Itraepidermal Autoimmune Bullous Dermatoses

State Medical And Pharmaceutical University.

“Nicolae Testemițanu”

Chisinau, Republic of Moldova.

General Medicine II.

Date:01/02/2016

Itraepidermal autoimmune bullous dermatoses: princeple 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 Dermatovenerology.

ABBREVIATIONS

DSG – desmoglein

IIF – Indirect immunofluorescence

CONTENTS

Introduction………………………………………….6

Aim of the Thesis…………………………………….8

Objectives……………………………….….……….8

Epidemiology……………………………….….……9

Trigger Factors……………………………….……..11

Genetic Epidemiology……………..………….11

Trauma………………………….………….….14

Infection……………….……………………..14

Pathogenesis…………………………………………….22

Immunupathogenesis……………………………..22

The Ying and Yang of cellular interaction…..23

Molecular Pathways of Inflammation………..27

Role of genetic factors………………………..31

Clinical Features…………………………….……….34

Treatment………………………………..………..…35

Subjects and Methods…………………..……..……44

Presumptive Conclusion……………………….……46

Conclusion……………………….………….…..….46

Acknowledgment…………….……………………..46

Reference ………………………………….………47

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 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 2: MATERIALS AND METHODS

In the process of my study, I have assessed and reviewed various books and 47 articles regarding autimmune bullous dermatoses. And various cross sectional studies have been done to evaluate the clinical and morphological features of autoimmune bullous dermatoses. Also were estimated a role and value of various laboratory tests in diagnostics of 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 3 LITERATURE REVIEW

3.1. 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)

Pemphigus erythematosus (Senear–Usher Syndrome)

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.

3.1.1 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].

3.1.2. 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.

3.1.3. 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.

3.1.4. 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.

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]

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]

3.1.5. 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. Flexural oozing and verrucous plaques may resembling pemphigus vegetans.

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]

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.

3.2. Subepidermal immunobullous diseases