Influence of the FCGR2A rs1801274 and FCGR3A rs396991 Polymorphisms on Response to Abatacept in Patients with Rheumatoid Arthritis.

Noelia Márquez Pete,Juan Enrique Martínez De La Plata,Cristina Pérez Ramírez,María Del Mar Maldonado Montoro,Fernando Martínez Martínez,Abdelali Daddaoua,Alberto Jiménez Morales

doi:10.3390/jpm11060573

Noelia Márquez Pete, Juan Enrique Martínez De La Plata + Show 5 more

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https://doi.org/10.3390/jpm11060573

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Abstract

Abatacept (ABA) is an immunosuppressant indicated for treatment of rheumatoid arthritis (RA). Effectiveness might be influenced by clinical RA variants and single-nucleotide polymorphisms (SNPs) in genes encoding protein FCGR2A (His131Arg) and FCGR3A (Phe158Val) involved in pharmacokinetics of ABA. An observational cohort study was conducted in 120 RA Caucasian patients treated with ABA for 6 and 12 months. Patients with the FCGR2A rs1801274-AA genotype (FCGR2A-p.131His) showed a better EULAR response (OR = 2.43; 95% CI = 1.01–5.92) at 12 months and low disease activity (LDA) at 6 months (OR = 3.16; 95% CI = 1.19–8.66) and 12 months (OR = 6.62; 95% CI = 1.25–46.89) of treatment with ABA. A tendency was observed towards an association between the FCGR3A rs396991-A allele (FCGR3A-p.158Phe) and better therapeutic response to ABA after 12 months of treatment (p = 0.078). Moreover, we found a significant association between the low-affinity FCGR2A/FCGR3A haplotypes variable and LDA after 12 months of ABA treatment (OR = 1.59; 95% CI = 1.01–2.58). The clinical variables associated with better response to ABA were lower age at starting ABA (OR = 1.06; 95% CI = 1.02–1.11) and greater duration of ABA treatment (OR = 1.02; 95% CI = 1.01–1.04), lower duration of previous biological therapies (OR = 0.99; 95% CI = 0.98–0.99), non-administration of concomitant disease-modifying antirheumatic drugs (DMARDs) (OR = 24.53; 95% CI = 3.46–523.80), non-use of concomitant glucocorticoids (OR = 0.12; 95% CI = 0.02–0.47), monotherapy (OR = 19.22; 95% CI = 2.05–343.00), lower initial patient’s visual analogue scale (PVAS) value (OR = 0.95; 95% CI = 0.92–0.97), and lower baseline ESR (OR = 0.92; 95% CI = 0.87–0.97). This study showed that high-affinity FCGR2A-p.131His variant, low-affinity FCGR3A-p.158Phe variant, and combined use of FCGR2A/FCGR3A genetic variations could affect ABA effectiveness. Further studies will be required to confirm these results.

Highlights

Abatacept (ABA) is an immunosuppressant indicated for treatment of rheumatoid arthritis (RA), psoriatic arthritis, and juvenile idiopathic arthritis1
The clinical variables that showed an association with satisfactory EULAR response were lower baseline levels of Disease Activity Score in 28 joints (DAS28) (OR = 0.42; 95% confidence interval (95% CI) = 0.90–1.89), number of painful joints (NPJ) (OR = 0.84; 95% CI = 0.75–0.92), number of swollen joints (NSJ) (OR = 0.79; 95% CI = 0.67–0.91), patient visual analogue scale (PVAS) (OR = 0.94; 95% CI = 0.92–0.97), erythrocyte sedimentation rate (ESR) (OR = 0.97; 95% CI = 0.94–0.99), and Health Assessment Questionnaire (HAQ) (OR = 0.32; 95% CI = 0.16–0.58) (Table S10)
Our results show that the FCGR2A rs1801274 polymorphism is associated with the clinical effectiveness of ABA

Summary

Introduction

Abatacept (ABA) is an immunosuppressant indicated for treatment of rheumatoid arthritis (RA), psoriatic arthritis, and juvenile idiopathic arthritis. ABA comprises a fusion of the extracellular domain of human cytotoxic T-lymphocyte-associated protein 4 (CTLA4). With the fragment crystallizable (Fc) region of human immunoglobulin G1 (IgG1) [1]. The mechanism of action of ABA is based on interaction of CTLA4 with the CD80/CD86 complex, preventing the latter from binding with the CD28 membrane receptor of T lymphocytes [2]. The co-stimulatory signal for T cell activation is blocked [2]. The function of the Fc region of IgG is to improve the pharmacokinetics of ABA, increasing its stability and prolonging the half-life of the drug [3,4].

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