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.

Sporadic pemphigus foliaceus and class II human leucocyte antigen allele associations in the white British and Indo-Asian populations in the UK.

BACKGROUND: Pemphigus foliaceus (PF) has both genetic and environmental susceptibility factors. Current data on human leucocyte antigen (HLA) in patients with sporadic PF are limited. AIM: To better define the distribution of HLA alleles in patients with PF in the UK. METHODS: We recruited 36 patients [26 of white British (WB) descent, 10 of Indo-Asian (IA) descent] with PF who were living in the UK and 159 ethnically matched normal controls, and analysed their class II HLA DRB1 and DQB1 allele distribution. RESULTS: There was an increased frequency of DRB1*1404 in association with DQB1*0503 in IA patients with PF. The DRB1*04 allele group as a whole had an increased frequency (P < 0.001) in the WB patient group compared with controls. The alleles contributing to this significance were DRB1*0401 (P = 0.03) and DRB1*0404 (P < 0.01). CONCLUSION: This is the largest HLA association study in sporadic PF from the UK to date. There appears to be a difference in PF susceptibility alleles between WB and IA patients, highlighting the importance of racial variation in genetic susceptibility to disease development.

CD59 polymorphisms are associated with gene expression and different sexual susceptibility to pemphigus foliaceus.

Pemphigus foliaceus (PF) is an autoimmune disease, endemic in Brazilian rural areas, characterized by acantholysis and accompanied by complement activation, with generalized or localized distribution of painful epidermal blisters. CD59 is an essential complement regulator, inhibiting formation of the membrane attack complex, and mediating signal transduction and activation of T lymphocytes. CD59 has different transcripts by alternative splicing, of which only two are widely expressed, suggesting the presence of regulatory sites in their noncoding regions. To date, there is no association study with polymorphisms in CD59 noncoding regions and susceptibility to autoimmune diseases. In this study, we aimed to evaluate if CD59 polymorphisms have a possible regulatory effect on gene expression and susceptibility to PF. Six noncoding polymorphisms were haplotyped in 157 patients and 215 controls by sequence-specific PCR, and CD59 mRNA levels were measured in 82 subjects, by qPCR. The rs861256-allele-G (rs861256*G) was associated with increased mRNA expression (p = .0113) and PF susceptibility in women (OR = 4.11, p = .0001), which were also more prone to develop generalized lesions (OR = 4.3, p = .009) and to resist disease remission (OR = 3.69, p = .045). Associations were also observed for rs831625*G (OR = 3.1, p = .007) and rs704697*A (OR = 3.4, p = .006) in Euro-Brazilian women, and for rs704701*C (OR = 2.33, p = .037) in Afro-Brazilians. These alleles constitute the GGCCAA haplotype, which also increases PF susceptibility (OR = 4.9, p = .045) and marks higher mRNA expression (p = .0025). In conclusion, higher CD59 transcriptional levels may be related with PF susceptibility (especially in women), probably due to the effect of genetic polymorphism and to the CD59 role in T cell signal transduction.

Mortality and Cause of Death in Patients with Pemphigus.

All-cause and cause-specific mortality among patients with pemphigus compared with the general population is yet to be established. This study investigated overall mortality and cause-specific mortality in a large immunopathologically validated cohort of patients with pemphigus. Mortality of patients with pemphigus was compared with age- and gender-matched control subjects in the general population. All-cause and cause-specific standardized mortality ratios (SMRs) were estimated. The study cohort included 245 patients newly-diagnosed with pemphigus between January 1990 and June 2016, contributing 2,679.4 person-years of follow-up. Overall, 48 deaths were observed during a mean follow-up period of 10.9 ± 8.1 years, which was more than twice the number expected (SMR 2.4; 95% confidence interval (95% CI) 1.82-3.20). The SMRs for death due to infections (22.6; 95% CI 13.6-35.3), namely pneumonia (25.7; 95% CI 11.7-48.8) and septicaemia (8.6; 95% CI 1.7-25.0), and due to cardiovascular diseases (2.8; 95% CI 1.0-6.0) were significantly higher than expected. Overall mortality among patients with pemphigus is 2.4-times greater than for the general population, mainly due to infections.

