Polymorphism at position +896 of the toll-like receptor 4 gene interferes with rapid response to treatment in rheumatoid arthritis

Abstract

The aim of this study was to determine whether the +896 ARG substitution of the Toll-like receptor 4 (TLR4) gene, causing the Asp299RGly change in the extracellular domain of TLR4, influences treatment response in recent-onset rheumatoid arthritis. 169 patients with rheumatoid arthritis were genotyped from the Finnish Rheumatoid Arthritis Combination Therapy trial, in which they were treated either with only one disease-modifying antirheumatic drug (DMARD) with or without prednisolone (single group), or with three DMARDs and prednisolone (combination group). Patients homozygotic for the wild-type +896A allele were compared with those having the polymorphic G allele in terms of early clinical response (at 6 months) by the 28-joint Disease Activity Score (DAS28). 1 of 20 (5%; (95% (confidence interval (CI) 1 to 5)) patients of the single group with TLR4 +896AG or GG and 29 of 67 (43%; (95% CI 31 to 56)) patients with AA were in remission (p = 0.001). DAS28 of the single group with TLR4 +896AG or GG was higher than with AA (p = 0.019). In the combination group, remission rates and DAS28 values were comparable between the genotypes. The polymorphic TLR4 +896G allele may impair treatment response to single DMARD treatment in recent-onset rheumatoid arthritis.

Meta-analysis demonstrates association between TLR polymorphisms and rheumatoid arthritis

“…In the present study, meta-analysis of the TLR4 Asp299Gly polymorphism failed to reveal any association with RA susceptibility in Europeans. The single case-only study found that DAS28 differed significantly in RA patients according to the presence of this polymorphism (Kuuliala et al, 2006), but the 3 case-control studies failed to identify an association between this polymorphism and the clinical characteristics of RA (Kilding et al, 2003;Radstake et al, 2004;Sheedy et al, 2008).…”

“…Eleven studies met the study inclusion criteria (Kilding et al, 2003;Radstake et al, 2004;Sanchez et al, 2004;Kuuliala et al, 2006;Lee et al, 2006;Kang and Lee, 2007;Sheedy et al, 2008;Jaen et al, 2009;Enevold et al, 2010;Zheng et al, 2010;Etem et al, 2011 (Table 1). These studies involved 2078 patients with RA and 2581 controls.…”

“…Six studies (4 European and 2 Asian studies), including 5 case-control studies (Kilding et al, 2003;Radstake et al, 2004;Kang and Lee, 2007;Sheedy et al, 2008;Zheng et al, 2010) and 1 case-only study (Kuuliala et al, 2006), addressed the TLR4 Asp299Gly (rs4986790) polymorphism. Both TLR4 Asp299Gly (rs4986790) and Thr399Ile (rs4986791) were investigated in the 2 Asian studies (1 Korean and 1 Chinese), but these polymorphisms were not detected (Kang and Lee, 2007;Zheng et al, 2010).…”

“…These studies involved 2078 patients with RA and 2581 controls. Eight studies were casecontrol studies (Kilding et al, 2003;Radstake et al, 2004;Sanchez et al, 2004;Lee et al, 2006;Kang and Lee, 2007;Sheedy et al, 2008;Zheng et al, 2010;Etem et al, 2011), two were caseonly studies (Kuuliala et al, 2006;Enevold et al, 2010), and one was a family study (Jaen et al, 2009). Relevant features of the studies included in this systematic review are provided in Table 1.…”

“…In terms of clinical findings, the 3 European studies included in the meta-analysis found no association between this polymorphism and clinical characteristics. The aim of the case-only study, which was performed with 169 RA patients by Kuuliala et al (2006), was to determine whether the TLR4 Asp299Gly (rs4986790) polymorphism influences treatment response. The authors found that DAS28 was significantly different in RA patients with and those without this polymorphism who were treated with a disease-modifying anti-rheumatic drug (P = 0.019) but not between RA patients with and those without this polymorphism treated with 3 disease-modifying anti-rheumatic drugs and prednisolone (P = 0.31).…”