HLA-DRB1 risk alleles for RA are associated with differential clinical responsiveness to abatacept and adalimumab: data from a head-to-head, randomized, single-blind study in autoantibody-positive early RA

Abstract

Background: Certain risk alleles associated with autoantibody-positive rheumatoid arthritis (RA) have been linked to poorer prognoses. In patients with autoantibody-positive RA, abatacept shows differential efficacy to tumor necrosis factor inhibitors. Our aim was to investigate the relationship between clinical response to abatacept and to adalimumab and presence of risk alleles encoding human leukocyte antigen (HLA)-DRB1 shared epitope (SE) in RA.

Methods: In this head-to-head study, biologic-naïve adults with early (≤ 12 months), moderate-to-severe RA and inadequate response to methotrexate (MTX-IR), autoantibody-positive for both anti-cyclic citrullinated peptide 2 and rheumatoid factor, were randomized 1:1 to receive subcutaneous abatacept 125 mg weekly or subcutaneous adalimumab 40 mg every 2 weeks for 24 weeks with stable, weekly oral MTX. An open-label period to 48 weeks followed, during which adalimumab-treated patients were switched to abatacept. Patients were genotyped for HLA-DRB1 alleles and classified as SE-positive (≥ 1 SE allele) or SE-negative (no SE alleles). Efficacy was assessed at weeks 24 and 48.

Results: Forty patients each received abatacept (9 SE-negative, 30 SE-positive, one unknown) or adalimumab (9 SE-negative, 31 SE-positive). Mean age and disease duration were 46.0 years and 5.5 months, respectively. At week 24, a greater percentage of abatacept patients achieved 50% improvement in ACR criteria (ACR50) compared with adalimumab patients (73% vs 45%, respectively) and estimate of difference (95% confidence interval [CI]), 28 (5, 48). In SE-positive patients, ACR50 estimate of difference (95% CI) was 32 (7, 55). During the open-label period, responses were sustained in the abatacept non-switch group and showed trends toward further improvement in the adalimumab-to-abatacept switch group at week 48, in both the overall and the SE-positive subpopulation. No new safety signals were identified.

Conclusions: In MTX-IR patients with early, autoantibody-positive RA, abatacept resulted in numerically higher efficacy responses versus adalimumab after 24 weeks, with more pronounced treatment differences in SE-positive patients. After 48 weeks, responses were sustained in patients who continued abatacept while those who switched to abatacept showed further clinical improvement, overall, and in SE-positive patients. This supports co-stimulation blockade as an effective treatment strategy for patients with early, autoantibody-positive RA, particularly among SE-positive patients.

Trial registration: NIH US National Library of Medicine, NCT02557100 . Registered on September 23, 2015.

Keywords: Abatacept; Adalimumab; Anti-citrullinated protein antibodies; Arthritis, rheumatoid; Biological therapy; Therapeutics.

Conflict of interest statement

WR has acted as a consultant for AbbVie, Bristol Myers Squibb, Genentech, Gilead, and Pfizer. JB was a paid consultant for Eli Lilly, is on the advisory board of GentiBio, and received grant/research support from Bristol Myers Squibb, Eli Lilly, Janssen, Novo Nordisk, and Pfizer. SLB has nothing to declare. MN, SG, MP, and NR are shareholders in and employees of Bristol Myers Squibb. VB received grant/research support (paid to institution) from Amgen, Bristol Myers Squibb, the Cedar Hill Foundation, and the NIH; consulting fees from Bristol Myers Squibb; and financial support from Amgen, Bristol Myers Squibb, Gilead, Pfizer, and UCB.

© 2021. The Author(s).

Figures

Fig. 1

Study design. Asterisk indicates patients could discontinue after the short-term treatment period and continue to follow-up. Dagger indicates patients receiving adalimumab switched to abatacept at week 28, following a 6-week washout period (4-week biologic-free window). CCP2, cyclic citrullinated peptide 2; MTX, methotrexate; MTX-IR, inadequate response to methotrexate; PO, orally; R, randomization; RA, rheumatoid arthritis; RF, rheumatoid factor; SC, subcutaneous

Fig. 2

Proportion of patients with ACR responses over time a overall and b in the SE-positive subpopulation (as-treated analysis). Missing values were imputed as non-responders. Error bars represent 95% CI. ACR, American College of Rheumatology; ACR20/50/70, 20%/50%/70% improvement in ACR criteria; CI, confidence interval; SE, shared epitope. b Adapted from Rigby W, et al. EULAR Congress 2020; 4 June 2020; poster THU0160 (with permission of the authors)

Fig. 3

ACR responses at weeks 24 and 48 (as-treated analysis) a overall and b in the SE-positive subpopulation. Bolded values denote significance. ACR, American College of Rheumatology; ACR20/50/70, 20%/50%/70% improvement in American College of Rheumatology criteria; CI, confidence interval; SE, shared epitope. Figure adapted from Rigby W, et al. EULAR Congress 2020; 4 June 2020; poster THU0160 (with permission of the authors)

Fig. 4

Patient flow per DAS28 (CRP) categories over time (as-treated analysis) a abatacept non-switch and b adalimumab-to-abatacept switch. n = 40 for both groups. CRP, C-reactive protein; DAS28, Disease Activity Score in 28 joints. Figure adapted from Rigby W, et al. EULAR Congress 2020; 4 June 2020; poster THU0160 (with permission of the authors)