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1.  Bullous pemphigoid and pemphigus vulgaris—incidence and mortality in the UK: population based cohort study 
Objective To determine the incidence of and mortality from bullous pemphigoid and pemphigus vulgaris in the United Kingdom.
Design Retrospective historical cohort study.
Setting Computerised medical records from the health improvement network, a large population based UK general practice database.
Participants Patients with pemphigus vulgaris and bullous pemphigoid diagnostic codes and age, sex, and practice matched controls.
Main outcome measures Incidence and mortality compared with the control population by calendar period, age group, sex, geographical region, and degree of social deprivation.
Results 869 people with bullous pemphigoid and 138 people with pemphigus vulgaris were identified. The median age at presentation for bullous pemphigoid was 80 (range 23-102) years, and 534 (61%) patients were female. The median age at presentation for pemphigus vulgaris was 71 (21-102) years, and 91 (66%) patients were female. Incidences of bullous pemphigoid and pemphigus vulgaris were 4.3 (95% confidence interval 4.0 to 4.6) and 0.7 (0.6 to 0.8) per 100 000 person years. The incidence of bullous pemphigoid increased over time; the average yearly increase was 17% (incidence rate ratio=1.2, 95% confidence interval 1.1 to 1.2). An average yearly increase in incidence of pemphigus vulgaris of 11% (incidence rate ratio=1.1, 1.0 to 1.2) occurred. The risk of death for patients with bullous pemphigoid was twice as great as for controls (adjusted hazard ratio=2.3, 95% confidence interval 2.0 to 2.7). For pemphigus vulgaris, the risk of death was three times greater than for controls (adjusted hazard ratio=3.3, 2.2 to 5.2).
Conclusions Incidences of bullous pemphigoid and pemphigus vulgaris are increasing. The reasons for the changes in incidence are not clearly understood but have implications for identifying causative factors. Both disorders are associated with a high risk of death. Previous estimates may have underestimated the risk of death associated with these diseases.
doi:10.1136/bmj.a180
PMCID: PMC2483869  PMID: 18614511
2.  A Population-Based Study of the Association Between Bullous Pemphigoid and Neurologic Disorders 
Background
Bullous pemphigoid has been reported in association with neurologic disorders.
Objective
To analyze the association between bullous pemphigoid and neurologic disorders.
Methods
We retrospectively identified residents of Olmsted County, Minnesota, with a first lifetime diagnosis of bullous pemphigoid between January 1, 1960, and December 31, 2009. Three age- and sex-matched Olmsted County residents without bullous pemphigoid were selected as controls for each patient. We compared history of or development of neurologic disorders (dementia, Alzheimer disease, Parkinson disease, multiple sclerosis, cerebrovascular disease, and seizures) between groups using case-control and cohort designs.
Results
A total of 87 patients with bullous pemphigoid were identified and matched to 261 controls. The odds of a previous diagnosis of any neurologic disorder or a history of dementia were significantly increased among cases compared with controls (odds ratios: 6.85 (3.00–15.64); P<.001, and 6.75 (2.08–21.92); P=.002, respectively). Both Parkinson disease (hazard ratio, 8.56 (1.55–47.25); P=.01) and any type of neurologic disorder (hazard ratio, 2.02 (1.17–3.49); P=.01) were significantly more likely to develop during follow-up in patients with bullous pemphigoid than in those without bullous pemphigoid.
Limitations
Small geographic area; retrospective study design.
Conclusion
Our study confirmed an association of bullous pemphigoid with neurologic disorders, especially dementia and Parkinson disease.
doi:10.1016/j.jaad.2014.07.052
PMCID: PMC4326088  PMID: 25174542
bullous diseases; bullous pemphigoid; epidemiology; immunobullous; immunodermatology; pemphigoid
3.  Activating KIR and HLA Bw4 Ligands Are Associated to Decreased Susceptibility to Pemphigus Foliaceus, an Autoimmune Blistering Skin Disease 
PLoS ONE  2012;7(7):e39991.
The KIR genes and their HLA class I ligands have thus far not been investigated in pemphigus foliaceus (PF) and related autoimmune diseases, such as pemphigus vulgaris. We genotyped 233 patients and 204 controls for KIR by PCR-SSP. HLA typing was performed by LABType SSO reagent kits. We estimated the odds ratio, 95% confidence interval and performed logistic regression analyses to test the hypothesis that KIR genes and their known ligands influence susceptibility to PF. We found significant negative association between activating genes and PF. The activating KIR genes may have an overlapping effect in the PF susceptibility and the presence of more than three activating genes was protective (OR = 0.49, p = 0.003). A strong protective association was found for higher ratios activating/inhibitory KIR (OR = 0.44, p = 0.001). KIR3DS1 and HLA-Bw4 were negatively associated to PF either isolated or combined, but higher significance was found for the presence of both together (OR = 0.34, p<10−3) suggesting that the activating function is the major factor to interfere in the PF pathogenesis. HLA-Bw4 (80I and 80T) was decreased in patients. There is evidence that HLA-Bw4(80T) may also be important as KIR3DS1 ligand, being the association of this pair (OR = 0.07, p = 0.001) stronger than KIR3DS1-Bw4(80I) (OR = 0.31, p = 0.002). Higher levels of activating KIR signals appeared protective to PF. The activating KIR genes have been commonly reported to increase the risk for autoimmunity, but particularities of endemic PF, like the well documented influence the environmental exposure in the pathogenesis of this disease, may be the reason why activated NK cells probably protect against pemphigus foliaceus.
doi:10.1371/journal.pone.0039991
PMCID: PMC3388041  PMID: 22768326
4.  Prediction of survival for patients with pemphigus vulgaris and pemphigus foliaceus: a retrospective cohort study 
Background
Factors associated with survival in pemphigus have not yet been thoroughly addressed. Therefore, in the present study, risk factors for overall mortality in a large group of patients with pemphigus vulgaris and foliaceus were investigated.
