Genetic Predictors of Methotrexate Efficacy and Toxicity in Early Rheumatoid Arthritis: Results From the Treatment of Early Aggressive Rheumatoid Arthritis Trial

Stella Aslibekyan¹, Elizabeth Brown², Richard J. Reynolds³, David T. Redden⁴, Sarah L. Morgan⁵, Joseph Baggott¹, Jin Sha¹, Larry W. Moreland⁶, James R. O'Dell⁷, Jeffrey R. Curtis⁸, S. Louis Bridges Jr.⁹ and Donna K. Arnett¹, ¹University of Alabama at Birmingham, Birmingham, AL, ²Univ of Alabama at Birmingham, Birmingham, AL, Birmingham, AL, ³Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, ⁴Biostatistics, University of Alabama at Birmingham, Birmingham, AL, ⁵University of Alabama Birmingham, Birmingham, AL, ⁶Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, ⁷Dept of Internal Medicine, Univ of Nebraska Med Ctr, Omaha, NE, ⁸Rheumatology & Immunology, Univ of Alabama-Birmingham, Birmingham, AL, ⁹Division of Clinical Immunology & Rheumatology, University of Alabama at Birmingham, Birmingham, AL

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: genomics, methotrexate (MTX) and rheumatoid arthritis, treatment

Session Information

Title: Genetics and Genomics of Rheumatic Diseases

Session Type: Abstract Submissions (ACR)

Background/Purpose: Methotrexate (MTX) has emerged as first-line therapy for early moderate to severe rheumatoid arthritis (RA), but individual variation in treatment efficacy and toxicity remains unexplained. We test the hypothesis that genetic markers in genes involved in drug metabolism, excretion, and transport are associated with MTX response in early RA.

Methods: Treatment of Early Aggressive Rheumatoid Arthritis Trial participants (n=471) were analyzed for 863 markers spanning 224 genes from key pharmacogenetic pathways. Multiple regression models were fit with efficacy (Disease Activity Score on 28 joints at 24 weeks) and toxicity (self-report of any side effects or infections) as outcomes, adjusted for age, sex, race, and treatment, and single markers as predictors. Penalized regression models were used to test joint associations of markers and/or covariates with the outcomes.

Results: The strongest genetic associations with efficacy were in the CHST11 gene (five markers with P <0.0024), encoding carbohydrate (chondroitin 4) sulfotransferase 11. Top markers associated with MTX toxicity were in the cytochrome p450 superfamily genes CYP20A1 and CYP39A1, solute carrier genes SLC22A2 and SLC7A7, and the mitochondrial aldehyde dehydrogenase gene ALDH2 (P<0.004). Results from the penalized regression models included only genetic markers for the toxicity outcome, while clinical covariates were stronger predictors of MTX efficacy. The selected markers explained more variance in toxicity (9%) than efficacy (4%).

Conclusion: We identified several novel and biologically relevant genetic markers associated with MTX response in early RA. These preliminary findings could inform future development of personalized therapeutic approaches.

Disclosure:

S. Aslibekyan,
None;

E. Brown,
None;

R. J. Reynolds,
None;

D. T. Redden,
None;

S. L. Morgan,
None;

J. Baggott,
None;

J. Sha,
None;

L. W. Moreland,
None;

J. R. O’Dell,
None;

J. R. Curtis,

Roche/Genetech, UCB, Centocor, CORRONA, Amgen Pfizer, BMS, Crescendo, Abbott,

S. L. Bridges Jr.,
None;

D. K. Arnett,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetic-predictors-of-methotrexate-efficacy-and-toxicity-in-early-rheumatoid-arthritis-results-from-the-treatment-of-early-aggressive-rheumatoid-arthritis-trial/