Background/Purpose: 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) at 26 weeks.¹ Their effect on long-term responses is unclear. 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 yrs 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3.2 at wks 22 & 26) with ADA+MTX were re-randomized to continue ADA+MTX (ADA Continuation arm) or have ADA blindly withdrawn (ADA Withdrawal arm) for 52 wks (P2). Pts who achieved the stable LDA target with PBO+MTX continued blinded therapy (MTX Continuation arm). Pts who did not achieve the stable LDA target with initial combination therapy or MTX monotherapy were offered open-label (OL) ADA+MTX (OL ADA Carry On and Rescue ADA arms, respectively).

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.

 

Table. Percentage of Pts with DAS28 <3.2 at Week 78, n/N (%), non-responder imputation
Treatment	HLA-DRB1 SE			IL4R			FcγRIIb
	0x	1x	2x	AA	AG	GG	TT	TC	CC
ADA WITHDRAWAL	21/ 28 (75.0)	25/ 36 (69.4)	17/ 22 (77.3)	23/ 31 (74.2)	33/ 44 (75.0)	7/ 11 (63.6)	43/ 63 (68.3)	17/ 20 (85.0)	3/ 3 (100)
ADA CONTINUATION	16/ 22 (72.7)	36/ 45 (80.0)	18/ 20 (90.0)	23/ 31 (74.2)	33/ 39 (84.6)	14/ 17 (82.4)	54/ 67 (80.6)	14/ 18 (77.8)	2/ 2(100)
OL ADA CARRY ON	29/ 81 (35.8)	49/113 (43.4)	18/ 36 (50.0)	28/ 68 (41.2)	49/109 (45.0)	19/ 53 (35.8)	87/200 (43.5)	8/ 29 (27.6)	1/ 1 (100)
MTX CONTINUATION	30/ 40 (75.0)	25/ 38 (65.8)	10/ 15 (66.7)	18/ 24 (75.0)	31/ 44 (70.5)	16/ 25 (64.0)	47/ 69 (68.1)	18/ 24 (75.0)	0/ 0 (0)
RESCUE ADA	59/115 (51.3)	80/148 (54.1)	19/ 42 (45.2)	49/ 93 (52.7)	83/164 (50.6)	26/ 48 (54.2)	117/225 (52.0)	40/ 76 (52.6)	1/ 4 (25.0)

Conclusion: 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.

Reference: ¹Skapenko A, et al. EULAR 2011 [THU0309].

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetic-effects-of-hla-drb1-il4r-and-fc%ce%b3riib-on-long-term-treatment-responses-in-patients-with-early-rheumatoid-arthritis-78-week-results-of-a-phase-4-study/