ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2483

Folic Acid Pathway Single Neucelotide Polymorphisms Associated with Methotrexate-Related Significant Adverse Events

Lisa A. Davis1, Brooke Ivan Polk2, Alyse D. Mann3, Roger K. Wolff4, Gail S. Kerr5, Andreas M. Reimold6, Grant W. Cannon7, Ted R. Mikuls8 and Liron Caplan9, 1Div of Rheumatology, Univ of Colorado School of Med, Aurora, CO, 2University of Colorado Medical School, Aurora, CO, 3Research, Denver VA Medical Center, Denver, CO, 4University of Utah, Salt Lake City, UT, 5Rheumatology, Washington DC VAMC, Georgetown and Howard University, Washington, DC, 6Rheumatology, Dallas VA and University of Texas Southwestern, Dallas, TX, 7Division of Rheumatology, George E. Wahlen VA Medical Center, Salt Lake City, UT, 8Omaha VA Medical Center and University of Nebraska Medical Center, Omaha, NE, 9Div of Rheumatology, Denver VA and University of Colorado School of Medicine, Aurora, CO

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: , ,

Session Information

Session Title: Rheumatoid Arthritis - Clinical Aspects IV: Non-biologic Drugs for Rheumatoid Arthritis: New Insights on Comorbidities and Adverse Events

Session Type: Abstract Submissions (ACR)

  Background/Purpose: Methotrexate (MTX) is the cornerstone medication in the treatment of rheumatoid arthritis (RA). While MTX has been associated with a number of adverse events (AE), most are insignificant, and do not result in cessation of MTX. We examined whether single nucleotide polymorphisms (SNPs) in enzymes that participate in the folic acid pathway (folypoly-gamma-glutamate synthetase [FPGS], gamma-glutamyl hydrolase [GGH], and methylenetetrahydrofolate reductase [MTHFR]) are associated with significant adverse events (SigAE) complicating MTX treatment. Methods: Patients (n=319) enrolled in the prospective Veterans Affairs RA (VARA) registry and who were taking MTX were genotyped for multiple SNPs with DNA samples derived from whole blood. Genes and associated SNPs included:  FPGS (rs7033913, rs10760503, rs10106), GGH (12548933, rs7010484, rs4617146, rs719235, rs11988534), MTHFR (rs1801131, rs1801133). Patients were also genotyped for HLA-DRB1 polymorphisms. Covariates included: age, gender, Charlson-Deyo comorbidity index at VARA enrollment, glucocorticoid use concomitant with MTX, and mean 4-variable disease activity score. SigAE was defined as an AE leading to MTX discontinuation (operationalized as an AE occurring within 120 days prior to MTX cessation). Multivariate backward stepwise logistic and Cox regression were performed to determine factors associated with the presence of SigAE and time to SigAE, respectively. SNPs were modeled as a categorical variable comparing no minor alleles (homozygous major allele) and ≥ 1 copy of minor allele. A p-value <0.005 was deemed significant in the final model. Results: The SNP associated with an increased odds of SigAE by logistic regression was the minor allele of GGH rs12548933 (OR 3.43, 95% CI 1.58-7.48) (see Table). This same variable was also associated with an increased hazard ratio (HR) of SigAE (HR 2.42, 95% CI 1.32-4.41) (see Figure). Conclusion:  RA subjects on MTX may be at increased risk of AE leading to cessation of MTX if they have ≥ 1 copy of the minor allele in GGH rs12548933. Further investigation is warranted, as this SNP may indicate a susceptibility to MTX toxicity.

Table: Final Regression results for logistic and Cox models

Disclosure:

L. A. Davis,
None;

B. Ivan Polk,
None;

A. D. Mann,
None;

R. K. Wolff,
None;

G. S. Kerr,
None;

A. M. Reimold,
None;

G. W. Cannon,
None;

T. R. Mikuls,
None;

L. Caplan,
None.

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