Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease affecting the joints. A heterogeneous response to available therapies demonstrates the need to identify those patients likely to benefit from a particular therapy. Our objective was to identify genetic factors associated with response to tocilizumab, a humanized monoclonal antibody targeting the interleukin (IL)-6 receptor, recently approved for treating RA. We report the first genome-wide association study on the response to tocilizumab in 1683 subjects with RA from six clinical studies. Putative associations were identified with eight loci, previously unrecognized as linked to the IL-6 pathway or associated with RA risk. This study suggests that it is unlikely that a major genetic determinant of response exists, and it illustrates the complexity of performing genome-wide association scans in clinical trials.

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

“…Clinical, biochemical and genetic factors have been proposed as predictors of good response to TCZ in RA patients [10,11,[13][14][15][16]. Among clinical factors, the early administration of TCZ and an increased baseline DAS28 have shown better EULAR response and remission rates, although with conflicting results [10,14].…”

“…Since TCZ administration in the clinical practice is relatively recent, the influence of genetics on response to TCZ is scarcely investigated. To date, only one genome-wide association study (GWAS) has tried to identify gene polymorphisms involved in the response to TCZ [13]. This GWAS, recently conducted in 1683 subjects with RA from six clinical studies, has identified several single nucleotide polymorphisms (SNP) in CD69 (rs11052877), GALNT18 (rs4910008), CLEC2D…”

“…(rs1560011), KCNMB1 (rs703505), ENOX1 (rs9594987) genes and rs10108210, rs703297 variants, located in chromosomes 8 and 2, respectively [13]. Currently, there is no further information on the utility of these gene markers to identify RA patients candidates to good response to TCZ in other cohorts, and it would be useful to investigate if these genetic markers are capable to identify patients who will benefit from treatment with TCZ in the clinical practice.…”

Rheumatoid Arthritis: A Case for Personalized Health Care?

“…The identification of 31 risk loci in seropositive RA, a very strong genetic risk factor in HLA-DRB1, and the group of alleles referred to as the shared epitope demonstrate that RA has a strong but complex genetic etiology. As a result, a genetic approach to the identification of biomarkers of response has been taken as a candidate and genome-wide level for anti-TNF (14) and tocilizumab (18,19) interventions. While associations that may ultimately lead to a greater insight into the molecular etiology of RA have been established, the predictive capability so far has been insufficient to have meaningful clinical application.…”

“…While associations that may ultimately lead to a greater insight into the molecular etiology of RA have been established, the predictive capability so far has been insufficient to have meaningful clinical application. Indeed, 2 studies by Wang et al (18,19) reported that each polymorphism identified in a genome-wide association study accounted for Ͻ2% of the variance observed with a change in Disease Activity Score in 28 joints (DAS28) response to tocilizumab, while no significant association of polymorphisms of the target IL-6 receptor and its cognate ligand IL-6 was associated with change in DAS28 response, following correction for multiple testing. Baseline serum IL-6 levels also provided little discrimination between responders and nonresponders, indicating that the prevalence of the therapeutic target was not clinically useful, despite having been previously proposed as "low-hanging fruit" (20).…”