Genes Related to Stevens-Johnson Syndrome with Serious Ocular Complications

Severe drug eruptions are life-threatening serious drug eruptions and include SJS, TEN and drug-induced hypersensitivity syndrome. Among them, SJS and TEN cause serious ocular complications. Currently, a focus is placed on the relationship between the severe drug eruptions and human leukocyte antigens (HLAs).

HLAs and Gene Polymorphisms

Human leukocyte antigens (HLAs) were initially identified as blood types of leukocytes just as the name stands for. However, they have been revealed to be histocompatibility antigens, important molecules related to the human immune system. HLAs are categorized into Class I and Class II. While Class II HLAs are expressed in immune cells, mainly in antigen-presenting cells, Class I HLAs are expressed in all cells. In addition, based on a fact that Class I HLAs are presented to T-cells together with viral antigens in cells infected with viruses, it is currently known that the differences in Class I HLAs are involved in the differences in the defense mechanism at the time of viral infection. The type of the HLA is inherited from patients and is related to onset of various diseases.

People have different predispositions. Some people are likely to gain weight while others are less likely to. Some have a predisposition toward diabetes mellitus while others are less prone to it. Some are predisposed to experience hypertension while others are unlikely to. It has been gradually revealed that these predispositions derive from the individual differences in the genome, a blueprint of a life. The individual differences are located in hundreds of sites in the genome and are called gene polymorphisms. Gene polymorphisms responsible for the predispositions derive from individual genomic differences and therefore are different from hereditary disorders inherited from parents to children.

Position of Stevens-Johnson Syndrome with Serious Ocular Complications in Severe Drug Eruptions

Currently, a focus is placed on the relationship between severe drug eruptions and HLAs. On the other hand, it has been reported that the onset of severe drug eruptions due to carbamazepine, an antiepileptic drug, is strongly related to HLA-B*15:02 and HLA-A*31:01 respectively in Chinese and in Japanese and Europeans. It has also been reported that the onset of severe drug eruptions due to allopurinol, an antigout drug, is related to HLA-B*58:01 commonly in Chinese, Europeans and Japanese. However, there had been no reports on the onset due to cold medicines, and we recently reported a case for the first time in the world.

Cold Medicine-related Stevens-Johnson Syndrome and HLAs

We have reported not only that HLA-A*02:06 is strongly related to the onset of SJS with serious ocular complications but also that approximately 80% of patients with SJS with serious ocular complications experience the disease because of cold medicines. Among patients with SJS with serious ocular complications, an HLA analysis was performed only in patients with SJS caused by cold medicines. The results revealed strong relationships with HLA-A*02:06 and HLA-B*44:03. An HLA analysis performed in 131 patients with SJS caused by cold medicines (cold medicine-related SJS) regularly visiting the Department of Ophthalmology of Kyoto Prefectural University of Medicine and 419 healthy control individuals revealed a very strong relationship between cold medicine-related SJS and HLA-A*02:06 (p=2.8 x 10-16, odds ratio 5.7).

In addition, four HLA-A types (A*02:06, A*03:01, A*11:01, A*24:02), seven HLA-B types (B*13:01, B*15:01, B*44:02, B*44:03, B*46:01, B*52:01, B*54:01) and three HLA-C types (C*03:04, C*05:01, C*12:02), for which a relation was observed with p<0.05 with the samples from Kyoto Prefectural University of Medicine, were analyzed in 20 patients who had experienced serious ocular complications (keratoconjunctival epithelial erosion/pseudomembrane formation) in the acute phase out of the patients with cold medicine-related SJS collected by the National Institute of Health Sciences (NIHC) using the nationwide network for collecting the cases of serious adverse reactions and 220 healthy control individuals.

The results showed a significant relationship with HLA-A*02:06 and HLA-B*44:03. According to the results from 151 patients with SJS with serious ocular complications collected by Kyoto Prefectural University of Medicine or NIHS and 639 healthy control individuals, the p value and the odds ratio for HLA-A*02:06 were 2.7 x 10-20 and 5.6, respectively, and the p value and the odds ratio for HLA-B*44:03 were 0.001 and 2.0, respectively.

It is very interesting that HLA-A*02:06 and HLA-B*44:03, which were significantly correlated with cold medicine-related SJS with serious ocular complications, were not related to SJS with serious ocular complications caused by drugs other than cold medicines or cold medicine-related SJS without serious ocular complications. This shows that cold medicine-related SJS and SJS caused by drugs other than cold medicines have different genetic predispositions though both are accompanied by serious ocular complications and that cold medicine-related SJS with serious ocular complications and cold medicine-related SJS without serious ocular complications have different genetic predispositions though both are caused by cold medicines.

