Steroid hormone-related polymorphisms associate with the development of bone erosions in rheumatoid arthritis and help to predict disease progression: Results from the REPAIR consortium.

Here, we assessed whether 41 SNPs within steroid hormone genes associated with erosive disease. The most relevant finding was the rheumatoid factor (RF)-specific effect of the CYP1B1, CYP2C9, ESR2, FcγR3A, and SHBG SNPs to modulate the risk of bone erosions (P = 0.004, 0.0007, 0.0002, 0.013 and 0.015) that was confirmed through meta-analysis of our data with those from the DREAM registry (P = 0.000081, 0.0022, 0.00074, 0.0067 and 0.0087, respectively). Mechanistically, we also found a gender-specific correlation of the CYP2C9rs1799853T/T genotype with serum vitamin D3 levels (P = 0.00085) and a modest effect on IL1ß levels after stimulation of PBMCs or blood with LPS and PHA (P = 0.0057 and P = 0.0058). An overall haplotype analysis also showed an association of 3 ESR1 haplotypes with a reduced risk of erosive arthritis (P = 0.009, P = 0.002, and P = 0.002). Furthermore, we observed that the ESR2, ESR1 and FcγR3A SNPs influenced the immune response after stimulation of PBMCs or macrophages with LPS or Pam3Cys (P = 0.002, 0.0008, 0.0011 and 1.97•10-7). Finally, we found that a model built with steroid hormone-related SNPs significantly improved the prediction of erosive disease in seropositive patients (PRF+ = 2.46•10-8) whereas no prediction was detected in seronegative patients (PRF- = 0.36). Although the predictive ability of the model was substantially lower in the replication population (PRF+ = 0.014), we could confirm that CYP1B1 and CYP2C9 SNPs help to predict erosive disease in seropositive patients. These results are the first to suggest a RF-specific association of steroid hormone-related polymorphisms with erosive disease.

Correction: Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients.

The original version of this Article contained an error in the spelling of the author Ana Rodríguez-Ramos, which was incorrectly given as Ana Rodríguez Ramos. This has now been corrected in both the PDF and HTML versions of the Article.

Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients.

The aim of this case-control study was to evaluate whether 47 single-nucleotide polymorphisms (SNPs) in steroid hormone-related genes are associated with the risk of RA and anti-TNF drug response. We conducted a case-control study in 3 European populations including 2936 RA patients and 2197 healthy controls. Of those, a total of 1985 RA patients were treated with anti-TNF blockers. The association of potentially interesting markers in the discovery population was validated through meta-analysis with data from DREAM and DANBIO registries. Although none of the selected variants had a relevant role in modulating RA risk, the meta-analysis of the linear regression data with those from the DREAM and DANBIO registries showed a significant correlation of the CYP3A4rs11773597 and CYP2C9rs1799853 variants with changes in DAS28 after the administration of anti-TNF drugs (P = 0.00074 and P = 0.006, respectively). An overall haplotype analysis also showed that the ESR2GGG haplotype significantly associated with a reduced chance of having poor response to anti-TNF drugs (P = 0.0009). Finally, a ROC curve analysis confirmed that a model built with eight steroid hormone-related variants significantly improved the ability to predict drug response compared with the reference model including demographic and clinical variables (AUC = 0.633 vs. AUC = 0.556; PLR_test = 1.52 × 10-6). These data together with those reporting that the CYP3A4 and ESR2 SNPs correlate with the expression of TRIM4 and ESR2 mRNAs in PBMCs (ranging from P = 1.98 × 10-6 to P = 2.0 × 10-35), and that the CYP2C9rs1799853 SNP modulates the efficiency of multiple drugs, suggest that steroid hormone-related genes may have a role in determining the response to anti-TNF drugs.KEY POINTS• Polymorphisms within the CYP3A4 and CYP2C9 loci correlate with changes in DAS28 after treatment with anti-TNF drugs.• A haplotype including eQTL SNPs within the ESR2 gene associates with better response to anti-TNF drugs.• A genetic model built with eight steroid hormone-related variants significantly improved the ability to predict drug response.

