Role of IL6R Genetic Variants in Predicting Response to Tocilizumab in Patients with Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by chronic arthritis that may lead to irreversible joint damage and significant disability. Patients with RA are commonly treated with Tocilizumab (TCZ), an IL-6 receptor (IL-6R) antagonist, but many patients refractorily respond to this therapy. Identifying genetic biomarkers as predictors of TCZ response could be a key to providing a personalized medicine strategy. We aimed to evaluate whether functional single nucleotide polymorphisms (SNPs) in the IL6R gene could predict TCZ response in patients with RA. We retrospectively included 88 RA patients treated with TCZ. Six SNPs previously described in the IL6R gene (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625) were genotyped in DNA samples from these patients. Using parametric tests, we evaluated the association between these polymorphisms and clinicopathological features. Responses to treatments were assessed at six months using three variables: a quantitative improvement in Disease activity score including 28 joints (DAS28), a satisfactory European League Against Rheumatism (EULAR) response, and low disease activity (LDA) achievement. The three response variables studied were associated with genetic variant rs4845625, and no association was found with the other five SNPs. Our findings support the potential clinical value of SNPs in the IL6R gene as predictive biomarkers for TCZ response.

Clinical Value of IL6R Gene Variants as Predictive Biomarkers for Toxicity to Tocilizumab in Patients with Rheumatoid Arthritis

“…CC carriers of rs11265618 showed improved low disease activity rates at 12 months [ 28 ], while TT carriers of rs4329505 showed less joint swelling at three months [ 30 ]. Although we found similar trends relating to the same genotypes with efficacy outcomes at six months in our previous study, the results were not statistically significant [ 33 ].…”

“…Our results regarding rs4845625 show that carriers of the T allele (TT + TC) had a higher incidence of dyslipidemia compared to CC carriers (36.7% vs. 16.7%) when treated with tocilizumab. A recent study of patients with RA by our group also described a greater response to tocilizumab treatment at six months in carriers of the TT or CT genotypes for rs4845625 [ 33 ]. Additionally, in line with our results, in 2017, Arguinano et al described an association between rs4845625*T and high levels of LDL in a healthy cohort, suggesting that IL6R genetic variations may constitute a cardiovascular risk factor [ 36 ].…”

“…We found no association between the rs12083537, rs2228145, and rs4537545 genetic variants and AEs detected during tocilizumab treatment. The rs12083537 variant has previously been studied, with conflicting results; while Enevold et al [ 30 ] found that carriers of the AA genotype presented a poorer response to tocilizumab treatment, other studies found the opposite [ 29 , 31 ], and a recent study found no association [ 33 ]. As for the IL6R SNP rs2228145, this has only been proposed as a biomarker of response to tocilizumab by Enevold et al [ 30 ].…”

“…Given that tocilizumab inhibits IL-6R, we hypothesized that functional variations in its encoding gene could affect tocilizumab toxicity. While previous studies have assessed the influence of IL6R gene variants on tocilizumab response, the results are inconsistent and not applicable to clinical practice [ 28 , 29 , 30 , 31 , 32 , 33 ]. As for toxicity, no studies to date have evaluated the influence of IL6R gene variants on tocilizumab-induced toxicities.…”

Association Studies in Clinical Pharmacogenetics

“…Concerning autoimmune and inflammatory diseases, Chernov et al observed a relationship between ABCB1 rs1045642, rs1128503, and rs2032582 and cyclosporine response in patients with psoriasis [ 26 ]. Furthermore, Sainz et al observed a relationship between IL6R rs4845625 and tocilizumab response in patients with rheumatoid arthritis [ 27 ]. In relation to the latter disease, Madrid-Paredes et al [ 28 ] reviewed the genetic, epigenetic, and environmental factors related to the response of disease-modifying antirheumatic drugs.…”