Background Anti-tumour necrosis factor (anti-TNF) biologic therapy is a highly effective yet expensive treatment for patients with Rheumatoid Arthritis (RA). Patient eligibility for therapy and response to treatment is assessed using the 28 joint disease activity score (DAS-28). Eligibility is determined using baseline DAS-28 score and response is assessed by measuring the change in DAS-28 score at 6 months. The interleukin (IL) 6 inflammatory pathway is key in RA. Single nucleotide polymorphisms (SNPs) in the IL6 pathway genes are known to increase susceptibility to RA but have not been explored previously for their role in predicting response to therapy.
Objectives First, to correlate 5 SNPs in IL-6R and IL-6ST with baseline DAS-28, change in DAS-28 and change in C-reactive protein (CRP)-levels in RA patients receiving anti-TNF therapy. Second, to explore IL-6ST mRNA expression in whole blood as a predictor of treatment response.
Methods Previous genotype and clinical data was extracted from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) cohort. The strength of correlation between five SNPS (rs7518199, rs7529229, rs4129267, rs8192284 and rs2228043) and change in DAS28 and CRP levels was estimated using multivariate linear regression techniques in PLINK. RNA was extracted from blood samples of 24 patients in the BRAGGSS cohort to conduct q-PCR in order to assess levels of IL-6ST mRNA transcripts.
Results 1,458 samples with complete genotype and clinical data were available for analysis. The study had > 80% power to detect a clinically significant difference of 0.6 DAS28 units at all allele frequencies and adequately powered at > 90% to detect the change of 10mg/L of CRP for all allele frequencies. None of the SNPs showed significant association with treatment response, as measured by change in DAS-28 or change in CRP. Linear regression showed no evidence for a significant increase in IL-6ST mRNA transcripts with associated SNPs in RA patient serum when normalised to four housekeeping genes. Expression of IL6ST was not associated with treatment response (β coefficient = -0.14, P = 0.57).
Conclusions Genotyping of the IL6 pathway genes implicated in RA susceptibility is not predictive of treatment response to anti-TNF therapy in patients with RA. Levels of IL-6ST were not correlated with genotype in RA patient peripheral blood samples and were not predictive of treatment response to anti-TNF drugs; however, altered expression in selected cell types cannot be excluded. Future studies in RA patients receiving anti-IL6 therapy (tocilizumab) and in isolated cell types are planned.
References Hassan, B., J.R. Maxwell, K.L. Hyrich, A. Barton, J. Worthington, J.D. Isaacs, A.W. Morgan, and A.G. Wilson. 2010. Genotype at the sIL-6R A358C polymorphism does not influence response to anti-TNF therapy in patients with rheumatoid arthritis. Rheumatology (Oxford). 49:43-47.
Disclosure of Interest None Declared
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