Purpose: Antiepileptic drugs (AEDs) are extensively used to manage epilepsy and other comorbidities associated with seizures. Human Leukocyte Antigen (HLA) has a strong association with AED-induced severe cutaneous adverse drug reactions.
Objective: We aimed to perform a systematic review and meta-analysis to identify, critically evaluate, and synthesize the best possible evidence on HLA-associated AED-induced Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN).
Methods: MEDLINE/PubMed, Scopus, and the Cochrane Library were searched for literature from inception up to July 2022. We included case control studies analyzing association between HLA and AED-induced SJS/TEN. We assessed the studies' risk of bias in using Quality of genetic studies (Q-genie) tool. Outcomes focused on association (risk) between HLA and AED-induced SJS/TEN. The estimated risk was presented in the form of odds ratio (OR).
Results: We included 37 studies (51,422 participants; 7027 cases and 44,395 controls). There was a significantly higher risk of Carbamazepine-induced SJS/TEN with HLA-A (OR: 1.50; 95% CI: 1.03 to 2.17), HLA-B (OR: 1.94; 95% CI: 1.45 to 2.58), HLA-C (OR: 7.83; 95% CI: 4.72 to 12.98), and HLA-DRB1 (OR: 2.82; 95% CI: 1.94 to 4.12). Lamotrigine-induced SJS/TEN posed a higher risk with HLA-A (OR: 2.38; 95% CI: 1.26 to 4.46) and HLA-B (OR: 2.79; 95% CI: 1.75 to 4.46). Phenytoin-induced SJS/TEN showed a higher risk with HLA-A (OR: 3.47; 95% CI: 2.17 to 5.56), HLA-B (OR: 1.72; 95% CI: 1.38 to 2.15), and HLA-C (OR: 2.92; 95% CI: 1.77 to 4.83). Phenobarbital-induced SJS/TEN had a higher risk with HLA-A (OR: 6.98; 95% CI: 1.81 to 26.84), HLA-B (OR: 2.40; 95% CI: 1.39 to 4.17), and HLA-C (OR: 3.37; 95% CI: 1.03 to 11.01). Zonisamide-induced SJS/TEN was significantly associated with HLA-A*02:07 (OR: 9.77; 95% CI: 3.07 to 31.1), HLA-B*46:01 (OR: 6.73; 95% CI: 2.12 to 21.36), and HLA-DRB1×08:03 (OR: 3.78; 95% CI: 1.20 to 11.97). All other alleles of HLA were observed to have a non-significant association with AED-induced SJS/TEN. All included studies were of good quality, with a score of >50 and a mean score of 54.96 out of 77.
Conclusion: Our study showed a significant association between few variants of HLA alleles and AED-induced SJS/TEN. Evidences from our study could help in population-based studies and in implementation of individualized treatment regimens. These findings could be part of translational research helping in precision therapy.
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Role of human leukocyte antigen in anti-epileptic drugs-induced Stevens-Johnson Syndrome/toxic epidermal necrolysis: A meta-analysis.
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November 2022
Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India; Coordinator, Centre for Toxicovigilance and Drug Safety, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India. Electronic address:
Purpose: Antiepileptic drugs (AEDs) are extensively used to manage epilepsy and other comorbidities associated with seizures. Human Leukocyte Antigen (HLA) has a strong association with AED-induced severe cutaneous adverse drug reactions.
Objective: We aimed to perform a systematic review and meta-analysis to identify, critically evaluate, and synthesize the best possible evidence on HLA-associated AED-induced Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN).
Severe Cutaneous Adverse Reactions to Antiepileptic Drugs: A Nationwide Registry-Based Study in Korea.
Allergy Asthma Immunol Res
September 2019
Department of Pulmonology and Allergy, Hallym University Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong, Korea.
Article Synopsis
- This study focused on severe cutaneous adverse reactions (SCARs) linked to antiepileptic drugs (AEDs) in Korea, specifically looking at drugs like carbamazepine, lamotrigine, valproic acid, and levetiracetam.
- A total of 161 patients from various referral hospitals were analyzed to assess the causes, symptoms, treatment details, and outcomes related to AED-induced SCARs.
- The findings indicated that while carbamazepine was the most common drug associated with SCARs and generally led to shorter hospital stays, certain factors like thrombocytopenia could increase the duration of hospitalization, especially in cases of DRESS.
Significant HLA class I type associations with aromatic antiepileptic drug (AED)-induced SJS/TEN are different from those found for the same AED-induced DRESS in the Spanish population.
Pharmacol Res
January 2017
Department of Clinical Pharmacology, La Paz University Hospital-Carlos III, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain. Electronic address:
Aromatic antiepileptic drugs (AEDs) are among the drugs most frequently involved in severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). This study investigated the associations between the genetic polymorphisms of HLA class-I and AED-induced SCARs in the Spanish population. HLA class-I genotypes were determined in AED (phenytoin[PHT],lamotrigine[LTG],carbamazepine[CBZ],phenobarbital[PB])-induced SJS/TEN (n=15) or DRESS (n=12) cases included in the Spanish SCAR registry, PIELenRed.
View Article and Find Full Text PDFReal-world cost-effectiveness of pharmacogenetic screening for epilepsy treatment.
Neurology
March 2016
From the Department of Medicine (Z.C., D.L., P.K.), The University of Melbourne, Parkville; Melbourne Brain Centre (Z.C., D.L.), Melbourne EpiCentre (D.L.), and Department of Neurology (P.K.), Royal Melbourne Hospital, Parkville, Australia; and Department of Medicine and Therapeutics (P.K.), Chinese University of Hong Kong, China.
Objective: To assess the cost-effectiveness of the HLA-B*15:02 screening policy for the treatment of epilepsy in Hong Kong.
Methods: From all public hospitals and clinics in Hong Kong, 13,231 patients with epilepsy who started their first antiepileptic drug (AED) between September 16, 2005, and September 15, 2011 (3 years before and 3 years after policy implementation on September 16, 2015), were identified retrospectively. A decision tree model was constructed to incorporate the real-world data on AED prescription patterns, incidences of AED-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), costs of AED treatments, SJS/TEN treatment, and HLA-B*15:02 testing, and quality of life.
Antiepileptic drugs and adverse skin reactions: An update.
Pharmacol Rep
June 2015
Department of Pathophysiology, Medical University of Lublin, Lublin, Poland; Department of Physiopathology, Institute of Rural Health, Lublin, Poland.
This paper summarizes current views on clinical manifestation, pathogenesis, prognosis and management of antiepileptic drug (AED)-induced adverse skin reactions. Cochrane Central Register of Controlled Trials, MEDLINE (PubMed) and ISI Web of Knowledge were searched. The recent classification, among drug-induced skin injuries, points to Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis and hypersensitivity syndrome (HSS), which may be also recognized as a drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS).
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