HLA-B alleles confer susceptibility to sulfasalazine-induced severe cutaneous adverse reactions

Background: Sulfasalazine is a disease-modifying antirheumatic drug used to treat arthritis and ankylosing spondylitis. However, it may cause life-threatening severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. Objective: Genetic predisposition to sulfasalazine-induced SCARs was assessed. Methods: This multicountry genetic study involved discovery, replication, and meta-analysis cohorts. The discovery cohort comprised 62 cases of sulfasalazine-induced SCARs and 75 sulfasalazine-tolerant subjects as well as 657 population controls from China and Taiwan who underwent whole-exome sequencing. The replication cohort comprised additional 17 cases and 2038 population controls from Taiwan who underwent HLA genotyping. The meta-analysis cohort comprised a total of 105 cases from Japan, Thailand, Malaysia, Taiwan, and China, together with 23,743 country-matched population controls. Functional immune mechanisms were explored with ex vivo lymphocyte activation assays. Results: In the discovery cohort, rs9266217 in HLA-B exhibited the strongest association. HLA genotyping in replication cohort and phenotype stratification found 4 HLA-B alleles that jointly yielded 84.8% sensitivity (P = 2.3 × 10−24) in predicting sulfasalazine-induced SCARs in the Chinese population. Meta-analysis across 4 Asian countries confirmed significant associations for 3 alleles. Functional assays showed that sulfasalazine or its active metabolite, sulfapyridine, markedly increased granulysin release from CD8+ T cells of affected patients, supporting an HLA-restricted reaction. Conclusion: Multiple HLA-B alleles (B∗39:01, B∗13:01, and B∗38:02) are strongly associated with sulfasalazine-induced SCARs in Asians.