RESEARCH - Efficacy and toxicity of MTX in early RA are associated with polymorphisms in genes coding for folate pathway enzymes

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Arthritis Rheum. 2006 Mar 29;54(4):1087-1095 [Epub ahead of print]

Efficacy and toxicity of methotrexate in early rheumatoid arthritis are

associated with single-nucleotide polymorphisms in genes coding for folate

pathway enzymes.

Wessels JA, de Vries-Bouwstra JK, Heijmans BT, Slagboom PE,

Goekoop-Ruiterman YP, Allaart CF, Kerstens PJ, van Zeben D, Breedveld FC,

Dijkmans BA, Huizinga TW, Guchelaar HJ.

Leiden University Medical Center, Leiden, The Netherlands.

OBJECTIVE: To determine associations of methotrexate (MTX) efficacy and

toxicity with single-nucleotide polymorphisms (SNPs) in genes coding for

folate pathway enzymes in patients with early rheumatoid arthritis (RA).

METHODS: Patients (n = 205) with active RA received MTX at an initial dosage

of 7.5 mg/week, which was increased to 15 mg/week and combined with folic

acid (1 mg/day) after 4 weeks. If the Disease Activity Score in 44 joints

(DAS44) was >2.4 at 3 months, MTX was increased to 25 mg/week. MTX efficacy

was evaluated at 3 and 6 months and compared for genotypes in 3 analyses:

patients with and without good response (DAS44 </=2.4), patients with and

without good improvement (DeltaDAS44 >1.2), and patients with and without

moderate improvement (DeltaDAS44 >0.6). The association between MTX-related

adverse drug events (ADEs) and genotype was evaluated by comparing genotypes

between patients with and without ADEs, specifically pneumonitis,

gastrointestinal ADEs, skin and mucosal ADEs, and elevated liver enzyme

levels. The following SNPs were analyzed: methylenetetrahydrofolate

reductase (MTHFR) 677C>T, MTHFR 1298A>C, dihydrofolate reductase

(DHFR) -473G>A, DHFR 35289G>A, and reduced folate carrier 80G>A. In case of

significant differences, odds ratios (ORs) were calculated. RESULTS: At 6

months, MTHFR 1298AA was associated with good improvement relative to 1298C

(OR 2.3, 95% confidence interval [95% CI] 1.18-4.41), which increased with

increased copies of the MTHFR 677CC haplotype. In contrast, MTHFR 1298C

allele carriers developed more ADEs (OR 2.5, 95% CI 1.32-4.72).

CONCLUSION: Patients with MTHFR 1298AA and MTHFR 677CC showed greater

clinical improvement with MTX, whereas only the MTHFR 1298C allele was

associated with toxicity. In the future, MTHFR genotypes may help determine

which patients will benefit most from MTX treatment.

PMID: 16572443

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

6572443

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Mayo Clinic in Rochester

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s Hopkins Medicine

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