PMID- 22500513
OWN - NLM
STAT- MEDLINE
DCOM- 20120529
LR  - 20220309
IS  - 1878-1810 (Electronic)
IS  - 1878-1810 (Linking)
VI  - 159
IP  - 5
DP  - 2012 May
TI  - Genetic and immune predictors for hypersensitivity syndrome to antiepileptic 
      drugs.
PG  - 397-406
LID - 10.1016/j.trsl.2012.01.004 [doi]
AB  - 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-alpha 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.
CI  - Copyright (c) 2012 Mosby, Inc. All rights reserved.
FAU - Neuman, Manuela G
AU  - Neuman MG
AD  - 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
FAU - Cohen, Lawrence
AU  - Cohen L
FAU - Nanau, Radu M
AU  - Nanau RM
FAU - Hwang, Paul A
AU  - Hwang PA
LA  - eng
PT  - Journal Article
DEP - 20120126
PL  - United States
TA  - Transl Res
JT  - Translational research : the journal of laboratory and clinical medicine
JID - 101280339
RN  - 0 (Anticonvulsants)
RN  - 0 (HLA-B Antigens)
SB  - IM
MH  - Anticonvulsants/*adverse effects
MH  - Case-Control Studies
MH  - China
MH  - Drug Hypersensitivity/*genetics/*immunology
MH  - Ethnicity
MH  - HLA-B Antigens/genetics
MH  - Humans
EDAT- 2012/04/17 06:00
MHDA- 2012/05/30 06:00
CRDT- 2012/04/17 06:00
PHST- 2011/12/02 00:00 [received]
PHST- 2012/01/05 00:00 [accepted]
PHST- 2012/04/17 06:00 [entrez]
PHST- 2012/04/17 06:00 [pubmed]
PHST- 2012/05/30 06:00 [medline]
AID - S1931-5244(12)00005-9 [pii]
AID - 10.1016/j.trsl.2012.01.004 [doi]
PST - ppublish
SO  - Transl Res. 2012 May;159(5):397-406. doi: 10.1016/j.trsl.2012.01.004. Epub 2012 
      Jan 26.