title: Genetic and immune predictors for hypersensitivity syndrome to antiepileptic drugs.
abstract: Hypersensitivity syndrome reactions (HSR) to antiepileptic drugs (AED) are associated with severe clinical cutaneous adverse reactions (SCAR). We aimed (1) to assess HSRs to AEDs using the in vitro lymphocyte toxicity assay (LTA) in patients who manifested HSRs clinically; (2) to correlate LTA results with the clinical syndrome; (3) to correlate LTA results with the human leukocyte antigen (HLA) allele B∗1502 (HLA-B∗1502) positivity in a Han Chinese-Canadian population; and (4) to determine the cytokine network in this population. Patients that developed fever and cutaneous eruptions in the presence or absence of organ involvement within 8 weeks of exposure to carbamazepine (CBZ), phenytoin (PHY), or lamotrigine (LTG) were enrolled. Control patients received AEDs without presenting HSR. We investigated 10 CBZ-HSR patients (4 with Stevens-Johnson syndrome [SJS]), 24 CBZ-controls, 10 PHY-HSR patients (4 with drug-induced liver injury [DILI]), 24 PHY-controls,6 LTG-HSR patients (1 with SJS and 1 with DILI), and 24 LTG-controls. There were 30 Han Chinese individuals (14 HSR patients and 16 controls) in our cohort. LTA toxicity greater than 12.5%±2.5% was considered positive. Differences among groups were determined by analysis of variance. In addition, we measured cytokine secretion in the patient sera between 1 month and 3 years after the event. All Han Chinese individuals and 30% of Caucasians were genotyped for HLA-B∗1502. A perfect correlation (r=0.92) was observed between positive LTA and clinical diagnosis of DILI and SJS/toxic epidermal necrolysis (TEN). HLA-B∗1502 positivity in Han Chinese is a predictor of CBZ-HSR and PHY-HSR. HLA-B∗1502-negative Han Chinese receiving only CBZ or a combination of CBZ and PHY tolerated the drug(s) clinically, presenting negative CBZ-LTA and PHY-LTA. However, 3 patients presenting negative CBZ-LTA and PHY-LTA, as well as negative HLA-B∗1502, showed positive LTG-LTA (38%, 28%, and 25%, respectively), implying that they should not be prescribed LTG. Three patients had LTA positive to both PHY and CBZ, and 3 others had LTA positive to both PHY and LTG. Clinically, all 6 patients presented HSR to both drugs that they tested positive to (cross-reactivity). Patients were grouped based on the clinical presentation of their symptoms as only rash and fever or as a triad of rash, fever and DILI or SJS/TEN that characterizes "true" HSR. Levels of proinflammatory cytokines were significantly higher in patient sera compared with control sera. More specifically, the highest levels of tumor necrosis factor-α have been measured in patients presenting "true" HSR, as were the apoptotic markers Fas, caspase 8 activity, and M30. The LTA is sensitive for DILI and SJS/TEN regardless of drug or patient ethnicity. HSR prediction will prevent AED-induced morbidity. In Han Chinese, HLA-B∗1502 positivity is a predictor for CBZ-HSR and PHY-HSR. Its negativity does not predict a negative LTG-HSR. There is cross-reactivity between AEDs. Additionally, T-cell cytokines and chemokines control the pathogenesis of SJS/TEN and DILI, contributing to apoptotic processes in the liver and in the skin.
authors.affiliation: In Vitro Drug Safety and Biotechnology, Department of Pharmacology and Toxicology, University of Toronto, and North York General Hospital, Toronto, Ontario, Canada. manuela.neuman@utoronto.ca
authors.forename: Manuela G
authors.initials: MG
authors.lastname: Neuman
authors.forename: Lawrence
authors.initials: L
authors.lastname: Cohen
authors.forename: Radu M
authors.initials: RM
authors.lastname: Nanau
authors.forename: Paul A
authors.initials: PA
authors.lastname: Hwang
mesh_terms: D000927:Anticonvulsants / Q000009:adverse effects*; D016022:Case-Control Studies; D002681:China; D004342:Drug Hypersensitivity / Q000235:genetics* / Q000276:immunology*; D005006:Ethnicity; D015235:HLA-B Antigens / Q000235:genetics; D006801:Humans
chemical_list: D000927:Anticonvulsants; D015235:HLA-B Antigens