***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Objective . Low-dose methotrexate ( MTX ) is the anchor drug in the treatment for rheumatoid arthritis ( RA ) . Response to MTX is related to the intracellular MTX-polyglutamate ( MTX-PG ) levels and little is known about its determinants . We aim ed to define the determinants of erythrocyte MTX-PG concentrations in 2 prospect i ve cohorts of patients with RA . Methods . Patients with RA treated with MTX from 2 longitudinal cohorts were included : 93 from the MTX-R study ( Rotterdam , the Netherl and s derivation cohort ) , and 247 from the treatment in Rotterdam Early Arthritis Cohort study ( validation cohort ) .  MTX-PG concentrations were measured at 3 months of treatment using liquid chromatography/mass spectrometry . The  MTX-PG  were used as outcome measure . Various sociodemographic , clinical , biochemical , and genetic factors were assessed at baseline . Associations with MTX-PG levels were analyzed using multivariate regression analysis . Results . Age was positively associated with  MTX-PG1  ( stβ 0.23 , p = 0.033 ) and total MTX-PG  ( stβ 0.23 , p = 0.018 ) in the derivation cohort , and with all MTX-PG in the validation cohort ( MTX-PG1 : stβ 0.13 , p = 0.04 ; MTX-PG2 : stβ 0.21 , p = 0.001 ; MTX-PG3 : stβ 0.22 , p < 0.001 ; MTX-PG4 + 5 : stβ 0.25 , p < 0.001 ; and total MTX-PG : stβ 0.32 , p < 0.001 ) . Erythrocyte folate levels were positively associated with MTX-PG3  ( stβ 0.3 , p = 0.021 ) and total MTX-PG levels ( stβ 0.32 , p = 0.022 ) in the derivation cohort , which was replicated for MTX-PG3 ( stβ 0.15 , p = 0.04 ) in the validation cohort . Patients with the folylpolyglutamate synthase ( FPGS ) rs4451422 wild-type genotype had higher concentrations of MTX-PG3  ( p < 0.05 ) ,  MTX-PG4 + 5 ( p < 0.05 ) , and total MTX-PG  ( p < 0.05 ) in both cohorts . In the combined cohort , MTX dose was positively associated with levels of MTX-PG3  ( stβ 0.23 , p < 0.001 ) , MTX-PG4 + 5 ( stβ 0.30 , p < 0.001 ) , and total MTX-PG  ( stβ 0.20 , p = 0.002 ) , but negatively associated with MTX-PG2  levels ( stβ −0.22 , p < 0.001 ) . Conclusion . Our prospect i ve study shows that higher age , higher MTX dose , higher erythrocyte folate status , and the FPGS rs4451422 wild-type genotype are associated with higher MTX-PG concentrations . While only up to 21 % of interpatient variability can be explained by these determinants , this knowledge may aid in the development of personalized treatment in RA OBJECTIVE To study the possible relationship between the C677 T mutation in the methylenetetrahydrofolate reductase ( MTHFR ) gene and the toxicity and efficacy of treatment with  methotrexate ( MTX ) in patients with rheumatoid arthritis ( RA ) . METHODS Genotype analysis of the MTHFR gene was done in 236 patients who started MTX treatment with ( n = 157 ) or without ( n = 79 ) folic or folinic acid supplementation .  Outcomes were parameters of efficacy of MTX treatment , patient withdrawal due to adverse events , discontinuation of MTX treatment because of elevated liver enzyme levels , and the total occurrence of elevated liver enzyme levels during the study . Multivariate logistic regression analysis was used to study the relationship between the presence of the MTHFR C677 T mutation and toxicity outcomes of MTX treatment . RESULTS Forty-eight percent of the patients showed the homozygous ( T/T ) or heterozygous ( T/C ) mutation . The presence of the C677CT or C677TT genotypes was associated with an increased risk of discontinuing MTX treatment because of adverse events ( relative risk 2.01 ; 95 % confidence interval 1.09 , 3.70 ) , mainly due to an increased risk of elevated liver enzyme levels ( relative risk 2.38 ; 95 % confidence interval 1.06 , 5.34 ) . Efficacy parameters were not significantly different between the patients with and those without the mutation . CONCLUSION The C677 T mutation is the first identified genetic risk factor for elevated alanine aminotransferase values during MTX treatment in patients with RA . We postulate that the incidence of clinical ly important elevation of liver enzyme levels during MTX treatment is mediated by homocysteine metabolism . Supplementation with folic or folinic acid reduced the risk of toxicity-related discontinuation of MTX treatment both in patients with and in patients without the mutation OBJECTIVES We examined the association between c and i date single nucleotide polymorphisms ( SNPs ) and disease activity in RA patients on MTX .  METHODS Our population was drawn from the Brigham and Women 's Hospital Rheumatoid Arthritis Sequential Study ( BRASS ) , a prospect i ve , observational cohort of RA patients . A total of 556 participants were genotyped using the Affymetrix 100 K platform . Two hundred and sixty-two participants were on MTX therapy , including 120 on MTX monotherapy .  