Remarkable differences in the epidemiology of pemphigus among two ethnic populations in the same geographic region.

BACKGROUND: The epidemiology of pemphigus in different ethnic populations exposed to similar environments is unknown. Trends in the incidence of pemphigus based on an immunopathologically validated cohort have not been investigated. OBJECTIVES: We sought to estimate the incidence of pemphigus in Israel and to investigate differences between the 2 major ethnic populations. METHODS: Pemphigus incidence was retrospectively estimated from January 2000 to December 2015 in 2 Israeli regions with a total population of 1.56 million inhabitants. RESULTS: One hundred eighty patients with pemphigus (mean age, 54.70 ± 16 years) were identified. The overall estimated incidence was 7.2 per million inhabitants per year (95% confidence interval, 6.2-8.3). The incidence in the Jewish population was threefold higher than that in Arabs (9.6 vs 3.2 cases per million per year, respectively; P < .0001) and higher among women than men (9 vs 5.3 cases per million per year, respectively; P < .0001). The incidence decreased from 8.4 cases per million per year in 2000 to 2005 to 7.0 and 6.0 (95% confidence interval, 4.5-7.9) in 2006 to 2010 and 2011 to 2015, respectively (P = .068). LIMITATIONS: This study was limited by the retrospective design and the small population. CONCLUSIONS: The incidence of pemphigus in Israel is among the highest reported worldwide and is significantly more frequent among Jews.

Epidemiological data of 290 pemphigus vulgaris patients: a 29-year retrospective study.

Pemphigus vulgaris (PV), an autoimmune blistering disease involving the skin and mucosa, is traditionally considered to be prevalent among Jews, particularly those of Ashkenazi origin. Israel, where the Ashkenazi and non-Ashkenazi Jewish population live alongside a large Arab minority, is a particularly interesting place for epidemiological studies of PV. To characterise the epidemiological and clinical parameters of PV patients from a single tertiary medical centre in Israel. Data was retrieved retrospectively from the medical records of newly diagnosed PV patients referred to the Sheba Medical Center between 1980 and 2009. A total of 290 PV patients were diagnosed during the study period. The mean age at diagnosis was 49.7 years (range: 10-92 years) and a female predominance was identified (1.54:1; p<0.001). Among the Jewish patients, the ratio of Ashkenazi to non-Ashkenazi was 1.23:1, which was not statistically significant in comparison to the ratio of the general Jewish population in Israel (p = 0.289). We describe the comorbidities found among the patients. Disease severity at diagnosis was not found to be related to the epidemiological parameters examined. Studies from different countries reveal variations in the clinical and epidemiological characteristics of the disease. The epidemiology of PV in Israel, a Middle-Eastern country with a Western lifestyle and a diverse ethnic population, shows some characteristics that represent an "admixture" between European and Middle-Eastern or Asian countries. The associated comorbidities of PV emphasize the need for dermatologists to keep a high index of suspicion and actively evaluate patients to determine their presence.

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.

High susceptibility to pemphigus vulgaris due to HLA-DRB1*14:54 in the Slovak population.

The current work describes an association between pemphigus vulgaris (PV) and class II HLA alleles in the Slovak population, the first such study in Slovakia on the 'high-resolution level'. This work takes into account the new HLA allele nomenclature, officially adopted in 2010. In particular, we have focused on the associations between PV and DRB1*14:54 and DRB1*14:01. This case-control study was performed in a cohort of 43 PV Caucasian patients and 113 Caucasian control subjects from Slovakia. HLA typing was performed using PCR-SSP (polymerase chain reaction with sequence-specific primers). We found significantly positive associations between PV and the HLA alleles DRB1*04:02, DRB1*04:04, DRB1*14:54, DRB1*14:04, DRB1*14:05, DQB1*03:02 and DQB1*05:03. In contrast, HLA-DQB1*06, DRB1*07 and DRB1*13 were negatively associated with PV. Importantly, 93% of PV patients possessed at least one of two HLA haplotypes, DRB1*04-DQB1*03 or HLA-DRB1*14-DQB1*05. We confirmed the previously reported associations between HLA class II alleles and PV and described a new association between PV and DRB1*14:54. This allele was first described in 2005, and there has been only one report of its association with PV to date.

