THU0148 Asssociation of the 22 Genotype of Enhancer HS1,2A of the IG Heavy 3′ Regulatory Region with Non Response to Dmards and Response to Rituximab in Rheumatoid Arthritis Patients
Authors: B. Tolusso, E. Gremese, A. L. Fedele, E. Serone, D. Frezza, M. R. Gigante, M. Nowik, S. Canestri, A. Carbonella, G. Ferraccioli
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Several studies underline the relevance of the genetic background for the response to therapy in the Rheumatoid Arthritis (RA). <h3>Objectives</h3> To study the polymorphism in the enhancer HS1,2A of the Ig heavy 3′ regulatory region (IgH 3′RR-1) as a biomarker of response to therapy in different phases of RA disease. <h3>Methods</h3> 535 RA patients were enrolled in the study, of which: A) 326 with an early RA (ERA), treated according to a tight control strategy (Methotrexate for three months, and if an incomplete response was seen after 3 months they started a combination with Tumor Necrosis Factor (TNF) blockers), B) 89 TNF-treated patients with a long-standing RA (TNF-treated LSRA) and C) 120 seropositive LSRA patients treated with Rituximab (RTX-treated LSRA), not responsive to previous DMARDs and/or TNF-blockers. Patients were genotyped for HS1,2A enhancer polymorphism, as previously described (1). Diasease activity was assessed every three months according to the European League Against Rheumatism's (EULAR) criteria. <h3>Results</h3> The polymorphism of the HS1,2A enhancer of the 3' regulatory region respected the Hardy-Weinberg equilibrium in all the RA cohorts. The analysis of the genotype's distribution of the HS1,2A enhancer showed a similar frequency of the 2/2 genotype in ERA patients (28.2%) compared to RTX-treated LSRA (21.7%, <i>p=0.17</i>), but lower than in TNF-treated LSRA (40.4%, <i>p=0.03</i> vs ERA). Fifty percent of ERA patients reached a good-EULAR response at 3 months follow-up visit (FU) and 23% were in sustained EULAR-remission at 6 months FU. The percentage of good-EULAR response at 3-months FU and sustained EULAR-remission at 6-month FU was lower in ERA patients carrying the 2/2 genotype of HS1,2A enhancer compared with ERA patients without the 2/2 genotype (good-EULAR response: 35.9% vs 56.4%, OR(95%CIs): 0.43 (0.24-0.78); sustained EULAR-remission: 12.5% vs 26.1%, OR(95%CIs): 0.40 (0.18-0.91), respectively). Moreover, ERA patients carrying the 22 genotype were characterized by a more severe disease at baseline and by a higher percentage of subjects treated with TNF-blockers at 6 months FU compared to patients without the 22 genotype (26.1% vs 12.2%, <i>p=0.01</i>). In the cohort of TNF-treated LSRA patients (good-EULAR response: 32.6%) there was no association between the HS1,2A enhancer polymorphism and the response to therapy over time. The 25% of RTX-treated LSRA patients reached a good-EULAR response at 6 months FU. The percentage of good-EULAR response was more prevalent in RTX-treated LSRA patients carrying the 2/2 genotype compared to subjects without the 22 genotype (42.3% vs 20.2%, OR (IC 95%): 2.90 (1.15-7.32)). <h3>Conclusions</h3> The presence of the 2/2 genotype of HS1,2A enhancer seems to identify a more aggressive disease in ERA patients poorly responsive to DMARDs and it associates to a good EULAR response to RTX in seropositive LSRA. The demonstration of the presence of a binding site for NF-kB in the allele*2 of HS12A enhancer, (2) could explain the more aggressive phenotype. <h3>References</h3> Giambra V et al., Genes 2005 Frezza D et al., Ann Rheum Dis 2012. <h3>Disclosure of Interest</h3> None Declared