Impact of the HLA-DRB1 shared epitope on responses to treatment with tofacitinib or abatacept in patients with rheumatoid arthritis

Wataru Hirose,Kazuyoshi Kubo,Ikuko Masuda,Yuji Akiyama,Kimihiro Suzuki,Motohide Kaneko,Yusuke Okada,Ko Takamatsu,Yayoi Hashiba,Tsuneo Kondo,Akiko Shibata,Mitsuyo Matsumoto,Mikio Kawagoe ,S Ando ,Kenji Itoh,Kazutoshi Aoki,Toshihiko Hidaka,Hayato Nagasawa,Masayoshi Harigai,Koichi Amano,Masahiro Nakashima,Yukiko Komano,Hiroyuki Takei ,Toshihiro Nanki

doi:10.1186/s13075-021-02612-w

Abstract

ObjectivesThe aim of this study was to compare the clinical effectiveness of tofacitinib and abatacept and clarify the impact of the HLA-DRB1 shared epitope (SE) on responses to these treatments in patients with rheumatoid arthritis (RA).MethodsAfter adjustments by propensity score matching, 70 out of 161 patients receiving tofacitinib and 70 out of 131 receiving abatacept were extracted. The clinical effectiveness of both drugs over 24 weeks and the impact of the copy numbers of SE on effectiveness outcomes were investigated.ResultsThe percentage of patients in remission in the 28-joint count disease activity score using the erythrocyte sedimentation rate (DAS28-ESR) did not significantly differ between patients receiving tofacitinib and abatacept at week 24 (32% vs 37%, p = 0.359). The mean change at week 4 in DAS28-ESR from baseline was significantly greater in patients receiving tofacitinib than in those receiving abatacept (− 1.516 vs − 0.827, p = 0.0003). The percentage of patients in remission at week 4 was 30% with tofacitinib and 15% with abatacept (p = 0.016). When patients were stratified by the copy numbers of SE alleles, differences in these numbers did not affect DAS28-ESR scores of patients receiving tofacitinib. However, among patients receiving abatacept, DAS28-ESR scores were significantly lower in patients carrying 2 copies of SE alleles than in those carrying 0 copies at each time point throughout the 24-week period. Furthermore, the percentage of patients in remission with DAS28-ESR at week 24 was not affected by the copy numbers of SE alleles in patients receiving tofacitinib (p = 0.947), whereas it significantly increased as the copy numbers became higher in patients receiving abatacept (p = 0.00309). Multivariable logistic regression analyses showed a correlation between the presence of SE and DAS28-ESR remission in patients receiving abatacept (OR = 25.881, 95% CI = 3.140–213.351, p = 0.0025), but not in those receiving tofacitinib (OR = 1.473, 95% CI = 0.291–7.446, p = 0.639).ConclusionsAlthough the clinical effectiveness of tofacitinib and abatacept was similar at week 24, tofacitinib was superior to abatacept for changes from baseline in DAS28-ESR and the achievement of remission at week 4. SE positivity was associated with the achievement of DAS28-ESR remission by week 24 in patients receiving abatacept, but not in those receiving tofacitinib.

Highlights

Rheumatoid arthritis (RA) is a complex autoimmune disease that develops from the combined effects of genetic and environmental factors
Conclusions: the clinical effectiveness of tofacitinib and abatacept was similar at week 24, tofacitinib was superior to abatacept for changes from baseline in DAS28-Erythrocyte sedimentation rate (ESR) and the achievement of remission at week 4
shared epitope (SE) positivity was associated with the achievement of DAS28-ESR remission by week 24 in patients receiving abatacept, but not in those receiving tofacitinib

Summary

Introduction

Rheumatoid arthritis (RA) is a complex autoimmune disease that develops from the combined effects of genetic and environmental factors. Genetic factors make a significant contribution to the development of RA in population, accounting for approximately 60% of population susceptibility to the disease [1]. The SE hypothesis was initially proposed to explain genetic susceptibility to RA, subsequent investigations suggested that the primary role of SE may be in the development of more severe disease manifestations [3, 4]. SE may modulate the severity of RA in affected patients [3, 4, 6] Autoantibodies, such as the anti-citrullinated peptide antibody (ACPA), are more likely to occur in patients with RA who are positive for SE [7,8,9]. A recent study revealed that the presence of Val and Leu at HLA-DRB1 position 11, other than SE, were associated with more radiographic progression [11]. The role of SE alleles in therapeutic responses remains unclear

Objectives

Methods

Results

Discussion

Conclusion