SHP 08-172
Optimizing Rheumatoid Arthritis Disease Modifying Anti-rheumatic Drugs
Grant W. Cannon, MD VA Salt Lake City Health Care System, Salt Lake City, UT Salt Lake City, UT Funding Period: May 2008 - September 2008 Portfolio Assignment: Genomics |
BACKGROUND/RATIONALE:
Rheumatoid arthritis (RA) is a systemic inflammatory disorder that can progress to joint destruction, severe disability, and premature mortality. RA afflicts approximately 1% of the US population and the VHA serves over 67,000 RA patients. Disease modifying anti-rheumatic drug (DMARD) therapy has been proven efficacious and cost effective for RA. There is a critical need for improved health services systems to assure the appropriate DMARD treatment of RA patients as personalized medical care. To achieve these goals, the VA rheumatoid arthritis (VARA) registry has been developed. This prospective cohort study has full regulatory approval to collect clinical data and biologic materials - both serologic and DNA samples - on over 12,000 veteran RA patients. OBJECTIVE(S): Specific Aim #1. Expand the current VARA database to consolidate information from multiple sources for VARA patients. Specific Aim #2. Complete genotyping of all VARA patients for critical susceptibility alleles. Specific Aim #3. Develop a predictive model for DMARD response through analysis of clinical efficacy response and adverse event history associated with clinical, serologic, and genetic features in VARA patients. METHODS: Specific Aim #1. Step # 1. The first step has involved the work to develop supplemental software to expand the capacity of the VARA database to include the specific information on current and prior DMARD therapy and data on adverse events. These templates are in place and fully functional in the VARA database and can be updated routinely to add additional information as it become available in the future. Step #2 Data abstraction and extraction. A data abstraction template has been developed for the collection of DMARD therapy, clinical response, adverse events, and laboratory data in Salt Lake City and at the remote sites in the VARA registry. This extraction technology uses specifically designed templates and reminder systems within CPRS. Working with the Pharmacy Benefits Management Strategic Health Group (PBMSHG) at Hines VA, we have been able to extract prescription information on all VARA patients including start date, numbers of prescriptions dispensed, dose, directions for administration, and cost for each prescription and linked this information with VARA patients. Specific Aim #2. Genotyping has involved SNPs encompassing each of the critical genes under investigation: PTPN22, PADI4, CTLA4, STAT4, and TRAF1-C5 as well as FPGS, GGH, MTHFR, for methotrexate response and toxicity, and IL10, and TNF-alpha genes reported associated with other DMARD responses. Specific Aim #3. The population genetics will be evaluated to identify if an association exists between the polymorphism of the selected genes with DMARD response characteristics and adverse event histories. As an initial analysis, we will focus on methotrexate, the most commonly employed DMARD in RA patients and the VARA cohort. FINDINGS/RESULTS: There are currently 1241 patients in the VARA registry with the database providing the following information. The population is 90% male and 10% female with a median age of 64.0 years (range 23-94 years). The median RA disease duration is 18.4 years (range 3 months to 63.3 years). The RA disease characteristics show that the population is 84% positive for rheumatoid factor and 68% positive for anti-CCP antibody. Erosive disease on radiographs is reported in 64% of patients and rheumatoid nodules reported in 45% of patients. A detailed assessment of methotrexate treatment in this cohort has been completed and a similar analysis will be conducted for all DMARDs. There are 904 (73%) VARA patient who have received methotrexate. The data show that for our population the median duration of methotrexate therapy is 2.5 years with a range from (1 month to 9 years 11 months) with a median weekly dose of 17.5 mg per week (range 2.5 to 25 mg per week). An evaluation of medication compliance was determined by calculating the medication possession ratio. The mean medication possession ratio was 78% assuming a 90 day gap for detection of a new course of therapy. Genotyping information has been completed on 1097 VARA subjects. The laboratory results generated 106,409 genotypes from the 97 SNPs tested in these 1097 patients. Initial analysis of the genetic data demonstrates that allele frequencies seen in the VARA patient population mirrors that of the general population at the tested variants. IMPACT: This work with be the foundation for future HSR&D projects to prospectively test this model and prove that directed therapy will optimize outcomes in RA patients. The overall impact of this type of intervention could result in improved efficacy, reduced adverse events, and a more cost effective application of resources to the treatment of RA patients. External Links for this ProjectDimensions for VADimensions for VA is a web-based tool available to VA staff that enables detailed searches of published research and research projects.Learn more about Dimensions for VA. VA staff not currently on the VA network can access Dimensions by registering for an account using their VA email address. Search Dimensions for this project PUBLICATIONS:Journal Articles
DRA:
Aging, Older Veterans' Health and Care, Health Systems Science
DRE: Pathology, Treatment - Observational Keywords: Arthritis, Genomics, Pharmaceuticals MeSH Terms: none |