Intraepidermal Autoimmune Bullous Dermatoses

State Medical And Pharmaceutical University.

“Nicolae Testemițanu”

Chisinau, Republic of Moldova.

General Medicine II.

Date:01/02/2016

Intraepidermal autoimmune bullous dermatoses:

principles of diagnosis.

Husein Abu Eid

Nr. Matriculei:

Thesis submitted to the

Faculty of General Medicine II and State University

in partial fulfillment of the requirements for the degree of

MEDICAL DIPLOMA

In

General Medicine.

Dr. Vladislav GOGU, Chairman

MD, PhD, Associate Professor

Department of Dermatovenereology.

ABBREVIATIONS

DSG – desmoglein

IIF – indirect immunofluorescence

DIF- direct immunofluorescence

EBA- Epidermolysis bullosa acquisita 

SPD -subcorneal pustular dermatosis

PNP -paraneoplastic pemphigus

PAMS- paraneoplastic autoimmune syndrome

PF – pemphigus foliaceus

PV – pemphigus vulgaris

PE –  pemphigus erythematosus

IEN- intraepidermal neutrophilic type

MNGs -multinucleated giant cells

CONTENTS

Introduction…………………………………………………………..5

Background……………………………………………………..…….5

Aim of the Thesis……………………………..…………………7

Objectives……………………………………..………….….…7

Bibliographic analysis ……………………………..……………….…..8

Intraepidermal immunobullous diseases…………………….….8

Pemphigus vulgaris……………………………………….……9

Pemphigus vegetans……………………………………….…..10

Pemphigus foliaceus……………………………………….…..11

Pemphigus erythematosus………………………………………12

Pemphigus herpetiformis……………………………….………13

IgA Pemphigus…………………………….……….………….14

Paraneoplastic Pemphigus…………………………………..…15

Drugs – induced pemphigus………………………………. ….17

Material and research methods …………………………..….……18

Personal results and discussion……………………………….……19

Clinical and morphological features of autoimmune dermatosеs,

at a modern stage…………….…………………………..……19

The predictive value of Nikolsky`s sign in differential diagnostics

of intraepidermal autoimmune bullous dermatoses……………26

The importance of various laboratory tests in diagnostic

of intraepidermal autoimmune bullous dermatosеs……………31

The algorithm of the early diagnosis of intraepidermal

autoimmune bullous dermatosеs………………………………36

Conclusions ……………………………….……………..…………….41

Attachment………………………………………………….……….42

Bibliographic References…………………………………..……….46

CHAPTER 1: INTRODUCTION

1. 1. Background

Autoimmune bullous dermatoses are a group of skin diseases which are characterized by the presence of bullae or vesicles as main lesions. [1]

One of the major pathogenetic factors is an autoantibodies, directed to antigens of epidermal and dermal structures, similar for many autoimmune diseases.

These target points represent a adhesion molecules of the skin and are components of desmosomes or of the basement membrane which participate in maintenance intercellular and cellular adhesion. [2]

Autoimmune blistering skin diseases are a heterogeneous group of disorders and their classification is based on the location of the blister: intraepidermal and subepidermal.  Therefore, intraepidermal immunobullous diseases included pemphigus group (pemphigus vulgaris, pemphigus erythematosus, paraneoplastic pemphigus, IgA pemphigus, drug-indused pemphigus) which associated with autoantibodies that are directed against desmosomal structural proteins. Subepidermal immunobullous diseases in turn, are represented by pemphigoid group (bullous pemphigoid, cicatricial pemphigoid, pemphigoid gestations), epidermolysis bullosa acquisita, dermatitis herpetiformis and linear IgA dermatosis, which are associated with auto antibodies that are produced against hemidesmosomes, anchoring fibers and other proteins at the basement membrane zone. [3]

The majority autoimmune bullous dermatoses are associated with various severe damages of organs and systems which can lead to serious complications and even death of patients. [4]  

For example, before an era of corticosteroids, the most cases of pemphigus vulgaris and its variants led to death for quite short period, about 1-1.5 years from an onset of the illness. [5, 6]  

Only, the treatment with high doses of systemic corticosteroids during the long period of time combined by nonsteroidal immunosuppressants can keep these processes under control. Besides, these patients have to accept the supporting doses of systemic corticosteroids throughout all life. [7, 8]

Unfortunately, this treatment has many side effects, and sometimes patients die as a result of these complications. .[9]

Summarizing data it is possible to make a conclusion that early diagnostics of autoimmune bullous dermatosis has very much importance for the forecast of an illness as provides an initiation of treatment from minimum admissible shock dose of systemic glucocorticoids and respectively reduces risk of various side effects and complications that as a result influences on a life expectancy of these patients.

But, there are a several problems which don’t allow the clinical physician to establish the clinical diagnosis with confidence by the bed of the patient.

First of all, there are evident clinical similarities between most bullous dermatosis, and sometimes appear atypical manifestations in the early stages of pathological process with doubtful results of a phenomenon of Nikolsky. Secondly, recently in the group of autoimmune bullous dermatoses some new types were described: herpetiform pemphigus (1975) [12], IgA pemphigus (1982) with its two distinct types: the subcorneal pustular dermatosis (SPD) type and the intraepidermal neutrophilic (IEN) type. [13], IgG/ IgA pemphigus (1987) [14], paraneoplastic pemphigus (1990) [15, 16], and others.

Also, histological examination which is considered as a gold standard in diagnosis of most skin diseases, allow us to determine only the level of cleavage and differentiate autoimmune bullous dermatoses only between their various groups, such as groups of a pemphigus and the bullous dermatoses with defeat of dermo-epidermal connection. Unfortunately it do not allow to make differential diagnosis among the bullous dermatoses of the same group, on the one hand, between bullous pemphigoid, linear IgA- dermatosis and the epidermolysis bullosa acquisita, on the other hand between different types of pemphigus. [17]

And finally, the special laboratory examinations like direct immunofluorecense (DIF), indirect immunofluorecense (IIF),  enzyme-linked immunosorbent assay (ELISA) and immunoblot which allow to confirm the preliminary diagnosis are more expensive and aren’t available in all cases.

1.2. Aim

To improve the diagnosing of autoimmune bullous dermatoses step by step, by means of systematization of all available methods.

1.3. Objectives

To study clinical and morphological features of intraepidermal autoimmune dermatosеs, at a modern stage.

To estimate the predictive value of Nikolsky`s sign in differential diagnostics of autoimmune bullous dermatoses.

To study a role and value of various laboratory tests in diagnostics of intraepidermal autoimmune bullous dermatosеs.

To define stage-by-stage algorithm of the early diagnostics of autoimmune bullous dermatosеs.

CHAPTER 2: Bibliographic analysis

2.1. Intraepidermal immunobullous diseases

In fact, intraepidermal immunobullous diseases are represented by pemphigus group. In all cases cleavage are produced in different layers of epidermis and in all cases clinical features are presented by intraepidermal bullae or blisters. Most often, spinous or suprabasal layer is affected, but granular and even subcorneal layers also can be involved in some processes. Therefore, all types of pemphigus are divided into two subtypes: superficial and deep.

A. Deep subtypes of pemphigus included:

Pemphigus vulgaris,

Pemphigus vegetans

Neumann-type pemphigus vegetans is characterized by periorificial papillomas

Hallopeau-type pemphigus vegetans by pustular lesions, predominantly involving the large folds

Pemphigus herpetiformis

Paraneoplastic pemphigus (PNP)/paraneoplastic autoimmune syndrome (PAMS)

B Superficial subtypes of pemphigus are represented by

Pemphigus foliaceus (PF)

IgA pemphigus

subcorneal pustular dermatosis (SPD) type, with pustules on erythematous plaques on extremities

intraepidermal neutrophilic type (IEN) with pustules in sunflower arrangement on the trunk.

