Results of Detailed Investigations Into Stevens-Johnson Syndrome With Severe Ocular Complications

Abstract

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute inflammatory vesiculobullous reactions of the mucosa of the ocular surface, oral cavity, and genitals, and of the skin. Severe ocular complications (SOC) are present in about half of SJS/TEN patients diagnosed by dermatologists. We review our group's findings on the genetic predisposition for and the etiology of SJS/TEN with SOC. We suspected that abnormal innate mucosal immunity, resulting in an anomalous response to commensal bacteria that usually do not elicit such a response, contributes to the ocular surface inflammation seen in SJS/TEN with SOC. We found that cold medicines, including multi-ingredient cold medications and nonsteroidal anti-inflammatory drugs, were the main causative drugs especially in patients with SJS/TEN with SOC. Cold medicine-related SJS/TEN (CM-SJS/TEN) with SOC was strongly associated with HLA-A*02:06 in the Japanese populations, and significantly associated with HLA-B*44:03 in the Japanese and in Indian and Brazilian populations. Single nucleotide polymorphism association analysis showed that the Toll-like receptor 3 (TLR3), prostaglandin-E receptor 3 (PTGER3), and IKZF1 gene were significantly associated with CM-SJS/TEN with SOC and that they could regulate mucocutaneous inflammation including that of the ocular surface. As we found several HLA-SNP sets with a high odds ratio, we postulated that they may help to predict the possible development of SJS/TEN with SOC. From our findings we suggest that besides microbial infection and cold medicines, a combination of multiple gene polymorphisms and their interactions contribute strongly to the onset of CM-SJS/TEN with SOC.