STEVENS-JOHNSON SYNDROME, SUSCEPTIBILITY TO, INCLUDED
HYPERSENSITIVITY SYNDROME, CARBAMAZEPINE-INDUCED, SUSCEPTIBILITY TO, INCLUDED
Dermatostomatitis, Stevens Johnson type
Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are rare severe blistering mucocutaneous diseases that share clinical and histopathologic features but vary in the extent of epidermal detachment (Roujeau et al., 1995). Both disorders are characterized by high ... Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are rare severe blistering mucocutaneous diseases that share clinical and histopathologic features but vary in the extent of epidermal detachment (Roujeau et al., 1995). Both disorders are characterized by high fever, malaise, and a rapidly developing blistering exanthema of macules and target-like lesions accompanied by mucosal involvement (Rzany et al., 1999). When there is very extensive skin detachment and poor prognosis (death rates of 30 to 40%) the condition is usually called toxic epidermal necrolysis; milder forms are known as Stevens-Johnson syndrome or overlapping Stevens-Johnson syndrome and toxic epidermal necrolysis (Bastuji-Garin et al., 1993). The carbamazepine-induced hypersensitivity syndrome includes symptoms such as rash, fever, eosinophilia, hepatitis, and nephritis. This phenotype is associated with a mortality of up to 10% (summary by McCormack et al., 2011).
Chung et al. (2004) studied 44 patients with carbamazepine-induced Stevens-Johnson syndrome, including 5 with overlapping toxic epidermal necrolysis, in whom the clinical morphology fulfilled Roujeau's diagnostic criteria (Roujeau, 1994). Controls included 101 patients who had been treated with ... Chung et al. (2004) studied 44 patients with carbamazepine-induced Stevens-Johnson syndrome, including 5 with overlapping toxic epidermal necrolysis, in whom the clinical morphology fulfilled Roujeau's diagnostic criteria (Roujeau, 1994). Controls included 101 patients who had been treated with carbamazepine for at least 3 months without adverse reaction and 93 normal individuals. All participants were Han Chinese residing in Taiwan. Chung et al. (2004) found that 100% of the patients who developed Stevens-Johnson syndrome carried the HLA-B*1502 allele (142830.0002), while only 3% of the carbamazepine-tolerant group and 8.6% of normal controls carried that allele. When the carbamazepine-tolerant group was used as the control, the presence of the HLA-B*1502 allele had a 93.6% positive predictive value for carbamazepine-induced Stevens-Johnson syndrome, whereas its absence had a negative predictive value of 100%. In a test for carbamazepine-induced Stevens-Johnson syndrome, the HLA-B*1502 allele should therefore have 100% sensitivity and 97% specificity. In an expanded study of 60 Chinese patients with carbamazepine-induced Stevens-Johnson syndrome or toxic epidermal necrolysis, including the 44 patients reported by Chung et al. (2004), Hung et al. (2006) confirmed the association between these adverse drug reactions and the HLA-B*1502 allele (p = 1.6 x 10(-41), odds ratio of 1.357). Fifty-nine of the 60 patients had the susceptibility allele, compared to 6 (4.2%) of 144 tolerant controls. There was no association between HLA-B*1502 and 31 patients with nonbullous adverse drug reactions, suggesting that HLA-B*1502 is specific for bullous phenotypes. In addition, fine mapping in the HLA region showed significant linkage of SJS and/or TEN to the T allele of a T/G SNP (dbSNP rs3130690) near HLA-B. Hung et al. (2005) genotyped 51 patients with allopurinol-induced severe cutaneous adverse reaction and 228 controls (135 allopurinol-tolerant patients and 93 healthy individuals). The HLA-B*5801 allele (142830.0004) was present in all 51 of the patients with allopurinol-SCAR, but in only 15% of allopurinol-tolerant controls and 20% of healthy controls (p = 4.7 x 10(-24) and p = 8.1 x 10(-18), respectively). Hung et al. (2005) concluded that the HLA-B*5801 allele is an important genetic risk factor for severe cutaneous adverse reactions to allopurinol in the Han Chinese population. Ueta et al. (2007) examined the histocompatibility class I antigen genes HLA-A, -B, and -C of 40 Japanese SJS/TEN patients with ocular complications and 113 healthy Japanese volunteers. They found that HLA-A*0206 was strongly associated with SJS/TEN with ocular complications (Pc less than .0005, OR = 5.1), whereas HLA-B, HLA-C, and other HLA-A alleles were not. Because this finding was completely different from data reported on Taiwanese Han Chinese patients (Lonjou et al., 2006) and Caucasian patients (Roujeau et al., 1987), which showed strong association with HLA-Bw44 and HLA-B*1502, respectively, Ueta et al. (2007) suggested that there are strong ethnic differences in the HLA-SJS association. Chen et al. (2011) recruited 4,877 candidate subjects from 23 hospitals in Taiwan who had not taken carbamazepine. All were genotyped to determine whether they carried the HLA-B*1502 allele. Those testing positive (7.7% of the total) were advised not to take carbamazepine. None of the 92.3% who were advised to take carbamazepine developed SJS-TEN. Chen et al. (2011) concluded that the identification of subjects carrying the HLA-B*1502 allele and the avoidance of carbamazepine therapy in these subjects was strongly associated with a decrease in the incidence of carbamazepine-induced SJS-TEN. The estimated historical incidence of carbamazepine-induced SJS-TEN (0.23%) would translate into approximately 10 cases among study subjects (P less than 0.001). McCormack et al. (2011) performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3,987 control subjects, all of European descent. They replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions. The HLA-A*3101 allele, which has a prevalence of 2 to 5% in northern European populations, was significantly associated with the hypersensitivity syndrome (P = 3.5 x 10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A*3101 allele (P = 1.1 x 10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95 CI, 1.27-121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59-19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93-116.18). The presence of the HLA-A*3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%.
Chung et al. (2004) stated that the incidence of Stevens-Johnson syndrome in Han Chinese is higher than that in Caucasians (8 cases per million person-years in Han Chinese compared with 2 to 3 cases in Caucasians). Carbamazepine is ... Chung et al. (2004) stated that the incidence of Stevens-Johnson syndrome in Han Chinese is higher than that in Caucasians (8 cases per million person-years in Han Chinese compared with 2 to 3 cases in Caucasians). Carbamazepine is the drug most commonly associated with the syndrome in Asians, accounting for 25 to 33% of cases, whereas only 5 to 6% of Caucasian Stevens-Johnson syndrome cases are caused by it. The HLA-B*1502 allele is present in 8% of Han Chinese but in only 1 to 2% of Caucasians; Chung et al. (2004) postulated that this may explain the lower incidence of carbamazepine-induced Stevens-Johnson syndrome in Caucasians.