The immune response mediator genes polymorphic variants as predictors of the etanercept efficacy in juvenile idiopathic arthritis

Abstract

Objective-The aim of the study was to investigate the relationship of the alleles and genotypes of the immune response mediator genes polymorphic loci (rs1800629, rs909253, rs16944, rs6822844, rs2104286, rs1800795, rs1800872, rs3087243, rs755622 rs28362491, rs2240336, rs2476601) with the etanercept efficacy in juvenile idiopathic arthritis (JIA) patients. Material and Methods-The study included 39 JIA patients from Bashkortostan, Russia. Achieving the American College of Rheumatology Pediatric 70 (ACR Pedi 70) response was regarded as the presence of the response to etanercept (otherwise-as the absence), while achieving clinical remission on medication-as the sufficient response (otherwise-as the insufficient). Genotyping was performed using real-time polymerase chain reaction method. Results-The predictors of an increased risk of the non-response to etanercept were the IL1B rs16944*TT (p cor =0.023), NFKB1 rs28362491*II (p cor =0.042) genotypes, and of the increased risk of the insufficient response to etanercept-the IL2RA rs2104286*AA (p cor =0.010), NFKB1 rs28362491*II (p cor =0.026) genotypes. The markers of the decreased risk of the non-response to etanercept were the IL1B rs16944*C (p cor =0.046), NFKB1 rs28362491*D (p cor =0.029) alleles, and of the decreased risk of the insufficient response to etanercept-the IL2RA rs2104286*AG genotype (p cor =0.049), IL2RA rs2104286*G allele (p cor =0.005). Conclusion-In this study the association of the alleles and genotypes of the IL1B rs16944, IL2RA rs2104286, NFKB1 rs28362491 polymorphic loci with the etanercept efficacy in JIA patients was established.

The relationship of the immune response mediator genes’ polymorphic variants with the methotrexate efficacy in juvenile idiopathic arthritis

“…At the same time, an increased proinflammatory cytokine production in the NFKB1 rs28362491*D allele carriers may suggests a good effect of an anticytokine therapy. This hypothesis is confirmed by the data of Nazarova et al (2018), according to which the NFKB1 rs28362491*D allele reduces the risk of nonachieving the ACR Pedi 70 response to etanercept in JIA patients [33]. At the same time, in the present work it was shown that the NFKB1 rs28362491*DD genotype marks an increased susceptibility to the nonresponse to methotrexate in JIA (in girls).…”

“…In addition to the experimental features, these differences can also be associated with the samples characteristics, in particular with the sex ratio, since in the present work it has been shown that the IL1B rs16944*T allele increases the risk of the insufficient response to methotrexate only in boys with JIA. It should also be noted that the relationship of the IL1B rs16944*TT genotype with the nonachieving of the ACR Pedi 70 response to etanercept in JIA was previously established, which is important to consider when selecting the second-line therapy for these patients [33].…”

Genetic Variants and Therapeutic Response to Anti–TNF-α Agents in Juvenile Idiopathic Arthritis

“…Our meta-analysis of the most replicated polymorphism of TNF-α promoter, genotyped in an overall population of 414 JIA, showed that the presence of rare A allele at position −308 was definitely associated with treatment outcome postulating a dominant model and on average doubling the risk of nonresponse to TNF-α drugs. However, at an individual level, only one study reached the statistical significance unambiguously, 10 whereas 3 studies showed only a trend 9,11,12 and the last 2 did not find any association 13 or even an inverse association 8 . These inconsistencies are coherent with the characteristics of each study: low precision in the estimates can be explained by the low number of patients included in the study, the strength of association depends also on the proportion of responder/nonresponder patients, and this ratio can be affected by the study design (prospective vs retrospective), as potential bias could be introduced through the selection process.…”

“…1). [6][7][8][9][10][11][12][13] Comparing the current search with the previous review, 4 5 new articles were identified that investigated the potential effect of genetic variants on response to TNF-α blocking agents in JIA.…”

“…However, at an individual level, only one study reached the statistical significance unambiguously, 10 whereas 3 studies showed only a trend 9,11,12 and the last 2 did not find any association 13 or even an inverse association. 8 These inconsistencies are coherent with the characteristics of each study: low precision in the estimates can be explained by the low number of patients included in the study, the strength of association depends also on the proportion of responder/nonresponder patients, and this ratio can be affected by the study design (prospective vs retrospective), as potential bias could be introduced through the selection process. Of note, in Bašić et al, the association analysis could be altered by the singular distribution of the different genotypes being GG heavily less represented with respect to the frequencies detected in the other studies (30% vs 70%-80%, respectively).…”