Genetic variation in SLCO1B1 is associated with methotrexate intolerance symptoms in juvenile idiopathic arthritis patients

SLCO1B1

Variation in SLCO1B1, encoding the hepatic uptake transporter OATP1B1, associated with methotrexate intolerance symptoms

Methotrexate is poorly tolerated by roughly 30% of children treated for juvenile idiopathic arthritis, with anticipatory or postdose nausea, vomiting and behavioural symptoms that often lead to discontinuation. Associations between SLCO1B1 variants and methotrexate toxicity had only been described retrospectively in inflammatory bowel disease, with no prospective evaluation in juvenile idiopathic arthritis. The authors followed a prospective observational cohort of 217 patients receiving standard weekly doses of 5-25 mg/m2, assessed with the MISS questionnaire at 6 ± 2 months after initiation, using a zero-inflated Poisson analysis with forward stepwise inclusion of clinical covariates followed by SLCO1B1 alleles. Over 30% of patients met the intolerance threshold (MISS ≥ 6) and 62.7% reported any symptom (MISS > 0). The SLCO1B1 37 star allele was associated with lower odds of intolerance (odds ratio 0.60; P = 0.046) and a lower MISS score among symptomatic patients (incidence rate ratio 0.74; P < 0.001), suggesting protection, a finding consistent in sensitivity analyses stratified by folic acid supplementation.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The value of this work lies in its prospective design and use of a standardised instrument, the MISS, whereas the literature on methotrexate intolerance rests largely on heterogeneous retrospective collections. Caution is warranted on the primary result: a P of 0.046 for the binary association and an odds ratio of 0.60 on an uncommon star allele call for independent replication before any clinical translation, even though the effect on symptom intensity is markedly more robust. A protective star allele also remains hard to use in practice, since it does not identify the at-risk patients in whom supplementation or a change of route should be anticipated.

Analysis by Dr Thibaut Benquey