2.2. Pemphigus vulgaris

Pemphigus vulgaris is most common type of pemphiguses and its frequency – 0,6% of all dermatoses.[1] Pemphigus vulgaris usually affects people over 40 years, less children and adolescents.[2]

The onset of the illness is sudden, without the visible reasons and with insidious lesions in the mouth. In fact, the mucous membranes are affected more often but damage to the genitals, eyes, throat, vaginal or rectal area is also can be possible [3]. Usually the process is beginning on the oral mucosa in 70-80% of cases [4].

The debut of pemphigus vulgaris is characterized by emergence of single bullae which are quickly opened, leaving on erosions. Bullas are rarely caught lesions presenting as erosion irregular, painful, localized especially on the lips and cheeks, but often affecting gums. Erosions with red surface are bounded by an epithelial collar. Evolving confluent erosions are giving rise to ulceration covered by flaps or whitish deposits diphtheroid.

Skin damage usually occurs after weeks or months of mucosal lesions. It is characterized by bullous lesions with a thin tire. The skin surrounding bullous lesions is normal-appearing, but actually it is also struck. Bullas tend to the peripheral growth and merge. Contents of bullous lesions in the beginning are serous, transparent, are rare with a hemorrhagic shade, then grow turbid and can become purulent due to accession of a secondary infection. Very quickly these lesions are destroyed and transforming into erosions with a wet, damp, bright red surface which subsequently covered by gray-brown crusts. Erosions tend to the peripheral growth and merge, forming continuous widespread erosive sites. Sometimes isolated sites can exist quite long time, and there comes process generalization only later. It should be noted that without system treatment by immunosuppressive drugs, these erosion don't tend to healing. Only in the process of treatment erosions regressed by epithelialization and are followed by pigmentary spots.

In spite of that bullous lesions in all cases are healing without scars, pemphigus vulgaris is considered one of the most serious types among all autoimmune bullous dermatoses. Besides, the ratio of fatal cases of pemphigus vulgaris in pemfigus group is also the highest. The mortality in pemphigus is caused by increase of body`s catabolism with essential loss of proteins, liquids and microelements which is accompanied by different types of secondary infections which eventually lead to sepsis and cardiac failure [5].

The main pathophysiological mechanism in pemphigus vulgaris named acantholysis. It means the appearance of autoantibodies from group IgG 1 and IgG 4 against the desmogleins 3 and 1 which are desmosomal adhesion proteins, very important pieces in the epidermal integrity. The rupture of these desmosomes leads to the loss of cohesions between epidermal keratinocytes and appearance of the intraepidermal bullous lesions. [6].

2.3. Pemphigus vegetans

Pemphigus vegetans is considered a rare, but distinct subtype of pemphigus vulgaris, this verruciform, vegetant or pustular lesions of the periorificial regions or, more commonly, involving the large folds. It may present in two forms: Neumann-type described in 1876 with worse prognosis than pemphigus vulgaris, and Hallopeau-type described in 1889 which is more benign, has few recurrences and generally is in remission.

The debut of pemphigus vegetans is similar to the pemphigus vulgaris. Along with, lesions into oral mucosa or a little later, some bullae appear on the skin which arounded natural openings (perioral and perianal areas) and in natural folds of skin, especially axillar and inguinal areas.[7]

After opening, the bullous lesions are followed by bright red erosions where in 4-6 days appear juicy red vegetating plaques. In spite of both types of pemphigus vegetans are characterized by vegetating plaques, the first lesions are a little bit different. The similar evolution like in pemfigus vulgaris is more characteristic for the Neumann type, where vegetations appear during the repair process. The Hallopeau type begins with grouped pustular lesions, which have tendency to eccentric growing and predominantly involving the large folds and flexor surfaces. [8,9] The character of the separating exudate is serous and purulent with a putrefactive smell (because of maceration of erosions and accession of a secondary infection), which shrinks in dense crusts.

2.4. Pemphigus foliaceus

Pemphigus foliaceus meets less often, than the pemphigus vulgaris, but more often than vegetatnt. Mucous membranes are not affected. For this form of pemphigus are characteristic bullous lesions not such big, flat with a ceiling flabby and thin. The bullae usually occur on an erythematous background. Their ceiling breaks easily, even at a minimal mechanical trauma, or exudate under pressure from bullae, therefore, sometimes these lesions in the course of clinical examination can be missed.  Pinkish- red erosions are formed with abundant serous fluid, which dries to form lamellar crusts. Also, the crust can be formed without breaking the ceiling of the bullae, due to the drying of their contents.

Typical localization is on the hairy part of the head, on the face, a breast, a back. In the folds, erosions are partially covered by macerated epidermis, with sticky exudate with an unpleasant smell (due to development of bacterial and fungal flora).

On a place of the erosions formed before under scuamous-crusts apear new superficial blisters with poor contents that lead to formation of stratifications in the form of the yellowish-brown scuamous- crusts reminding puff pastry or the dried leaves. Nikolsky's sign is sharply expressed in the center and near it.

The central areas of defeat are inclined to the peripheral growth and merge up to development of a secondary exfoliative erythroderma. Skin becomes dark -reddish with fissures and oozing areas, predominantly in the folds and area of joints. The patient complains of continuous burning, an itch, pain in the field of defeat, cold, deterioration of the general state and fever. In process of progressing of a secondary exfoliative erythroderma, weakness and cachexia are increasing and also dystrophy of the hair and nails is noted.

2.5. Pemphigus erythematosus (Senear–Usher syndrome)

Senear-Usher syndrome, also known as pemphigus erythematosus, is a localized and easier variant of pemphigus foliaceus which combines the clinical signs of lupus erythematosus and pemphigus foliaceus. For the first time It was described in 1926 by F. E. Senear and B. Usher, as unusual type of pemphigus.[15]

Pemphigus erythematosus is considered a rare condition and some epidemiological studies reported 3.0-4.4 cases per million population, that is ten times less than incidence of all types of pemphigus [16]. Pemphigus erythematosus can appear in any age, without sexual differences.

Beginning and development of pemphigus erythematosus are usually slow. In spite of general opinion that pemphigus erythematosus is an abortive and localized type of PF, some autors noted that it can by early stage of pemphigus foliaceus and with lesions onset on the oral mucosa may even progress to pemphigus vulgaris. [17,18] .

Although the distribution of the lesions in pemphigus erythematosus could suggest induction by UVB light or sunlight, patients may be completely unaware of the photosensitive nature of this disorder.

Pemphigus erythematosus lesions typically involve the scalp, the face, the upper part of the chest, and the back and don’t typically lead to mucous membrane involvement

The skin lesions in classic pemphigus erythematosus are presented by small, flaccid blisters and superficial erosions, which may be followed with oozing and covered by yellowish crusts.

More often lesions of pemphigus foliaceus are on the sun-exposed areas, across the malar area of the face and on other seborrheic areas, where lesions have butterfly distribution as in CLE. Latter lesions can be associated with secondary infection and finally heal by pigmented maculae or by scars as in CLE.

Pemphigus erythematosus may remain localized for years, or it may evolve into more generalized PF. With extensive involvement, pemphigus erythematosus patients may present with an exfoliative erythroderma. The skin becomes tender and in these cases appears electrolyte imbalance and loss of temperature control.

