Elsevier

Joint Bone Spine

Volume 79, Issue 6, December 2012, Pages 591-596
Joint Bone Spine

Original article
Effects of polymorphisms in TRAILR1 and TNFR1A on the response to anti-TNF therapies in patients with rheumatoid and psoriatic arthritis

https://doi.org/10.1016/j.jbspin.2012.02.003Get rights and content

Abstract

Objectives

As the role of polymorphisms in death receptors (DRs) such as Tumor Necrosis Factor–related Apoptosis-inducing Ligand Receptor 1 (TRAIL-R1) and Tumor Necrosis Factor Receptor 1A (TNF-R1A) on the response to anti-TNF therapy remains unknown, we evaluated the association between TRAILR1 and TNFR1A gene polymorphisms (rs20575/C626G and rs767455/G36A) and the pharmacogenetics of patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) treated with TNFα blockers.

Methods

One hundred and forty-five patients (90 RA and 55 PsA) treated with anti-TNFα therapy (RA: 75 infliximab, 8 etanercept, 7 adalimumab. PsA: 27 infliximab, 19 etanercept, 9 adalimumab) were genotyped for TRAILR1 and TNFR1A polymorphisms by allelic discrimination. The response to anti-TNFα was assessed by EULAR criteria.

Results

In RA, the TRAILR1 CC genotype was associated with a better response after 3 and 6 months of anti-TNFα treatment (CC: 91.7% vs. CG/GG: 62.2%; P = 0.019, and CC: 82.6% vs. CG/GG: 56.1%; P = 0.019, respectively). Similar results were observed in only infliximab-treated RA patients. With respect to the TNFR1A polymorphism, there was an association between the AA genotype and a poorer response at 3 months in RA patients (AA: 39.3% vs. AG/GG: 19.0%; P = 0.04).

In PsA, TRAILR1 CC genotype was only associated with EULAR response to infliximab at 6 months (CC: 71.4% vs CG/GG: 50%P = 0.048). In contrast to RA, the TNFR1 polymorphism in PsA was associated with a better response at 3 months (AA 88% vs AG/GG 58.9%; P = 0.04).

Conclusions

This study provides the first evidence that a polymorphism in TRAILR1 influences the response to anti-TNFα therapy in RA and also suggests that TNFR1A polymorphism may have opposing effects on the response to anti-TNFα in RA and PsA.

Introduction

Tumor necrosis factor alpha (TNFα) is a pro-inflammatory cytokine which acts as the ligand for TNF-R1 and TNF-R2 and plays a key role in the pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) [1], [2]. Although the introduction of anti-TNFα therapy has resulted in spectacular improvements in the management of these diseases, a substantial proportion of patients do not adequately benefit from these therapies or suffer adverse events [2].

Pharmacogenomic biomarkers could improve the efficacy of biological therapies by correct patient selection. Various polymorphic genes have been investigated in relation to the response to anti-TNFα therapies in RA, of which the most-studied are those related to TNFα (TNFA, TNF promoter, TNFA haplotypes and TNFs receptors) [3], [4], [5], and the polymorphic genes of cell-receptors for the Fc part of IgG, FCGRIIIA and FCGRIIA [6], [7]. The results of these studies are contradictory and a useful genetic marker has still not been identified.

Given the importance of death receptors associated with TNFα receptors in maintaining homeostasis of the immune system, due to their implication in chronic inflammatory diseases and susceptibility to cancer [8], [9], [10], [11], [12], we hypothesized that some of the studied polymorphisms in genes coding for TNF-Rs, such as rs20575 (C626G) in the Tumor Necrosis Factor–related Apoptosis-inducing Ligand Receptor 1 (TRAILR1) and rs767455 (G36A) in the Tumor Necrosis Factor Receptor 1A (TNFR1A) gene, might influence the response to anti-TNFα therapies. Therefore, we analyzed the effects of TRAILR1 and TNFR1A polymorphisms on the response to anti-TNFα therapies in RA and PsA patients.

Section snippets

Patients

Study patients were recruited from the out-patient clinics of Rheumatology Departments from two hospitals (HC and HUSMR) located in different geographical regions of Spain (Table 1). All patients were Caucasians and fulfilled the corresponding classification criteria for RA and PsA [13], [14] and none had or had had neoplastic disease. The study was approved by the respective hospital ethics committees and written informed consent was obtained from all participants.

