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. 2005 Jan 27;64(8):1180–1185. doi: 10.1136/ard.2004.033399

Pharmacogenetic and metabolite measurements are associated with clinical status in patients with rheumatoid arthritis treated with methotrexate: results of a multicentred cross sectional observational study

T Dervieux 1, D Furst 1, D Lein 1, R Capps 1, K Smith 1, J Caldwell 1, J Kremer 1
PMCID: PMC1755602  PMID: 15677700

Abstract

Objective: To investigate the contribution of red blood cell (RBC) methotrexate polyglutamates (MTX PGs), RBC folate polyglutamates (folate PGs), and a pharmacogenetic index to the clinical status of patients with rheumatoid arthritis treated with MTX.

Methods: 226 adult patients treated with weekly MTX for more than 3 months were enrolled at three sites in a multicentred cross sectional observational study. Clinical status was assessed by the number of joint counts, physician's global assessment of disease activity, and a modified Health Assessment Questionnaire (mHAQ). RBC MTX PG and folate PG metabolite levels were measured by high performance liquid chromatography fluorometry and radioassay, respectively. A composite pharmacogenetic index comprising low penetrance genetic polymorphisms in reduced folate carrier (RFC-1 G80A), AICAR transformylase (ATIC C347G), and thymidylate synthase (TSER*2/*3) was calculated. Statistical analyses were by multivariate linear regression with clinical measures as dependent variables and metabolite levels and the pharmacogenetic index as independent variables after adjustment for other covariates.

Results: Multivariate analysis showed that lower RBC MTX PG levels (median 40 nmol/l) and a lower pharmacogenetic index (median 2) were associated with a higher number of joint counts, higher disease activity, and higher mHAQ (p<0.09). Multivariate analysis also established that higher RBC folate PG levels (median 1062 nmol/l) were associated with a higher number of tender and swollen joints after adjustment for RBC MTX PG levels and the pharmacogenetic index (p<0.05).

Conclusion: Pharmacogenetic and metabolite measurements may be useful in optimising MTX treatment. Prospective studies are warranted to investigate the predictive value of these markers for MTX efficacy.

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Figure 1.

Figure 1

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 Pharmacogenetic index. The index ranged from 0 to 5 (median 2). Two patients had an index of 5, which corresponded to the presence of the three homozygous variant genotypes (value of 2 for ATIC 347GG + value of 2 for TSER*2/*2 + value of 1 for RFC-1 80AA). Fifteen patients had an index of 0, which corresponded to the presence of ATIC 347CC (value of 0), TSER*3/*3 (value of 0), and the presence of either the RFC-1 80GG or GA genotype (value of 0 for wild-type and heterozygous). The number of patients (percentage of the total group) is given for each index.

Figure 2.

Figure 2

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 Association between the pharmacogenetic index and clinical status. In a univariate analysis, a lower pharmacogenetic index was associated with (A) a higher number of tender joints (p = 0.002); (B) a higher number of swollen joints (p = 0.003); (C) a higher physician's global assessment of disease activity VAS (p = 0.032); and (D) a higher mHAQ (p = 0.047). Results are expressed as mean (SEM). The linear regression line is shown.

Figure 3.

Figure 3

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 Association between MTX PGs, pharmacogenetic index, and the physician's assessment of patient's response to MTX. Patients having RBC MTX PG levels <60 nmol/l were 4.4-fold (95% CI 2.0 to 8.5; p = 0.0001) more likely to present a physician's assessment of patient's response to MTX VAS >2 cm (poor response). A lower pharmacogenetic index was also associated with a higher likelihood of physician's assessment of patient's response to MTX VAS >2 cm (p = 0.034). Probability (95% CI) is given.

Figure 4.

Figure 4

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 Association between RBC folate PG concentrations and the number of tender and swollen joints. (A) Higher daily folic acid doses resulted in higher RBC folate PGs (p = 0.009). (B) In a univariate linear regression, higher folate PGs were associated with a higher number of tender (p = 0.002) and swollen joints (p = 0.006). The number of tender and swollen joints calculated from the univariate regression is given for folate PGs in the 10th (622 nmol/l), 25th (738 nmol/l), 50th (1062 nmol/l), 75th (1447 nmol/l), and 90th centile (1736 nmol/l) of the patient population. Bars represent values with 95% CI.

Selected References

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