2.6. Pemphigus herpetiformis

Pemphigus herpetiformis (PH) is considered a clinical variant of pemphigus that resembles clinical features similar to dermatitis herpetiformis and diverse histological and immunological findings consistent with pemphigus.

Pemphigus herpetiformis is considered a rare type of pemphigus, according to same studies its incidence is about 6-7% of all cases of pemphigus [19]. It usually affects people between 31 to 83 years, less during childhood, and equally affects both sexes. [20].

Before immunological studies, this type of pemphigus was described using various terms, including acantholytic herpetiform dermatitis, herpetiform pemphigus, pemphigus controlled or mixed bullous disease. [21] The term pemphigus herpetiformis (PH) was firstly proposed by polish group of dermatologist (1975, Jablonska et al) which described a case with early atypical clinical and histological features, that may evolve into classical pemphigus.[22]

The clinical features are polymorph and variable, with urticarial plaques, erythematous, papular or vesiculo- bullous lesions usually coalescent annular or gyrate aspects which demonstrate a "herpetiform" pattern.[23]

Clinical presentation of pemphigus herpetiformis is usually atypical, and may resemble clinical features of other disorders such as linear IgA bullous dermatosis,  dermatitis herpetiformis, bullous pemphigoid, pemphigus vulgaris, pemphigus erythematosus and pemphigus foliaceus. [24]

Most patients with herpetiform pemphigus have not got mucous lesions, therefore oral erosion has been observed only occasionally.

Extraordinary violent itching is frequently associated and might be in approximately half an cases [25]

As a rule pemphigus herpetiformis is not associated with significant mortality; and have a subacute onset of disease with owns features, some clinical particularities and benign course. [26]

2.7. IgA Pemphigus

IgA pemphigus is a recently described intraepidermal neutrophilic acantholytic autoimmune blistering disease that is characterized by IgA autoantibodies that target on keratinocyte cell surfaces, especially the desmosomal proteins of the epidermis. [27, 28]. Wallach and colleges described this type of pemphigus in 1982 and named it subcorneal pustular dermatosis with monoclonal IgA [29]. IgA pemphigus has a lot of synonyms which were used before: intercellular IgA dermatosis, IgA herpetiform pemphigus, intraepidermal neutrophilic IgA vesiculopustular dermatosis, intraepidermal IgA pustulosis, dermatosis, intercellular IgA and IgA pemphigus foliaceus [30, 31,32, 33, 34, 35, 36].

Approximately 70 cases of IgA pemphigus have reported until 2010, therefore its sex, race distribution and frequency is not well defined yet.[37] The average age of onset is 53 years, but IgA pemphigus occur since 1 month till 85 years.[38]

There are two subtypes of this disease according to clinically and histopatologically aspects: superficial type which is named subcorneal pustular dermatosis (SPD), and deeper variant named intraepidermal neutrophilic (IEN) type.

The onset of IgA pemphigus is usually subacute[39]. In more than one half of cases, the patients complain of an pruritus which may interfere with the patient's daily life.

In both types of IgA pemphigus skin lesions are presented by flaccid vesiculopustular irruptions on erythematous or normal skin. At the beginning blisters are filled with transparent liquid which is supplemented with neutrophils later and thus blisters turn into pustules. Sometimes these lesions have herpetiform appearance [40], but more often are coalescing into annular or circinate pattern, called "sunflower-like" configuration and are covered by crusts. In any cases, vesiculo-pustular lesions mimicking subcorneal pustular dermatosis of Sneddon–Wilkinson, pemphigus foliaceus or pemphigus herpetiformis [42]. Flexural oozing and verrucous plaques may resembling pemphigus vegetans. [43] Other cases have been linked with HIV infection [44], inflammatory bowel disease, gluten sensitive enteropathy [45], rheumatoid arthritis [46] and thiol drugs [47].

Lesions usually are localized on the trunk and proximal extremities. The scalp, postauricular areas and intertriginous areas (axillary and groin folds) are also involved in the pathological process, but less often. Mucous membranes, palms and soles involvement is rare. [35, 41]

2.8. Paraneoplastic Pemphigus

Paraneoplastic pemphigus is the type of pemphigus which is associated with diverse malignant and benign neoplasms. This type of pemphigus is involving women more often than men and as a rule begins after 60 years. The most commonly associated neoplasms include Waldenström’s macroglobulinemia, chronic lymphocytic leukemia, Castleman's disease, non-Hodgkin lymphoma, malignant and benign thymomas, sarcomas. [10, 11, 12]

The main and earliest clinical symptom of paraneoplastic pemphigus is intractable stomatitis. Severe stomatitis usually is presented represented painful, multiple, persistent erosions and ulcers. [13]

The most common sites on a mucous membrane which are involved in process are lips and oropharynx. The oropharyngeal involvement may lead to dysphagia and sore throat. Esophageal, nasopharyngeal, vaginal, labial and penile mucosal lesions may also be seen. Most patients also have a severe bilateral conjunctivae involvement, which may follow by scarring and obliteration of the conjunctivas furnaces. [13]

Injuries of skin are extensive and quite polymorphic with various forms and the sizes. Skin eruptions can remind some dermatoses, such as a pemphigus vulgaris with sluggish blisters and erosions, bullous pemphigoid with tense bullous lesions and erythema multiforme-like lesions with the darkish centers or the central vesicles. In difference from pephigus vulgaris, palmo-plantar blisters are characteristic for a paraneoplastic pemphigus. Sometimes eruptions may be with itching.

Some patients with a paraneoplastic pemphigus can get to bronchiolitis obliterans which can be fatal as a result of respiratory insufficiency, but its pathophysiologic mechanism remain unclear [14]

There were no described cases of IgA pemphigus with a fatal outcome. Actually, the clinical course of this type of pemphigus is considered easier that IgG-mediated types of pemphigus.

2.9. Drugs – induced pemphigus

Drugs may exacerbate or induce pemphigus. Drugs containing a sulphydryl group (thiol drugs) such as penicillamine and captopril are the best studied, but pemphigus can also been attributed to non-thiol drugs, including other ACE inhibitors, for example enalapril [48], ramapril [49], and the angiotensin II receptor blockers candesartan and telmisartan [50]. Other drugs which may induced pemphigus are some antibiotics, pyrazolon derivatives, antimalaric drugs, montelukast and interferon [51,52,53,54].

Where described some cases of pemphigus which have been induced physical triggers like radiotherapy [55], thermal burns [56] and electrical injury [57]. Probably, dietary factors, particularly vegetables of the Allium group, have triggered pemphigus [58]. Human herpes virus-8 was incriminated by some authors, who detected DNA sequences in peripheral blood mononuclear cells and skin from pemphigus patients [59], but their significance is disputed.

Pemphigus foliaceus or pemphigus erythematosus are the most common patterns of pemphigus induced by drugs. Drug-induced pemphigus vulgaris and pemphigus vegetans are rare. Most patients have circulating autoantibodies with the same antigenic specificities as in other forms of pemphigus [60,61].

About half of patients with thiol-drug-induced pemphigus recover spontaneously when the drug was suspended [51] with rapid decline in desmoglein antibody levels [62].

Chapter N3 “Material and research methods”

In the process of my study, I have assessed and reviewed 77 books and articles regarding autimmune bullous dermatoses. And various cross sectional studies have been done to evaluate the clinical and morphological features of intraepidermal autoimmune bullous dermatoses. Also were estimated a role and value of various laboratory tests in diagnostics of intraepidermal autoimmune bullous dermatosеs. I have been used here the most accurate and scientific studies conducted by various governmental and non-governmental organizations and institutions.

