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AB0257 Genetic effects of HLA-DRB1, IL4R, and FCΓRIIB on long-term treatment responses in patients with early rheumatoid arthritis: 78-week results of optima
  1. A. Skapenko1,
  2. J.S. Smolen2,
  3. A. Kavanaugh3,
  4. S. Santra4,
  5. H. Kupper5,
  6. H. Schulze-Koops1
  1. 1Univ Munich, Munich, Germany
  2. 2Medical Univ of Vienna, Vienna, Austria
  3. 3UCSD, La Jolla
  4. 4Abbott, Abbott Park, United States
  5. 5Abbott GmBH, Ludwigshafen, Germany

Abstract

Background Previous analyses suggested that the HLA-DRB1 shared epitope (SE), and the IL4R V50I and the FcγRIIb I232T single nucleotide polymorphisms (SNPs) affected response to adalimumab (ADA) plus methotrexate (MTX)1. Their effect on long-term responses is unclear.

Objectives To examine 78-wk clinical responses according to 3 candidate loci: HLA-DRB1 SE, and IL4R I50V and FcγRIIb I232T SNPs.

Methods MTX-naïve patients (pts) ≥18 yr with RA <1 yr, active disease [DAS28 (CRP)>3.2, ESR≥28 mm/hr or CRP≥1.5 mg/dL], and >1 erosion, RF+, or anti-CCP+ were randomized to ADA+MTX or placebo (PBO)+MTX for 26 wks (Period 1, P1). Pts who achieved a stable LDA target (DAS28<3.2 at wks 22 & 26) with ADA+MTX were re-randomized to continue ADA+MTX or have ADA blindly withdrawn for 52 wks (P2). Pts who achieved the target with PBO+MTX continued blinded therapy. Pts who did not achieve the target were offered open-label (OL) ADA+MTX.

Results Baseline demographics were similar across alleles. The table shows the percentage of pts achieving DAS28<3.2 at wk 78. There were no consistent patterns for the IL4R alleles in any group. While limited by small sample sizes, pts with FcγRIIb-CC appeared to have higher responses at wk 78 among groups initially exposed to ADA+MTX during P1. The positive influence of SE was apparent at wk 78 in groups originally exposed to ADA+MTX, particularly in pts who did not achieve the stable LDA target at wks 22 & 26 but continued ADA+MTX. However, this pattern was not observed in pts who failed to achieve the target with MTX and were subsequently treated with ADA+MTX. The interaction between SE and IL4R observed during P1 was not apparent in long-term responses to ADA+MTX.

Percentage of Pts with DAS28<3.2 at Week 78, n/N (%), non-responder imputation

Conclusions Regardless of genetic background, wk 78 responses were generally higher for pts who achieved the stable LDA target at wks 22 & 26. The positive effects of HLA-DRB1 SE and FcγRIIb-CC in response to ADA+MTX previously noted at wk 26 were less apparent at wk 78, but noticeable in pts who failed to achieve the target. Further, while SE predicted clinical response to ADA+MTX, particularly when combined with IL4R alleles, it had no influence on the ability to withdraw ADA in pts who achieved LDA. These findings may indicate that genetic factors have a stronger influence on initial treatment response than on sustained disease control.

  1. Skapenko et al. EULAR 2011 #THU0309.

Disclosure of Interest A. Skapenko: None Declared, J. Smolen Grant/Research support from: Abbott, Amgen, Astra-Zeneca, BMS, Celgene Centocor-Janssen, Glaxo, Lilly, Pfizer (Wyeth), MSD (Schering-Plough), Novo-Nordisk, Roche, Sandoz, UCB, Consultant for: Abbott, Amgen, Astra-Zeneca, BMS, Celgene Centocor-Janssen, Glaxo, Lilly, Pfizer (Wyeth), MSD (Schering-Plough), Novo-Nordisk, Roche, Sandoz, UCB, A. Kavanaugh Grant/Research support from: Abbott, Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, Consultant for: Abbott, Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, S. Santra Shareholder of: Abbott, Employee of: Abbott, H. Kupper Shareholder of: Abbott, Employee of: Abbott, H. Schulze-Koops Consultant for: Abbott

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