RESEARCH - Common polymorphisms in the folate pathway predict efficacy of MTX and sulfasalazine combinations in early RA

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J Rheumatol. 2008 Mar 1 [Epub ahead of print]

Common Polymorphisms in the Folate Pathway Predict Efficacy of

Combination Regimens Containing Methotrexate and Sulfasalazine in

Early Rheumatoid Arthritis.

HM, Gillis D, Hissaria P, Lester S, Somogyi AA, Cleland LG, Proudman SM.

From the Division of Human Immunology, Institute of Medical and

Veterinary Science; Arthritis Research Laboratory, Hanson Institute;

Discipline of Pharmacology, School of Medical Sciences, University of

Adelaide; and Rheumatology Unit, Royal Adelaide Hospital, Adelaide,

Australia.

OBJECTIVE: To study genetic polymorphisms in the folate pathway, a

site of action of methotrexate (MTX) and sulfasalazine (SSZ), as

predictors of efficacy of combination disease modifying antirheumatic

drug (DMARD) regimens containing MTX and SSZ in early rheumatoid

arthritis (RA). METHODS: Ninety-eight Caucasian patients with early RA

received MTX with SSZ, hydroxychloroquine, and folate according to a

standardized protocol. Efficacy was evaluated using the Disease

Activity Score (DAS28) and European League Against Rheumatism response

criteria at 12 months. Nine polymorphisms in 7 genes of the folate

pathway were studied. RESULTS: Response to therapy was associated with

SLC19A1, MTR, and TYMS polymorphisms. Two favorable allele

combinations associated with responder status at 12 months were

identified: the MTR 2756A allele in combination with either the

SLC19A1 80A allele or the TYMS 3R-del6 haplotype (multivariate

analysis, p = 0.0002, p = 0.009 respectively). Seventy of the 72

patients with these allele combinations responded compared to 12/24

patients without [odds ratio (OR) 35.0, 95% confidence interval (CI)

6.9-176, p < 0.0001]. An association with remission (DAS28 < 2.6) was

also observed (OR 3.4, 95% CI 1.1-10.0, p = 0.04). When analyzed over

3 years, both the change in DAS score from baseline and the final DAS

scores were significantly higher and lower, respectively, with the

favorable genotype group (p < 0.0001, p < 0.0001).

CONCLUSION: Polymorphic variations in the MTR, SLC19A1, and TYMS genes

were associated with better clinical response to combination DMARD

regimens containing MTX and SSZ. Allele combinations of these genes

may predict response to combination DMARD and assist in treatment

decisions in patients with early RA.

PMID: 18322994

http://www.ncbi.nlm.nih.gov/pubmed/18322994

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