Various comparative and literary estimates were made by means of analytical, metaanalytical and comparative methods.

Chapter N4 "Personal results and discussion"

4.1. Clinical and morphological features of autoimmune dermatosеs, at a modern stage.

Statement of the diagnosis of autimmune bullous dermatoses presents sometimes certain difficulties, and from the moment of manifestation of the first symptoms of a disease can vary from 1 month to 5 years, on average — about six months.

At most of patients with an autoimmune bullous dermatoses the pathological process has been localized mainly on skin (93,6%) with simultaneous involvement of mucous membranes (53,2%). In some cases (6,4%) damage only of a mucous membrane of an oral cavity without clinical manifestations on skin has been noted.[63] Besides, most of authors, note change of a clinical picture of the intraepidermal autimmune bullous dermatoses at the present stage.

Not only clinical similarity among a different autoimmune bullous dermatosis (for example, as in case of pemphigus herpetiformis and a dermatitis herpetiformis Duhring, or pemphigus vulgaris and bullous pemphigoid), but also clinical imitation by other skin diseases, such as a erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, prurigo, is quite often observed.

Such variety of clinical manifestations can be observed also in cases of the paraneoplasic autoimmune bullous dermatoses and during early development of bullous pemfigoid with his atypical manifestations.

All this interferes with early establishment of clinical diagnosis and forces the clinical physician to resort to use of various clinical and laboratory diagnostic methods.

The clinical method provides an attention point as on features of morphology, localization, evolution and regress of skin manifestations at various bullous dermatoses and also epidemiological aspects (incidence frequency, age, a sexual character, mortality еtс).

A complex study which was made in Russia (Mahneva N. 2009) determined that among the patients suffering from an autoimmune bullous dermatoses there were both men, and women aged from 18 till 87 years (an average 61,8±14,5 years). Women suffered more often than men (a ratio women to men are made by 2,5:1). At the same time the incidence peak at women fell on age from 61 year to 70 years, and at men – of 51 year to 60 years (fig. 1).[63]

Fugure N 1

Incidence of autoimmune bullous dermatoses among men and women depending on age

The main group of them was patients with an diverse types of autoimmune pemphigus (61,4%) and a quite less with bullous pemfigoid (33,3%). A linear IgA dermatosis (1,9%) and epidermolysis bullosa acquisita  (3,4%) were diagnosed extremely rare (fig. 2).

Figure 2

Percentage ratio of autoimmune bullous dermatoses on the relation to each other.

The epidemiological study made in UK (Langan SM et al. 2008) showed that among more than one thousand patients with autoimmune bullous dermatoses 869 patients have had bullous pemphigoid and just 138 people have had pemphigus vulgaris. (fig 3)

Figure N3

The incidence of pemphigus vulgaris and bullous pemphigoid in UK in dependence of age

This trial showed also that median age at presentation for bullous pemphigoid was 80 (range 23-102) years, and for pemphigus vulgaris was 71 (21-102) years. 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).

The Russian trial also shows that pemphigus vulgaris is the most common type in pemhigus group (fig 4) [63]

Figure N4

The distribution of different types of intraepidermal autoimmune bullous dermatoses (pemphigus groop) betheen 164 pacients

The acute onset with damage of mucous membrane of an oral cavity is more characteristic for pemphigus vulgaris which appears like this more than 70% of cases. Also pemphigus vegetans may begin with lesions on the oral mucosa like pemphigus vulgaris. The damage of oral mucosa can be unique symptom of a disease, for a long period of time.

Sometimes, process begins with damage of a mucous membrane of genitals, throats, tracheas. In the beginning appear single or not numerous bullous lesions which are often involve retro-malar area or a lateral surface of language. Under influence of teeth the thin and flabby tire of blisters is quickly opening and appearing bright red erosions with peripheral oddments of walls from blisters.

The erosive sites of mucous membrane are very painful with expressed salivation and patients can't chew and take a sip of food. Deep fissures in mouth corners which aren't allowing opening it are noted. Don’t forget, that similar erosive lesions with hemorrhagic crusts around the mouth are very characteristics in paraneoplastic pemphigus.

Patients with defeat of oral mucosa usually address the stomatologist and long time receives treatment concerning stomatitis. And only 3-6 months later emergence of single blisters on skin is noted and a bit later during progressing process generalization begins.

Appearance of sluggish bullous lesions (monomorphic character of rash) on normal looking skin or less often on erythematous skin is more characteristic for a pemphigus than for subepidermal bullous processes.

Bullae can be small or large, with serous, and after some time – rather turbid, sometimes hemorrhagic contents. Over time bullae tend to the peripheral growth, merge among themselves to formation of the large scalloped centers. After a while contents of bubbles dry up, forming yellowish crusts at which falling away there are hyper pigmented secondary spots.

Though it is considered that bullous lesions in pemphigus vulgaris usually apear on normal looking skin they can appear sometimes on an edematous and erythematous background and have tendency to group as in herpetiform dermatitis Duhring. In these cases we must recollect about the rare type of pemphigus, like pemphigus herpetiformis where blisters are followed by burning and itching. Further along with herpetiform lesions patients even more often have large sluggish blisters on normal looking skin, and the clinical picture accepts the classical aspects of pemphigus vulgaris.

The pemphigus vegetans differs from other types of pemphigus by existence in areas of erosions the verruciform, vegetant or pustular lesions of the periorificial regions or, more commonly, involving the large folds. At some patients the affected areas can be similar to those at a pyoderma vegetans due to appearance of vegetant and pustulous lesions. A differential diagnostic sign in such cases is detection of IgG against desmogleins 1 and 3 in epidermis by direct immunofluorescence.

The pemphigus foliaceus is characterized by a superficial arrangement of bullae therefore they are clinically poorly noticeable, quickly become covered by yellowish-brown scuamous- crusts, often layered because of repeated formation of bullous lesions under them. Process is usually generalized. In difference from pemphigus vulgaris, blisters are added by inflammatory reaction that gives similarity of eruptions with an exfoliative erythroderma, psoriasis, seborreic dermatitis and other dermatoses. Mucous membranes are involved very rare.

Important clinical sign of pemphigus foliaceus is repeated, sometimes continuous, formation of superficial blisters under crusts on the places of former erosions.

If the clinical features are polymorph and variable, with urticarial plaques, erythematous, papular or vesiculo- bullous lesions usually coalescent annular or gyrate aspects which demonstrate a "herpetiform" pattern associated with violent itching and respect oral mucoza, but after all localized in epidermis it is probably herpetiform pemphigus.

IgA pemphigus sometimes also may be presented by "herpetiform" lesions or flaccid vesiculo-pustular irruptions on erythematous or normal skin, but more often are coalescing into annular or circinate pattern, called "sunflower-like" configuration and are covered by crusts.

The differential clinical features of all types of pephiguses (intraepidermal immunobullous diseases) are presented in the table N1

Tab. N1

The intraepidermal immunobullous diseases: clinical features.

4.2. The predictive value of Nikolsky`s sign in differential diagnostics of intraepidermal autoimmune bullous dermatoses.

Clinical signs which reveal characteristics of blisters have a significant importance in clinical examination of patients with vesiculo-bullous disorders. There are several signs which evaluate the integrity of cells cohesion in the skin: Nikolsky sign, Asboe-Hansen sign /bulla spread sign, pseudo-Nikolsky sign/epidermal peeling sign and Sheklakov sign/false-Nikolsky sign. Nikolsky's sign is considered one of the most important which has been described by the Russian dermatologist Pyotr Nikolskiy in 1894.