C-reactive protein (CRP,

Demographic and clinical features

We included 145 patients (90 RA and 55 PsA) starting anti-TNFα therapy for the first time. RA patients were aged (mean ± SD) 61.3 (13.7) years, 83.3% were female, disease duration was 16.1 (9.9) years, 86.7% were RF positive and 95.6% had taken DMARDs (77.8% methotrexate, 17.8% leflunomide). Seventy-five out of 90 RA patients were treated with infliximab, 8 with etanercept and 7 with adalimumab (Table 2). Infusions of 3 mg/kg of infliximab were administered at weeks 0, 2 and 6 and then each 8

Discussion

We analyzed the effects of polymorphisms in the TRAILR1 and TNFRA1 genes on the EULAR response to infliximab, adalimumab and etanercept in 90 RA patients and 55 PsA patients with the aim of searching for biomarkers to optimize the use of anti-TNFα therapies.

EULAR responses to anti-TNFα in RA patients were similar to those of other series with established RA, with low rates of good EULAR response and clinical remission [6]. However, in PsA patients, rates of good EULAR response and remission

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

Acknowledgements

We are grateful to Javier Corral and Miguel Pérez-Guillermo for critical review of the manuscript, to all staff at the Day Hospital and Rheumatology Department of both hospitals for their help in carrying out the study, and to Diego Arcas and David Buss for reviewing the English version of this manuscript.

Funding: this work was supported by two grants (references: CM/09/08, CM/06/08) from Fundación Cajamurcia, Murcia Region, Spain. JDC is supported by FIS PI080206 from Ministry of Health, and

References (33)

  • J.D. Cañete et al.

    Influence of variants of Fc{gamma}receptors IIA and IIIA on the ACR and EULAR responses to anti-TNF{alpha} therapy in rheumatoid arthritis

    Ann Rheum Dis

    (2009)
  • A. Kastbom et al.

    Fcgamma receptor type IIIA genotype and response to tumor necrosis factor alpha-blocking agents in patients with rheumatoid arthritis

    Arthritis Rheum

    (2007)
  • P. Dieudé et al.

    European Consortium on Rheumatoid Arthritis Families: a TNFR1 genotype with a protective role in familial rheumatoid arthritis

    Arthritis Rheum

    (2004)
  • K.A. Waschke et al.

    Tumor necrosis factor receptor gene polymorphisms in Crohn's disease: association with clinical phenotypes

    Am J Gastroenterol

    (2005)
  • A. Hazra et al.

    Death receptor 4 and bladder cancer risk

    Cancer Res

    (2003)
  • B. Frank et al.

    Death receptor 4 variants and colorectal cancer risk

    Cancer Epidemiol Biomarkers Prev

    (2006)
  • Cited by (60)

    • Unraveling the complexities of psoriatic arthritis by the use of -Omics and their relevance for clinical care

      2021, Autoimmunity Reviews
      Citation Excerpt :

      The high-affinity FCGR2A-131H allele in the Fc gamma receptor has been associated with increased EULAR response rate at 6 months in PsA patients treated with etanercept, a TNFa inhibitor [43]. In a comparative study evaluating RA and PsA patients, Tumor Necrosis Factor–related Apoptosis-inducing Ligand Receptor 1 (TRAIL-R1) CC genotype was associated with better response to TNF inhibitors at 3- and 6-months for RA patients and better response to infliximab at 6 months in PsA patients [44]. In the same study, the presence of Tumor Necrosis Factor Receptor 1A (TNFR1A) AA genotype, was combined with better EULAR response to TNFa inhibitors at three months for PsA.

    • Unmet needs in psoriatic arthritis

      2021, Best Practice and Research: Clinical Rheumatology
    • Clinical and molecular significance of genetic loci associated with psoriatic arthritis

      2021, Best Practice and Research: Clinical Rheumatology
      Citation Excerpt :

      The TNF receptor 1 A (TNFR1A) variant rs767455/G36A in PsA patients treated with infliximab has been associated with better EULAR response at 3 months [29]. Similarly, infliximab was significantly associated with response in PsA patients with TNFRSF10A (rs20575) and TNFRSF1A (rs767455) variants [29,30]. Furthermore, the TNF-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) rs20575 variant and the presence of the high affinity FCGR2A-131H allele was associated with EULAR response to infliximab and etanercept, respectively [31,32].

    View all citing articles on Scopus
    1

    The first two authors contributed equally to the study (joint first authors).

    View full text