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THU0239 Association of the 2/2 Genotype of the Enhancer Hs1,2A of the IG Heavy 3' Regulatory Region with Early Rheumatoid Arthritis
  1. B. Tolusso1,
  2. E. Gremese1,
  3. A.L. Fedele1,
  4. D. Frezza2,
  5. S. Canestri1,
  6. F. Cianci1,
  7. M.R. Gigante1,
  8. C. Di Mario1,
  9. G. Ferraccioli1
  1. 1Division Of Rheumatology, Institute Of Rheumatology And Affine Sciences, Catholic University Of The Sacred Heart
  2. 2Laboratory of Genetics, Department of Biology Enrico Calef, University of Rome, Tor Vergata, Italy, Rome, Italy


Background The allele*2 of the enhancer HS1,2A (IgH 3'RR-1) has been shown to have a binding site for NK-kB and to be associated to Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus and Systemic Sclerosis.

Objectives To study a polymorphism in the enhancer HS1,2A as a biomarker of disease activity and response to therapy in early RA.

Methods 320 early RA (ERA) (age: 54.4±14.1 years; 76.3% female; 62.8% anti-CCP positive) were enrolled in the study. ERA patients fulfilled the 2010 American College of Rheumatology classification criteria for RA and were treated according to a tight control strategy. At baseline and every 3 months demographic and immunological data and the ACR/EULAR core data set were recorded. At each visit, clinical improvement and remission were evaluated according to DAS [1,2]. Patients were genotyped for HS1,2A enhancer polymorphism, as previously described [3]. Baseline IL-6 and BAFF plasma levels were evaluated by ELISA's methods.

Results The analysis of the genotype's distribution of the HS1,2A enhancer showed a higher frequency of the 2/2 genotype in ERA patients (28.1%) compared to healthy subjects (14.9%, p<0.001).

At diagnosis, ERA patients carrying the 2/2 genotype had a higher baseline inflammatory status (ESR: 49.6±30.5 mm/1st hr, CRP: 30.6±40.5 mg/l, IL6: 27.3±45.8 pg/ml) and higher disease activity (DAS28: 5.6±1.3, SDAI: 33.3±15.6) and disability (HAQ:1.3±0.8) compared to patients without the 22 genotype (ESR: 37.6±25.7 mm/1st hr, p=0.002; CRP: 20.1±27.3 mg/l, p=0.04; IL6: 20.6±38.5 pg/ml, p=0.04; DAS28: 5.3±1.3,p=0.05; SDAI: 29.2±14.1, p=0.06; HAQ:1.1±0.7, p=0.03). Similar autoantibody patterns were seen in the different genotypes.

Fifty-three percent of ERA patients reached a good-EULAR response at 3 months follow-up visit (FU) and 24% 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 compared with ERA patients without the 2/2 genotype [good-EULAR response: 36.2% vs 58.8%, OR (95%CIs): 0.40 (0.21-0.74); sustained EULAR-remission: 10.9% vs 27.9%, OR: 0.32 (0.13-0.79)]. Moreover, ERA patients carrying the 2/2 genotype were characterized by a higher percentage of subjects treated with TNF-blockers at 6 months FU compared with patients without the 2/2 genotype (20.3% vs 8.8%, p=0.02).

Circulating B cells of subjects carrying the allele*2 showed a higher expression (fold change) of BAFF-R (7.6±3.7) and IL6 (4.1±6.4) than carriers of the 1/1 genotype (BAFF-R: 3.3±1.5, p=0.05; IL-6: 0.9±0.8, p=0.07).

Conclusions The presence of the 2/2 genotype of the enhancer HS1,2A seems to identify a more active and aggressive disease in ERA patients poorly responsive to DMARDs. The presence of a binding site for NF-kB in the allele*2 (4), could explain the more aggressive phenotype.


  1. van Gestel AM., Arthritis and Rheumatism, 1996.

  2. Prevoo ML, British Journal of Rheumatology, 1996.

  3. Tolusso B et al., Ann Rheum Dis 2009.

  4. Frezza D et al., Ann Rheum Dis 2012.

Disclosure of Interest : None declared

DOI 10.1136/annrheumdis-2014-eular.3591

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