Presence of anti-nuclear antibodies is a risk factor for the appearance of anti-drug antibodies during infliximab or adalimumab therapy in patients with rheumatoid arthritis

Ayano Mori,Miho Shibata,Soshi Takahashi,Goh Tsuji,Toshiharu Saito,Shunichi Kumagai,Miho Takahashi,Saori Hatachi,Masataka Kuwana

doi:10.1371/journal.pone.0243729

Abstract

This study aimed to directly analyze the potential relationship of anti-nuclear antibodies (ANA) before and after the administration of TNF-α inhibitors (TNFi) with the appearance of anti-drug antibodies (ADrA) in patients with rheumatoid arthritis (RA). A total of 121 cases, viz., 38, 53, and 30 cases treated with infliximab (IFX), adalimumab (ADA), and etanercept (ETN), respectively, were enrolled. The ANA titers were measured using indirect immunefluorescence assay (IF-ANA) and multiplex flow immunoassay (ANA Screen) before and serially during the therapy. The anti-IFX antibodies (HACA) and anti-ADA antibodies (AAA) were measured with a radioimmunoassay. ADrA turned positive in 14 (36.8%) among 38 patients treated with IFX, and 16 (30.2%) among 53 treated with ADA. All of them were positive for IF-ANA before TNFi administration, while ADrA never appeared in any of the 15 patients negative for IF-ANA (< 40). IF-ANA of high titers (≥ 320 and ≥ 640) before IFX treatment showed a significant association with the appearance of HACA 52 weeks after IFX (P = 0.040 and 0.017, respectively), whereas AAA appearance was not related to IF-ANA titers before treatment. Moreover, IF-ANA of high titers before IFX treatment was significantly associated with inefficacy and discontinuation of the treatment. The positivity of anti-SS-A antibodies before therapy might be a risk factor for ADrA appearance in patients treated with IFX or ADA. The percentage of patients whose IF-ANA titers increased was significantly higher with IFX than with ADA or ETN treatments (P = 0.026 and 0.022, respectively). High ANA titers and positive ANA Screen after IFX therapy showed a significant association with HACA appearance and possibly led to treatment failure. Among the three TNFi, only IFX showed a close relationship with IF-ANA and ADrA appearance, suggesting the interaction of immunogenicity with autoimmunity as well as the advantage of ANA measurement before TNFi therapy.

Highlights

TNF-α inhibitors (TNFi) such as infliximab (IFX), adalimumab (ADA), etanercept (ETN), golimumab, and certolizumab pegol are dramatically effective for the treatment of rheumatoid arthritis (RA)
This article was an observational study of anti-nuclear antibodies (ANA) change in RA patients treated with biologics, and was incorporated with a study of anti-drug antibodies (ADrA) in part prospectively to clarify the direct relationship of ANA to ADrA appearance in 121 RA patients treated with TNFi
Our findings suggest that the presence of immunofluorescent ANA (IF-ANA) before TNFi therapy is a risk factor for ADrA appearance as well as for treatment inefficacy

Summary

Introduction

TNF-α inhibitors (TNFi) such as infliximab (IFX), adalimumab (ADA), etanercept (ETN), golimumab, and certolizumab pegol are dramatically effective for the treatment of rheumatoid arthritis (RA). A certain proportion of RA patients do not respond well to TNFi from the beginning (primary failure) or lose treatment efficacy following an initially good response (secondary failure) [1]. These biologics have been shown to have immunogenicity and often generate anti-drug antibodies (ADrA) against TNFi such as anti-IFX antibody (HACA: human anti-chimeric antibodies) and anti-ADA antibodies (AAA) [2]. Autoantibodies such as anti-nuclear antibodies (ANA) and anti-double-stranded (ds) DNA antibodies (dsDNA Ab) can be newly induced (seroconversion) or increase their titers during anti-TNF therapy [9,10]

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