The primary outcome was the disease activity score in 28 joints ( DAS28-CRP ) . High disease activity was defined as DAS28-CRP > 3.2 . Low disease activity was defined as DAS28-CRP < or = 3.2 . We studied three c and i date alleles in the ATIC , ITPA and MTHFR genes for association with DAS28-CRP . RESULTS Among participants on MTX monotherapy  , those carrying the minor allele of ATIC SNP rs4673993 were more likely to have low disease activity ( P = 0.01 ) . None of the other SNPs was associated with disease activity . Among patients on any MTX ( combination or monotherapy ) , the minor allele of ATIC rs4673993 was also associated with low disease activity ( P = 0.04 ) . CONCLUSIONS In this cross-sectional analysis , ATIC SNP rs4673993 was associated with low disease activity in patients on MTX .  Further studies are needed to clarify the relationship between ATIC polymorphisms , disease activity and treatment response Abstract Rheumatoid arthritis ( RA ) is a common illness of global significance for public health . Methotrexate ( MTX ) is the most broadly used disease-modifying antirheumatic drug for the treatment of RA , but it displays marked person-to-person variation in its propensity for toxicity . Several studies have suggested that polymorphisms in methylenetetrahydrofolate reductase ( MTHFR ) C677 T and A1298C , reduced folate carrier ( RFC1 ) G80A , and ABCB1 C3435 T , could be related to methotrexate toxicity . This prospect i ve study examined the different frequencies of MTHFR , RFC1 , and ABCB1 pharmacogenetic variations between patients who have RA and those without RA . We also sought to assess the association between these polymorphisms and  MTX toxicity . Four single-nucleotide polymorphisms ( SNPs ) were genotyped : C677 T and A1298C from MTHFR , G80A from RFC1 , and C3435 T from ABCB1 . The efficacy and toxicity of MTX  were evaluated through clinical follow-up during 1 year of treatment . RA patients showed a higher frequency of the T allele at MTHFR C677 T than patients without RA ( p=0.049 ) . There was a significant association between the presence of both the T allele at MTHFR C677 T ( p=0.006 ) , and the C allele at ABCB1 C3435 T ( p=0.046 ) , with toxicity development after 12 months of MTX treatment . However , there was no correlation between  MTX toxicity and either the A allele at MTHFR A1298C or the G allele at RFC1 A80 G . These data suggest that the presence of the MTHFR C677 T and ABCB1 C3435 T SNPs contribute to  MTX toxicity in patients with RA . These observations contribute to a rapidly-growing knowledge base on the pharmacogenetics of RA and personalized medicine 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 OBJECTIVE To investigate the accumulation of  methotrexate ( MTX ) in circulating erythrocytes and the association with pharmacokinetic variables , weekly dose , and clinical efficacy in 2 cohorts of patients with chronic active rheumatoid arthritis ( RA ) undergoing MTX monotherapy .  METHODS Seventy-six patients with RA were included in this open prospect i ve study : 40 were included before initiation of MTX therapy .  Laboratory analyses , intracellular MTX concentrations in erythrocytes ( Ery-MTX ) , and clinical examinations including toxicity data were performed prospect ively for 52 weeks . Plasma concentrations of MTX  were measured and area under the plasma concentration versus time curve ( AUC ) was estimated along with other pharmacokinetic variables in a population based software model . RESULTS Ery-MTX rose after initiation of therapy and reached a steady state after 6 - 8 weeks . The correlation between steady-state Ery-MTX and dose was poor ( r(2 ) = 0.16 ) , whereas steady-state Ery-MTX levels correlated strongly with the estimated AUC ( r(2 ) = 0.51 , log-transformed variables ) . Both steady-state Ery-MTX levels and estimated AUC were significantly higher in patients responding to MTX therapy than in patients classified as nonresponders according to American College of Rheumatology core criteria and were similar to patients on longterm MTX therapy . CONCLUSION Our results indicate that clinical efficacy and Ery-MTX may have a causal relation and that measurement of Ery-MTX or estimation of AUC in a software model provides useful guidelines to the clinician when starting MTX therapy in patients with RA . The latter can be performed immediately after initiation of therapy Methylenetetrahydrofolate reductase ( MTHFR ) gene polymorphisms have been reported to be associated with response to methotrexate ( MTX ) in certain population s of patients with rheumatoid arthritis ( RA ) . This study aims at investigating any relationship of two single nucleotide polymorphisms ( SNPs ) in MTHFR gene , C677 T and A1298C with response to therapy with MTX in Pakistani RA patients . Allelic frequencies of the two polymorphisms ( C677 T and A1298C ) were determined in 67 RA patients ( 9 males and 58 females ; mean age 42.87 ± 13.5 years ) who had previously participated in a prospect i ve clinical trial . Fifty-one patients had received MTX and were followed up for response up to 6 months . Genotyping of the two MTHFR polymorphisms was carried out using PCR-RFLP , 
    Output:
    
Polymorphisms in AMPD1 34C > T and ATIC T675C predict responsiveness .
The absence of TYMS 1494 del6 and FPGS rs10106 and presence of MTHFR C677 T predict adverse events in RA patients treated with MTX .
Moreover , variations of the associations were found between Caucasians and non-Caucasians