Genetic Predisposition to Stevens-Johnson Syndrome With Severe Ocular Surface Complications

Stevens-Johnson syndrome (SJS) is an acute inflammatory vesiculobullous reaction of the skin and mucosa, including the ocular surface, oral cavity, and genitals. In patients with extensive skin detachment and a poor prognosis, the condition is termed toxic epidermal necrolysis (TEN). This review covers 4 topics: (1) ophthalmic SJS, (2) human leukocyte antigen (HLA) analysis, (3) genome-wide association studies, and (4) other pathogenic factors. Severe ocular complications (SOCs) develop in some SJS/TEN patients diagnosed by dermatologists. Cold medicine-related SJS/TEN (CM-SJS/TEN) with SOCs is associated with HLA-A*02:06 in Japanese and Koreans and HLA-B*44:03 in Japanese, Indians, and Brazilian whites. We conducted a genome-wide association study for CM-SJS/TEN with SOCs and found that IKZF1 single-nucleotide polymorphisms (SNPs) were significantly associated with CM-SJS/TEN with SOCs, and that the ratio of the Ik2/Ik1 isoforms might be influenced by these IKZF1 SNPs. Moreover, HLA-A*02:06 with TLR3 polymorphisms and HLA-A*02:06 with EP3 polymorphisms exerted additive effects in SJS/TEN with SOCs. EP3 is strongly downregulated in the conjunctival epithelium of SJS/TEN. Cold medicines including nonsteroidal antiinflammatory drugs, which are the main causative drugs for SJS/TEN with SOCs, downregulate the production of prostanoids, including PGE(2). Because the PGE(2)-EP3 pathway suppresses the inflammation of the ocular surface, skin, and respiratory tract, downregulation of PGE(2) by nonsteroidal antiinflammatory drugs or acetaminophen might significantly contribute to the onset of CM-SJS/TEN with SOCs. Cold medicines and infectious agents such as viruses or other microbes are both important in triggering the onset of SJS/TEN with SOCs.