Methods
A retrospective hospital-based cohort study was carried out, between October 1998 and November 2012, in the Department of Dermatology of the University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca, Romania. The investigated prognostic endpoint was the overall survival of the patients.
Results
A total of 130 patients were studied (108 with pemphigus vulgaris and 22 with pemphigus foliaceus). In pemphigus vulgaris group, univariate analysis found a statistically significant association between the age of onset ≥ 65 years (p < 0.001), presence of coronary heart disease (p = 0.006), presence of cardiac arrhythmia (p = 0.004), level of anti-desmoglein1 autoantibodies ≥ 100 U/mL (p = 0.047) at diagnosis and the survival of the patients. An age-adjusted analysis showed significant results for coronary heart disease. Multivariate analysis identified the age of onset ≥ 65 years and the presence of coronary heart disease at diagnosis as independent risk factors associated with overall mortality. In patients with pemphigus foliaceus, age of onset ≥ 65 years (p = 0.021) was associated with poor survival.
Conclusions
In addition to common prognostic factors, including older age and cardiovascular comorbidities, level of autoantibodies was found to be a disease-specific factor associated with overall mortality in pemphigus vulgaris. The newly identified factors have major implications for the stratification of patients and should greatly facilitate further epidemiological studies in pemphigus. In addition, they provide useful information for the design of personalized therapeutic plans in the clinical setting.
doi:10.1186/s13023-015-0263-4
PMCID: PMC4411722  PMID: 25896794
Risk factors; Pemphigus; Survival rate; Age factor; Cardiovascular disease; Anti-desmoglein 1 autoantibodies
5.  Recurrent venous thrombosis in an adequately anticoagulated patient with pemphigus vulgaris 
Thrombosis Journal  2016;14:6.
Background
Several autoimmune skin disorders are characterised by an increased risk of thrombosis, with bollous pemphigoid carrying a higher risk than pemphigus vulgaris (PV). We describe the case of a middle aged gentleman who developed recurrent venous thromboembolism despite adequate oral anticoagulation during very active PV that required escalation of treatment to bring the disease under control.
Case presentation
In May 2014 a 49 year gentleman was admitted for widespread mucocutaneous blistering diagnosed as PV by histology and immunofluorescence. After 6 weeks of treatment with systemic steroids and azathioprine the patient developed pulmonary emboli and started oral anticoagulation with warfarin. In late September, the patient re-presented with a severe flare of PV and a recurrent deep vein thrombosis despite oral anticoagulation within therapeutic range. Warfarin was changed to subcutaneous low molecular heparin in therapeutic dose while treatment for pemphigus was escalated: first azathioprine was switched to mycophenolate mofetil and the steroids dose increased; then due to poor response, intravenous immunoglobulins were given for three courses and finally he received four infusions of Rituximab that induced sustained remission. In April 2015 the dose of mycophenolate was decreased but anticoagulation was continued until the beginning of July 2015 to ensure that decreasing immune suppression did not allow the emergence of another flare with attendant thrombotic risk.
Conclusion
The case highlights the risk of thrombosis and re-thrombosis in aggressive PV and demands further clinical research in this area to assess the need for thromboprophylaxis in aggressive bollous skin disease.
doi:10.1186/s12959-016-0080-6
PMCID: PMC4778297  PMID: 26949375
Pemphigus vulgaris; Thrombosis
6.  Absorption of pathogenic autoantibodies by the extracellular domain of pemphigus vulgaris antigen (Dsg3) produced by baculovirus. 
Pemphigus vulgaris (PV) is an autoimmune blistering disease, in which autoantibodies against PV antigen (PVA or Dsg3) play a pathogenic role in inducing blister formation. Bacterial fusion proteins of PVA failed to absorb pathogenic autoantibodies from PV patients' sera probably because they did not represent the proper conformation. Therefore, a chimeric protein, PVIg, consisting of the whole extracellular domain of PVA and the constant region of human IgG1, was produced in either in COS7 or in insect Sf9 eucaryotic cells. Both PVIg-COS7 and PVIg-Sf9 were recognized by all of the 35 PV sera tested, but not by any of 10 pemphigus foliaceus (PF), 16 Brazilian PF, 10 bullous pemphigoid, or five normal control sera. Incubation of PV patients' sera with PVIg-Sf9 removed heterogeneous autoantibodies and significantly reduced their immunofluorescence titers on normal human epidermis, although PVIg-Sf9 did not affect the titers of PF sera at all. Furthermore, PVIg-Sf9 absorbed pathogenic autoantibodies from patients' sera and prevented gross blister formation in a neonatal mouse model for pemphigus. These results indicate that this baculovirus product has the proper conformation of the authentic PVA and that its conformation is important in pathogenicity of pemphigus.
Images
PMCID: PMC296282  PMID: 8040292
7.  The Protease Inhibitor Alpha-2-Macroglobuline-Like-1 Is the p170 Antigen Recognized by Paraneoplastic Pemphigus Autoantibodies in Human 
PLoS ONE  2010;5(8):e12250.
Background
Paraneoplastic pemphigus (PNP) is a devastating autoimmune blistering disease, involving mucocutaneous and internal organs, and associated with underlying neoplasms. PNP is characterized by the production of autoantibodies targeting proteins of the plakin and cadherin families involved in maintenance of cell architecture and tissue cohesion. Nevertheless, the identity of an antigen of Mr 170,000 (p170), thought to be critical in PNP pathogenesis, has remained unknown.
