RESEARCH - Biomarkers in the folate pathway and their association with MTX effects during dosage escalation in RA

[Guest guest]

Arthritis Rheum. 2006 Sep 28;54(10):3095-3103 [Epub ahead of print]

Pharmacogenomic and metabolic biomarkers in the folate pathway and their

association with methotrexate effects during dosage escalation in rheumatoid

arthritis.

Dervieux T, Greenstein N, Kremer J.

Prometheus, San Diego, California.

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).

CONCLUSION: 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.

PMID: 17009228

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=PubMed & list_uids=1\

7009228

Not an MD

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org