Carbamazepine Hypersensitivity: Progress Toward Predicting the Unpredictable

Commentary

HLA-A*3101 and Carbamazepine-Induced Hypersensitivity Reactions in Europeans.

McCormack M, Alfirevic A, Bourgeois S, Farrell JJ, Kasperaviciute D, Carrington M, Sills GJ, Marson T, Jia X, de Bakker PI, Chinthapalli K, Molokhia M, Johnson MR, O'Connor GD, Chaila E, Alhusaini S, Shianna KV, Radtke RA, Heinzen EL, Walley N, Pandolfo M, Pichler W, Park BK, Depondt C, Sisodiya SM, Goldstein DB, Deloukas P, Delanty N, Cavalleri GL, Pirmohamed M.N Engl J Med. 2011:364;1134–114321428769

BACKGROUND: Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamaze-pine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations. METHODS: We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions. RESULTS: 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=3.5×10(−8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A*3101 allele (P=1.1×10(−6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18). CONCLUSIONS: 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%. (Funded by the U.K. Department of Health and others.)

Cutaneous adverse drug reactions are among some of the most frequent adverse events associated with a number of our commonly used aromatic ring–containing antiepileptic drugs (AEDs), including carbamazepine, phenytoin, oxcarbazepine, and lamotrigine (1–3).

In its mildest form, maculopapular exanthema may occur in perhaps up to 10% of patients receiving carbamazepine. In some patients, however, more severe dermatologic hypersensitivity reactions such as drug reaction with eosinophilia and systemic symptoms [DRESS]) may occur and has been associated with a mortality rate of about 10%. This hypersensitivity syndrome is associated with rash, fever, and organ dysfunction such as nephritis or hepatitis (4), and most commonly presents within the first 2 months of therapy, with flu-like symptoms such as fever and malaise. For patients receiving carbamazepine or phenytoin, the incidence of DRESS is estimated to be 1 in 5,000.

Among the most severe of these reactions are Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN). Treatment with commonly used AEDs such as carbamazepine, phenytoin, phenobarbital, and lamotrigine is considered to increase the risk of SJS/TEN. For carbamazepine, the risk of developing SJS/TEN in individuals of European decent is about 1 to 6 cases of 10,000 patients exposed (5, 6).

SJS and TEN are considered to be variants of the same process, with the mortality rate for patients developing TEN approaching 30%. Clearly, it would be advantageous to be able to identify patients at possible risk for developing any sort of hypersensitivity reaction to these commonly used medications.

Until relatively recently, dermatologic reactions were considered to be idiosyncratic events, and thus, largely unpredictable. This notion changed however following the demonstration of a relationship between these potentially life-threatening reactions and the human leukocyte antigen (HLA)-B*1502 in various Asian populations (7, 8). Indeed, avoidance of carbamazepine in patients carrying the HLA-B*1502 allele has recently been shown to substantially reduce the incidence of SJS/TEN in Asian patients (9). The discovery of the involvement of human leukocyte antigen– dependent presentation of a drug for T-cell activation has led to the recognition that a direct, noncovalent binding between a drug and T-cell receptor with an HLA molecule is responsible, leading to T-cell activation and clonal expansion of CD8+ cytotoxic T cells in the skin (10).

Clinically, recognition of the association of this allelic variant represent an important step forward in our ability to predict (and presumably prevent) serious hypersensitivity reactions to carbamazepine. Important questions, however, remained unanswered. For example, would genotype screening for HLA-B*1502 be of value in those patients of other ethnic Asian or European decent? Could these genetic variants be relevant for treatment with other aromatic ring–containing AEDs, such as phenytoin, oxcarbazepine, or lamotrigine?

With respect to generalizability to the broader population, while the HLA-B*1502 allele is quite prevalent in individuals from Southern China (~15%), as well as those from several other Southeast Asian countries (~2–8%), (11) this allele is quite uncommon in Japanese and European Caucasians (<1%). Although the incidence of SJS/TEN is lower in European Caucasians than certain Asian populations, it does clearly still occur.