The Nicolsky sign is eliciting by applying lateral pressure with the finger pad to the affected skin, peri-lesional skin, or normal skin in patients with bullous lesions suspected for autoimmune bullous dermatoses especially for pemphigus.

Nicolsky sign is considered positive if there is a dislodging of the affected or normal looking skin, extension of the blister or removal of epidermis in the rubbed area.

There are described two variants of Nicolsky sign:

"Marginal Nikolskiy sign" elicited on the surrounding normal-appearing skin by rubbing the skin close to existing lesions.

"Direct Nikolsky's sign" is the induction of an erosion on normal-looking skin at a distant site. 

The term "Nikolsky phenomenon" is used when the superficial layer of the epidermis is felt to move over the deeper layer but instead of immediately forming erosion as in classical Nikolskiy’s sign, a blister develops after some time. 

The "modified Nikolsky" sign is meaning peripheral extension of blisters on applying pressure to their surface. This is helpful in patients in whom a new vesicle or bulla is not available for biopsy.  The advantage here is that the artificially extended blister cannot show epithelial regeneration, which is sometimes seen in the floor of older subepidermal blisters making them appear as intraepidermal.

The term pseudo-Nikolsky’s sign is used by some authors for cases where the epidermal separation was actually subepidermal instead of intraepidermal. It can be elicited only on the affected or erythematous areas of the skin.

Another term likes false- Nikolsky's sign or Sheklakov's sign is positive in sub-epidermal blistering disorders. It involves pulling the peripheral remnant roof of a ruptured blister, thereby extending the erosion on the surrounding normal skin. The erosions thus induced are limited in size, without tendency to extend spontaneously, and heal rapidly.

Another sign used in diagnosis of bullous disorders is Asboe-Hansen sign (bulla spread sign). Described originally by Wilhelm Lutz, it is meaning the enlargement of an intact blister by the application of mechanical pressure on its roof. If one carefully presses upon the blister, it enlarges towards its periphery due to the mechanical pressure of the blister fluid.  

The utility and significance of Nicolsky sign and its variant in different types of intraepidermal autoimmune bullous deratoses are tested many times. And in most studies the result was similar.

Uzun and Durdu revealed that a positive Nicolsky sign was demonstrated in 24 (19.5%) of the 123 patients. Most of patients with positive Nicolsky sign had diverse variants of pemphigus -18 (75%), only 4 patients had bullous pemphigoid (17%) and 1 patient had linear IgA dermatosis. The sensitivity of “direct” Nicolsky sign (38%) was less than of the “marginal” from (69%), but the specificity of “direct” Nicolsky sign (100%) was higher than that of the “marginal” form (94%) in the diagnosis of pemphigus. [64] The result of this study is present bellow on the tables N 2 and 3

Table N2

Presence of the Nikolsky sign with modifications of “direct” and “marginal” in various cutaneous diseases presenting as intact blisters, erosions, or both (Uzun S, Durdu M. 2005)

Table N3

Sensitivity, specificity, and predictive value results for clinical diagnosis of pemphigus by Nikolsky sign (Uzun S, Durdu M. 2005)

In another study Mahneva N. (2009) has got the similar results. High specificity of this symptom allows suspecting directly at a bed of the patient such life-endangering disease as an autoimmune pemphigus. However negative results in some cases of autoimmune pemphigus (28%) and identification of a similar symptom at other autoimmune bullous dermatosis, such as bullous pemphigoid (3,4%) and epidermolysis bullosa acquisita  (66,7%) do not allow to carry out differential diagnostics between this dermatoses. (Figure N 5)

Figure N5

The incidence of positive Nicolsky sign between autoimmune bullous dermatoses (Mahneva N. 2009)

Microscopic Nikolsky's sign is the subclinical counterpart of Nikolsky's sign. Tangential pressure on apparently normal skin, exerted as in eliciting clinical Nikolsky's sign, produces the classical microscopic changes of pemphigus vulgaris or pemphigus foliaceus in the epidermis that can be visualized on skin biopsy. Hameed and Khan (1999) demonstrated a positive microscopic Nikolsky's sign in 73.9% of pemphigus patients who were biopsied after applying tangential pressure. There were no changes in the biopsies of healthy controls. This technique could be of value in areas where immunofluorescence is not readily available[65]. Nikolsky's sign is usually positive in diseases with epidermal acantholysis and typically negative in diseases with dermo-epidermal separation,[66] thus helping to distinguish pemphigus from bullous pemphigoid [67]. False Nikolsky's sign or Sheklakov's sign is positive in sub-epidermal blistering disorders. It involves pulling the peripheral remnant roof of a ruptured blister, thereby extending the erosion on the surrounding normal skin. The erosions thus induced are limited in size, lack the tendency to extend spontaneously, and heal rapidly. Pseudo-Nikolsky's sign is positive in Stevens-Johnson syndrome, toxic epidermal necrolysis and in some cases of burns and bullous ichthyosiform erythroderma. However, it can be elicited only on the affected or erythematous areas. Here, the underlying mechanism is necrosis of epidermal cells and not acantholysis as in true Nikolsky's sign. [68]

Thus value of the Nikolscy sign differs both depending on depth of defeat and from type of an autoimmune pemphigus. In all clasical types of pemphigus Nikolscy sign is more expressive than in recently described forms. And among diferent clasical types of pemphigus this sign is more expresive in superficial types like especialy in pemphigus erythematosus. The differences are presented in table N4

Table N4

The expressivity of Nicolsky sign in autoimmune bullous dermatoses.

4.3. The importance of various laboratory tests in diagnostic of intraepidermal autoimmune bullous dermatosеs.

If the clinical features are unconvincing and result of Nikolsky’s sign is doubtful as a first diagnostic "tool", the doctor is forced to address laboratory diagnostic testings. The cytological and pathomorphological methods are considered more available and simplest to make in most medical institutions.

A typical acantholytic cell of pemphigus vulgaris as seen in a Tzanck smear is called a “Tzanck cell”. It is a rounded keratinocyte with a hypertrophic or dysmorphic nucleus, hazy or absent nucleoli, increased nuclear to cytoplasmic ratio due to the loss of normal intercellular cohesion and abundant eosinophilic to basophilic cytoplasm. The staining is more intensely basophilic near the cell membrane ('mourning edge') because of cytoplasmic condensation at the periphery, resulting in a perinuclear halo.[69, 70] Other findings, not pathognomonic to pemphigus but frequently detectable, are Sertoli's rosettes and 'streptocytes’. Sertoli's rosettes are composed of a central necrobiotic keratinocyte with a surrounding leukocyte rosette. A 'streptocyte' is a chain of leukocytes, joined by a filamentous, glue-like substance. Sertoli's rosettes and 'streptocytes' can be observed in herpes zoster and the pemphigoid group, respectively. [71] The presence of typical Tzanck cells in large numbers, either discretely or as loosely adherent clumps, without significant surrounding inflammation substantiates the diagnosis of pemphigus. [72,73]

Although acantholysis does occur in a variety of conditions, subtle differences in the appearance of acantholytic cells, site of involvement, and the associated findings aid us in clinching the diagnosis. For example, Tzanck smears from bullous impetigo show abundant neutrophils along with acantholytic cells in contrast to a bland picture in pemphigus vulgaris. It is worthwhile to mention here that in herpes simplex and zoster, the acantholytic cells either occur as a single cell or as multinucleated giant cells (MNGs).