The different genetic predispositions depending on their causative drugs (HLA-B*15:02HLA-A*31:01 against carbamazepine , HLA-B*58:01 against allopurinol and HLA-A*02:06HLA-B*44:03 against cold medicines [that cause serious ocular complications]) and the different genetic predispositions between presence and absence of serious ocular complications suggest that there are differences in their clinical conditions and that SJS/TEN is a complex of various clinical conditions and disorders.

In addition, HLA-A*02:06 has a very strong correlation with cold medicine-related SJS with serious ocular complications in Japanese. However, HLA-A*02:06 is very rare in Europeans and North Americans and Chinese. On the other hand, HLA-B*44:03 is seen at a certain level not only in Japanese but also in Europeans and North Americans and Chinese. Besides, HLA-B12 (HLA-Bw44), a serum type whose relationship with SJS/TEN was reported by Mondino, an ophthalmologist, et al. in 1982 and by Roujeau, a dermatologist, et al. in 1986 and 1987 has been revealed to correspond to genotypes HLA-B*44:03 and HLA-B*44:02. HLA-B*44:03 can be an HLA marker commonly seen in cold medicine-related SJS and needs to be analyzed further in a global study.

Stevens-Johnson Syndrome with Serious Ocular Complications and Gene Polymorphisms

We are analyzing gene polymorphisms related to the onset of SJS with serious ocular complications as well as HLAs. Patients with SJS with serious ocular complications often experience common cold-like clinical presentations suggestive of viral infections and mycoplasma infection before receiving drugs and frequently have MRSA and MRSE not only in the acute phase but also in the chronic phase, which can easily cause inflammation and infections on the ocular surface. The authors considered a possibility of involvement of innate immune response as a predisposition of the onset of SJS with serious ocular complications and performed gene expression and gene polymorphism analyses.

A gene expression analysis with peripheral blood monocytes revealed a difference in interleukin-4 receptor (IL-4R) gene expression against lipopolysaccharide (LPS), a bacterial component, between patients with SJS and healthy control individuals. A gene polymorphism analysis with its focus on the genes strongly related to innate immune-related genes and IL-4R revealed a relationship with gene polymorphisms of Toll-like receptor 3 (TLR3), IL4R and Fas ligand (FasL). TLR3 belongs to the Toll like receptor family, a mechanism of pathogen recognition, and is a receptor that recognizes virus-derived double-stranded RNA.

Additionally, FasL has been reported to increase in the serum of patients in the acute phase. Regarding IL4R Gln551Arg(rs.1801275), Arg551 alleles were significantly increased in patients with allergic diseases such as asthma as compared with healthy individuals. On the contrary, Gln551 alleles were significantly increased in patients with SJS with serious ocular complications as compared with healthy individuals. Furthermore, a gene polymorphism analysis by analyzing whole genomes revealed a relationship with EP3, one of PGE2 receptors.

The authors also discovered a remarkable decrease in expression of this EP3 protein on the ocular surface of patients with SJS with serious ocular complications.

In the conjunctival tissues with conjunctivochalasis, which presents almost normal conjunctiva, immunostaining shows clearly stained EP3 in conjunctival epithelial cells, while there is a significant decrease in the expression of EP3 proteins in the tissues on the ocular surface of patients with SJS with serious ocular complications.

Suppression of PGE2, a ligand of EP3, by acetaminophen and NSAIDs contained in cold medicines may also be greatly involved in the onset of SJS with serious ocular complications. Generally, people without predisposition of SJS experience accelerated decline of fever and promoted anti-inflammatory action and recover from common cold as a result of microbial infection by an innate immune response after taking cold medicines. On the contrary, we consider that when people with the predispositions of SJS experience some microbial infection, abnormal innate immune response may be caused and further aggravated with intake of the drugs, resulting in the onset of SJS.

Conclusion

It is clear that the genetic predispositions such as HLA is involved in the onset of SJS with serious ocular complications. By narrowing the focus further on cold medicines as the causative drugs, a stronger relationship has been gradually revealed. In addition, multiple gene polymorphisms related to the onset of the disease have been detected, and it has been gradually revealed that certain combinations further increase the incidence of SJS with serious ocular complications.

For example, it has been revealed that people with both TLR3 rs.3775296T/T and HLA-A*02:06 are 263 times more prone to experience SJS with severe ocular complications than people with neither of them as shown by the odds ratio of 47.8. One day in the future, the predispositions of SJS with serious ocular complications can be predicted with a combination of multiple gene polymorphisms and HLAs for prevention and early diagnosis. In addition, identification of the genes related to the onset of SJS with serious ocular complications is expected to reveal the mechanism of onset and lead to development of methods to prevent the onset of the disease and new treatment methods.