Genetic Variant Linked To Severe Skin Reaction To Seizure Medication

upcoming JAMA publication:
Shuen-Iu Hung, PhD, for the Taiwan SCAR consortium Associate Professor, Department of Pharmacology, National Yang-Ming University, Taipei, 112 Interview with:
Shuen-Iu Hung, PhD, for the Taiwan SCAR consortium
Associate Professor, Department of Pharmacology,
National Yang-Ming University, Taipei, 112 Taiwan


Medical Research: What are the main findings of the study?

Reply: Phenytoin, a widely prescribed antiepileptic drug, can cause severe cutaneous adverse reactions (SCAR) (e.g., Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) ), which carry high mortality and morbidity. The genomic basis of phenytoin-induced SCAR has not been known. This study identifies CYP2C variants, including CYP2C9*3 known to reduce drug clearance, as the key genetic factors associated with phenytoin-related severe cutaneous adverse reactions. These findings have potential to improve the safety profile of phenytoin in clinical practice and offer the possibility of prospective testing for preventing phenytoin-related SCAR.

Medical Research: Were any of the findings unexpected?

Reply: This study highlights that genetic variants of metabolizing enzymes contribute to severe cutaneous adverse reactions (i.e., CYP2C variants and phenytoin-related SCAR), which is different from the previous HLA stories (e.g., HLA-B*15:02 and carbamazepine-induced SJS/TEN, HLA-B*58:01 and allopurinol-related SCAR, HLA-B*57:01 and abacavir hypersensitivity). These data suggest that both drug metabolism and immune recognition contribute to drug hypersensitivity.

Medical Research: What should clinicians and patients take away from your report?

Reply: Phenytoin is a widely prescribed antiepileptic drug and remains the most frequently used first-line antiepileptic drug in hospitalized patients. Before prescribing phenytoin to a new user, clinicians shall consider any presence of risk factors of phenytoin-related SCAR, including CYP2C variants (e.g., CYP2C9*3), specific HLA alleles (e.g. HLA-B*1502), and the renal or hepatic function. The genetic factors can be evaluated by a simple genetic test. Clinicians and patients shall be aware that renal insufficiency, hepatic dysfunction, and concurrent use of substances that compete or inhibit the drug metabolic enzymes can also affect phenytoin metabolism and contribute to severe cutaneous adverse reactions.

Medical Research: What recommendations do you have for future research as a result of this study?

Reply: More research is required to replicate the genetic association in different populations and to determine the test characteristics and clinical utility. Further investigation is required to determine how a complex interplay of impaired drug metabolism, accumulation of reactive drug compounds, HLA presentation of the drug/peptide antigens, T cell receptor recognition, and historical immune memory triggers drug hypersensitivity.