RESEARCH - A single TNF haplotype influences the response to Humira in RA

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ls of the Rheumatic Diseases 2008;67:478-484

Copyright © 2008 BMJ Publishing Group Ltd & European League Against

Rheumatism

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EXTENDED REPORTS

A single tumour necrosis factor haplotype influences the response to

adalimumab in rheumatoid arthritis

C Miceli- 1, E Comets 2, C Verstuyft 3, R Tamouza 4, P Loiseau

4, P Ravaud 2,5, H Kupper 6, L Becquemont 3, D Charron 4, X Mariette 1

1 Rhumatologie, Institut Pour la Santé et la Recherche Médicale

(INSERM) U 802, Université Paris-Sud 11, Hôpital Bicêtre, Assistance

Publique-Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France

2 INSERM U 738, Paris, France; Université Paris 7, Paris, France

3 Pharmacologie, Centre d'Investigation Biologique (CIB), Hôpital

Bicêtre, AP-HP, Le Kremlin Bicêtre, France

4 INSERM U 396, Immunologie et Histocompatibilité, Hôpital

Saint-Louis, AP-HP, Paris, France

5 Département d'Epidémiologie, Biostatistique et Recherche Clinique,

Hôpital Bichat, AP-HP, Paris, France

6 Abbott GmbH & Co. KG, Ludwigshafen, Germany

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.

http://ard.bmj.com/cgi/content/abstract/67/4/478

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