Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis.
OBJECTIVE
To evaluate the contribution of metabolites (methotrexate [MTX] and folate polyglutamate [PG] levels) and pharmacogenetic biomarkers in the folate pathway to the effects of MTX in patients with rheumatoid arthritis not previously treated with this antifolate.


METHODS
Forty-eight MTX-naive adult patients were enrolled in a prospective longitudinal study. MTX therapy was initiated at 7.5 mg/week and was increased every 4-6 weeks until a therapeutic response was achieved. Response was assessed using the Disease Activity Score in 28 joints (DAS28). Red blood cell (RBC) MTX and folate PG levels were measured with 9 common polymorphisms in the folate pathway. Statistical analyses consisted of generalized linear models and multivariate regressions.


RESULTS
After 6 months of therapy, the median weekly MTX dosage was 17.5 mg and the median decrease in the DAS28 was 2.0. There was a large interpatient variability in RBC MTXPG levels (median 35 nmoles/liter [interquartile range 28-51] at month 6). Patients with a lesser decrease in the DAS28 (fewer improvements) had lower RBC MTXPG levels (P < 0.05) despite the higher MTX dose administered (P < 0.05). RBC folate PG levels decreased significantly during treatment, and a lesser decrease in RBC folate PGs was associated with a lesser decrease in the DAS28 (P < 0.05). Primary side effects were gastrointestinal and neurologic in nature. Risk genotypes associated with toxicity were in gamma-glutamyl hydrolase (-401CC), 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (347GG), methylenetetrahydrofolate reductase (1298AC/CC), methionine synthase (2756AA), and methionine synthase reductase (66GG).


CONCLUSIONS
RBC MTXPG levels are a useful means by which to monitor therapy. The genetic associations presented generate hypotheses, and confirmation in independent cohorts is warranted.
Dervieux
Thierry
T
Prometheus, San Diego, California, USA.
Greenstein
Neal
N
Kremer
Joel
J
D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004798:Enzymes / Q000235:genetics; D005493:Folic Acid Antagonists / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008137:Longitudinal Studies; D008727:Methotrexate / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D008875:Middle Aged; D015999:Multivariate Analysis; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011624:Pteroylpolyglutamic Acids / Q000097:blood* / Q000235:genetics; D012720:Severity of Illness Index
D004798:Enzymes; D005493:Folic Acid Antagonists; D011624:Pteroylpolyglutamic Acids; D008727:Methotrexate