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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.  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
3.  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
4.  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
5.  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
6.  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
7.  Vitamin D deficiency and lower TGF-β/IL-17 ratio in a North Indian cohort of pemphigus vulgaris 
BMC Research Notes  2014;7(1):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
8.  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
9.  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
10.  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
11.  Severe Multi-Resistant Pemphigus vulgaris: prolonged remission with a single cycle of Rituximab* 
Anais Brasileiros de Dermatologia  2013;88(4):639-642.
Pemphigus vulgaris is an autoimmune bullous disease whose therapy is based on systemic corticosteroids, with or without immunosuppressants. Rituximab is a chimeric monoclonal antibody of the IgG class, directed at a specific CD20 B cell surface antigen, used in pemphigus vulgaris empirically since 2002, with success in 90% of the cases and long periods of remission. Male patient, 33 years old, diagnosed with pemphigus vulgaris, confirmed by histopathology and direct immunofluorescence. He was treated for seven months with numerous treatments, including immunosuppressive drugs, with an unsatisfactory response, until he had complete remission with the use of rituximab. During a 34-month follow-up period, the patient presented a slight clinical relapse, which was successfully controlled with prednisone in a daily dose of 120mg, soon reduced to 20mg.
doi:10.1590/abd1806-4841.20131990
PMCID: PMC3760947  PMID: 24068143
Desmogleins; Drug resistance; Pemphigus; Treatment failure
12.  Endemic pemphigus in the Peruvian Amazon: epidemiology and risk factors for the development of complications during treatment* 
Anais brasileiros de dermatologia  2012;87(6):838-845.
BACKGROUND
Pemphigus is an autoimmune blistering disease. According to a report, in areas of endemic pemphigus foliaceus (EPF) in Peru there are cases of pemphigus vulgaris with epidemiologic, clinical and histopathologic characteristics similar to those of "endemic pemphigus vulgaris" (EPV) in Brazil.
OBJECTIVES
To determine the clinical and epidemiologic characteristics of endemic pemphigus and the risk factors of patients for developing complications during treatment.
METHODS
A study was carried out from July 2003 to March 2008. The study population was 60 patients with EPF and 7 patients with EPV evaluated in hospitals and clinics in the Peruvian Amazon and Lima. A multivariate analysis was carried out using binary logistic regression.
RESULTS
The average age of EPF patients was 31.4 years; 55% were men; 60% presented the generalized clinical variant. Non-compliance with the treatment was seen in 57.1% of the patients. Thirty-five percent presented complications (e.g. pyodermitis and pyelonephritis) during treatment. The risk factors for developing complications during treatment were non-compliance with the treatment and having the generalized clinical form. In the EPV group, the average age was 21.7 years; 71.4% were men. All patients presented with the mucocutaneous clinical variant and the initial presentation consisted of oral mucosa lesions; 71.4% presented complications during treatment, pyodermitis being the most frequent.
CONCLUSIONS
Non-compliance with the treatment and the generalized clinical form are risk factors for the development of complications during treatment of patients with EPF. Peru indeed has EPV cases with epidemiologic characteristics similar to EPF. Living in a rural area may represent a risk factor for the development of complications during treatment of patients with EPV.
doi:10.1590/S0365-05962012000600003
PMCID: PMC3699914  PMID: 23197201
Epidemiology; Pemphigus; Peru
13.  Intravenous immunoglobulin therapy in two patients with myasthenia gravis and pemphigus vulgaris 
Acta Myologica  2009;28(3):101-102.
Summary
Various forms of pemphigus have been reported to occur with myasthenia gravis (MG), with and without thymoma. We described two cases of pemphigus vulgaris associated with MG without thymoma.
Case 1. A 44 year-old woman presented with 3 years history of pemphigus vulgaris. Three years later, she developed myasthenic symptoms with elevated level of anti-acetylcholine receptor (AChR) antibodies - 5.2 nmol/L. She was thymectomised and we revealed only hyperplastic thymus.
Case 2. A 64-year-old woman had a general fatigue and intermittent double vision. She was diagnosed as MG three years later. Two months before she diagnosed as MG, she had pruritic erythematous, erosive and bullous lesions on her body and extremities.
Oral prednisolon, pyridostigmine bromide and azathioprine or cyclophosphamide didn`t adequately control MG and pemphigus in our patients, so they received intravenous immunoglobulins of 0.4 g/kg for 5 consecutive days. After that therapy, our patients markedly improved.
Conclusion: The precise pathological mechanisms of the association between pemphigus and MG are not fully understood. The thymus has been suggested to be a possible common origin of autoimmune response in these disorders.
PMCID: PMC2858944  PMID: 20476669
Myasthenia gravis; pemphigus vulgaris; intravenous immunoglobulins
14.  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
15.  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
16.  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
17.  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
18.  Response of ocular pemphigus vulgaris to therapy. Case report and review of literature 
Background
Pemphigus vulgaris is an autoimmune bullous disease characterized by blistering and erosions within skin and mucous membranes. Lesions appear most commonly on mucosal surfaces of the oral cavity. Ocular involvement in patients with PV has rarely been reported.
