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Original Investigation
April 2018

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

Author Affiliations
  • 1Center of Excellence for Environmental Health and Toxicology, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
  • 2Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
  • 3Pharmacokinetic Research Unit, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
JAMA Dermatol. 2018;154(4):441-446. doi:10.1001/jamadermatol.2017.6484
Key Points

Question  Is HLA-B*1301 genotype associated with dapsone-induced cutaneous adverse reactions?

Findings  In this systematic review and meta-analysis of 3 studies that included 111 patients with dapsone-induced cutaneous adverse drug reactions, 1165 dapsone-tolerant patients, and 3026 healthy controls, a statistically significant association between HLA-B*1301 and dapsone-induced cutaneous adverse reactions was found.

Meaning  Because HLA-B*1301 is associated with dapsone-induced cutaneous adverse reactions, genetic screening for HLA-B*1301 before initiating dapsone therapy is warranted.

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.

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