IL-1beta, IL-6, and TNF gene polymorphisms do not affect the treatment outcome of rheumatoid arthritis patients with leflunomide.

Leflunomide is an isoxazole derivative that is structurally and functionally unrelated to other known immunomodulatory drugs. Previous studies have revealed that therapy with leflunomide causes decreased production of mediators such as IL-1beta, IL-6, and TNF-alpha, which are involved in inflammatory process. The aim of the present study was to examine whether the polymorphisms in genes IL1B, IL6, and TNF may affect treatment outcomes in RA patients treated with leflunomide. The study was carried out on 129 patients (106 women, 23 men, mean age 52.9 +/- 11.03) diagnosed with RA and treated with leflunomide 20 mg daily. Clinical improvement was evaluated according to the American College of Rheumatology (ACR) 20% and 50% response criteria. There were no statistically significant associations between the studied genotypes and improvement of disease activity parameters. The results of the present study suggest that IL1beta, IL6, and TNF gene polymorphisms are not significant factors influencing the therapy outcome of RA patients with leflunomide.

The effect of exon (19C>A) dihydroorotate dehydrogenase gene polymorphism on rheumatoid arthritis treatment with leflunomide.

OBJECTIVE: Leflunomide is an isoxazole derivative structurally and functionally unrelated to other known immunomodulatory drugs. The main molecular target of leflunomide is dihydroorotate dehydrogenase (DHODH), a key enzyme of de novo pyrimidine synthesis. The human DHODH gene sequence is highly conserved and contains only one common missense polymorphism in the coding regions. This SNP (refSNP ID: rs3213422) is localized in the first exon of the DHODH gene (19C>A) and leads to Gln7Lys amino acid substitution in the cationic N-terminal region of the DHODH polypeptide, and it has not yet been investigated in relation to enzyme activity or DHODH inhibitor efficacy. The aim of the study was to examine the effect of this polymorphism on leflunomide treatment outcome in rheumatoid arthritis (RA) patients. MATERIALS & METHODS: The study was carried out on 147 patients (123 women, 24 men, mean age: 52.8 +/- 11.03 years) diagnosed with RA and treated with leflunomide 20 mg daily. Clinical improvement was evaluated according to the American College of Rheumatology 20% and 50% response criteria. RESULTS: The frequency of remission was increased in C allele carriers compared with patients with the A allele. CONCLUSION: The results of this study suggest that DHODH polymorphism may be associated with leflunomide treatment outcome in RA patients.

677C>T and 1298A>C MTHFR polymorphisms affect methotrexate treatment outcome in rheumatoid arthritis.

INTRODUCTION: Methotrexate (MTX), widely used in the treatment of rheumatoid arthritis (RA), inhibits dihydrofolate reductase and folate-dependent enzymes. Methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism and has been shown to be polymorphic, affecting the enzyme activity. METHODS: To examine the association between 677C>T and 1298A>C MTHFR polymorphisms and MTX efficacy in the treatment of RA, a total of 174 RA patients, treated with MTX plus methylprednisone 4 mg and folic acid 5 mg were analyzed. RESULTS: In univariate regression analysis model, the MTHFR 677T allele was associated with significantly higher frequency of remission, whereas in the case of the 1298C allele, a tendency for higher remission rate was observed. In multivariate regression analysis, the presence of both 677T and 1298C alleles was associated with an increased frequency of remission. CONCLUSION: The results of our study suggest that the MTHFR 677T and 1298C alleles may be associated with an increased rate of RA remission in patients treated with MTX receiving high doses of folic acid supplementation.

NOD2 allele variants in patients with rheumatoid arthritis.

Recent reports have proven the importance of genetic factors and inflammation in the pathogenesis of rheumatoid arthritis (RA). In the current study, the frequency of NOD2/CARD15 gene variants (R702W, G908R, and L1007fsinsC) was examined in a group of 243 RA patients and 220 healthy controls. There were no statistically significant differences in distribution of NOD2 variant alleles between RA patients and controls. Moreover, there was no significant association between NOD2 variant alleles and joint erosions, extraarticular manifestations, rheumatoid factor, number of swollen and tender joints, and erythrocyte sedimentation rate. The results of the present study suggest that NOD2 allele variants have no significant influence on RA susceptibility, activity, and severity.

The effect of 3435C>T MDR1 gene polymorphism on rheumatoid arthritis treatment with disease-modifying antirheumatic drugs.

