Abstract
Phenytoin (PHT) is one of the most commonly reported aromatic anti-epileptic drugs (AEDs) to cause cutaneous adverse reactions (CADRs), particularly severe cutaneous adverse reactions (SCARs). Although human leukocyte antigen (HLA)-B*15:02 is associated with PHT-induced Steven Johnson syndrome/toxic epidermal necrosis (SJS/TEN) in East Asians, the association is much weaker than it is reported for carbamazepine (CBZ). In this study, we investigated the association of pharmacogenetic variants of the HLA B gene and CYP2C9*3 with PHT-CADRs in South Indian epileptic patients. This prospective case-controlled study included 25 PHT-induced CADRs, 30 phenytoin-tolerant patients, and 463 (HLA-B) and 82 (CYP2C9*3) normal-controls from previous studies included for the case and normal-control comparison. Six SCARs cases and 19 mild-moderate reactions were observed among the 25 cases. Pooled data analysis was performed for the HLA B*51:01 and PHT-CADRs associations. The Fisher exact test and multivariate binary logistic regression analysis were used to identify the susceptible alleles associated with PHT-CADRs. Multivariate analysis showed that CYP2C9*3 was significantly associated with overall PHT-CADRs (OR = 12.00, 95% CI 2.759–84.87, p = 003). In subgroup analysis, CYP2C9*3 and HLA B*55:01 were found to be associated with PHT-SCARs (OR = 12.45, 95% CI 1.138–136.2, p = 0.003) and PHT-maculopapular exanthema (MPE) (OR = 4.041, 95% CI 1.125–15.67, p = 0.035), respectively. Pooled data analysis has confirmed the association between HLA B*51:01/PHT-SCARs (OR = 6.273, 95% CI 2.24–16.69, p = <0.001) and HLA B*51:01/PHT-overall CADRs (OR = 2.323, 95% CI 1.22–5.899, p = 0.037). In this study, neither the case nor the control groups had any patients with HLA B*15:02. The risk variables for PHT-SCARs, PHT-overall CADRs, and PHT-MPE were found to be HLA B*51:01, CYP2C9*3, and HLA B*55:01, respectively. These alleles were identified as the risk factors for the first time in the South Indian Tamil population for PHT-CADRs. Further investigation is warranted to establish the clinical relevance of these alleles in this population with larger sample size.
Highlights
Phenytoin (PHT) is still the most effective treatment for generalized tonic-clonic seizures (GTCS) despite newer anti-epileptic drugs’ (AED) availability [1,2]
The human leukocyte antigen (HLA) B*51:01 allele was found to be strongly associated with PHTSCARs, especially drug rash with eosinophilia and systemic symptoms (DRESS), and the pooled data analysis corroborated this relationship with both severe cutaneous adverse reactions (SCARs) and overall cutaneous adverse reactions (CADRs)
CYP2C9*3 and HLA B*51:01 were found to be associated with PHT-SCARs and PHTDRESS
Summary
Phenytoin (PHT) is still the most effective treatment for generalized tonic-clonic seizures (GTCS) despite newer anti-epileptic drugs’ (AED) availability [1,2]. Cutaneous adverse drug reactions (CADRs) may limit its use; the estimated relative risk of PHT-severe cutaneous adverse reactions (SCARs) was reported to be 13% [3]. PHT and carbamazepine (CBZ) are the worst offenders of CADRs, with incidence rates of 13 and 18%, respectively [5]. In 2004, the association between HLA B*15:02 and CBZ-Steven Johnson syndrome/toxic epidermal necrosis (SJS/TEN) was reported among the Han Chinese populations [6]. Later this association has been confirmed with PHT-SJS/TEN in the Thai and Chinese Asian population [7,8]. The FDA issued a warning for HLA B*15:02/PHT-SJS/TEN cross-reactivity. The strength of this association is weaker than CBZ-SJS/TEN and not demonstrated well enough in many populations [9,10]
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