P75 Relation between polymorphism of folic acid cycle genes and effectiveness of methotrexate in children with juvenile idiopathic arthritis

BackgroundMethotrexate (MTX) is the basic treatment of patient with Juvenile Idiopathic Arthritis (JIA), but effectiveness of this therapy is different. We aimed to study effectiveness of MTX in children with JIA with different genotypes of folic acid cycle genes.MethodsThe study included 8 patients with JIA. For determination of MTX effectiveness the American College of Rheumatology pediatric criteria (ACR-pedi) was used. Patients were divided into 2 groups according the effectiveness of MTX treatment. Group I included 4 patients, who were non-responders because ACR-pedi was less than 10%. Second group contained 4 patients, who had ACR-pedi more than 10%. The megerment of genotypes of genes of folate cycle, such as 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), 5,10methylenetetrahydrofolate reductase C677T and A1298C variants (MTHFR-677 and MTHFR129) by polymerase chain reaction (PCR) was performed for all patients.ResultsIn II group effectiveness of therapy according ACR-pedi was from 30% to 70% in 75% of children and more then 70% - in 25% of patients. In general, MTR gene indicated AA-genotype in 50% of patients, AG and GG-genotypes - in 25%; MTRR gene was performed with AA-genotype in 25%, AC-genotype in 12.5% and CC-genotype in 62.5%. MTHFR1298 gene was presented in 50% of patients with AA-alleles, in 25% - with AC and CC-genotypes. 50% of children had CC-genotype of MTHFR677 gene and other 50% - AC-genotype of MTHFR677 gene. CC-genotype of MTHFR1298 gene more frequently was determined in II group (p< 0.01). In group of non-responders AA-genotype of MTR gene was found more frequent in comparison with patients from group II (p< 0.01).ConclusionResponse to standard therapy in patients with JIA depends on time of prescription of MTX and genotype of MTHFR1298 and MTR genes.Disclosure(s)Nothing to disclose

ABCB1andABCC3Gene Polymorphisms Are Associated with First-year Response to Methotrexate in Juvenile Idiopathic Arthritis

Objective.Although methotrexate (MTX) is the most widely prescribed drug in juvenile idiopathic arthritis (JIA), 30% of patients fail to respond to it. To individualize treatment strategies, the genetic determinants of response to MTX should be identified.Methods.A cohort of 287 patients with JIA treated with MTX was studied longitudinally over the first year of treatment. MTX response was defined as the American College of Rheumatology pediatric 70 criteria (ACRped70). We genotyped 21 single-nucleotide polymorphisms in 13 genes related to MTX polyglutamylation and to cellular MTX uptake and efflux. Potential associations between ACRped70 and genotypes were analyzed in a multivariate model and corrected for these 3 covariates: disease duration prior to MTX treatment, physician’s global assessment of disease activity at baseline, and MTX dose at all study visits.Results.MTX response was more often achieved by patients variant for the adenosine triphosphate-binding cassette transporter B1 (ABCB1) gene polymorphism rs1045642 (OR 3.80, 95% CI 1.70−8.47, p = 0.001) and patients variant for theABCC3gene polymorphism rs4793665 (OR 3.10, 95% CI 1.49−6.41, p = 0.002) than by patients with other genotypes. Patients variant for the solute carrier 19A1 (SLC19A1) gene polymorphism rs1051266 were less likely to respond to MTX (OR 0.25, 95% CI 0.09−0.72, p = 0.011).Conclusion.ABCB1rs1045642,ABCC3rs4793665, andSLC19A1rs1051266 polymorphisms were associated with response to MTX in 287 patients with JIA studied longitudinally. Upon validation of our results in other JIA cohorts, these genetic determinants may help to individualize treatment strategies by predicting clinical response to MTX.

Delayed Clinical Response in Patients with Juvenile Idiopathic Arthritis Treated with Etanercept

Objective.To evaluate response in patients with juvenile idiopathic arthritis (JIA) who failed to meet response criteria after 3 months of etanercept treatment.Methods.This was a prospective ongoing multicenter observational study of all Dutch patients with JIA using etanercept. Response according to American College of Rheumatology Pediatric 30 criteria was assessed at study start and at 3 and 15 months.Results.In total we studied 179 patients of median age 5.8 years at disease onset; 70% were female. Thirty-four patients did not respond after 3 months, of which 20 continued etanercept and 11 achieved response thereafter.Conclusion.The delayed clinically relevant response in a substantial proportion of patients who initially did not respond justifies the consideration of continuing therapy to at least 6 months.