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Common Polymorphisms in the Folate Pathway Predict Efficacy of Combination Regimens Containing Methotrexate and Sulfasalazine in Early Rheumatoid Arthritis
HEATHER M. JAMES, DAVID GILLIS, PRAVIN HISSARIA, SUSAN LESTER, ANDREW A. SOMOGYI, LESLIE G. CLELAND, and SUSANNA M. PROUDMAN
ABSTRACT. 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. (J Rheumatol First Release Mar 1 2008) Key Indexing Terms:
METHOTREXATE
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. Supported by a Royal Adelaide Hospital Clinical Project Grant, Adelaide, and the National Health and Medical Research Council of Australia. H.M. James, MSc; D. Gillis, MBBS, FRCPA, FRACP; P. Hissaria, MD, FRCPA, Division of Human Immunology, Institute of Medical and Veterinary Science; S. Lester, BSc (Hons), Arthritis Research Laboratory, Hanson Institute; A.A. Somogyi, PhD, Discipline of Pharmacology, School of Medical Sciences, University of Adelaide and Royal Adelaide Hospital; L.G. Cleland, MD, FRACP; S.M. Proudman, MBBS (Hons), FRACP, Rheumatology Unit, Royal Adelaide Hospital. Address reprint requests to Dr. H.M. James, Division of Human Immunology, Institute of Medical and Veterinary Science, PO Box 14, Rundle Mall, Adelaide SA 5000 Australia. E-mail: heather.james@imvs.sa.gov.au Accepted for publication November 20, 2007.
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