In the genome-wide association study by McCormack and colleagues, samples were obtained from 26 patients with confirmed carbamazepine hypersensitivity syndrome, 106 patients with carbamazepine associated maculopapular exanthema (rash without systemic involvement), and 12 patients who had developed SJS/TEN. These individuals were then compared with genotype data derived from the Wellcome Trust Case Control Consortium, U.K. National Blood Services Collection, and the 1958 British Birth Cohort. In addition, a clinical control group (n = 257) of patients receiving carbamazepine for at least 3 months with no evidence of hypersensitivity were also compared.

For both patients with DRESS and SJS/TEN, a strong signal in the HLA-A region on chromosome 6 was seen with HLA-A*3101 being most strongly associated. This variant, which has a prevalence of up to 5% in Northern Europeans, was observed in 40% of patients with either DRESS or SJS/TEN as compared with only 4 to 5 percent of control subjects. With regard to maculopapular exanthema, HLA-A*3101 was again the most strongly associated allele, being seen in 27% of patients versus 4% of controls.

Although the population of this study was of Caucasian decent, it is interesting to note that HLA-A*3101, which is found in about 9% of Japanese and 2% of Han Chinese, has also been associated with carbamazepine hypersensitivity including SJS/TEN and maculopapular exanthema in these patient populations (12).

Taken together, these data provide compelling evidence that HLA-A*3101 is yet another important predictor of carbamazepine-associated cutaneous hypersensitivity reactions. Confidence in these findings is enhanced when one considers the consistency of the data across several independent groups of case subjects as well as controls. Now, can we use these data to reliably screen and identify potentially at-risk patients and thereby avoid serious hypersensitivity? Perhaps.

McCormack and colleagues suggest that the presence of this allele increases the risk of a hypersensitivity reaction to 26%, whereas its absence lowers that risk to just under 4%. If one assumes that the prevalence of carbamazepine hypersensitivity is 5% in the European Caucasian population, then about 83 patients would need to be screened to prevent one hypersensitivity reaction. Of course, the number of patients needed to be screened would fall if, in fact, the actual prevalence of hypersensitivity were greater. For example, a carbamazepine hypersensitivity incidence of 10% would reduce the number needed to be screened to 39.

Chen et al. (9) recently reported that prospective screening for the HLA-B*1502 allele and subsequent avoidance of carbamazepine prescription in genetically susceptible Han Chinese patients did in fact reduce the occurrence of SJS/TEN, as compared with historical controls. Interestingly, the absence of the HLA-A*1502 allele did not appear to reduce the incidence of more mild rash and itching in these patients.

Finally, it is reasonable to speculate that given the strong association between either HLA-*1502 in certain Asian populations or HLA-B*3101 in Northern Europeans and severe carbamazepine hypersensitivity, that we might expect to see similar risk in those patients receiving alternative AEDs such as oxcarbazepine, phenytoin, or lamotrigine. Unfortunately, the supportive evidence is still lacking. With respect to Han Chinese carriers of HLA-B*1502, the data is conflicting. Hung and coworkers (13) suggest an increased risk for oxcarbazepine and phenytoin in these patients. For lamotrigine, however, the presence of this allele (or any other) does not appear to be associated with increased risk of either maculopapular exanthema or SJS/TEN (14–16).

The U.S. FDA now recommends that patients of Asian ancestry be screened for HLA-B*1502 prior to starting treatment with carbamazepine. While helpful, until the study by McCormack et al., clinicians were left with a great deal of uncertainty as to how to apply this information to other patient groups. Will screening for HLA-A*3101 prove to be as beneficial in patients of European (and perhaps Japanese) ancestry as it appears that HLA-B*1502 identification is in Han Chinese? Only additional prospective studies will be able to answer this. For now, however, it seems only reasonable that screening for HLA-A*3101 be strongly considered prior to initiation of carbamazepine in those patients. Clearly, much work remains to be done. Optimistically, one can now realistically envision a time when genomic profiling will lead to safer pharmacological management in patients with epilepsy.