Eficacia a 2 años de tocilizumab en pacientes con artritis reumatoide activa en la práctica clínica habitual / Two-year efficacy of tocilizumab in patients with active rheumatoid arthritis in clinical practice

Objetivos. Evaluar la eficacia del tratamiento con tocilizumab (TCZ) en pacientes con artritis reumatoide (AR) en práctica clínica, las tasas de supervivencia del fármaco y variables clínicas predictoras de respuesta. Métodos. Es un estudio descriptivo, prospectivo, longitudinal y abierto en el que se incluyó a pacientes en condiciones de práctica clínica que recibieron TCZ (8mg/kg/cada 4 semanas). Las respuestas clínicas se midieron utilizando los criterios de respuesta de la European League Against Rheumatism (EULAR), las tasas de actividad baja y remisión según el Disease activity score-28 (DAS28-VSG) y Clinical Disease Activity Index (CDAI). Resultados. La tasa de respuesta EULAR fue del 86,63%, con una tasa de remisión DAS28 del 53,7% a los 6 meses de tratamiento. El 52,9% de los pacientes presentaron baja actividad de la enfermedad a los 24 meses según CDAI y 47,1% según DAS28. No hubo diferencias significativas en cuanto a respuesta EULAR, baja actividad y remisión DAS28 entre pacientes en tratamiento con TCZ en monoterapia y terapia combinada, ni entre pacientes positivos y negativos para factor reumatoide (FR) y/o anticuerpo antipéptido cíclico citrulinado (anti-PCC). Los pacientes que recibieron TCZ de primera línea presentaron mejores tasas de remisión y baja actividad a los 6 meses. La tasa de supervivencia fue del 61% a los 24 meses, siendo una de las causas de discontinuación más frecuente los efectos adversos. Conclusión. El TCZ es efectivo en pacientes con AR, tiene eficacia similar cuando se utiliza en monoterapia o en combinación con fármacos antirreumáticos modificadores de la enfermedad (FAME) sintéticos y presenta altas tasas de supervivencia (AU)

Objectives. To evaluate the efficacy of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) in clinical practice, retention rates of the drug and predictors of response. Methods. We performed a descriptive, prospective, longitudinal, open-label study in patients receiving TCZ (8mg/kg/4 weeks) in a clinical practice setting. The clinical responses were evaluated using the European League Against Rheumatism (EULAR) response criteria, and the low activity and remission rates according to the Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) and the Clinical Disease Activity Index (CDAI). Results. The EULAR response rate was 86.63% and the DAS28 remission rate was 53.7% after 6 months of treatment; rates of low disease activity were 52.9% on CDAI and 47.1% on DAS28 at month 24. There were no statistically significant differences in EULAR response, rates of low activity and remission on DAS28 between patients receiving TCZ alone and those receiving TCZ in combination therapy, or between patients positive or negative for rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide (anti-CCP) antibodies. The naïve biological therapy patients showed better remission and low activity rates after 6 months of treatment. The retention rate was 61% at month 24. Adverse events were among the most frequent causes of discontinuation. Conclusions. Tocilizumab is effective in RA, has a similar efficacy when used alone or in combination with synthetic disease-modifying antirheumatic drugs (DMARDs) and shows high retention rates (AU)

Two-year efficacy of tocilizumab in patients with active rheumatoid arthritis in clinical practice. / Eficacia a 2 años de tocilizumab en pacientes con artritis reumatoide activa en la práctica clínica habitual.

