Rheumatoid Arthritis: Tamouza R

Miceli-Richard C, Comets E, Verstuyft C, Tamouza R, Loiseau P, Ravaud P, Kupper H, Becquemont L, Charron D, Mariette X. · Rhumatologie, Institut Pour la Santé et la Recherche Médicale U 802, Université Paris-Sud 11, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France. · Ann Rheum Dis. · Pubmed #17673491 No free full text.

Abstract: 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.

Loiseau P, Lepage V, Djelal F, Busson M, Tamouza R, Raffoux C, Menkes CJ, Meyer O, Charron D, Goldberg D. · Laboratoire d'Immunologie et d'Histocompatibilité, Hôpital Saint-Louis AP-HP, Paris, France. · Hum Immunol. · Pubmed #11423179 No free full text.

Abstract: Primary Sjögren syndrome (pSS) is an autoimmune disease characterized by progressive destruction of the exocrine glands leading to mucosal and conjunctival dryness. It is marked by lymphocytic infiltration of the glands and the accumulation of several types of autoantibodies such as rheumatoid factor (RF), antinuclear, anti-SS-A (anti-Ro) and anti-SS-B (anti-LA) autoantibodies. The susceptibility to pSS and/or the presence of SS-A/SS-B autoantibodies in pSS patients is associated with DRB1*03-DQB1*02 and DRB1*02-DQB1*06 haplotypes, whereas no associations have been described with any HLA class I allele. To define the impact of HLA class I alleles in predisposition to pSS, 46 patients responding to the European criteria and 222 healthy unrelated Caucasians were analyzed for their HLA class I and class II haplotypes. Our results confirm the association of the DRB1*03-DQB1*02 haplotype with SS-A/SS-B autoantibodies positive pSS and demonstrate a significant association of the HLA-A24 with the disease. Moreover, HLA-A24 is more often associated with DRB1*11-DQB1*0301 and/or DRB1*0301-DQB1*02 in pSS patients than in the controls. The novel association of HLA class I alleles with susceptibility to pSS provides new insights to the genetic predisposition to this disease and subsequently to its physiopathology.