The -174G/C Interleukin-6 Gene Promoter Polymorphism as a Genetic Marker of Differences in Therapeutic Response to Methotrexate and Leflunomide in Rheumatoid Arthritis

Abstract

Objective. To evaluate the association of -174G/C IL-6 polymorphism with failure in therapeutic response to methotrexate (MTX) or leflunomide (LEF). This prospective, observational cohort included 96 Mexican-Mestizo patients with moderate or severe rheumatoid arthritis (RA), initiating MTX or LEF, genotyped for IL-6 -174G/C polymorphism by PCR-RFLP. Therapeutic response was strictly defined: only if patients achieved remission or low disease activity (DAS-28 < 3.2). Results. Patients with MTX or LEF had significant decrement in DAS-28 (p < 0.001); nevertheless, only 14% and 12.5% achieved DAS-28 < 3.2 at 3 and 6 months. After 6 months with any of these drugs the -174G/G genotype carriers (56%) had higher risk of therapeutic failure compared with GC (RR: 1.19, 95% CI: 1.07–1.56). By analyzing each drug separately, after 6 months with LEF, GG genotype confers higher risk of therapeutic failure than GC (RR = 1.56; 95% CI = 1.05–2.3; p = 0.003), or CC (RR = 1.83; 95% CI = 1.07–3.14; p = 0.001). This risk was also observed in the dominant model (RR = 1.33; 95% CI = 1.03–1.72; p = 0.02). Instead, in patients receiving MTX no genotype was predictor of therapeutic failure. We concluded that IL-6 -174G/G genotype confers higher risk of failure in therapeutic response to LEF in Mexicans and if confirmed in other populations this can be used as promissory genetic marker to differentiate risk of therapeutic failure to LEF.

Relationship Between Interleukin-6 −174G/C Genetic Variant and Efficacy of Methotrexate Treatment in Psoriatic Arthritis Patients

“…33 In addition, in a study by Ruiz et al the IL-6 −174 GG genotype was associated with a higher risk of failure in therapeutic response to MTX or leflunomide (lef). 34 However, after stratifying patients’ groups in accordance to MTX or lef, a significant association was observed only in patients treated with lef.…”

“…However, two groups examined the association of the IL-6 −174 G/C polymorphism with efficacy of the MTX treatment in patients with RA. 33 , 34 Pawlik et al reported significantly worse response to MTX therapy among patients possessing the IL-6 −174 GG genotype. 33 In addition, in a study by Ruiz et al the IL-6 −174 GG genotype was associated with a higher risk of failure in therapeutic response to MTX or leflunomide (lef).…”

“…The mean age at the onset of psoriasis was 29.4 ± 14.2 years. Mean age at PsA onset was 37.5 ± 12.1 RA susceptibility C allele associated with increased disease risk [21] Susceptibility to juvenile idiopathic arthritis G allele associated with disease risk [12,22] Disease severity in RA G allele correlated with higher disease activity [23] Disease severity in RA CC genotype correlated with higher disease activity [24] Severity and progression of bone erosive damage G allele correlated with increased progression of bone [25] Radiographic damage in RA GG genotype correlated with increased radiographic damage [26] Hypertension in RA Lack of association [27] Endothelial dysfunction in RA GG genotype associated with more severe endothelial dysfunction [28] Risk of cardiovascular disease in RA Lack of association [29] Risk of cardiovascular disease in RA C allele correlated with cardiovascular disease risk [30] Response to anti-TNF therapy in RA G allele associated with better response [19,31,32] Response to MTX therapy in RA patients GG genotype correlated with worse response [33,34] Response to rituximab in RA CC genotype associated with worse response [35] Disease activity and clinical pattern in PsA GG genotype associated with peripheral form of PsA [36] PsA susceptibility and severity Lack of association [37] Psoriasis susceptibility and response to phototherapy GG genotype associated with disease risk [38] Response to anti-TNF treatment in psoriasis C allele correlated with better response [39] Psoriasis susceptibility Lack of association [40] Psoriasis susceptibility GG genotype associated with decreased risk of disease [41]…”

Toward Overcoming Treatment Failure in Rheumatoid Arthritis

“…Patients with folylpolyglutamate synthetase (FPGS) rs1544105-AA or -AG and TYMS rs2853539-AA genotype were associated with poor response to methotrexate ( 53 ). An analysis of the -174 (rs1800795) -GC IL-6 gene promoter polymorphism in RA patients revealed that genotype -GG may be associated with a poorer response to methotrexate when compared to genotypes -GC and -CC ( 54 ), which was in disagreement with another study identifying no association between -GG genotype or G allele and risk of therapeutic failure using different measures for defining response to therapy ( 55 ) ( Table 1 ).…”

The role of regulatory T cells and genes involved in their differentiation in pathogenesis of selected inflammatory and neoplastic skin diseases. Part III: Polymorphisms of genes involved in Tregs’ activation and function

“…Rausz et al have found no association of mastocytosis and the IL6-174G/C polymorphism, however, analysis of the IL6R Asp358Ala polymorphism showed that carriers of the AA genotype had a 2.5-fold lower risk of mastocytosis than those with the AC or CC genotypes [ 85 ]. Ruiz-Padilla et al have found that IL-6 -174G/G genotype confers a higher risk of failure in therapeutic response to Lefludomid in Mexicans patients with rheumatoid arthritis [ 82 ].…”