OBJECTIVES: To evaluate the efficacy of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) in clinical practice, retention rates of the drug and predictors of response. METHODS: We performed a descriptive, prospective, longitudinal, open-label study in patients receiving TCZ (8mg/kg/4 weeks) in a clinical practice setting. The clinical responses were evaluated using the European League Against Rheumatism (EULAR) response criteria, and the low activity and remission rates according to the Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) and the Clinical Disease Activity Index (CDAI). RESULTS: The EULAR response rate was 86.63% and the DAS28 remission rate was 53.7% after 6 months of treatment; rates of low disease activity were 52.9% on CDAI and 47.1% on DAS28 at month 24. There were no statistically significant differences in EULAR response, rates of low activity and remission on DAS28 between patients receiving TCZ alone and those receiving TCZ in combination therapy, or between patients positive or negative for rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide (anti-CCP) antibodies. The naïve biological therapy patients showed better remission and low activity rates after 6 months of treatment. The retention rate was 61% at month 24. Adverse events were among the most frequent causes of discontinuation. CONCLUSIONS: Tocilizumab is effective in RA, has a similar efficacy when used alone or in combination with synthetic disease-modifying antirheumatic drugs (DMARDs) and shows high retention rates.

Genetic and clinical biomarkers of tocilizumab response in patients with rheumatoid arthritis.

The aim of this study was to investigate the influence of clinical and genetic factors on response to tocilizumab (TCZ) response, remission, low disease activity (LDA) and DAS28 improvement. A retrospective cohort study in 79 RA patients treated with TCZ during 6/18 months of therapy was conducted. CD69(rs11052877), GALNT18(rs4910008), CLEC2D(rs1560011), KCNMB1(rs703505), ENOX1(rs9594987), rs10108210, and rs703297 gene polymorphisms, identified in a recent GWAS as putative predictors of TCZ response, were analysed. Variables independently associated to satisfactory EULAR response at 6 months were GALNT18-CC genotype (ORCC/T-:12.8; CI95%:1.5,108.7; p=0.02), CD69 gene polymorphism (ORAA/GG:17.2; CI95%:2.5,119.6; p=0.004) and lower number of previous biological therapy, BT (OR: 0.45; CI95%:0.3, 0.7; p=0.001). The factors independently associated to higher remission were lower number of previous BT (OR:0.56; CI95%:0.38, 0.82; p=0.003), and GALNT18 CC genotype (ORCT/CC:0.09; CI95%:0.02,0.45;p=0.004; ORTT/CC:0.14; CI95%:0.02,0.79; p=0.026). The A-allele of CD69 (ORA_/GG:6.68;CI95%:1.68,26.51;p=0.007) and lower number of previous BT (OR:0.50; CI95%:0.32,0.77; p=0.002) were independent factors capable to predict higher LDA rates at 6 months. Independent factors associated to higher improvement in DAS28 at 6 months were CD69-AA genotype (B=-0.56; CI95%:-1.09, -0.03; p=0.039), GALNT18-CC genotype (B=-0.88;CI95%:-1.49, -0.27; p=0.005), subcutaneous administration (B=1.03; CI95%:0.44,1.62; p=0.001) and higher baseline DAS28 (B=0.82; CI95%:0.59, 1.05; p=4.9×10(-10)). Lower number of previous BT was the only independent predictor of satisfactory EULAR response (OR:0.60; CI95%:0.34,0.88; p=0.010) and higher remission (OR:0.65; CI95%:0.46,0.93; p=0.018) at 18 months. The C-allele of GALNT18 (ORC-/TT:4.60; CI95%:1.16, 18.27; p=0.03) and lower number of previous BT (OR:0.47; CI95%:0.29,0.74; p=0.001) were independent factors capable to predict higher LDA rates at 18 months. In conclusion, RA patients treated with TCZ showed better EULAR response, remission, LDA and DAS28 improvement rates in patients carrying the GALNT18 C-allele or the CD69 A-allele, particularly when lower number of BT were previously administered.