OBJECTIVE: Rheumatoid arthritis (RA) is a multifactorial disease, with immunological, genetical as well as environmental factors being implicated in its pathogenesis. Treatment of RA is based mainly on drugs modulating the course of the disease, e.g. methotrexate (MTX) or sulfasalazine (SL). The MDR1 gene product, P-glycoprotein (P-gp), is probably one of the most important and best defined transporters for drug delivery in humans. P-gp transports a wide range of substrates with diverse chemical structures, among them anticancer agents, cardiac drugs, and immunosuppressants. The aim of this study was to examine the effect of the 3435C>T MDR1 gene polymorphism on the efficacy of RA treatment with disease-modifying antirheumatic drugs, i.e. MTX plus methylprednisolone (MP), and SL. METHODS: The study was carried out on 255 patients with RA treated according to two regimes: (1) MTX (7.5-15.0 mg weekly) plus low doses of MP (n=174), (2) SL (1.5-3 g daily, n=81). RESULTS: The probability of remission of RA symptoms after MTX plus MP therapy was 4.65-fold higher in carriers of the TT genotype compared to patients with CC genotype (P=0.003, OR 4.65, 95%CI 1.66-13.05), whereas the probability of remission of RA symptoms in patients treated with SL was 2-fold higher in carriers of TT genotype compared to patients with CC genotype, but did not reach statistical significance (P=0.358, OR=2.00 95% CI=0.58-6.87). CONCLUSION: The results from the present study suggest that the 3435C>T MDR1 gene polymorphism may influence the efficacy of RA therapy with disease-modifying antirheumatic drugs.

Interleukin-10 promoter polymorphism in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease in which interleukin (IL)-10 plays an important role. There are, however, controversial reports that IL-10 promoter polymorphism may be an independent marker of susceptibility and severity of RA. The aim of the present study was to examine the IL-10 promoter polymorphism in patients with RA. We examined 95 patients with rheumatoid arthritis diagnosed according to the criteria of the American College of Rheumatology. Polymerase chain reaction amplification was used for analysis of the promoter polymorphism of the IL-10 gene. In RA patients, the prevalence of genotypes encoding high expression of IL-10 was observed. Nevertheless, there was no association between IL-10 genotypes and age at disease diagnosis, disease activity in a physician's global assessment, and joint and extra-articular involvement. There was also no correlation between IL-10 polymorphism and disease activity parameters--erythrocyte sedimentation rate, C-reactive protein, number of swollen and tender joints, and duration of morning stiffness. We suggest that IL-10 promoter polymorphism is not a genetic risk factor for RA activity.

The -590 IL-4 promoter polymorphism in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease in which cytokines play an important role. The aim of the present study was to evaluate the -590 IL-4 promoter polymorphism in patients with RA and its association with disease activity and severity. We enrolled 94 patients with RA diagnosed according to the criteria of the American College of Rheumatology. Polymerase chain reaction amplification was used for analysis of the polymorphism at position -590 of the promoter of the IL-4 gene. The distribution of IL-4 genotypes in RA patients did not differ from control subjects. Nevertheless, the active form of RA was more frequently diagnosed in patients with T allele (genotypes CT and TT) as compared with homozygous CC patients. Moreover, in carriers of the T allele, parameters of disease activity (DAS 28 score, ESR, number of swollen and tender joints) were significantly increased. We suggest that the IL-4 -590 promoter polymorphism may be a genetic risk factor for RA severity.

[The influence of IL-6 polymorphism on efficacy of treatment of rheumatoid arthritis patients with methotrexate and prednisone]. / Wplyw polimorfizmu interleukiny-6 na skutecznosc leczenia chorych na reumatoidalne zapalenie stawów metotreksatem i prednizonem.

Rheumatoid arthritis (RA) is a chronic inflammatory disease in which cytokines play an important role. The therapy of RA is associated with application of the drugs modulating the immune response via inhibiting the cytokine production. The common drugs used in RA therapy are methotrexate and prednisone. Recent investigations showed the importance of genetically determined differences in cytokine production in RA activity and therapy. The aim of the present study was to examine the influence of - 174 interleukin-6 (IL-6) promoter polymorphism on the efficacy of treatment of RA patients with methotrexate and prednisone. Polymerase chain reaction amplification was used for analysis of the polymorphism at IL-6 gene. Seventy patients with RA diagnosed according to the criteria of the American College of Rheumatology were investigated. The patients were divided into two subgroups. The first subgroup included patients who have obtained remission for at least 6 months after therapy with methotrexate and glucocorticosteroids. The second subgroup included patients with active disease despite at least 6 months of therapy with methotrexate and glucocorticosteroids. It has been shown that the incidence of remission after therapy with methotrexate and glucocorticosteroids was significantly lower in patients with GG genotype as compared with GC and CC genotypes p< 0.05. We suggest that -174 IL-6 promoter polymorphism may be a genetic risk factor determining the effectiveness of RA treatement with methotrexate and glucocorticosteroids.