The sensitivity and specificity of finding acantholytic cells in Tzanck smears for pemphigus vulgaris is reported to be 100% and 43.4%, respectively. [74] Even if clinical features are very close to pemphigus and Tzank’s cells are founded, don’t forget that these cells are found not only at this pathology (76,2%), but also at a bullous pemfigoid (9,9%) and the epidermolysis bullosa acquisita  (11,1%). [63].

The significance of Tzanck smear test in different types of autoimune pemphiguses are presented in table N5.

Table N5

The significance of Tzanck smear test in different types of autoimune pemphiguses

Pathomorphological examination from the bullous and erosive lesions has allowed to reveal a typical morphological picture of pemhigus in 79,9% of cases, a bullous pemfigoid in 83,1% of cases and in one case of a IgA linear dermatitis and the epidermolysis bullosa acquisita. In two last cases the pathomorphological picture corresphonded to a bullous pemfigoid. [63]. Sometimes is very difficult to differentiate various forms of pemphigus each to other. But at all cases of a pemphiguses to a greater or lesser extent there has to be a process of an acantholysis. (See the table N6)

Table N6

The result of pathomorphological examination in different types of autoimmune pemphiguses

Although acantholysis is present virtually in all forms of pemphigus, sometimes it may also be absent and may be present with other histopathological changes as acanthosis, parakeratosis, spongiosis, that can lead us into error. However intraepidermal cleavage let us certainly to differentiate pemphigus group of subepidermal bullous dermatosis group.

The results of one of studies (Baican Corina 2011) which reveal the sensitivity of clinical, histologic and immunologic findings for the diagnosis of autoimmune bullous disease [75] are presented bellow in the tables N7 and 8

Table N7

The sensitivity of clinical, histologic and immunologic findings for the diagnosis of autoimmune bullous disease (C. Baican 2011)

Table N8

The level of circulate antibodies evaluated by ELISA in autoimmune bullous diseases (C. Baican 2011)

Therefore, despite rather high informational content of a histological method, similar morphological changes oblige dermatologists to address more perfect and reliable methods of research with use of a direct and indirect immunofluorescence for the purpose of identification of circulating antibodies and also the fixed immune complexes.

Direct immunofluorescence reveals immunoglobulin and/or complement at the basement membrane zone as well as on the surfaces of keratinocytes.

Indirect immunofluorescence is positive in both non-stratifying (simple and transitional) epithelia and stratifying epithelia

Table N9

The intraepidermal immunobullous diseases: immunopathology and immunogenetics.

The algorithm of the early diagnosis of intraepidermal autoimmune bullous dermatosеs.

In 2014 the final version of the pemphigus guideline was finally passed on to the European Dermatology Forum (EDF) for a final consensus with the European Academy of Dermatology and Venereology (EADV) and the European Union of Medical Specialists (UEMS). This guidline consider that the diagnosis of pemphigus is based on four criteria:

Clinical presentation (described earlier)

Histopathology

Direct immunofluorescence microscopy (DIF) of perilesional skin

Serological detection of serum autoantibodies against epithelial cell surface by indirect immunofluorescence microscopy (IIF) and/or enzyme-linked immunosorbent assay (ELISA)

Histopathology

Preferentially, a 4-mm-punch excision should be taken of a fresh (<24 h) small vesicle or 1/3 of the peripheral portion of a blister and 2/3 perilesional skin (placed in 4% formalin solution) for routine histopathological analysis: intraepidermal suprabasal acantholysis in PV and PNP, or acantholysis at the granular layer in PF. Epidermal acantholysis, suprabasal cleft formation, dyskeratotic keratinocytes, vacuolar change of the basilar epidermis and epidermal exocytosis of inflammatory cells (PNP).

Direct immunofluorescence microscopy (DIF)

Skin biopsy of perilesional skin (up to 1 cm from a fresh lesion), put into a cryotube for transportation in a cylinder of liquid nitrogen or in saline (delivery <36 h) or Michel’s fixative for DIF analysis:

• DIF: IgG and/or C3 deposits at the surface of epidermal keratinocytes

• The epithelial cell surface staining for in vivo IgG depositions is normally granular in DIF and smooth in IIF

• IgA deposits with an epithelial cell surface pattern in addition to IgG may be present in a minority of cases. When only IgA is found, the diagnosis of IgA pemphigus is established

• Epithelial cell surface deposits can sometimes be associated with linear deposits of IgG or C3 along the dermal–epidermal junction, suggestive of PNP/PAMS or pemphigus erythematosus, or the coexistence of pemphigus and pemphigoid

• In specialized laboratories, plugged hairs can be utilized for DIF for the diagnosis of pemphigus/

Immune serological tests In addition to DIF, IIF and additional techniques with defined native or recombinant proteins are commonly used to detect serum autoantibodies in patients with pemphigus.

Indirect immunofluorescence microscopy (IIF)

• IIF test on monkey oesophagus or human skin to search for autoantibodies against surface proteins of epidermal keratinocytes. The smooth and reticular staining pattern is also referred to as ‘chicken wire’, ‘honeycomb’ or ‘fishnet-like’

• In case of atypical presentation or the suspicion of an unrelated autoimmune bullous disorder, additional immunopathological tests may be performed, such as IIF on rat bladder and immunoblot/immunoprecipitation

• IIF on rat bladder (in suspected cases of PNP/PAMS with extracts of epidermal keratinocytes) is highly specific but less sensitive

ELISA

• Detection of anti-desmoglein 1 (Dsg1) (PF/mucocutaneous PV) and/or anti-desmoglein 3 (Dsg3) IgG autoantibodies (mucosal PV) by ELISA (MBL, Euroimmun)

• The detection of IgG autoantibodies by ELISA is positive in more than 90% of cases

• In general, the ELISA index correlates with the extent and/or activity of disease (see remark above and prognostic value for relapse, helping to guide treatment). Large prospective cohort studies are, however, missing in this context to provide reliable data about predictive value Immunoblot and immunoprecipitation Diagnosis of PNP/PAMS: immunoblot and immunoprecipitation with keratinocyte extracts will reveal evidence of serum IgG/IgA autoantibodies against:

• Envoplakin (210 kDa) and periplakin (190 kDa) (Euroimmun)

• Desmoglein 3 (130 kDa), desmoglein 1 (160 kDa), desmocollins, desmoplakins I and II, BP180/BPAG2, BP230/BPAG1, plectin (500 kDa) and alpha-2-macroglobulin-like-1 (A2ML-1, 170 kDa)

• IgG antibodies against envoplakin and periplakin and/or A2ML1 confirm the clinical diagnosis of PNP/PAMS. IgG against desmoplakins I and II, BP230/BPAG1 and plectin may be present in other forms of pemphigus

• Combining two of three serological techniques (IIF on rat bladder, immunoblot and immunoprecipitation) is sufficient for making the diagnosis of PNP/PAMS (sensitivity almost 100%).

Based on this guideline any authors propose some algorithms in standardization of diagnosis of pemphigus group. For example in 2014, J.V. Otten, T. Hashimoto et al proposed diagnostic criteria for pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus and IgA pemphigus [76] (tables 10,11,12,13)

Table 10

Table 11

Table 12

Table 13

A little bit earlier Y. Shoenfeld et al (2008) proposed the standardization of diagnosis in pemphigus vulgaris which content two groups of criteria: major and minor. Obligatory conditions for definitive diagnosis: three major criteria or two major (one of which is positive DIF) and one minor criteria. In fact authors remarked the importance of direct immunofluorescence assay which mast be positive in all cases. [77]. (table 14)

Table N14

Diagnostic criteria for pemphigus vulgaris (Yehuda Shoenfeld et al 2008)

(Diagnostic criteria in Autoimmune diseases Yehuda Shoenfeld, Ricard Cervera, M.Eric Gershwin 2008)

Chapter N5 "Conclusions"

To study clinical and morphological features of autoimmune dermatosеs, at a modern stage.

