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TNF-α is a transmembrane protein which requires cleavage by ADAM17 in order to act systemically. The activation of ADAM17 to generate soluble TNF-α results in an increased inflammatory activity. We hypothesized that variants spanning the ADAM17 gene contribute towards the observed variation in patient response defined by the number of changes in TNF-α inhibitors. Patients and Methods: Seven single-nucleotide polymorphisms (SNPs) of ADAM17 in 63 patients with rheumatoid arthritis who received TNF-α inhibitors were analyzed: rs57467365, rs62117540, rs117645314, rs6432013, rs532704607, rs117179141, and rs12692386. Univariate and multivariate regression analysis were employed to investigate the independent predictable factors for changes in TNF-α inhibitors. Results: ADAM17 rs117645314 and rs117179141 showed significant association with the number of changes in TNF-α inhibitors. Patients with GA in rs117645314 and AT in rs117179141 had significantly higher chance of two or more changes of TNF-α inhibitors than those with wild homozygous alleles. Multivariate analysis showed that rs117179141 explained 5.7% of the 23.8% variability in TNF-α inhibitor response. Conclusion: This study showed that the number of changes in TNF-α inhibitor is associated with ADAM17 SNPs.

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Aim: This study aimed to examine the effects of polymorphisms in nuclear factor of activated T cells C2 (NFATC2), a TNF-α transcription factor, on remission in RA patients receiving TNF-α inhibitors. Methods: This prospective observational study was performed in two centers. Nine single nucleotide polymorphisms (SNPs) were investigated, and haplotype analyses were performed. Logistic regression analyses were used to investigate the association between genetic polymorphisms and remission of RA. Results: This study included 88 patients, among whom 26 had remission of RA. We identified a haplotype, H2 (CCT), which carried 3 NFATC2 SNPs (rs1052649, rs1569736, and rs763944) and showed a significant relationship with remission. After adjusting for covariates, H2 carriers exhibited approximately 2.86-fold higher rates of remission than others (p=0.049). In subgroup analysis with patients with the TT genotype of rs1799964 of TNF-α, patients with the CC genotype in NFATC2 rs763944 showed an approximately 4.1-fold lower remission rate than T-allele carriers (p = 0.028), after adjusting for related covariates. In another subgroup analysis among patients with the GG genotype of TNF-α rs361525, patients with the CC genotype in NFATC2 rs763944 showed an approximately 3.2-fold lower remission rate than T-allele carriers (p = 0.04) after adjusting for covariates. Conclusion: This study suggested an association between NFATC2 polymorphisms and remission in RA patients receiving TNF-α inhibitors.

Background: Despite the improvement from the introduction of tumor necrosis factor inhibitors (TNFi) in the rheumatoid arthritis (RA), TNFi therapy fails for more than 30% or results in a partial response. Thus, we aimed to explore treatment marker by examining the association of single nucleotide polymorphisms (SNPs) with response to TNFi therapy.Method: Genes associated with RA or RA treatment were reviewed and fourteen SNPs with minor allele frequency ≥ 20% in the East Asian populations were selected and analyzed. Data were collected from 105 RA patients. Our primary endpoint was the disease activity score using 28-joint count after six months of treatment (DAS28-6month). The secondary outcomes were the subcomponents of DAS28.Results: A total of 88 patients were included in the final analyses. Among the 14 SNPs analyzed, one SNP showed statistical significance in DAS28-6month: patients with the GG allele of RETN rs1862513 had a 4.7 times higher chance of low disease activity at 6-months than GC or CC-carriers (p = 0.033), as indicated by multivariable logistic regression analysis. Rs3397 was marginally significant in univariate analysis (p=0.059), but was significant in the multivariable model (p=0.041). The final model explained 24.5% (Nagelkerke R2) of the variance in DAS28-6month.Conclusion: Our results demonstrated that, among the genes related to RA, SNPs in RETN and TNFRSF1B were associated with the response of TNFi treatment.