Update-1/14/2009:

Hot Topic:
Carbamazepine- and Phenytoin-Related Stevens-Johnson Syndrome Linked to HLA Allele in a Thai Population


Seizures and Epilepsy

Potentially fatal skin reactions including Stevens Johnson syndrome (SJS) have been reported with various antiepileptic drugs. In December of 2007, the United States Food and Drug Administration (FDA) issued a warning, based on a number of studies, that Asian individuals carrying a particular human leukocyte antigen (HLA) allele, HLA-B*1502, were at particularly high risk of developing serious skin reactions with carbamazepine. The warning urged physicians to screen all Asian patients for this particular allele prior to initiating therapy with carbamazepine. A recent study extends the range of populations that have been implicated in this association and raises the possibility that the allele is also a risk factor for skin reactions during phenytoin treatment.

The authors examined the records of 31 Thai patients with epilepsy who had an episode of either SJS (n = 10) or maculopapular eruption (MPE, n = 21), a condition that can precede SJS. Another 50 epileptic patients without skin reactions were recruited as controls. Each of the skin conditions was defined by standard criteria. All patients had peripheral blood tested for HLA-B genotypes.

The 10 patients with SJS were taking either carbamazepine (n = 6) or phenytoin (n = 4), and all 10 tested positive for the HLA-B*1502 allele. Of the 50 controls, 8 (16%) tested positive for the HLA-B*1502 allele. The HLA-B*1502 allele frequency in the SJS group taking carbamazepine was significantly higher compared with the control group taking carbamazepine (p = .0005); presence of the HLA-B*1502 allele in this study had a 100% (95% CI, 61%-100%) sensitivity and 75% (95% CI, 67%-90%) specificity for carbamazepine-induced SJS.

In addition, the authors found a significantly higher HLA-B*1502 allele frequency in the SJS group taking phenytoin compared to the control group taking phenytoin (p = .005); presence of the HLA-B*1502 allele had a 100% (95% CI, 51-100%) sensitivity and 82% (95% CI, 69-91%) specificity for phenytoin-induced SJS.

Interestingly, all 10 of the patients with the HLA-B*1502 allele and SJS had received other AEDs previously without skin reactions including three of the carbamazepine-induced SJS patients who had previously taken phenytoin and one of the phenytoin-induced SJS patients who had taken carbamazepine in the past. This observation argues for environmental factors mediating this association and requires further study. Although MPE can precede SJS, there was no significant association found between HLA-B genotype and carbamazepine- or phenytoin-induced MPE.

This study is an important contribution to the emerging field of pharmacogenomics. It demonstrates that antiepileptic drug-induced SJS is associated with the HLA-B*1502 allele in yet another Asian population, those of Thai decent. Additionally, the association between phenytoin and this HLA-B allele appears to also be strong. For clinicians, patients of any Asian decent should probably be tested for the HLA-B*1502 allele prior to initiating treatment with either of these drugs; current recommendations do not recommend testing for this allele in non-Asian populations due to its low frequency. This advance once again demonstrates that we are moving toward an era where clinicians can use genetic testing on an individual patient level in order to best optimize their choice and dosage of medication.

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For your Reference



Updates: Harrison's Online: Chapter 363. Seizures and Epilepsy



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