To estimate the predictive value of Nikolsky`s sign in differential diagnostics of autoimmune bullous dermatoses.

To study a role and value of various laboratory tests in diagnostics of autoimmune bullous dermatosеs.

To define stage-by-stage algorithm of the early diagnostics of autoimmune bullous dermatosеs.

Chapter N6 "Attachment"

Picture N1 Pemphigus vulgaris

Picture N2 Pemphigus vegetans

Picture N3 Pemphigus foliaceus

Picture N4 Pemphigus eritematosus

Picture N5 IgA pemphigus

Picture N6 Pemphigus herpetiformis

Picture N7 Pemphigus paraneoplastic

Chapter N7 “Bibliographic References”

Hietanen J, Salo OP. Pemphigus: an epidemiological study of patients treated in Finnish hospitals between 1969 and 1978. Acta Derm Venereol1982;62:491-6.

Pisanti S, Sharav Y, Kaufman E, Posner LN. Pemphigus vulgaris: incidence in Jews of different ethnic groups, according to age, sex, and initial lesion. Oral Surg Oral Med Oral Pathol1974;38:382-7.

Kneisel A, Hertl M. Autoimmune bullous skin diseases. Part 1: clinical manifestations. J Dtsch Dermatol Ges 2011; 9: 844–856; quiz 857

Plemons JM, Gonzales TS, Burkhart NW. Vesiculobullous diseases of the oral cavity. Periodontology 2000, 1999:21; 158-175.

M. Hertl, H. Jedlickova, S. Karpati, et al. Pemphigus. S2 Guideline for diagnosis and treatment –guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV). JEADV 2015, 29, 405–414

Mihai S, Sitaru C. Immunopathology and molecular diagnosis of autoimmune bullous diseases. J Cell Mol Med 2007; 11:462.

Bastianes MT, Zwan NV, Stooe TJ, Verschueren GLA, Nieboer C. Report three cases of pemphigus vegetans: induction by enalapril – association with internal malignancy. Int J Dermatol. 1994;33:168-71.

Azulay-Abulafia L, Bonalumi Filho A, Azulay DR, Leal FRPC. Atlas de Dermatologia: da semiologia ao diagnóstico. Rio de Janeiro: Elsevier; 2007. p. 565-6.         

Azulay RD. Dermatologia. 5 ed. Rio de Janeiro: Guanabara Koogan; 2008. p. 130-5.

Anhalt GJ, Kim S, Stanley JR, et al: Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia.  N Engl J Med  1990; 323:1729-1735.

Anhalt GJ: Paraneoplastic pemphigus.  J Invest Dermatol Symp Proc  2004; 9:29-33.

Lee I J, Kim SC, Kim HS, Bang D, Yang WI, Jung WH, et al. Paraneoplastic pemphigus associated with follicular dendritic cell sarcoma arising from Castleman’s tumor. J Am Acad Dermatol 1999;40 (2 pt 2):294-7.

Sklavounou A, Laskaris G. Paraneoplastic pemphigus: a review. Oral Oncol 1998;34:437-40.

Nousari HC, Deterding R, Wojtczack H, et al: The mechanism of respiratory failure in paraneoplastic pemphigus.  N Engl J Med  1999; 340:1406-1410.

F. E. Senear and B. Usher, “Unusual type of pemphigus combining features of lupus erythematosus,”Archives of Dermatology, vol. 13, article 761, 1926

Kumar KA. Incidence of pemphigus in Thrissur district, south India. Indian J Dermatol Venereol Leprol. 2008 Jul-Aug. 74(4):349-51.

Bean SF, Lynch FW. Senear-Usher syndrome (pemphigus erythematosus). Immunofluorescent studies in a patient. Arch Dermatol. 1970;101:642–5

Jablońska S, Chorzelski T, Blaszczyk M, Maciejewski W. Pathogenesis of pemphigus erythematosus. Arch Dermatol Res. 1977;258:135–40.

 Micali G, Musumeci ML, Nasca MR. Epidemiologic analysis and clinical course of 84 consecutive cases of pemphigus in eastern Sicily. Int J Dermatol. 1998;37:197–200.

 Duarte IB, Bastazini I, Jr, Barreto JA, Carvalho CV, Nunes AJ. Pemphigus herpetiformis in childhood. Pediatr Dermatol. 2010;27:488–491.

Kasperkiewicz M, Kowalewski C, Jablonska S. Pemphigus herpetiformis: from first description until now. J Am Acad Dermatol. 2014 Apr. 70(4):780-7

Jablonska, T. P. Chorzelski, E. H. Beutner, and J. Chorzelska, “Herpetiform pemphigus, a variable pattern of pemphigus,” International Journal of Dermatology, vol. 14, no. 5, pp. 353–359, 1975. 

Ohata C, Koga H, Teye K, Ishii N, Hamada T, Dainichi T, et al. Concurrence of bullous pemphigoid and herpetiform pemphigus with IgG antibodies to desmogleins 1/3 and desmocollins 1-3. Br J Dermatol. 2012 Aug 27.

Maciejowska E, Jablonska S, Chorzelski T. Is pemphigus herpetiformis an entity? Int J Dermatol. 1987;26:571–577

Robinson ND, Hashimoto T, Amagai M, Chan LS. The new pemphigus variants. J Am Acad Dermatol. 1999;40:649–671.

Tateishi C, Tsuruta D, Nakanishi T, Uehara S, Kobayashi H, Ishii M, et al. Antidesmocollin-1 antibody-positive, antidesmoglein antibody-negative pemphigus herpetiformis. J Am Acad Dermatol. 2010;63:e8–10.

Tsuruta D, Ishii N, Hamada T, Ohyama B, Fukuda S, Koga H, et al. IgA pemphigus. Clin Dermatol. 2011 Jul-Aug. 29(4):437-42. [Medline].

Sticherling M, Erfurt-Berge C. Autoimmune blistering diseases of the skin. Autoimmun Rev. 2012 Jan. 11(3):226-30. [Medline].

 Wallach D, Foldès C, Cottenot F. Pustulose sous-cornee,acantholyse superficielle et IgA monoclonale. Ann Dermatol Venereol. 1982;109:959–963

Wallach D. Intraepidermal IgA pustulosis. J Am Acad Dermatol. 1992;7:993–1000.

Gengoux P, Tennstedt D, Lachapelle JM. Intraepidermal neutrophilic IgA dermatosis: pemphigus-like IgA deposits. Dermatology. 1992;185:311–313.

Chorzelski TP, Beutner EH, Kowalewski C, Olszewska M, Maciejowska E, Seferowicz E, et al. IgA pemphigus foliaceus with a clinical presentation of pemphigus herpetiformis. J Am Acad Dermatol. 1991;24:839–844. 

Beutner EH, Chorzelski TP, Wilson RM, Kumar V, Michel B, Helm F, et al. IgA pemphigus foliaceus: report of two cases and a review of the literature. J Am Acad Dermatol. 1989;20:89–97

Huff JC, Golitz LE, Kunke KS. Intraepidermal neutrophilic IgA dermatosis. N Engl J Med. 1985;313:1643–1645. 

Hashimoto T, Inamoto N, Nakamura K, Nishikawa T. Intercellular IgA dermatosis with clinical features of subcorneal pustular dermatosis. Arch Dermatol. 1987;123:1062–1065. 