Methodology/Principal Findings
Using an immunoprecipitation and mass spectrometry based approach, we identified p170 as alpha-2-macroglobuline-like-1, a broad range protease inhibitor expressed in stratified epithelia and other tissues damaged in the PNP disease course. We demonstrate that 10 PNP sera recognize alpha-2-macroglobuline-like-1 (A2ML1), while none of the control sera obtained from patients with bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus and normal subjects does.
Conclusions/Significance
Our study unravels a broad range protease inhibitor as a new class of target antigens in a paraneoplastic autoimmune multiorgan syndrome and opens a new challenging investigation avenue for a better understanding of PNP pathogenesis.
doi:10.1371/journal.pone.0012250
PMCID: PMC2923615  PMID: 20805888
8.  Vitamin D deficiency and lower TGF-β/IL-17 ratio in a North Indian cohort of pemphigus vulgaris 
BMC Research Notes  2014;7:536.
Background
Pemphigus vulgaris (PV) is an autoimmune bullous disease caused by acantholysis of keratinocytes due to pathogenic desmoglein-3 autoantibodies. Role of vitamin D has been recently implicated in various autoimmune conditions due to its immunomodulatory effects on innate and adaptive immune responses. One of the key mechanisms of the immune regulation by vitamin D is through its anti-inflammatory effects by suppression of Th17 functions. Thus, vitamin D may be involved in pathogenesis of PV. In this study, the serum vitamin D, IL-17 and TGF-β levels in PV patients as well as healthy controls were estimated in order to understand the underlying immune mechanism involved in disease pathogenesis.
Results
This retrospective study included 30 biopsy proven PV patients’ sera. Ten age matched volunteers without any cutaneous or autoimmune conditions were recruited as healthy control (HC). Serum Vitamin D levels were measured using chemiluminescence, whereas IL-17 and TGF-β levels were determined using ELISA. All patients showed deficient vitamin D levels (11.1 ± 5.8 ng/ml). Moreover, all the PV patients had elevated serum IL-17 levels (210.7 ± 105.3), whereas it was not detectable in any (n = 10) of the healthy controls sera (ELISA sensitivity ≥ 8 pg/ml). The mean serum TGF-β concentration was also lower in patient sera as compared to healthy control, and the TGF-β/IL-17 ratio was drastically reduced in patients (30.30 ± 28), as compared to healthy controls (1363.34 ± 559.52).
Conclusions
Hypovitaminosis is common in North India, as ascertained by deficient levels in healthy controls, and was also consistently observed in PV patient. These low levels were not related to age or gender. The increased serum IL-17 and dramatic reduction in TGF-β/IL-17 ratio in diseased patients further indicate that dysregulation of the Treg/Th-17 axis of T effector cells may be of significance in pathogenesis of PV. Thus, the study indicates that vitamin D insufficiency may be a predisposing factor in PV, contributing through its role in any of the various adaptive immune mechanisms that regulate T cell functions in vivo. Thus, there is a need to further evaluate the Treg/Th-17 axis, as it may have an important role in disease progression.
doi:10.1186/1756-0500-7-536
PMCID: PMC4246498  PMID: 25128193
Autoimmune bullous disease; Pemphigus vulgaris; Vitamin-D; IL-17; TGF-b
9.  Evaluation of cases of pemphigus vulgaris and pemphigus foliaceus from a reference service in Pará state, Brazil*  
Anais Brasileiros de Dermatologia  2014;89(4):556-561.
BACKGROUND
Pemphigusis a bullous, rare and chronic autoimmune disease. There are two major forms of pemphigus: vulgaris and foliaceus. Epidemiological data and clinical outcome in patients diagnosed in the Brazilian Amazon states are still rare.
OBJECTIVES
To study the occurrence of the disease during the study period and analyze the epidemiological profile of patients, the most common subtype of pemphigus, and the clinical evolution of patients.
METHODS
Retrospective analysis of medical records of hospitalized patients with pemphigus foliaceus and pemphigus vulgaris in the period from 2003 to 2010 in Dermatology Service of Hospital Fundação Santa Casa de Misericórdia do Pará, Belém, Northern Brazil.
RESULTS
We found a total of 20 cases of pemphigus during the study period, 8 of which were of foliaceus pemphigus and 12 of vulgaris pemphigus. Pemphigus foliaceus had the predominance of male patients (75%), showed satisfactory clinical evolution, and was characterized by absence of pediatric cases. Pemphigus vulgaris affected more women (66.7%), showed mean hospital stay of 1 to 3 months (50%), and there were three cases of death (25%). The prescribed immunosuppressive drugs included prednisone with or without combination of azathioprine and/or dapsone. Sepsis was associated with 100% of the deaths.
