Literature Review

Genetic Screening May Reduce Carbamazepine-Induced Cutaneous Adverse Reactions

Data may enable a more consistent approach to the safe administration of a commonly prescribed therapy.


Preemptive HLA-A*31:01 genetic screening may significantly decrease the incidence of carbamazepine-induced cutaneous adverse reactions among a cohort of Japanese patients, according to a report published online ahead of print April 2 in JAMA Neurology. According to the researchers, their finding suggests that such screening may be warranted in routine clinical practice.

Carbamazepine, which is widely used to treat seizures, neuropathic pain, and other disorders, is a common cause of cutaneous adverse drug reactions worldwide. The allele HLA-A*31:01 has been associated with carbamazepine-induced cutaneous drug reactions in Japanese and European populations. The clinical utility of HLA-A*31:01 screening, however, has not been evaluated.

Genetic Screening Informed Treatment

To assess the use of HLA-A*31:01 genetic screening to identify individuals at risk of carbamazepine-induced cutaneous drug reactions, researchers from the Genotype-Based Carbamazepine Therapy Study Group conducted a cohort study in 36 hospitals in Japan from January 2012 to November 2014. The investigators enrolled 1,202 patients who were eligible to receive carbamazepine during the study period. Preemptive HLA-A*31:01 screening was performed for 1,187 study participants. Patients who did not start treatment with carbamazepine or alternative drugs were excluded. Participants were interviewed once weekly for eight weeks to monitor the development of cutaneous adverse drug reactions.

Neuropsychiatrists were asked to prescribe carbamazepine for patients who tested negative for HLA-A*31:01 and alternative drugs for those who tested positive for the allele. The study’s main outcome was the incidence of carbamazepine-induced cutaneous adverse drug reactions.

Of the 1,130 patients who were prescribed carbamazepine or alternative drugs, the mean age was 37.4; 614 (54.3%) were men, and 198 (17.5%) were positive for HLA-A*31:01. Dermatologists identified 23 patients (2.0%) who had carbamazepine-induced cutaneous adverse drug reactions, of whom four patients required hospitalization. Drug-induced hypersensitivity syndrome was observed for three patients, maculopapular eruption for nine patients, erythema multiforme for five patients, and an undetermined type of cutaneous adverse drug reaction for six patients. No patient developed Stevens-Johnson syndrome or toxic epidermal necrolysis.

Comparison with a historical control indicated that the preemptive use of HLA-A*31:01 screening was associated with a 40% reduction in the incidence of carbamazepine-induced cutaneous adverse drug reactions.

Two Alleles

The researchers noted that the clinical utility of the HLA-B*15:02 genetic test for reducing carbamazepine-induced cutaneous drug reactions has already been established by preemptive screening. However, the frequency of the HLA-B*15:02 allele is low in Korean, Japanese, African, and European populations. In contrast, the frequency of the HLA-A*31:01 allele is 7% to 9% in Japanese, 5% in Korean, 2% in Chinese, 2% to 3% in European, and 1% in African populations. Moreover, HLA-A*31:01 has been associated with a full spectrum of carbamazepine-induced cutaneous adverse drug reactions. Therefore, “HLA-A*31:01 genetic screening prior to prescribing carbamazepine would be useful for preventing many types of carbamazepine-induced cutaneous adverse drug reactions in a range of patient populations,” the researchers concluded.

A First Step in Precision Neurology?

The present study “provides initial data that preemptive strategies may allow for a more consistent approach to safely administer this commonly used medication,” said Yijing He, MD, PhD; Lucia Seminario-Vidal, MD, PhD; and Howard L. McLeod, PharmD, in an accompanying editorial. A substantial decrease in the incidence and severity of carbamazepine-associated cutaneous adverse drug reactions was documented. While the study did not have the statistical power to definitively demonstrate complete avoidance of the high morbidity and mortality forms of severe cutaneous adverse drug reactions (ie, Stevens-Johnson syndrome and toxic epidermal necrolysis), it had statistical power to detect an important reduction in mild or moderately severe forms of cutaneous adverse drug reactions. “However, 23 patients experienced a carbamazepine-associated cutaneous adverse drug reaction,” and four patients required hospitalization, the editorialists noted. “Therefore, the use of HLA-A*31:01 testing will not eliminate the risk of carbamazepine-associated events, nor will it decrease the need for neurologists to provide skin-focused monitoring as part of their management of cases involving carbamazepine-treated patients.

This research, the editorialists said, indicates that there is still more to discover. “To date, a small number of heroes has relentlessly pursued mechanistic and preventive research on drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis. However, the field needs to build on these efforts with a more systematic approach that will aid more rapid progress and provide more consistent influence across the globe.” Much still needs to be learned about the basic mechanisms, clinical confounders, biomarkers, and epidemiologic aspects of the various drug reactions that become Stevens-Johnson syndrome and toxic epidermal necrolysis. Attributing this clinical, immunologic, and therapeutic problem to various idiosyncratic reactions does not serve patients well, said the editorialists.

A key first step, the editorialists said, is to “apply existing preemptive strategies, including genomic analysis. Whether this is initially implemented broadly or in regions with higher probability of the risk alleles is less important than learning how to change a culture that tolerates adverse drug events and inventing informatics tools to make proactive approaches less of a burden. Although we will not get it completely right the first time, we need to start the iterative process to eradicate severe cutaneous adverse drug reactions.”

—Glenn S. Williams

Suggested Reading

Mushiroda T, Takahashi Y, Onuma T, et al. Association of HLA-A*31:01 screening with the incidence of carbamazepine-induced cutaneous adverse reactions in a Japanese population. JAMA Neurol. 2018 Apr 2 [Epub ahead of print].

He Y, Seminario-Vidal S, McLeod HL. Avoidance of severe cutaneous adverse drug events as a first step in precision neurology. JAMA Neurol. Apr 2 [Epub ahead of print].

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