Genetic variants within immune-modulating genes influence the risk of developing rheumatoid arthritis and anti-TNF drug response: a two-stage case-control study.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease that arises as a result of the interaction between genetic and environmental factors. A growing body of research suggests that genetic variants within immune-related genes can influence the risk of developing the disease and affect drug response. MATERIALS AND METHODS: To test this hypothesis, we carried out a comprehensive two-stage case-control study in a White population of 1239 White RA patients and 1229 healthy controls to investigate whether 49 single nucleotide polymorphisms within or near 17 immune-related genes modulate the risk of developing RA and antitumor necrosis factor (anti-TNF) drug response. RESULTS: Logistic regression analyses showed that carriers of the IL4rs2070874T and IL4rs2243250T and IL8RBrs1126580A alleles or the IL8RBrs2230054C/C genotype had a significantly increased risk of developing RA [odds ratio (OR)=1.37, 95% confidence interval (CI) 1.13-1.67, P=0.0016; OR=1.24, 95% CI 1.03-1.49, P=0.020; OR=1.23, 95% CI 1.08-1.41, P=0.002 and OR=1.19, 95% CI 1.04-1.36, P=0.01, respectively]. The association of the IL4 variants was further supported by a meta-analysis including 7150 individuals (P =0.0010), whereas the involvement of the IL8RB locus in determining the susceptibility to RA was also supported by gene-gene interaction analyses that identified significant two-locus and three-locus interaction models including IL8RB variants that act synergistically to increase the risk of the disease (P=0.014 and 0.018). Interestingly, we also found that patients harbouring the IFNGrs2069705C allele showed a significantly better response to anti-TNF drugs than those patients carrying the wild-type allele (P=0.0075). CONCLUSIONS: Our data suggest that IL4 and IL8RB loci may have a small-effect genetic impact on the risk of developing RA, whereas IFNG might be involved in modulating the response to anti-TNF drugs.

Genetic variants within the TNFRSF1B gene and susceptibility to rheumatoid arthritis and response to anti-TNF drugs: a multicenter study.

BACKGROUND: Recent research suggests that genetic variants in the tumor necrosis factor receptor 2 (TNFRSF1B) gene may have an impact on susceptibility to rheumatoid arthritis (RA) and drug response. The present population-based case-control study was carried out to evaluate whether 5 tagging single-nucleotide polymorphisms (SNPs) within the TNFRSF1B gene are associated with the risk of RA and response to antitumor necrosis factor (TNF) drugs. METHODS: The study population included 1412 RA patients and 1225 healthy controls. A subset of 596 anti-TNF-naive RA patients was selected to assess the association of TNFRSF1B SNPs and drug response according to the EULAR response criteria. RESULTS: We found that carriers of the TNFRSF1Brs3397C allele had a significantly increased risk of developing RA (P=0.0006). Importantly, this association remained significant after correction for multiple testing. We also confirmed the lack of association of the TNFRSF1Brs1061622 SNP with the risk of RA in the single-SNP analysis (P=0.89), but also through well-powered meta-analyses (PDOM=0.67 and PREC=0.37, respectively). In addition, our study showed that carriers of the TNFRSF1Brs3397C/C, TNFRSF1Brs1061622G/G, and TNFRSF1Brs1061631A/A genotypes had an increased risk of having a worse response to anti-TNF drugs at the level of P less than 0.05 (P=0.014, 0.0085 and 0.028, respectively). We also observed that, according to a log-additive model, carriers of the TNFRSF1Brs3397C or TNFRSF1Brs1061622G alleles showed an increased risk of having worse response to anti-TNF medications (P=0.018 and 0.0059). However, the association of the TNFRSF1Brs1061622 SNP only reached marginal significance after correction for multiple testing according to a log-additive model (P=0.0059) and it was not confirmed through a meta-analysis (PDOM=0.12). CONCLUSION: Our results suggest that the TNFRSF1Brs3397 variant may play a role in modulating the risk of RA, but does not provide strong evidence of an impact of TNFRSF1B variants in determining response to anti-TNF drugs.

Gender-specific effects of genetic variants within Th1 and Th17 cell-mediated immune response genes on the risk of developing rheumatoid arthritis.

