Pharmacogenomics of methotrexate in Juvenile Rheumatoid Arthritis (JRA)
David N. Glass, MD, is the Principal Investigator for the Multidisciplinary Clinical Research Center (MCRC) and the Genome Project.
Methotrexate is the most commonly used second-line therapy for Juvenile Rheumatoid Arthritis (JRA) with approximately 60 percent showing a favorable response. With the increasing availability of more effective medicines and their use early in the course of disease, choice of therapy for JRA has become an even more important clinical issue that it was in the past. However, the proportion of patients who do not respond to a given therapy is sometimes substantial suggesting a need for early screening for treatment effectiveness.
For example, some 30 to 40 percent of patients do not benefit from methotrexate and a small proportion fail to respond to any therapy. It is likely that the capacity to respond to a drug, and the observed variation between patients in toxicity, are genetically determined. Methotrexate, one of the most widely used and effective treatments for JRA, will be studied as a paradigm in this regard. The human genome project and its databases as well as a local JRA genomics database can be leveraged to study methotrexate pharmacokinetics and used to test the hypothesis that methotrexate resistance (or responsiveness) in JRA is a function of genetic diversity as is overall susceptibility to JRA.
This hypothesis will be tested in three ways:
- We will determine if specific methotrexate responsiveness and/or toxicity genes exist in children using a candidate gene approach in a responder/non-responder study.
- The association study findings will be replicated by linkage analysis using transmission disequilibrium testing (TDT) in simplex and multiplex JRA families.
- A modified genome-wide screen for methotrexate responsiveness and toxicity will be performed.
Our long-term goals are to match JRA patients to therapies most likely to give the best clinical effect with the least toxicity (i.e., have a good at risk / benefit profile) thus improving the quality of life for these clinically disabled patients.
Publications:
Rosen P, Moroldo MB, Lovell DJ, Thompson SD, Giannini EH, Glass DN: Discordant phenotypes for methotrexate response in juvenile rheumatoid arthritis. Arthritis Rheum 46:S470, 2002.
Rosen P, Thompson S, Glass D. Non-HLA gene polymporphisms in juvenile rheumatoid arthritis. Clin. Exp. Rheumatol. 2003 21(5): 650-656.
