Association Between HLA-B*1301 and Dapsone-Induced Cutaneous Adverse Drug Reactions: A Systematic Review and Meta-analysis

Abstract

Importance: Dapsone-induced hypersensitivity syndrome (DHS) is a life-threatening adverse drug reaction. Based on available epidemiologic studies, HLA genotypes may play an important role in DHS.

Objective: To assess the association between HLA-B*1301 and dapsone-induced cutaneous adverse drug reactions (cADRs).

Data sources: Human studies investigating associations between HLA-B*1301 and dapsone-induced cADRs were systematically searched without language restriction from the inception of each database until September 12, 2017, in PubMed, the Human Genome Epidemiology Network), and the Cochrane Library. Combinations of HLA genotypes, dapsone, and synonymous terms were used; reference lists were searched in selected articles.

Study selection: Two reviewers identified studies investigating the associations between HLA-B*1301 and dapsone-induced cADRs that reported sufficient data for calculating the frequency of HLA-B*1301 carriers among case and control patients, in which all patients received dapsone before HLA-B*1301 screening. An initial search of the databases identified 391 articles, of which 3 studies (2 in Chinese populations and 1 in a Thai population) met the inclusion criteria.

Data extraction and synthesis: Overall odds ratios (ORs) with 95% CIs were calculated using a random-effects model to determine the association between HLA-B*1301 and dapsone-induced cADRs. Subgroup analyses by type of cADR were also performed. PRISMA guidelines were used to abstract and assess data.

Main outcomes and measures: Primary outcomes were associations between HLA-B*1301 and dapsone-induced cADRs in dapsone-tolerant controls. The outcomes are reported as overall OR. Statistical heterogeneity was assessed using the Q statistic and I2 tests.

Results: From the 3 included studies, there were 111 unique patients with dapsone-induced cADRs (subsequently used in the meta-analysis), 1165 dapsone-tolerant patients, and 3026 healthy controls. The cases included 64 men and 49 women (2 patients were missing from the meta-analysis; 1 each from 2 of the 3 studies); mean age was 39.7 years. An association between HLA-B*1301 and dapsone-induced cADRs was identified (summary OR, 43.0; 95% CI, 24.0-77.2). Subgroup analyses among types of cADRs produced similar findings in DHS (OR, 51.7; 95% CI, 16.9-158.5), dapsone-induced severe cADRs (Stevens-Johnson syndrome and toxic epidermal necrolysis [SJS/TEN] plus drug rash [adverse skin reaction to a drug] along with eosinophilia and systemic symptoms [DRESS]) (OR, 54.0; 95% Cl, 8.0-366.2), dapsone-induced SJS/TEN (OR, 40.5; 95% CI, 2.8-591.0), and dapsone-induced DRESS (OR, 60.8; 95% CI, 7.4-496.2). There was no heterogeneity (I2 = 0%, P = .38).

Conclusions and relevance: Associations between HLA-B*1301 and dapsone-induced cADRs were found in dapsone-tolerant and healthy control groups. For patient safety, genetic screening for HLA-B*1301 in Asian populations before dapsone therapy is warranted.

Figure 1.. PRISMA Flow Diagram of HLA-B*1301 and Dapsone-Induced Cutaneous Adverse Drug Reactions (cADRs)

Summary of study identification, inclusion, and exclusion. HuGENet indicates Human Genome Epidemiology Network.

Figure 2.. Associations Between HLA-B*1301 and Dapsone-Induced Cutaneous Adverse Drug Reactions (cADRs)

Forest plot shows associations between HLA-B*1301 and dapsone-induced cADRs using dapsone-tolerant controls. Each data marker and its size indicate a mean value and a magnitude of the data point compared with the total. Error bars indicate 95% CIs and vertical dotted line, overall estimated odds ratio (OR). Data marker size reflects the weight of the study using random-effects meta-analysis. Data were evaluated using R, version 3.4.3 (The R Foundation).