Background/Purpose: Biological agents (boDMARDs) have modified the therapeutic management of patients with rheumatoid arthritis (RA). However, boDMARDs can induce sustained remission in only 30% of RA patients. Identify predictive markers of response to boDMARDs would be a real progress in clinical practice. Wang et al. previously explored response to tocilizumab (TCZ) by genome-wide association in 1,683 RA patients. They found out eight loci not recognized to be linked with the interleukin (IL)-6 pathway. More recently, Enevold et al. have shown a haplotype of 3 single-nucleotide polymorphisms (SNPs) on IL6Rgene associated with clinical response to TCZ (AAC haplotype for rs12083537, rs2228145, and rs4329505, respectively) in a retrospective cohort of 79 RA Caucasian patients. Our study aimed to test the association of these 3 SNPs with TCZ response in two populations of French RA patients.

Methods: Patients: Two independent RA cohort were used for this study: 1) TOCI, a multicentric retrospective French study including 160 RA patients treated with TCZ, 2) ROC, a multicentric prospective French randomized controlled trial comparing the efficacy of a second TNF blocker to another boDMARD (abatacept, TCZ or rituximab) in RA patients who failed to a first TNF blocker. Among the 292 patients included in ROC, 62 patients received TCZ after randomization in the non-TNF blocker arm. Patients were evaluated at 0 and 3 months after initiation of TCZ. Efficacy of TCZ was assessed using the European League Against Rheumatism (EULAR) response criteria. Genotyping:3 SNPs on IL6R were genotyped using KasPar method on both samples (LGC-genomics, UK). Statistics:the proportion of patients with EULAR response (moderate or good) was compared across the genotypes of the 3 SNPs on TOCI and ROC studies. A meta-analysis was performed, by allele analysis, to confirm the association on the 2 samples with Mantel-Haenszel method.

Results: Fourty height patients in the TOCI group (78.7 %) and 125 patients in the ROC group (79.6 %) reached good or moderate EULAR responses. The SNP rs2228145 did not respect the Hardy Weinberg equilibrium. The GG genotype of rs12083537 was significantly associated with a lower response rate in both cohort [TOCI: 89.2% of responders for AA genotype vs 65.2 % for AG or GG genotype (p=0.044), ROC patients: 87.2% of responders for AA genotype vs 72.2 % for AG or GG genotype, p=0.018]. Combining these two studies, we confirmed the lower response rate with G allele carriage (OR (95% CI) = 0.35 (0.16-0.61), p=0.001). No association was found with the SNP rs4329505 (alone or in a haplotype with rs12083537).

Conclusion: In this study, the rs12083537 of IL6R was associated with response to TCZ in two different independent RA cohorts. Although insufficient to be used in the daily practice, these results strengthen literature data in the search of predictive markers to the response to TCZ.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-single-nucleotide-polymorphism-of-il6-receptor-is-associated-with-response-to-tocilizumab-in-rheumatoid-arthritis-results-from-toci-and-roc-studies/