Original articleEffects of polymorphisms in TRAILR1 and TNFR1A on the response to anti-TNF therapies in patients with rheumatoid and psoriatic arthritis
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.
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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
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The first two authors contributed equally to the study (joint first authors).