The present study was conducted to explore whether single nucleotide polymorphisms (SNPs) in Th1 and Th17 cell-mediated immune response genes differentially influence the risk of rheumatoid arthritis (RA) in women and men. In phase one, 27 functional/tagging polymorphisms in C-type lectins and MCP-1/CCR2 axis were genotyped in 458 RA patients and 512 controls. Carriers of Dectin-2 rs4264222T allele had an increased risk of RA (OR = 1.47, 95%CI 1.10-1.96) whereas patients harboring the DC-SIGN rs4804803G, MCP-1 rs1024611G, MCP-1 rs13900T and MCP-1 rs4586C alleles had a decreased risk of developing the disease (OR = 0.66, 95%CI 0.49-0.88; OR = 0.66, 95%CI 0.50-0.89; OR = 0.73, 95%CI 0.55-0.97 and OR = 0.68, 95%CI 0.51-0.91). Interestingly, significant gender-specific differences were observed for Dectin-2 rs4264222 and Dectin-2 rs7134303: women carrying the Dectin-2 rs4264222T and Dectin-2 rs7134303G alleles had an increased risk of RA (OR = 1.93, 95%CI 1.34-2.79 and OR = 1.90, 95%CI 1.29-2.80). Also five other SNPs showed significant associations only with one gender: women carrying the MCP-1 rs1024611G, MCP-1 rs13900T and MCP-1 rs4586C alleles had a decreased risk of RA (OR = 0.61, 95%CI 0.43-0.87; OR = 0.67, 95%CI 0.47-0.95 and OR = 0.60, 95%CI 0.42-0.86). In men, carriers of the DC-SIGN rs2287886A allele had an increased risk of RA (OR = 1.70, 95%CI 1.03-2.78), whereas carriers of the DC-SIGN rs4804803G had a decreased risk of developing the disease (OR = 0.53, 95%CI 0.32-0.89). In phase 2, we genotyped these SNPs in 754 RA patients and 519 controls, leading to consistent gender-specific associations for Dectin-2 rs4264222, MCP-1 rs1024611, MCP-1 rs13900 and DC-SIGN rs4804803 polymorphisms in the pooled sample (OR = 1.38, 95%CI 1.08-1.77; OR = 0.74, 95%CI 0.58-0.94; OR = 0.76, 95%CI 0.59-0.97 and OR = 0.56, 95%CI 0.34-0.93). SNP-SNP interaction analysis of significant SNPs also showed a significant two-locus interaction model in women that was not seen in men. This model consisted of Dectin-2 rs4264222 and Dectin-2 rs7134303 SNPs and suggested a synergistic effect between the variants. These findings suggest that Dectin-2, MCP-1 and DC-SIGN polymorphisms may, at least in part, account for gender-associated differences in susceptibility to RA.

Pharmacogenetic polymorphisms contributing to toxicity induced by methotrexate in the southern Spanish population with rheumatoid arthritis.

Abstract Rheumatoid arthritis (RA) is a common illness of global significance for public health. Methotrexate (MTX) is the most broadly used disease-modifying antirheumatic drug for the treatment of RA, but it displays marked person-to-person variation in its propensity for toxicity. Several studies have suggested that polymorphisms in methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, reduced folate carrier (RFC1) G80A, and ABCB1 C3435T, could be related to methotrexate toxicity. This prospective study examined the different frequencies of MTHFR, RFC1, and ABCB1 pharmacogenetic variations between patients who have RA and those without RA. We also sought to assess the association between these polymorphisms and MTX toxicity. Four single-nucleotide polymorphisms (SNPs) were genotyped: C677T and A1298C from MTHFR, G80A from RFC1, and C3435T from ABCB1. The efficacy and toxicity of MTX were evaluated through clinical follow-up during 1 year of treatment. RA patients showed a higher frequency of the T allele at MTHFR C677T than patients without RA (p=0.049). There was a significant association between the presence of both the T allele at MTHFR C677T (p=0.006), and the C allele at ABCB1 C3435T (p=0.046), with toxicity development after 12 months of MTX treatment. However, there was no correlation between MTX toxicity and either the A allele at MTHFR A1298C or the G allele at RFC1 A80G. These data suggest that the presence of the MTHFR C677T and ABCB1 C3435T SNPs contribute to MTX toxicity in patients with RA. These observations contribute to a rapidly-growing knowledge base on the pharmacogenetics of RA and personalized medicine.