Main observation
A 47-year-old male patient with a 2 month history of oral erosions and dysphagia developed severe conjunctivitis with periodical presence of purulent discharge, photophobia and burning sensations. The diagnosis of pemphigus vulgaris was confirmed by histopathology, direct immunofluorescence and detection of anti-desmogelin 3 antibodies in patients' serum. Treatment was introduced with prednisone at a dose of 80 mg per day (1 mg/kg) and cyclophosphamide at a dose of 100 mg daily (1.25 mg/kg). After 7 days of therapy a significant reduction of eye symptoms was observed and after 4 weeks of treatment full clinical remission was achieved.
Conclusions
The grounds for rare involvement of conjunctiva in pemphigus vulgaris is unclear. We hypothesize that inactivation of conjunctival desmoglein 3 may be compensated by other desmosomal proteins. Severe conjunctivitis may be the dominating clinical manifestation in pemphigus vulgaris. This implies a need of establishing distinct severity criteria and therapeutic standards for ocular pemphigus. In our patient rapid clinical response was achieved after introducing combined treatment with prednisone and oral cyclophosphamide.
doi:10.3315/jdcr.2008.1006
PMCID: PMC3157773  PMID: 21886701
conjunctival diseases; cyclophosphamide; desmoglein 1; desmoglein 3; eye diseases; pemphigus
19.  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
20.  Rituximab in the Treatment of Pemphigus Vulgaris 
Dermatology and Therapy  2012;2(1):17.
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
21.  Randomized Controlled Trials Needed for Bullous Pemphigoid Interventions 
Archives of dermatology  2012;148(2):243-246.
Background
Bullous pemphigoid (BP) is the most common autoimmune blistering disease in the West. Oral steroids are the standard treatment. This is an update of the review published in 2005.
Objectives
To assess treatments for bullous pemphigoid.
Search Strategy
In August 2010 we updated our searches of the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (Clinical Trials), MEDLINE, EMBASE, and the Ongoing Trials registers.
Selection Criteria
Randomized controlled trials of treatments for participants with immunofluorescence-confirmed bullous pemphigoid.
Data Collection And Analysis
At least two authors evaluated the studies for the inclusion criteria, and extracted data independently.
Main Results
We included 10 randomized controlled trials (with a total of 1049 participants) of moderate to high risk of bias. All studies involved different comparisons, none had a placebo group. In 1 trial plasma exchange plus prednisone gave significantly better disease control at 1 month (0.3 mg/kg: RR 18.78, 95% CI 1.20 to 293.70) than prednisone alone (1.0 mg/kg:RR1.79, 95% CI 1.11 to 2.90), while another trial showed no difference in disease control at 6months. No differences in disease control were seen for different doses or formulations of prednisolone (one trial each), for azathioprine plus prednisone compared with prednisone alone (one trial), for prednisolone plus azathioprine compared with prednisolone plus plasma exchange (one trial), for prednisolone plus mycophenolate mofetil or plus azathioprine (one trial), for tetracycline plus nicotinamide compared with prednisolone (one trial). Chinese traditional medicine plus prednisone was not effective in one trial. There were no significant differences in healing in a comparison of a standard regimen of topical steroids (clobetasol) with a milder regimen (RR 1.00, 95% 0.97 to 1.03) in one trial. In another trial, clobetasol showed significantly more disease control than oral prednisolone in people with extensive and moderate disease (RR 1.09, 95% CI 1.02 to 1.17), with significantly reduced mortality and adverse events (RR 1.06, 95% CI 1.00 to 1.12).
Authors’ Conclusions
Very potent topical steroids are effective and safe treatments for BP, but their use in extensive disease may be limited by side-effects and practical factors. Milder regimens (using lower doses of steroids) are safe and effective in moderate BP. Starting doses of prednisolone greater than 0.75 mg/kg/day do not give additional benefit, lower doses may be adequate to control disease and reduce the incidence and severity of adverse reactions. The effectiveness of adding plasma exchange, azathioprine or mycophenolate mofetil to corticosteroids, and combination treatment with tetracycline and nicotinamide needs further investigation.
doi:10.1001/archdermatol.2011.826
PMCID: PMC4333149  PMID: 22351828
22.  Early invasive vulvar squamous cell carcinoma arising in a woman with vulvar pemphigus vulgaris and systemic lupus erythematosus 
BMC Cancer  2010;10:324.
Background
Pemphigus vulgaris (PV) is an autoimmune blistering disease of the skin and mucous membranes. Genital involvement occurs when most other common sites are concurrently affected or are in remission. Systemic lupus erythematosus (SLE) is an autoimmune disease that may affect many parts of the body and the skin with occasional bullous lesions. Pemphigus vulgaris and SLE may be associated, albeit rarely. Here, we report the first case of a woman affected with SLE presenting with early invasive squamous cell carcinoma (SCC) arising from Pemphigus Vulgaris of the vulva.
