Medications for the treatment of RA include disease modifying anti-rheumatic drugs (DMARDs) such as methotrexate (MTX), sulfasalazine (SSZ), hydroxychloroquine (HCQ), and the TNF inhibitor etanercept. Multiple new biologic agents currently in development. As the number and expense of treatments increase, clinicians need information to guide treatment in individual RA patients. TNF plays an important role in the pathogenesis of RA and its gene lies in the MHC region near HLA DRB1 (for which alleles containing the shared epitope [SE] have established roles in RA). Thus, genetic variants in the MHC region are logical candidate pharmacogenetic markers. Most previous studies analyzing association between MHC markers and treatment response have been limited by lack of standardized DMARD and corticosteroid regimens, suboptimal outcome measures, short periods of observation, retrospective design, or lack of statistical power due to small numbers of patients. Our preliminary analysis of 457 subjects in the Immunex Early Rheumatoid Arthritis Trial comparing. MTX and etanercept indicates that response is predicted by haplotypes comprising HLA DRB1 alleles and TNF/LTA single nucleotide polymorphisms (SNPs). Neither the SE nor TNF/LTA SNPs account for this finding alone, so it is not clear which area of the MHC influences treatment response. The 1,000 Kb region between HLA DRB1 and TNF/LTA is gene-dense, with many non-HLA immune-related genes that may influence treatment response in RA through as yet undefined mechanisms. The TEAR (Treatment of Early Aggressive RA) trial is a unique, double-blind, multicenter, investigator-initiated, pharmaceutically-sponsored study to compare the efficacy of 2 years of treatment with MTX, triple DMARDs (MTX + SSZ + HCQ), and MTX plus etanercept in 750 subjects. TEAR represents a special and unique opportunity to analyze genetic markers of response in early RA in a rigorous, adequately powered, prospective clinical trial. We believe that these analyses will ultimately lead to information useful in guiding treatment decisions of clinicians caring for patients with RA, which is becoming increasingly important as the number and cost of therapies for RA continue to increase.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR052658-02S1
Application #
7192281
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Serrate-Sztein, Susana
Project Start
2004-09-28
Project End
2008-05-31
Budget Start
2006-02-01
Budget End
2006-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$24,386
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Charles-Schoeman, Christina; Yin Lee, Yuen; Shahbazian, Ani et al. (2017) Improvement of High-Density Lipoprotein Function in Patients With Early Rheumatoid Arthritis Treated With Methotrexate Monotherapy or Combination Therapies in a Randomized Controlled Trial. Arthritis Rheumatol 69:46-57
Charles-Schoeman, Christina; Wang, Xiaoyan; Lee, Yuen Yin et al. (2016) Association of Triple Therapy With Improvement in Cholesterol Profiles Over Two-Year Followup in the Treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheumatol 68:577-86
Hwang, Yong Gil; Balasubramani, Goundappa K; Metes, Ilinca D et al. (2016) Differential response of serum amyloid A to different therapies in early rheumatoid arthritis and its potential value as a disease activity biomarker. Arthritis Res Ther 18:108
Aslibekyan, S; Brown, E E; Reynolds, R J et al. (2014) Genetic variants associated with methotrexate efficacy and toxicity in early rheumatoid arthritis: results from the treatment of early aggressive rheumatoid arthritis trial. Pharmacogenomics J 14:48-53
Aslibekyan, Stella; Sha, Jin; Redden, David T et al. (2014) Gene-body mass index interactions are associated with methotrexate toxicity in rheumatoid arthritis. Ann Rheum Dis 73:785-6
Cui, Jing; Stahl, Eli A; Saevarsdottir, Saedis et al. (2013) Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis. PLoS Genet 9:e1003394
Navarro-Millán, Iris; Charles-Schoeman, Christina; Yang, Shuo et al. (2013) Changes in lipoproteins associated with methotrexate or combination therapy in early rheumatoid arthritis: results from the treatment of early rheumatoid arthritis trial. Arthritis Rheum 65:1430-8
Umi?evi? Mirkov, Maša; Cui, Jing; Vermeulen, Sita H et al. (2013) Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis. Ann Rheum Dis 72:1375-81
Curtis, Jeffrey R; McVie, Theresa; Mikuls, Ted R et al. (2013) Clinical response within 12 weeks as a predictor of future low disease activity in patients with early RA: results from the TEAR Trial. J Rheumatol 40:572-8
O'Dell, James R; Curtis, Jeffrey R; Mikuls, Ted R et al. (2013) Validation of the methotrexate-first strategy in patients with early, poor-prognosis rheumatoid arthritis: results from a two-year randomized, double-blind trial. Arthritis Rheum 65:1985-94

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