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Genetic variation in SLCO1B1 is associated with methotrexate intolerance symptoms in juvenile idiopathic arthritis
Felicia Gooden1,2, Lisa J Martin3,4, Marc Sudman5
1Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine.
Abstract:
Methotrexate (MTX) treatment of juvenile idiopathic arthritis (JIA) is complicated by severe intolerance in approximately 30% of patients. MTX intolerance typically presents as nausea (anticipatory and postdose), vomiting, and behavioral symptoms. Although genetic variants in SLCO1B1 have been associated with MTX toxicity in retrospective studies of inflammatory bowel disease, prospective evaluation of this relationship in JIA patients is lacking. This study examined SLCO1B1-MTX intolerance associations accounting for clinical covariates in a prospective observational cohort of patients receiving standard weekly MTX doses (5-25 mg/m2). We performed a zero-inflated Poisson analysis using forward stepwise inclusion of clinical covariates followed by SLCO1B1 alleles. Among 217 JIA patients who completed the MTX Intolerance Severity Score (MISS) survey at 6 ± 2 months post-MTX initiation, the cohort was predominantly female (69.1%), White (76.5%), and received supplementation with folic acid (70.5%). Over 30% of patients met the threshold for MTX intolerance (MISS ≥ 6), and 62.7% of patients reported any MTX intolerance symptoms (MISS > 0). The SLCO1B1*37 allele was associated with lower odds of MISS > 0 (odds ratio = 0.60, P = 0.046) and a lower reported MISS score (incidence rate ratio = 0.74, P < 0.001) among individuals with non-zero intolerance, suggesting protection from MTX intolerance symptoms. These associations were consistent in sensitivity analyses stratified by folic acid supplementation. Further validation of these findings is needed to support future pharmacogenetic-guided MTX dosing strategies, including evaluation of other SLCO1B1 alleles.
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