Association of SLCO1B1 *14 Allele with Poor Response to Methotrexate in Juvenile Idiopathic Arthritis Patients

Abstract

ObjectiveVariants in the SLCO1B1 gene, encoding a hepatic methotrexate (MTX) transporter, affect clearance of high‐dose MTX. We tested whether in the *14 and *15 alleles of SLCO1B1 influenced the response to low‐dose MTX in juvenile idiopathic arthritis (JIA) patients.MethodsThe study included 310 JIA patients genotyped for three single nucleotide polymorphisms (SNPs) in SLCO1B1 (rs4149056, rs2306283, and rs11045819). A patient's SLCO1B1 diplotype was determined by combining the SNPs into the *1a, *1b, *4, *5, *14, and *15 alleles. Number of active joints at follow‐up (visit closest to 6 months of treatment and prior to starting a tumor necrosis factor inhibitor) was used as the dependent variable in a negative binomial regression model that included active joint count at baseline as a covariate.ResultsThe SLCO1B1*14 allele was associated with less response to MTX (P = 0.024) and the *15 allele was not associated with response to MTX (P = 0.392).Conclusion SLCO1B1 alleles may be associated with poor response to MTX in JIA patients. The *14 allele has been associated with fast clearance (low exposure) after high‐dose MTX in patients with leukemia. Thus, the SLCO1B1 gene may be informative for precision dosing of MTX in JIA patients. Patients carrying the *14 allele may require a higher dose than noncarriers to achieve a similar response to MTX.

Toward pharmacogenetic SLCO1B1‐guided dosing of methotrexate in arthritis using a murine Slco1b2 knockout model

“…This work provides pre-clinical evidence for prospective PGx studies in pediatric patients and supports the use of PGx testing of SLCO1B1 for patients with RA and JIA receiving low-dose MTX. Additional clinical support recently determined that patients with RA and JIA receiving low-dose MTX had poor treatment outcomes if they were harboring an increased function SLCO1B1 allele (24,25). Results from our study also support a possible dose reduction for patients carrying decreased function SLCO1B1 alleles, which may have a more pronounced effect in children than adults (46).…”

“…Additional clinical support recently determined that patients with RA and JIA receiving low‐dose MTX had poor treatment outcomes if they were harboring an increased function SLCO1B1 allele. 24 , 25 Results from our study also support a possible dose reduction for patients carrying decreased function SLCO1B1 alleles, which may have a more pronounced effect in children than adults. 46 Our genotype‐guided dose modification would suggest that patients homozygous for decreased function alleles would benefit from a 50% dose reduction of MTX, reducing their normal starting dose of 15 mg/m 2 to a 7.5 mg/m 2 dose.…”

“…Additional clinical studies have confirmed that the *5 variant significantly reduced the clearance of MTX by more than 18% per dysfunctional C allele, leading to an increase in MTX exposure and risk for severe toxicity (23). Subsequent studies have also demonstrated the pharmacogenetic (PGx) impact of SLCO1B1 variants rs2306283 (c.388A>G, Asn130Asp) and rs11045819 (c.463C>A, Pro155Thr) on low-dose MTX and therapeutic response in patients with rheumatoid arthritis (24) and JIA (25). However, further studies linking SLCO1B1 to MTX are required in order to increase the level of evidence for this gene-drug pair and establish dosing recommendations.…”

“… 23 Subsequent studies have also demonstrated the pharmacogenetic (PGx) impact of SLCO1B1 variants rs2306283 (c.388A>G, Asn130Asp) and rs11045819 (c.463C>A, Pro155Thr) on low‐dose MTX and therapeutic response in patients with RA 24 and JIA. 25 However, further studies linking SLCO1B1 to MTX are required in order to increase the level of evidence for this gene‐drug pair and establish dosing recommendations.…”

Biomarkers of Response to Biologic Therapy in Juvenile Idiopathic Arthritis

“…Various genetic biomarkers have been investigated to assess their potential as predictor biomarkers of clinical response in JIA, with the majority of studies focused on response to methotrexate treatment as first line therapy in JIA ( Hinks et al, 2011 ; Ramsey et al, 2019 ). Human leukocyte antigen B27 (HLA-B27) positivity in JIA patients was associated with double the odds of not being in clinical remission of treatment at the end of 8 years follow-up irrespective of treatment ( Berntson et al, 2013 ).…”