Case presentation
A 27-year-old Caucasian woman was admitted to our Gynaecology Unit for bleeding vegetant lesions of the vulva. Her history was characterized by systemic lupus erythematosus and PV. Biopsy showed concomitant PV and vulvar intraepithelial neoplasia (VIN) grade 3. One month later a new biopsy revealed progression from VIN 3 to early SCC. Despite chemotherapy, no remission of disease was observed. She died six months after diagnosis
Conclusion
Our case underlines PV as another chronic inflammatory disease of the lower genital tract predisposing to VIN-SCC. It suggests the need for careful follow-up of patients with chronic inflammatory disease, especially when concomitant autoimmune disorders are present. Moreover, a biopsy should be always performed if there are PV lesions because of the possibility of neoplastic disease.
doi:10.1186/1471-2407-10-324
PMCID: PMC3087320  PMID: 20573220
23.  URIC ACID: A NEW ANTIOXIDANT IN PATIENTS WITH PEMPHIGUS VULGARIS 
Indian Journal of Dermatology  2011;56(3):278-281.
Background:
Increased reactive oxygen species (ROS) and lipid peroxidation are seen in many dermatologic disorders, for example, atopic dermatitis, psoriasis, vitiligo, acne vulgaris, pemphigus vulgaris (PV), lichen planus, and alopecia areata. ROS has an important role in the inflammation process. In PV, increased production of ROS leads to decline of antioxidants in plasma and red blood cells which results in oxidative stress. We aimed to evaluate the level of these antioxidants in PV patients and compare it to the controls.
Materials and Methods:
Among patients attending the dermatology clinics, 30 patients with PV, who had never been on treatment, were enrolled to the study. The control group consisted of 30 age- and sex-matched healthy non-smoker individuals. Venous blood was collected from the subjects for the evaluation of plasma levels of glutathione peroxidase, vitamin C, selenium, bilirubin, and uric acid.
Results:
Age mean and standard deviation of the patients (40.83, 12.74) was comparable to the controls (41.96, 13.08). Mean level of uric acid was significantly lower in PV patients compared to the controls (P = 0.006). Other antioxidants were not different between the two groups. Uric acid of the patients with mucosal involvement was significantly lower than patients with mucocutaneous involvement (P = 0.049).
Limitations:
The blood level of other antioxidants (e.g. malondialdehyde) was not evaluated.
Conclusions:
Uric acid as an antioxidant in our study had similar changes to previous studies in the field of other diseases but selenium, bilirubin, and glutathione peroxidase did not differ between patients and controls.
doi:10.4103/0019-5154.82480
PMCID: PMC3132903  PMID: 21772587
Antioxidants; pemphigus vulgaris; uric acid
24.  Tumour necrosis factor-alpha polymorphism as one of the complex inherited factors in pemphigus. 
Mediators of Inflammation  2003;12(5):303-307.
The aim of our study was to analyse a significance of tumour necrosis factor (TNF)-alpha promoter gene polymorphisms in relation to the HLA-DR locus in genetic predisposition to pemphigus. TNF-alpha gene polymorphisms in position -238 and -308 were identified using a modified polymerase chain reaction-restriction fragment length polymorphism method in 53 patients with pemphigus (38 with pemphigus vulgaris, 15 with pemphigus foliaceus) and 87 healthy controls. The HLA-DRB1 locus was typed using the polymerase chain reaction SSO method in all the patients and 152 population controls. Carriers of the TNF-alpha polymorphic -308 A allele were found to be more frequent in the pemphigus foliaceus group in comparison with the control group (odds ratio (OR) = 8.12; p = 0.0005). A significant association between HLA-DRB1*04 (OR = 3.86; pcor = 0.0001) and DRB1*14 (OR = 8.4; pcor = 0.0001) and pemphigus vulgaris was found. In this group of patients a decreased frequency of HLA-DRB1*07 (OR = 0.08; pcor = 0.006) was also identified. We have shown for the first time a positive association of TNF-alpha polymorphism in position -308 with pemphigus foliaceus.
PMCID: PMC1781627  PMID: 14760938
25.  Pemphigus Vulgaris Confined to the Gingiva: A Case Report 
Pemphigus Vulgaris (PV) is an autoimmune intraepithelial blistering disease involving the skin and mucous membranes. Oral mucosa is frequently affected in patients with PV, and oral lesions may be the first sign of the disease in majority of patients. In some patients, oral lesions may also be followed by skin involvement. Therefore, timely recognition and therapy of oral lesions is critical as it may prevent skin involvement. Early oral lesions of PV are, however, often regarded as difficult to diagnose, since the initial oral lesions may be relatively nonspecific, manifesting as superficial erosions or ulcerations, and rarely presenting with the formation of intact bullae. Lesions may occur anywhere on the oral mucosa including gingiva; however; desquamtive gingivitis is less common with PV than other mucocutaneous conditions such as pemphigoid or lichen planus. This paper describes the case of a patient presenting with a one-year history of painful gingival, who is finally diagnosed as having PV.
doi:10.1155/2011/207153
PMCID: PMC3124259  PMID: 21747856

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