 12. Neither the number of HLA-DRB1 SE copies nor presence of the 3 TNF polymorphisms tested separately was significantly associated with ACR50 response at week 12. However, haplotype reconstruction of the TNF locus revealed that the GGC haplotype (-238G/-308G/857C) in a homozygous form, (i.e. present in more than half of the patients) was significantly associated with a lower ACR50 response to ADA at 12 weeks (34% vs. 50% in patients without the haplotype) (P=0.003; Pa=0.015). This effect was more important in the subgroup of patients concomitantly treated with MTX.
Conclusion: This large pharmacogenetic study provides preliminary data indicating that a single TNF locus haplotype (-238G/-308G/-857C), present on both chromosomes is associated with a lower response to ADA, mainly in patients treated with ADA and MTX.
- TNF á
- genetic polymorphism
- rheumatoid arthritis