Abstract
Methotrexate (MTX) is the recommended first-line conventional synthetic disease-modifying antirheumatic drug for rheumatoid arthritis (RA), endorsed by current ACR and EULAR guidelines as the anchor agent for both monotherapy and combination regimens [2, 5]. Despite proven efficacy, MTX therapy is limited by hepatotoxicity, occurring in 15–25% of patients and necessitating dose reduction or discontinuation in 5–10% of cases. The CYP2C9 enzyme participates in oxidative metabolism of various drugs including MTX metabolites and concomitant nonsteroidal anti-inflammatory drugs. The CYP2C9*2 polymorphism (Arg144Cys, rs1799853) is a common loss-of-function variant reducing enzymatic activity by 30–50% [1, 3]. The Clinical Pharmacogenetics Implementation Consortium has published guidelines for CYP2C9 genotype-guided drug dosing [6]. Population-specific data on CYP2C9*2 frequency and clinical impact in Central Asian populations remain limited [7].
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