Relationship Between the HLA-B*1502 Allele and Carbamazepine-Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Systematic Review and Meta-analysis

Abstract

IMPORTANCE: The US Food and Drug Administration recommends screening for the HLA-B*1502 allele before initiation of carbamazepine therapy in patients of Asian ancestry, but there remains unclear evidence of a relationship between HLA-B*1502 and Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) among carbamazepine users, especially in some racial/ethnic populations. OBJECTIVE: To determine the relationship between the HLA-B*1502 allele and carbamazepine-induced SJS and TEN. DATA SOURCES: A comprehensive search of the following data sources was performed without language restriction from the inception of the database until January 8, 2013: EMBASE, PubMed, clinicaltrials.gov, Cochrane Library, IPA (International Pharmaceutical Abstracts), HuGENet (Human Genome Epidemiology Network), and CINAHL (Cumulative Index to Nursing and Allied Health Literature), and the reference lists of identified studies. STUDY SELECTION: Inclusion criteria were studies that investigated the relationship between HLA-B*1502 and carbamazepine-induced SJS and TEN and that reported sufficient data for calculating the frequency of HLA-B*1502 carriers among cases and controls. The search yielded 525 articles, of which 16 met the inclusion criteria. The studies included 227 SJS or TEN cases, 602 matched control subjects, and 2949 population control subjects. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted the following data: study design, eligibility criteria, diagnostic criteria, patient demographics, genotype distribution, HLA-B genotyping technique, selection of cases and controls, dosage of carbamazepine and duration of use, and results of Hardy-Weinberg equilibrium in the control group. The Newcastle-Ottawa Scale was used to assess the quality of studies. The overall odds ratios (ORs) with corresponding 95% CIs were calculated using a random-effects model. The primary analysis was based on matched control studies. Subgroup analyses by race/ethnicity were also performed. MAIN OUTCOME AND MEASURE: The primary outcome was carbamazepine-induced SJS and TEN. The outcome measure is given as an overall OR. RESULTS: The summary OR for the relationship between HLA-B*1502 and carbamazepine-induced SJS and TEN was 79.84 (95% CI, 28.45-224.06). Racial/ethnic subgroup analyses yielded similar findings for Han-Chinese (115.32; 18.17-732.13), Thais (54.43; 16.28-181.96), and Malaysians (221.00; 3.85-12 694.65). Among individuals of white or Japanese race/ethnicity, no patients with SJS or TEN were carriers of the HLA-B*1502 allele. CONCLUSIONS AND RELEVANCE: We found a strong relationship between the HLA-B*1502 allele and carbamazepine-induced SJS and TEN in Han-Chinese, Thai, and Malaysian populations. HLA-B*1502 screening in patients requiring carbamazepine therapy is warranted.