CONCLUSIONS
The occurrence of the disease is rare, there are no familiar/endemic outbreaks in the sample. Evolution is usually favorable, but secondary infection is associated with worse prognosis. The choice of best drugs to treat pemphigus remains controversial.
doi:10.1590/abd1806-4841.20142679
PMCID: PMC4148267  PMID: 25054740
Autoimmunity; Immunosuppressive agents; Pemphigus; Skin diseases, vesiculobullous
10.  Absence of Human Herpesvirus 8 in Pemphigus and Bullous Pemphigoid 
Pemphigus and pemphigoid are vesicobullous disorders characterized by an autoimmune attack on intercellular or basement membrane antigens, resulting in defective keratinocyte adhesion. Recently there have been reports of human herpesvirus 8 (HHV8) associated with cases of pemphigus using polymerase chain reaction (PCR) techniques, in situ hybridization, and serologic data. However, data to date is contradictory, and the relationship between this virus and autoimmune vesiculobullous disorders is unclear. No reports have attempted immunohistochemical localization of HHV8 in tissue affected by PV or BP. We studied immunohistochemical expression of HHV8 on paraffin-embedded tissue in 10 cases of pemphigus vulgaris (PV), 1 case of pemphigus foliaceous (PF) and 14 cases of bullous pemphigoid (BP). Five cases of normal skin were included as controls. Confirmatory PCR for HHV8 was performed on 4 selected cases, including 2 cases of PV and 2 cases of BP. Immunohistochemistry failed to identified the presence of HHV8 in all cases of PV (10 cases), PF (1 case) and BP (14 cases). Molecular detection of HHV8 DNA was not detected in selected PV (2 cases) and BP (2 cases). Published studies have shown contradictory evidence regarding the presence of HHV8 in vesiculobullous diseases such as pemphigus and pemphigoid. Our results refute a causal relationship between HHV8 and PV, PF and BP.
PMCID: PMC2655157  PMID: 19294004
Pemphigus; bullous pemphigoid; human herpesvirus 8 (HHV8); immunohistochemistry; polymerase chain reaction
11.  Prevalence of pemphigus and pemphigoid autoantibodies in the general population 
Background
Mucocutaneous blistering is characteristic of autoimmune bullous dermatoses (AIBD). Blisters are caused by autoantibodies directed against structural components of the skin. Hence, detection of specific autoantibodies has become a hallmark for AIBD diagnosis. Studies on prevalence of AIBD autoantibodies in healthy individuals yielded contradictory results.
Methods
To clarify this, samples from 7063 blood donors were tested for presence of anti-BP180-NC16A, anti-BP230 and anti-Dsg1/3 IgG by indirect immunofluorescence (IF) microscopy using a biochip.
Results
Cumulative prevalence of these autoantibodies was 0.9 % (CI: 0.7–1.1 %), with anti-BP180-NC16A IgG being most prevalent. Validation of IF findings using ELISA confirmed presence of autoantibodies in 7/15 (anti-Dsg1), 6/7 (anti-Dsg3), 35/37 (anti-BP180-NC16A) and 2/3 (anti-BP230) cases. Moreover, in 16 samples, anti-BP180-NC16A autoantibody concentrations exceeded the cut-off for the diagnosis of bullous pemphigoid. Interestingly, these anti-BP180-NC16A autoantibodies from healthy individuals formed immune complexes with recombinant antigen and dose-dependently activated neutrophils in vitro. However, fine-epitope mapping within NC16A showed a different binding pattern of anti-BP180-NC16A autoantibodies from healthy individuals compared to bullous pemphigoid patients, while IgG subclasses were identical.
Conclusions
Collectively, we here report a low prevalence of AIBD autoantibodies in a large cohort of healthy individuals. Furthermore, functional analysis shows differences between autoantibodies from healthy donors and AIBD patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-015-0278-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13023-015-0278-x
PMCID: PMC4436865  PMID: 25971981
Autoimmunity; Skin; Type XVII collagen; BP180; Desmoglein; Pemphigoid; Pemphigus
12.  Serum Selenium, Zinc, and Copper in Early Diagnosed Patients with Pemphigus Vulgaris 
Iranian Journal of Public Health  2012;41(5):105-109.
Background:
Pemphigus vulgaris is a life threatening, blistering skin disease. It is an autoimmune abnormality. Due to involvement of oral cavity and pharynx, patients are at risk of nutrients deficiency. The aim of this study was to evaluate the status of selenium, copper, and zinc in these patients.
Methods:
In a case-control study, 43 newly diagnosed pemphigus vulgaris patients were compared with 58 healthy people from 2009 to 2010. The severity of the disease was estimated according to Harman’s scores. Serum selenium was measured with atomic absorption but serum zinc and copper concentrations were determined spectrophotometrically. Data were compared with independent t test. Correlations were evaluated by Pearson correlation test.
Results:
Both groups were the same based on sex, age, and weight and body mass index. The mean duration of disease was 5.6 month. The oral and skin severities were 1.79 and 2.3 respectively, based on Harman’s scores. Serum selenium of pemphigus patients was significantly less than that of healthy people (P<0.001). Serum copper was negatively correlated with duration of disease in males (P=0.02, r=−0.5).
Conclusions:
Pemphigus vulgaris negatively affects on serum selenium, copper and zinc. It seems that serum selenium, copper and zinc decrease as the disease lasts longer.
PMCID: PMC3468983  PMID: 23113184
Selenium; Zinc; Copper; Pemphigus vulgaris
13.  A Clinicopathological Study of Pemphigus in Eastern India with Special Reference to Direct Immunofluorescence 
Indian Journal of Dermatology  2016;61(3):288-294.
Background:
Pemphigus is a group of chronic autoimmune vesico-bullous disorders in which the epidermis and the basement membrane zone are the focus of attack resulting in cutaneous and mucosal blister formation. Direct immunofluorescence (DIF) test is a very sensitive test for the diagnosis
Aim:
To study the clinico histopathological patterns of pemphigus in eastern India. The study also aims to correlate DIF with clinical and histologic findings as well as severity of skin involvement [scoring systems].
Materials and Methods:
Total 41 patients were studied over a period of 1 year in the Post-graduate centre of Dermatology in Eastern India. DIF, histopathology and clinical data were correlated.