Tagami H, Iwatsuki K, Iwase Y, Yamada M. Subcorneal pustular dermatosis with vesiculo-bullous eruption: demonstration of subcorneal IgA deposits and a leukocyte chemotactic factor. Br J Dermatol. 1983;109:581–587.

Tajima M, Mitsuhashi Y, Irisawa R, Amagai M, Hashimoto T, Tsuboi R. IgA pemphigus reacting exclusively to desmoglein 3. Eur J Dermatol. 2010;20:626–629.

Robinson ND, Hashimoto T, Amagai M, Chan LS. The new pemphigus variants. J Am Acad Dermatol. 1999;40:649–671

 E-medicine. medscape.com. Chan LS. IgA Pemphigus. [cited 2010 Apr 9]. [homepage on the Internet] Available from:http://www.emedicine.medscape.com/article/1063776-overview.

Huff JC, Golitz LE, Kunke KS. Intraepidermal neutrophilic IgA dermatosis. N Engl J Med. 1985;313:1643–1645

Hodak E, David M, Ingber A, Rotem A, Hazaz B, Shamai-Lubovitz O, et al. The clinical and histopathological spectrum of IgA- pemphigus: report of two cases. Clin Exp Dermatol. 1990;15:433–437.

Chorzelski TP, Beutner EH, Kowalewski C et al. IgA pemphigus foliaceus with a clinical presentation of pemphigus herpetiformis. J Am Acad Dermatol 1991; 24: 839–44.

Weston WL, Friednash M, Hashimoto T et al. A novel childhood pemphigus vegetans variant of intraepidermal neutrophilic IgA dermatosis. J Am Acad Dermatol 1998; 38: 635–8.

Barnadas M, Nadal C, Verger G et al. Intraepidermal IgA pustulosis with monoclonal IgA gammopathy in an HIV-infected patient. Dermatology 1997; 194: 308–9.

Borradori L, Saada V, Rybojad M et al. Intraepidermal neutrophilic IgA pustulosis and Crohn’s disease. Br J Dermatol 1992; 126: 383–6.

Amagai M, Klaus-Kovtun V, Stanley JR. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell 1991; 67: 869–77.

Kishimoto K, Iwatsuki K, Akiba H et al. Subcorneal pustular dermatosis-type IgA pemphigus induced by thiol drugs. Eur J Dermatol 2001; 11: 41–4.

Kuechle MK, Hutton KP, Muller SA. Angiotensin-converting enzyme inhibitorinduced pemphigus: three case reports and literature review. Mayo Clin Proc 1994; 69: 1166–71.

Vignes S, Paul C, Flageul B et al. Ramipril-induced superfi cial pemphigus. Br J Dermatol 1996; 135: 657–8.

Bae YI, Yun SJ, Lee SC et al. Pemphigus foliaceus induced by an angiotensin II receptor blocker. Clin Exp Dermatol 2008; 33: 721–3

Brenner S, Bialy-Golan A, Ruocco V. Drug-induced pemphigus. Clin Dermatol 1998; 16: 393–7.

Ghaffarpour G, Jalali MH, Yaghmaii B et al. Chloroquine/hydroxychloroquine-induced pemphigus. Int J Dermatol 2006; 45: 1261–3.

Fleischmann M, Celerier P, Bernard P et al. Long-term interferon-alpha therapy induces autoantibodies against epidermis. Dermatology 1996; 192: 50–5.

Cetkovska P, Pizinger K. Childhood pemphigus associated with montelukast administration. Clin Exp Dermatol 2003; 28: 328–9.

23. Robbins AC, Lazarova Z, Janson MM et al. Pemphigus vulgaris presenting in a radiation portal. J Am Acad Dermatol 2007; 56: S82–5.

Hogan P. Pemphigus vulgaris following a cutaneous thermal burn. Int J Dermatol 1992; 31: 46–9.

Tan SR, McDermott MR, Castillo CJ et al. Pemphigus vulgaris induced by electrical injury. Cutis 2006; 77: 161–5.

Ruocco V, Brenner S, Ruocco E. Pemphigus and diet: does a link exist? Int J Dermatol 2001; 40: 161–3.

Memar OM, Rady PL, Goldblum RM et al. Human herpesvirus 8 DNA sequences in blistering skin from patients with pemphigus. Arch Dermatol 1997; 133: 1247–51

Korman NJ, Eyre RW, Zone J et al. Drug-induced pemphigus: autoantibodies directed against the pemphigus antigen complexes are present in penicillamine and captopril-induced pemphigus. J Invest Dermatol 1991; 96: 273–6.

Brenner S, Bialy-Golan A, Anhalt GJ. Recognition of pemphigus antigens in drug-induced pemphigus vulgaris and pemphigus foliaceus. J Am Acad Dermatol 1997; 36: 919–23.

Nagao K, Tanikawa A, Yamamoto N et al. Decline of anti-desmoglein 1 IgG ELISA scores by withdrawal of D-penicillamine in drug-induced pemphigus foliaceus. Clin Exp Dermatol 2005; 30: 43–5.

Махнева Н.В. Клинико-морфологические и иммунологические аспекты в ранней диагностике и лечении аутоиммунных буллёзных дерматозов 2009 Mocква.286. стр

Uzun S, Durdu M. The specificity and sensitivity of Nikolskiy sign in the diagnosis of pemphigus. J Am Acad Dermatol 2006;54:411-5.   

Hameed A, Khan AA. Microscopic Nikolsky's sign. Clin Exp Dermatol 1999;24:312-4

Channual J, Wu JJ. The Nikolskiy sign. Arch Dermatol 2008;144:1140.

Grando SA, Grando AA, Glukhenky BT, Doguzov V, Nguyen VT, Holubar K. History and clinical significance of mechanical symptoms in blistering dermatoses: A reappraisal. J Am Acad Dermatol 2003;48:86-92.

Sachdev D. Sign of Nikolskiy and related signs. Indian J Dermatol Venereol Leprol 2003;69:243-4.

Barr RJ. Cutaneous cytology. J Am Acad Dermatol 1984;10:163-80

Kelly B, Shimoni T. Reintroducing the Tzanck smear. Am J Clin Dermatol 2009;10:141-52

Ruocco E, Brunetti G, Del Vecchio M, Ruocco V. The practical use of cytology for diagnosis in dermatology. J Eur Acad Dermatol Venereol 2011;25:125-9.   

Barr RJ. Cutaneous cytology. J Am Acad Dermatol 1984;10:163-80

Durdu M, Seçkin D, Baba M. The Tzanck smear test: Rediscovery of a practical diagnostic tool. Skinmed 2011;9:23-32.

Durdu M, Baba M, Seçkin D. The value of Tzanck smear test in diagnosis of erosive, vesicular, bullous, and pustular skin lesions. J Am Acad Dermatol 2008;59:958-64

Baican Corina, Baican A, Rogojan L, Ciuce D, Samasca G, Macovei V, Perta A, Maier N, Sitaru C. The sensitivity of clinical, histologic and immunologic findings for the diagnosis of autoimmune bullous disease. Dermatovenerologie 2011;56:11-19

J.V. Otten, T. Hashimoto, M. Hertl, A.S. Payne, C. Sitaru. Molecular Diagnosis in Autoimmune Skin Blistering Conditions. Curr Mol Med. 2014 Jan; 14(1): 69–95.

Yehuda Shoenfeld, Ricard Cervera, M.Eric Gershwin Diagnostic criteria in Autoimmune diseases 2008