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AB0230 Polymorphism of cytotoxic T-lymphocyte 4 +49A/G is associated with early prescribing the biological therapy in active early rheumatoid arthritis patients (ERA PTS) refractory to the previous subcutaneous methotrexate (SC MTX) monotherapy
  1. I Guseva1,
  2. AS Avdeeva1,
  3. EL Luchikhina1,
  4. DD Abramov2,
  5. NV Demidova1,
  6. EN Alexandrova1,
  7. AA Novikov1,
  8. MY Krylov1,
  9. EY Samarkina1,
  10. DY Trofimov2,
  11. DE Karateev1,
  12. EL Nasonov1
  1. 1V.A.Nasonova Research Institute of Rheumatology
  2. 2NRC Institute of Immunology of FMBA of Russia, Moscow, Russian Federation, Moscow, Russian Federation


Background Monotherapy with MTX is the first step of RA therapy as recommended by EULAR. According to “Treat to Target” (T2T) strategy principles insufficient response to MTX requires prompt switch to a combination therapy with biological agents.

Objectives To find out whether polymorphisms of immune response genes are associated with early prescribing the biological treatment in eRA pts, refractory to the SC MTX monotherapy.

Methods By January 2014, 210 pts with RA were included in the REMARCA study (Russian InvEstigation of MethotrexAte and biologics in eaRly aCtive inflammatory Arthritis), and 88 pts have passed the 12 months control point. All pts started SC MTX monotherapy with rapid up-titration of the dose from 10 to 25–30 mg/week. Therapy was revised every 3 months using DAS28, SDAI and CDAI indices. Combination with biologics (in most cases TNF inhibitors) was used in 57 (65%) of pts at (median) 3 [3;6] month [1]. Retrospectively, 45 out of 88 active eRA pts (35 woman, mean age 53,5; 46–59,5 years, mean disease duration 7,0; 4,0–11,5 months, mean DAS28 5,8; 4,9–6,4, mean hs-CRP 27,0; 9,7–61,0 mg/l) were selected to evaluate the changes in cytokine profile in MTX-naive pts during SC MTX and SC MTX + adalimumab (SC MTX+ADA) therapy [2]. These 45 pts were genotyped for the following gene polymorphisms (SNPs): PTPN22 (+1858 C/T, rs2476601), CTLA4 (+49A/G, rs231775), TNFAIP3 (rs675520, rs6920220, rs10499194), IL6 (-174G/C, rs1800795), IL6R (+358A/C, rs8192284), TNFA (-308A/G, rs1800629), MCP1/ CCL2 (+2581A/G, rs1024611), IL10 (-592A/C, rs1800872, -1082 A/G, rs1800896), IL1A (-889C/T, rs1800587), IL1B (+3953C/T, rs1143634).

Results By the end of 3 months of SC MTX therapy, 23 out of 45 eRA pts (51,1%) adequately responded to SC MTX (EULAR criteria) and continued on SC MTX monotherapy. In 22 pts (48,9%) SC MTX monotherapy failed, thus they were switched to SC MTX + ADA combination therapy. CTLA-4 gene polymorphism (+49A/G) was the only predictor for the administration of biological therapy in eRA pts, that was confirmed by a logistic regression analysis [OR=7,7 95% CI 1,4–40,9, p=0,017]. The carriers of at least one G allele (AG/GG genotypes) received the biological therapy more often than subjects with AA genotype (20/22, 90,9% and 13/23, 56,5% respectively). Moreover, the CTLA-4 (+49A/G) genotypes (AG/GG vs AA respectively) were associated with DAS28 (3,6±1,1 and 4,6±1,6, p=0,04), the number of tender joints (3,1±3,1 and 7,1±5,1, p=0,016), the number of swollen joints (2,7±2,5 and 5,3±4,9 p=0,024), SDAI (11,1±7,2 and 20,2±12,1, p=0,018), CDAI (10,6±7,1 and 18,6±10,6, p=0,025) and CRP (6,3±12,1 and 21,8±37,1 p=0,018) values after 3 months of SC MTX monotherapy.

Conclusions Our data suggest that CTLA-4 (+49A/G) genetic polymorphism is associated with more severe rheumatoid arthritis and may predict the need for early administration of biological therapy.


  1. Karateev D., E. Luchikhina E., N. Demidova N. et al. Ann Rheum Dis 2014;73(Suppl2): 235–236.

  2. Avdeeva A.S. Novikov A. A, Aleksandrova E. N. et al. Ann Rheum Dis 2014;73(Suppl2): 215–216.


Disclosure of Interest None declared

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