HLA-E*0103X is associated with susceptibility to Pemphigus vulgaris.

Non-classical human leucocyte antigen-E (HLA-E) mediates natural killer and CD8+ T-cell activity, suggesting a role in the regulation of autoimmunity. HLA-E*0103X/*0103X has been associated with Behcet's disease and HLA-E *0101/*0103X with childhood onset diabetes. We investigated HLA-E allele status in 52 Caucasian and Ashkenazi Jewish Pemphigus vulgaris (PV) patients and 51 healthy controls by restriction fragment length polymorphism-polymerase chain reaction and amplification refractory mutation system. Associations were determined via chi-square test, Fisher's exact test and logistical regression analysis. HLA-E outcomes included presumed homozygous *0101/*0101 or *0103X/*0103X genotype status or *0101/*0103X heterozygous status. PV did not significantly associate with either *0101/*0101 or *0101/*0103X genotypes. HLA-E*0103X/*0103X (presumed homozygote) is significantly increased in patients with PV versus controls (P = 0.0146, OR = 3.730, 95%CI = 1.241-11.213). Our data provide the first evidence that HLA-E*0103X is a marker for genetic risk in PV.

Profile of Trypanosoma cruzi reactivity in a population at high risk for endemic pemphigus foliaceus (Fogo selvagem).

Fogo selvagem (FS) is an autoimmune bullous disease with pathogenic IgG autoantibodies recognizing desmoglein 1 (Dsg1), a desmosomal glycoprotein. In certain settlements of Brazil, a high prevalence of FS (3%) is reported, suggesting environmental factors as triggers of the autoimmune response. Healthy individuals from endemic areas recognize nonpathogenic epitopes of Dsg1, and exposure to hematophagous insects is a risk factor for FS. Fogo selvagem and Chagas disease share some geographic sites, and anti-Dsg1 has been detected in Chagas patients. Indeterminate Chagas disease was identified in a Brazilian Amerindian population of high risk for FS. In counterpart, none of the FS patients living in the same geographic region showed reactivity against Trypanosoma cruzi. The profile of anti-Dsg1 antibodies showed positive results in 15 of 40 FS sera and in 33 of 150 sera from healthy individuals from endemic FS sites, and no cross-reactivity between Chagas disease and FS was observed.

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.

Pemphigus, analysis of 155 patients.

BACKGROUND: Pemphigus vulgaris is a chronic autoimmune mucocutaneous blistering disease. In the last 20 years, immunomodulatory agents have been added to the therapeutic armamentarium. Only few recent studies have evaluated the long-term outcome of pemphigus and possible prognostic parameters in a large group of patients. The aim of this study was to evaluate and analyse the course and prognostic factors of pemphigus in patients followed from 1976 to 2004. PATIENTS AND METHODS: The study group consisted of 155 patients attending the pemphigus clinic of a major tertiary-care medical centre. Background, clinical and treatment data were derived from the patient files and telephone contact. Statistical analysis was performed with Pearson correlation, Fisher exact test, and univariate and multivariate logistic regression models. RESULTS: Age < 40 years at disease onset, Sephardic Jewish origin, and mucosal involvement at diagnosis and high number of relapses were found to be independent prognostic factors of poor outcome. A long (> 1 year) primary remission was a good prognostic factor. During the 26-year study period, 16 patients died. None of the deaths was directly related to either the disease or a complication of treatment. CONCLUSIONS: The course and outcome of pemphigus are worse in patients who are young at diagnosis (< 40 years) or of Sephardic Jewish origin. Mucosal involvement at diagnosis and poor response to treatment also predict poor outcome. The mortality rate of pemphigus is apparently lower than reported in the literature, perhaps because of the contemporary use of adjuvant immunomodulatory therapeutic agents.