Single-nucleotide polymorphisms associated with pemphigus vulgaris: Potent markers for better treatment and personalized medicine.

Pemphigus vulgaris (PV) is a rare autoimmune blistering disorder, which could affect both skin and mucosal surfaces. There is increasing evidence that genetics plays a critical role in PV development, severity and prognosis. Single-nucleotide polymorphisms (SNPs) are the most common type of genetic variation among people and have been widely evaluated in most diseases. However, there are few studies regarding the roles of SNPs in the PV. Here, we reviewed both pathogenic and protective roles of the SNPs in non-HLA genes regarding the PV. Among the large number of studied SNPs, it was found that several SNPs in different genes might control the susceptibility of PV, including TNFA (rs361525, rs1800629, rs1800629), IL10 (rs1800871, rs1800896, rs1800871, and rs1800872), IL6 (rs1800795), CTLA4 (rs231775), ICOS (rs10932029), CD86 (rs1129055), DSG3 (rs8085532, rs3911655, rs3848485, rs3794925, rs1466379), ST18 (rs2304365, rs17315309) and TAP2 (rs7454108), probably in a population-specific manner. Moreover, SNPs in glucocorticoid receptor, also known as nuclear receptor subfamily 3 group C member 1 (NR3C1) gene, including rs11745958, rs17209237, rs33388, rs7701443 as well as rs116855232 at NUDT15, seem to be associated with therapeutic outcomes in PV patients. Additionally, variations in the other genes involved in the drugs' metabolisms, pharmacokinetics and pharmacodynamics such as rs396991 in FCGR3A gene could be used for the prediction of clinical response to drugs and side effects. Taken together, SNPs seem to be valuable tools for better management of PV patients. Further studies need to be conducted to evaluate SNPs in genes that control immune responses and apoptosis.

Epiplakin Is a Paraneoplastic Pemphigus Autoantigen and Related to Bronchiolitis Obliterans in Japanese Patients.

All plakin family proteins are known to be autoantigens in paraneoplastic pemphigus (PNP). In this study, we first examined whether PNP sera also react with epiplakin, another plakin protein, by various immunological methods using 48 Japanese PNP sera. Immunofluorescence confirmed that cultured keratinocytes expressed epiplakin. Epiplakin was detected by 72.9% of PNP sera by immunoprecipitation-immunoblotting with KU-8 cell extract, but not by immunoblotting of either normal human epidermal extract or KU-8 cell extract. Epiplakin was essentially not detected by 95 disease and normal control sera. Statistical analyses of various clinical and immunological findings revealed a significant correlation of the presence of anti-epiplakin antibodies with both bronchiolitis obliterans and mortality. No epiplakin-negative PNP case developed bronchiolitis obliterans. However, although 29.4% of European patients with PNP had bronchiolitis obliterans, significant correlation with anti-epiplakin autoantibodies was not observed. In further studies for lung, immunofluorescence showed the presence of epiplakin in normal human lung, particularly respiratory bronchiole, immunoprecipitation-immunoblotting showed that PNP sera reacted with epiplakin in cultured lung cells, and mice injected with polyclonal antibody specific to epiplakin histopathologically showed abnormal changes in small airway epithelia. These results indicated that epiplakin is one of the major PNP autoantigens and is related to PNP-related bronchiolitis obliterans.

Incidence, mortality, and causes of death of patients with pemphigus in Taiwan: a nationwide population-based study.

Pemphigus is a potentially life-threatening autoimmune blistering disease. However, little is known about the all-cause and cause-specific mortality among patients with pemphigus compared with the general population. The incidence of pemphigus in Taiwan has not been described previously. The objective of this study was to estimate the incidence of pemphigus in Taiwan and to investigate the overall mortality, causes of death, and cause-specific mortality in a nationwide population-based cohort of pemphigus patients. The study cohort included 853 patients newly diagnosed with pemphigus between 2002 and 2009 in the National Health Insurance Research Database. Survival status, date of death, and cause of death were ascertained by linking the study cohort with the National Register of Deaths Database of Taiwan. All-cause and cause-specific standardized mortality ratios (SMRs) were estimated. The incidence of pemphigus in Taiwan was 4.7 (95% confidence interval (CI), 3.2-6.2) per million per year. Overall, 88 deaths were observed during a mean follow-up period of 3.8 years, which was more than two times the number expected (SMR, 2.36; 95% confidence interval, 1.92-2.91). In the analysis of causes of death, the SMRs for death due to pneumonia (3.64; 95% CI, 1.30-10.21), septicemia (11.57; 95% CI, 2.95-45.34), cardiovascular disease (2.69; 95% CI, 1.18-6.12), and peptic ulcer disease (8.44; 95% CI, 1.22-58.21) were significantly higher than expected. We concluded that the incidence of pemphigus is not low in Taiwan, and the overall mortality among pemphigus patients is two times greater than that of the general population. In particular, patients with pemphigus have higher risk of mortality from systemic and respiratory tract infections, cardiovascular disease, and peptic ulcer disease.