scholarly journals A single tumour necrosis factor haplotype influences the response to adalimumab in rheumatoid arthritis

2007 ◽  
Vol 67 (4) ◽  
pp. 478-484 ◽  
Author(s):  
C Miceli-Richard ◽  
E Comets ◽  
C Verstuyft ◽  
R Tamouza ◽  
P Loiseau ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Tumour Necrosis Factor ◽  
Gene Polymorphisms ◽  
Tumour Necrosis ◽  
Shared Epitope ◽  
Pharmacogenetic Study ◽  
Genetic Predictors ◽  
Extended Haplotypes ◽  
Phase Iiib ◽  
Necrosis Factor

Objective:To determine whether tumour necrosis factor (TNF) gene polymorphisms and/or the shared epitope are genetic predictors of the 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 three TNF gene polymorphisms (–238A/G,–308A/G and–857C/T). Extended haplotypes involving HLA-DRB1 and TNF loci were reconstructed using the PHASE program.Results:A total of 151 patients (40%) had an ACR50 response at week 12. Neither the number of HLA-DRB1 shared epitope copies nor presence of the three 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.

scholarly journals Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 susceptibility variants, with anti-tumour necrosis factor response in rheumatoid arthritis

2008 ◽  
Vol 68 (1) ◽  
pp. 69-74 ◽  
Author(s):  
C Potter ◽  
K L Hyrich ◽  
A Tracey ◽  
M Lunt ◽  
D Plant ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Rheumatoid Factor ◽  
Treatment Response ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Shared Epitope ◽  
Response To Therapy ◽  
Cyclic Citrullinated Peptide ◽  
Citrullinated Peptide ◽  
Necrosis Factor

Objective:To determine whether rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibodies, or carriage of shared epitope (SE) and PTPN22 genetic susceptibility variants predict response to therapy in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor (TNF) agents.Methods:UK-wide multicentre collaborations were established to recruit a large cohort of patients treated with anti-TNF drugs for RA. Serum RF, anti-CCP antibody and SE status were determined using commercially available kits. PTPN22 R620W genotyping was performed by Sequenom MassArray. Linear regression analyses were performed to investigate the role of these four factors in predicting response to treatment by 6 months, defined as the absolute change in 28-joint Disease Activity Score (DAS28).Results:Of the 642 patients analysed, 46% received infliximab, 43% etanercept and 11% adalimumab. In all, 89% and 82% of patients were RF and anti-CCP positive, respectively. Patients that were RF negative had a 0.48 (95% CI 0.08 to 0.87) greater mean improvement in DAS28 compared to patients that were RF positive. A better response was also seen among patients that were anti-CCP negative. No association was demonstrated between drug response and SE or PTPN22 620W carriage.Conclusion:The presence of RF or anti-CCP antibodies was associated with a reduced response to anti-TNF drugs. However, these antibodies only account for a small proportion of the variance in treatment response. It is likely that genetic factors will contribute to treatment response, but these do not include the well established RA susceptibility loci, SE and PTPN22.

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