Time to treatment as an important factor for the response to methotrexate in juvenile idiopathic arthritis

Abstract

Objective. Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug in juvenile idiopathic arthritis (JIA). Currently, individual response to MTX cannot be reliably predicted. Identification of clinical and genetic factors that influence the response to MTX could be helpful in realizing the optimal treatment for individual patients. Methods. A cohort of 128 JIA patients treated with MTX were studied retrospectively. Eleven clinical parameters and genotypes of 6 single nucleotide polymorphisms in 5 genes related to the mechanism of action of MTX were compared between MTX responders and nonresponders using a multivariate regression analysis. Results. The time from diagnosis to start of MTX treatment, physician's global assessment at baseline, and the starting dose were significantly associated with the response to MTX at 6 months after initiation. Patients with a shorter time from diagnosis to start of MTX and a higher disease activity according to the physician but with a lower MTX dose showed an increased response. The effect of the starting dose on MTX response seemed to be mainly due to the influence of the systemic JIA subtype. The time from diagnosis to start of MTX treatment and physician's global assessment at baseline were highly correlated. Therefore, the precise effect size of each independent variable could not be determined. Conclusion. In children with JIA, the time from diagnosis to start of MTX appears to be an important factor for MTX response. Our results suggest that an earlier start of MTX treatment will lead to an increased response.

Influence of polymorphisms within the methotrexate pathway genes on the toxicity and efficacy of methotrexate in patients with juvenile idiopathic arthritis

“…However, results are conflicting, and there are marked differences between racial groups in pharmacogenetic studies [10]. We could find only two studies on the pharmacogenetics of MTX in patients with JIA in Caucasian patients [5,6], but not one in an Asian population. This is the first reported study on pharmacogenetics of MTX in patients with JIA in an Asian population.…”

“…Clinical predictors that may influence a patient's disease state and the toxicity and efficacy of MTX were selected on the basis of previous reports [5,6,15,16]. The following factors were included: sex; age at disease onset; duration of MTX treatment; time interval from disease onset to MTX treatment; rheumatoid factor (RF) status; anti-cyclic citrullinated peptide (anti-CCP) status; and concomitant use of prednisolone and folic acid.…”

“…The following eight single nucleotide polymorphisms (SNPs) within the MTX pathway genes encoding RFC, MTHFR, FPGS, GGH, ATIC and BCRP were selected according to previous reports [4][5][6][7][8][9]. Genotyping for the SNPs of RFC G80A (rs1051266), MTHFR A1298C (rs1801131), MTHFR C677T (rs1801133), FPGS A1994G (rs10106), GGH C452T (rs11545078), GGH T16C (rs1800909), ATIC C347G (rs2372536) and BCRP C421A (rs2231142) was performed using the TaqMan assay (Applied Biosystems, Foster City, CA, USA).…”

“…The effects of polymorphisms within the MTX pathway genes on the toxicity and efficacy of MTX in patients with rheumatoid arthritis (RA) and JIA have been studied [4][5][6]. The influence of polymorphisms within the MTX pathway genes encoding solute carrier family 19 member 1 (SLC19A1), also known as reduced folate carrier (RFC), 5,10-methylenetetrahydrofolate reductase (MTHFR), folypolyglutamate synthetase (FPGS), g-glutamyl hydrolase (GGH), 5-aminomidazole-4-carboxamide ribonucleotide transformylase (ATIC) and breast cancer resistance protein (BCRP/ABCG2) on the toxicity and efficacy of MTX in patients with RA, JIA and other diseases has been studied [4][5][6][7][8][9]. However, results regarding the influence of these polymorphisms on the toxicity and efficacy of MTX are conflicting, and there are marked differences in pharmacogenetics between racial groups [10].…”

Access to Pediatric Rheumatology Care — A Major Challenge to Improving Outcome in Juvenile Idiopathic Arthritis: Table 1.

“…The longterm impact of delay is unknown, but a longer interval from disease onset to definitive treatment is likely to adversely affect clinical outcomes 4,5,6 . In one study 7 , many children with delay (defined as > 10 weeks from symptom onset to first pediatric rheumatology assessment) had prolonged untreated active disease, many presented with multiple restricted joints, none had been referred for eye screening (to detect chronic anterior uveitis), and the median interval from onset of symptoms to starting methotrexate was 10 months.…”