Results:
In our study Pemphigus vulgaris (PV) was the predominant type with 32 cases followed by 8 cases of pemphigus foliaceus (PF) and a single case of IgA pemphigus. Mean age at presentation was late middle age. Majority of the patients, 26 (63.41%) initially had cutaneous involvement followed by mucosal involvement. In this study group 36 (87.80%) patients showed acantholytic cells on histopathological examination. Most patients of PV showed suprabasal blister 20 (62.50%) followed by intraspinous 5 (15.62%) and subcorneal 5 (15.62%) blister. In majority 28 (87.50%) of the PV patients IgG and C3 antibodies were deposited throughout the epidermis. The strength of antibody positivity was strong in most of the patients (71.87%). In cases of PF mostly IgG 6 (75%) antibodies were deposited in the upper epidermis. DIF intensity had poor correlation with disease activity/severity except in PF.
Conclusion:
Almost 85.36% cases of pemphigus were diagnosed clinicopathologically. But 6 cases couldn’t be diagnosed accurately on clinicopathological basis and in them DIF was confirmatory. Two cases of pure mucosal PV and 1 case of IgA pemphigus was confirmed by DIF. Two cases of bullous pemphigoid clinico-histologically mimicking PV were also excluded by DIF. So it appears from our study that DIF is confirmatory for diagnosis of pemphigus in all cases.
doi:10.4103/0019-5154.182422
PMCID: PMC4885181  PMID: 27293249
Direct immunofluorescence; Mahajan's score; pemphigus area and activity score; pemphigus foliaceus; pemphigus vulgaris
14.  Epidemiology of Pemphigus in Tehran, Iran: A 20-Year Retrospective Study  
Background and aims
Pemphigus is a chronic autoimmune and vesiculobollous disease that can affect skin and different mucous membrane surfaces. Primary manifestations occur in oral cavity in almost 60% of cases. The purpose of the present study was to evaluate the epidemiology of pemphigus in Tehran, Iran in a 20-year period.
Materials and methods
A retrospective study was conducted on the records of 1560 patients diagnosed with different types of pemphigus in Razi Hospital of Dermatology in Tehran from March 1985 to March 2005. A questionnaire was prepared to collect information regarding age, sex, bedridden duration, pemphigus subtype, sites of involvement, recurrence and mortality rate. Data was analyzed using chi-square test with significant level of P < 0.05.
Results
There was a female predominance with a male to female ratio of 1:1.53. In nearly half of the patients, only the oral mucous membranes were affected. One hundred and fifty had only skin lesions and 261 cases had both skin and oral mucosal lesions. Involvement of esophageal and vaginal mucous membranes without skin lesions was observed in 150 patients and 298 cases had esophageal and vaginal mucosal involvement as well as skin lesions. Pemphigus vulgaris was the most common type, with the mean age of 44.6 years. Oral mucous membrane was the most frequent location where pemphigus vulgaris was observed. 1265 patients recovered which 52.2% of them had only oral lesions. Average of bedridden duration was 2.9 months. The highest recurrence rate was seen in patients with skin lesions exclusively. There was a significant difference between recurrences of lesions and location of involvement (P < 0.05). Thirty six patients had died from of the disease.
Conclusion
The mean age of the disease onset in the present study was found to be a decade earlier than the other parts of the world. Recurrence and mortality rates were lower in patients with only oral lesions and their prognosis was better.
doi:10.5681/joddd.2007.019
PMCID: PMC3529885  PMID: 23277844
Epidemiology; Iran; pemphigus; vesiculobullous
15.  Pemphigus Foliaceus Associated with Psoriasis during the Course of Narrow-Band UVB Therapy: A Simple Coincidence? 
Annals of Dermatology  2011;23(Suppl 3):S281-S284.
Although psoriasis and bullous diseases are considered to be completely different disease entities, the literature has reported a few cases of psoriasis associated with bullous diseases, most of which are bullous pemphigoid. In limited cases, pemphigus foliaceus has also been reported in association with psoriasis. In most of them, pemphigus lesions usually developed on an untreated patient with a chronic history of psoriasis. Herein, we report a case of 53-year-old male with a chronic history of psoriasis who first developed generalized erosive lesions after 26 cycles of narrow-band ultraviolet B (NBUVB) therapy. A diagnosis of pemphigus foliaceus was made based on skin biopsy and direct immunofluorescence assay. Pemphigus lesions were well controlled with combination therapy of oral steroid and azathioprine. This is the first case where pemphigus foliaceus co-occurred with psoriasis during NBUVB therapy.
doi:10.5021/ad.2011.23.S3.S281
PMCID: PMC3276776  PMID: 22346257
Narrow-band UVB; Pemphigus foliaceus; Psoriasis
16.  Quality of Life Assessment in Korean Patients with Pemphigus 
Annals of Dermatology  2015;27(5):492-498.
Background
Measuring the quality of life (QOL) is important in the evaluation of nonclinical aspects of diseases, for the discovery of functional and psychological limitations, and in choosing treatment in the initial phase of the disease. Pemphigus is a potentially fatal autoimmune bullous disease caused by autoantibodies against desmogleins (cadherin family proteins in desmosomes). Thus far, there has been no published study on QOL in Korean patients with pemphigus.
Objective
To study the impact of pemphigus on the QOL in a large number of Korean patients.
Methods
Sixty-six patients enrolled at the Gangnam Severance Hospital from March 2012 to March 2013 were assessed for QOL by using the Dermatology Life Quality Index (DLQI), and for anxiety and depression by using the General Health Questionnaire (GHQ). Spearman's rank-order correlation, t-test, and ANOVA were used to identify the relations between the DLQI score and other clinical variables.
