Current Pharmacogenetic Perspective on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Lin Cheng

doi:10.3389/fphar.2021.588063

Abstract

Adverse drug reactions are a public health issue that draws widespread attention, especially for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) which have high mortality and lack of efficacious treatment. Though T-cell-mediated HLA-interacted immune response has been extensively studied, our understanding of the mechanism is far from satisfactory. This review summarizes infection (virus, bacterial, and mycoplasma infection), an environmental risk factor, as a trigger for SJS/TEN. The mutations or polymorphisms of drug metabolic enzymes, transporters, receptors, the immune system genes, and T-cell-mediated apoptosis signaling pathways that contribute to SJS/TEN are discussed and summarized. Epigenetics, metabolites, and mobilization of regulatory T cells and tolerogenic myeloid precursors are emerged directions to study SJS/TEN. Ex vivo lymphocyte transformation test has been exploited to aid in identifying the causative drugs. Critical questions on the pathogenesis of SJS/TEN underlying gene polymorphisms and T cell cytotoxicity remain: why some of the patients carrying the risky genes tolerate the drug and do not develop SJS/TEN? What makes the skin and mucous membrane so special to be targeted? Do they relate to skin/mucous expression of transporters? What is the common machinery underlying different HLA-B alleles associated with SJS/TEN and common metabolites?

Highlights

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two forms of the same severe adverse drug reactions and are characterized by epidermal necrolysis
To overview the current understanding of SJS and TEN, this review summarizes the past understanding and recent advances on pharmacogenetics of druginduced SJS and TEN, discusses unresolved questions, and foresees potential targets for prevention and treatment of the disease
A recent report identified a network of Toll-like receptor 3 (TLR3), prostaglandin-E receptor 3 (PTGER3), and IKAROS family zinc finger 1 (IKZF1) gene polymorphisms was significantly associated with cold medicine-SJS/TEN with severe ocular surface complications (SOC), and these genes may regulate mucocutaneous inflammation

Summary

INTRODUCTION

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two forms of the same severe adverse drug reactions and are characterized by epidermal necrolysis. Studies identified preferential TCR usage, clonal expansion, and similar CDR3 (third complementarity-determining region) clonotypes in the blister cells and PBMC of patients with carbamazepine-SCARs (Chung et al, 2015; Pan et al, 2019) They conducted an adoptive transfer of this specific αβTCR-T cells to the HLA-B*15:02 transgenic mice, and these mice which received carbamazepine developed a phenotype mimicking SCARs while those mice received vehicle control drug did not show SCARs phenotypes. While the mechanism of SJS/TEN is not fully addressed, accumulating studies strongly support the disease is an immune-mediated hypersensitivity induced by drug presentation by human leucocyte antigen (HLA). Taiwan Han Chinese Taiwan Han Chinese Thai Thai Thai Indian Malaysian Central Chinese Southern Han Chinese Central and northern Han Chinese Hong Kong Han Chinese Indonesian European Korean Japanese Korean Japanese Thai Thai Filipino Spanish Caucasian Taiwan Han Chinese Hong Kong Han Chinese Thai Malaysian Malaysian Thai Thai Spanish Caucasian Thai Taiwan Han Chinese Thai Hong Kong Han Chinese Korean Thai Spanish Caucasian Thai Thai Taiwan Han Chinese Taiwan Han Chinese and Thai Taiwan Han Chinese Japanese Korean 89% of European Caucasian Thai Hong Kong Han Chinese Mainland Han Chinese Mainland Han Chinese Thai Korean Mainland Han Chinese Korean Mainland Han Chinese

DISCUSSION AND FUTURE

Findings

ETHICS STATEMENT