PII-081 - MISS SCORES VARY IN ACCORDANCE WITH SLCO1B1 STATUS IN A COHORT OF JIA PATIENTS

F. Gooden¹, Z. Taylor², M. Becker³, S. Thompson², L. Ramsey⁴; ¹Cincinnati Children's Hospital Medical Center/ University of Cincinnati, ²CCHMC, ³Duke University, ⁴Children's Mercy.

Background: Low-dose (15-25 mg/m2) methotrexate (MTX) is a front-line disease modifying anti-rheumatic drug used to treat autoimmune diseases such as juvenile idiopathic arthritis (JIA). Single nucleotide polymorphisms (SNPs) in the gene SLCO1B1 encoding the liver transporter organic anion transporting protein 1B1 resulting in reduced functionality are expressed in 15-30% of the population and have been associated with an increased number of dose reductions and side effects, as well as increased MTX exposure in pediatric leukemia and JIA patients. Increased function SNPs are also expressed by 8-20% of the population and have been associated with reduced efficacy in retrospective meta-analyses of JIA patients. The purpose of this study was to evaluate whether MTX intolerance differs with SLCO1B1 function in an observational cohort study of JIA patients.

Methods: Patients < 18 years of age prescribed weekly MTX for management of JIA were enrolled at multiple sites for observation. SLCO1B1 SNPs (rs4149056, rs2306283, and rs11045819) were determined using an Illumina Omni 2.5 array. Diplotypes were determined by combining the SNPs into the *1, *5, *14, *15, and *37 alleles. Expression of >1 *14 allele was considered to be increased function. MTX intolerance was quantified by the methotrexate intolerance severity score (MISS) questionnaire with intolerance defined as MISS >6. The initial cohort was composed of 275 JIA patients. Both genotype and MISS data from the 6-month follow-up were available for 209 patients. Odds-ratio and Kruskal-Wallis ANOVA were used with statistical significance of p < 0.05.

Results: The cohort was composed of 58.4% normal, 23.0% decreased, 17.2% increased, and 1.4% poor function SLCO1B1 activity. MTX-intolerance was noted in 31.1% of patients in the cohort, and while significant differences in MISS scores amongst SLCO1B1 genotypes were not detected (p = 0.084), patients with increased function had lower odds of behavioral-related intolerance (OR=2.423, p=0.023) and intolerance during dosing instead of anticipatory effects (OR=2.435, p=0.035).

Conclusion: Our data demonstrates that the relationship between SLCO1B1 function and MTX-intolerance is complex in pediatric JIA patients. Next steps include creation of a mixed-model analysis including demographic, route of administration, drug dose, and other factors.