Results
Pemphigus vulgaris and pemphigus foliaceus significantly reduced the QOL of patients. The average DLQI score for all patients was 10.18. The mean DLQI score was 13.45 in patients in the active state and 5.15 in the patients in the remission state. The DLQI score highly correlated with disease severity, titer of anti-desmoglein 1 in enzyme-linked immunosorbent assay, and the corticosteroid dose. However, the QOL was not affected by sex, age, subtype of pemphigus, duration of disease, or comorbidities. Forty-two percent of the patients showed a positive result in the GHQ, reflecting probable minor psychiatric nonpsychotic conditions, and the GHQ score positively correlated to the DLQI score.
Conclusion
Pemphigus significantly impairs the QOL of patients. The QOL of Korean pemphigus patients significantly correlates with clinical severity. Therefore, considerable attention should be paid to the patients' QOL and psychological states as well as clinical status.
doi:10.5021/ad.2015.27.5.492
PMCID: PMC4622882  PMID: 26512162
Dermatology Life Quality Index; General Health Questionnaire-12; Pemphigus; Quality of life
17.  Human autoantibodies against a desmosomal core protein in pemphigus foliaceus 
The Journal of Experimental Medicine  1984;160(5):1509-1518.
Pemphigus foliaceus (PF) is a human autoimmune disease in which antibodies are directed against the cell surface of epidermal cells with resultant blister formation. The histopathology of these blisters indicates that cells have detached from each other, and electron microscopy of early blisters shows diminished numbers, to complete loss, of desmosomes as well as abnormalities of the tonofilament- desmosome complex. In this study we demonstrate that autoantibodies from certain PF patients bind to a desmosomal core glycoprotein called desmoglein (DG) I. Proteins in extracts of normal human epidermis were separated by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis (PAGE), then transferred to nitrocellulose or 2- aminophenylthioether paper for immunoperoxidase staining. Results of these immunoblots indicated that sera from 6 of 13 PF patients specifically and intensely stained an approximately 160,000 mol wt polypeptide, "PF antigen". Such staining was not seen with normal human sera or sera from patients with pemphigus vulgaris or bullous pemphigoid, two autoimmune blistering skin diseases that are clinically, histologically, and immunochemically distinct from PF. However, rabbit antiserum directed against DGI, that was isolated from bovine muzzle desmosomes, stained a polypeptide band which co-migrated with PF antigen. Furthermore, when proteins from extracts of normal human epidermis were electrophoresed in two dimensions (isoelectric focusing, then SDS-PAGE) before transfer to nitrocellulose for immunoperoxidase staining, PF antibodies and antibodies to DGI stained identical spots. Finally, PF sera as well as PF IgG that was affinity purified with PF antigen from normal human epidermis, both selectively bound to DGI extracted from bovine muzzle desmosomes. These studies demonstrate that the human autoantibodies from certain patients with PF, a disease of epidermal cell adhesion, are directed against a desmosomal core protein.
PMCID: PMC2187488  PMID: 6491602
18.  Intermittent cyclophosphamide in pemphigus vulgaris and bullous pemphigoid 
Cyclophosphamide, given in widely spaced doses, was used in the treatment of a patient with pemphigus vulgaris and a patient with bullous pemphigoid. To our knowledge, this form of therapy has not previously been reported in these two diseases. The distinct advantages of the larger intermittent dose method of cyclophosphamide therapy over the more conventional daily dose regimen are discussed.
Images
PMCID: PMC1947663  PMID: 4852512
19.  Association between HLA-DRB1 polymorphisms and pemphigus vulgaris: a meta-analysis 
The British Journal of Dermatology  2012;167(4):768-777.
Summary
Background Several studies have reported that HLA-DRB1 may be correlated with pemphigus vulgaris (PV), but most have been based on small samples and the results remain inconsistent and unclear.
Objectives To investigate the correlation between DRB1 and PV by a meta-analysis of case–control/nonfamily studies.
Methods PubMed, Wiley Online Library, ScienceDirect, Google Scholar, Cochrane Library, Chinese National Knowledge Infrastructure and Wanfang databases were searched for studies including: (i) ‘pemphigus’; and (ii) ‘human leukocyte antigen’, ‘HLA’, ‘major histocompatibility complex’, ‘MHC’ or ‘DRB1’. Eighteen selected studies were used in meta-analyses to evaluate DRB1 alleles and phenotypes by calculating the respective odds ratios (ORs) and 95% confidence intervals (CIs). Stratified meta-analyses and meta-regression analysis were also conducted.
Results The frequencies of three genotypes (allele and phenotype, respectively) were significantly increased in PV: DRB1*04 [P-value for comparability (Pc) < 0·00001, OR 3·61, 95% CI 2·28–5·71; Pc = 0·0002, OR 4·14, 95% CI 1·98–8·65], DRB1*08 (Pc = 0·03, OR 2·25, 95% CI 1·07–4·70; Pc = 0·0003, OR 2·46, 95% CI 1·51–4·01) and DRB1*14 (Pc < 0·00001, OR 6·47, 95% CI 4·52–9·26; Pc < 0·00001, OR 9·68, 95% CI 4·47–20·98). Three others (allele and phenotype, respectively) were significantly decreased in PV: DRB1*03 (Pc < 0·00001, OR 0·28, 95% CI 0·19–0·41; Pc = 0·0001, OR 0·25, 95% CI 0·12–0·51), DRB1*07 (Pc = 0·004, OR 0·45, 95% CI 0·26–0·78; Pc = 0·0002, OR 0·27, 95% CI 0·14–0·54) and DRB1*15 (Pc = 0·001, OR 0·35, 95% CI 0·18–0·66; Pc = 0·002, OR 0·32, 95% CI 0·16–0·65). Ethnicity partially explained the heterogeneity of DRB1*07, DRB1*08 and DRB1*14 phenotypes.
Conclusions Our findings suggest that DRB1*04, DRB1*08 and DRB1*14 are statistically significant susceptibility factors for PV. Conversely, DRB1*03, DRB1*07 and DRB1*15 may be negatively associated with PV. Specific HLA-DRB1 types may influence the susceptibility or resistance to PV, which needs further investigations.
doi:10.1111/j.1365-2133.2012.11040.x
PMCID: PMC3485671  PMID: 22564118
20.  Incidence and Mortality Rates of Bullous Pemphigoid in Olmsted County, Minnesota, Over 6 Decades 
Background
Bullous pemphigoid (BP) is an autoimmune blistering disease that is associated with an increased mortality rate.
Objective
To determine the incidence and mortality rate of patients with bullous pemphigoid.
Methods
Eighty-seven residents of Olmsted County, Minnesota, were identified who had their first lifetime diagnosis of BP from January 1960 – December 2009. Incidence and mortality rate were compared to age- and sex-matched control patients from the same geographic area.
Results
The adjusted incidence of BP was 2.4 per 100,000 person-years (95% CI, 1.9–2.9). Incidence of BP increased significantly with age (P<.001) and over time (P=0.034). Trend tests indicate increased diagnosis of localized disease (P=.006) may be a contributing factor. Survival observed in the incident BP cohort was significantly poorer than expected (P<.001). Survival was not different among patients with multisite vs localized disease (P=.90).
Limitations
Retrospective study design and study population from a small geographic area.
Conclusion
Incidence of BP in the United States is comparable to that found in Europe and Asia. The mortality rate of BP is lower in the United States than Europe, but higher than previous estimates.
doi:10.1016/j.jaad.2014.02.030
PMCID: PMC4324601  PMID: 24704091
Bullous pemphigoid; autoimmune blistering disorder; epidemiology; incidence; mortality; geriatric
21.  Identification of a Functional Risk Variant for Pemphigus Vulgaris in the ST18 Gene 
PLoS Genetics  2016;12(5):e1006008.
Pemphigus vulgaris (PV) is a life-threatening autoimmune mucocutaneous blistering disease caused by disruption of intercellular adhesion due to auto-antibodies directed against epithelial components. Treatment is limited to immunosuppressive agents, which are associated with serious adverse effects. The propensity to develop the disease is in part genetically determined. We therefore reasoned that the delineation of PV genetic basis may point to novel therapeutic strategies. Using a genome-wide association approach, we recently found that genetic variants in the vicinity of the ST18 gene confer a significant risk for the disease. Here, using targeted deep sequencing, we identified a PV-associated variant residing within the ST18 promoter region (p<0.0002; odds ratio = 2.03). This variant was found to drive increased gene transcription in a p53/p63-dependent manner, which may explain the fact that ST18 is up-regulated in the skin of PV patients. We then discovered that when overexpressed, ST18 stimulates PV serum-induced secretion of key inflammatory molecules and contributes to PV serum-induced disruption of keratinocyte cell-cell adhesion, two processes previously implicated in the pathogenesis of PV. Thus, the present findings indicate that ST18 may play a direct role in PV and consequently represents a potential target for the treatment of this disease.
Author Summary
Pemphigus vulgaris is a life-threatening autoimmune skin blistering disease. A large body of evidence indicates that the propensity to develop this condition is in part genetically determined. Using a genome wide association approach, we recently identified pemphigus vulgaris-associated genetic variations in the vicinity of the ST18 gene. In the present study, we identify a risk variant residing within the ST18 promoter region which drives ST18 gene promoter activity in a p53/p63-dependent manner, which is in line with the fact that ST18 is up-regulated in the skin of PV patients. Using functional assays, we show that ST18 overexpression increases PV serum-induced expression of pro-inflammatory mediators, as well as augments PV serum-induced disruption of keratinocyte cell-cell adhesion, which are hallmarks of pemphigus pathogenesis. Our findings therefore support a direct role for ST18 in the pathogenesis of pemphigus vulgaris, and position ST18 as a new molecular target of potential interest for the treatment of disease. From a broader perspective, these observations underscore the importance of genetic variations affecting the susceptibility of target tissues to autoimmunity.
doi:10.1371/journal.pgen.1006008
PMCID: PMC4858139  PMID: 27148741
22.  Pemphigus and Pemphigoid in Domestic Animals: An Overview 
The Canadian Veterinary Journal  1985;26(6):185-189.
Pemphigus and pemphigoid are uncommon dermatological entities in domestic animals and of a presumed autoimmune nature. In one form or another, they have been reported in the dog, cat, horse and goat. Although these diseases are considered to be bullous dermatoses, the clinical presentation may vary from ulcerative to exfoliative to proliferative depending on the individual condition. Currently, four variants of pemphigus are recognized (vulgaris, vegetans, foliaceus, erythematosus) and two of pemphigoid (bullous, cicatricial) although cicatricial pemphigoid has not yet been conclusively demonstrated in animals. Diagnosis is based on history, clinical signs, histopathology and immunopathology. Therapy must be immunosuppressive to be effective and is palliative rather than curative.
Images
PMCID: PMC1680036  PMID: 17422541
Pemphigus; pemphigus vulgaris; pemphigus vegetans; pemphigus foliaceus; pemphigus erythematosus; pemphigoid; bullous pemphigoid; dog; cat; horse; goat
23.  Reliability of the Autoimmune Bullous Disease Quality of Life (ABQOL) questionnaire in the United States 
Purpose
To evaluate the reliability of the Autoimmune Bullous Diseases Quality of Life (ABQOL) questionnaire in a North American patient cohort.
Methods
Patients attending the Dermatology clinics of the University of Pennsylvania with a histological diagnosis of an autoimmune bullous disease (AIBD) and self-reported proficiency in English were recruited to participate in the study. Patients completed the ABQOL questionnaire at Day 0 and Day 3. Internal consistency was calculated through Cronbach’s alpha. Test-retest reliability was determined by the intraclass correlation coefficient.
Results
Of the 45 patients enrolled in the study, 39 patients (87%) participated to completion. The mean age was 60.7 years with an equal sex distribution observed. Patients had a range of AIBD including pemphigus vulgaris, bullous pemphigoid, pemphigus foliaceus, epidermolysis bullosa aquisita, mucous membrane pemphigoid and linear IgA disease. Cronbach’s alpha was calculated to be 0.90. The intraclass correlation coefficient was calculated to be 0.93 (95% confidence interval: 0.88–0.94).
Conclusion
The ABQOL was found to be reliable tested by internal consistency and test-retest reliability in an American patient cohort. It represents a promising disease-specific outcome measure for patients with AIBD.
doi:10.1007/s11136-015-0965-z
PMCID: PMC4767525  PMID: 25795375
quality of life; vesiculobullous skin diseases; pemphigus; bullous pemphigoid
24.  Paraneoplastic pemphigus: a short review 
Paraneoplastic pemphigus (PNP) is a fatal autoimmune blistering disease associated with an underlying malignancy. It is a newly recognized blistering disease, which was first recognized in 1990 by Dr Anhalt who described an atypical pemphigus with associated neoplasia. In 2001, Nguyen proposed the term paraneoplastic autoimmune multiorgan syndrome because of the recognition that the condition affects multiple organ systems. PNP presents most frequently between 45 and 70 years old, but it also occurs in children and adolescents. A wide variety of lesions (florid oral mucosal lesions, a generalized polymorphous cutaneous eruption, and pulmonary involvement) may occur in patients with PNP. The earliest and most consistent finding is severe stomatitis. There is a spectrum of at least five clinical variants with different morphology. Similarly, the histological findings are very variable. Investigations to diagnose PNP should include checking for systemic complications (to identify tumor), skin biopsies (for histopathological and immunofluorescence studies), and serum immunological studies. PNP is characterized by the presence of autoantibodies against antigens such as desmoplakin I (250 kD), bullous pemphigoid aniygen I (230 kD), desmoplakin II (210 kD), envoplakin (210 kD), periplakin (190 kD), plectin (500 kD), and a 170 kD protein. Unlike other forms of pemphigus, PNP can affect other types of epithelia, such as gastrointestinal and respiratory tract. Treatment of PNP is difficult, and the best outcomes have been reported with benign neoplasms that have been surgically excised. The first-line treatment is high-dose corticosteroids with the addition of steroid-sparing agents. Treatment failures are often managed with rituximab with or without concomitant intravenous immunoglobulin. In general, the prognosis is poor, not only because of eventual progression of malignant tumors but also because treatment with aggressive immunosuppression therapy often results in infectious complications, which is unfortunately at this time the most common cause of death in PNP.
doi:10.2147/CCID.S100802
PMCID: PMC5042195  PMID: 27729809
paraneoplastic pemphigus; direct and indirect immunofluorescence; mucositis; rituximab
25.  Rituximab in the Treatment of Pemphigus Vulgaris 
Introduction
Rituximab is increasingly used in patients with pemphigus vulgaris (PV) who are nonresponders to conventional therapy.
Methods
A PubMed search was conducted using the words pemphigus vulgaris and rituximab therapy from papers published between 2000 and 2012. Two protocols were used. In the lymphoma protocol, patients received four weekly infusions of rituximab (dose 375 mg/m2). The rheumatoid arthritis (RA) protocol consisted of two infusions of 1,000 mg each 15 days apart. The variables recorded from each study included clinical remission off or on therapy, relapse rate, incidence of serious adverse events, concomitant therapies, duration of follow-up, and when available, levels of B cells and autoantibodies.
Results
Forty-two studies were found, which reported 272 patients; 180 were treated by the lymphoma protocol and 92 by the RA protocol. Both protocols were effective in treating recalcitrant PV. The lymphoma protocol had a lower response rate, relapse rate and serious infections, but higher mortality, and there were nonresponders. The RA protocol produced a higher response rate, relapse rate, number of infections, but lower mortality rate, and lacked nonresponders. The cumulative follow-up for patients treated with the lymphoma protocol was 15.44 months (range 1–41) and 21.04 months (range 8.35–29) for the RA protocol. A major concern in both protocols was the high infection rates, some of which were fatal. A different protocol using a combination of rituximab with intravenous immunoglobulin in a defined manner with a definitive endpoint, used in a limited cohort of patients, showed promising results.
Conclusion
Neither protocol produced a sustained clinical remission and both required continued systemic therapy. Before initiation of treatment, physicians should have a specific goal and endpoint and be aware of its potential side effects and lack of information on its long-term effects. Patients should be carefully monitored during and after therapy.
doi:10.1007/s13555-012-0017-3
PMCID: PMC3510419  PMID: 23205339
Clinical outcomes; Immunology and inflammatory skin diseases; Lymphoma protocol; Pemphigus vulgaris; Rheumatoid arthritis protocol; Rituximab

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