State Medical And Pharmaceutical University.

Nicolae Testemianu
Chisinau, Republic of Moldova.

Intraepidermal
autoimmune bullous
dermatoses:
principles of
diagnosis.
Husein Abu Eid
medicine faculty nr.2 - gr.1041
Dr. Vladislav GOGU, Chairman
MD, PhD, Associate Professor
Department of Dermatovenereology
 Background
Intraepidermal autoimmune bullous dermatoses
(pemphigus family) include a group of skin diseases which
are characterized by the presence of bullae or vesicles
and are caused by autoantibodies that are directed
against desmosomal structural proteins. [1]
The majority intraepidemal autoimmune bullous
dermatoses are associated with various severe damages
of organs and systems which can lead to serious
complications and even death of patients. [2]
Clinical common features between the majority types of
pemphigus, not always convincing results of Nikolsky`s
sign, limited access to special laboratory examinations
which allow to confirm the preliminary diagnosis.

1. Kelly M. Bickle, Tom R. Roark. Autoimmune Bullous Dermatoses: A Review Am Fam

Physician. 2002 May 1;65(9):1861-1871.
2. Patrcio P, Ferreira C, Gomes MM, Filipe P. Autoimmune bullous dermatoses: a review. Ann N Y Acad Sci. 2009
Sep;1173:203210.
 Aim

To improve the diagnosing of

intraepidermal autoimmune bullous
dermatoses step by step, by means
of systematization of all available
methods.
 Objectives
To study clinical and morphological features of
intraepidermal autoimmune dermatoss, 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 dermatoss.
To define stage-by-stage algorithm of the early
diagnostics of autoimmune bullous dermatoss.
Material and research methods
In the process of my study, I have assessed and
reviewed 86 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 dermatoss. I have
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.
 PERSONAL
RESULTS AND DISCUSSION
 The diagnosis of
pemphigus is based on four criteria
1. Clinical presentation (see Clinical Examination)
2. Histopathology
3. Direct immunouorescence microscopy (DIF) of
perilesional skin
4. Serological detection of serum autoantibodies
against epithelial cell surface by indirect
immunouorescence microscopy (IIF) and/or
enzyme-linked immunosorbent assay(ELISA)
 Clinical features of autoimmune dermatoss, at a
modern stage.
Disease Patients Cutaneous Mucosal Lesions Itching Prognosis
distribution involvement
Pemphigus Middle age Scalp, face, Always Flaccid blisters, uncharacteristic Variable, may
Vulgaris exures, oropharynx, erosions, Remit
may be conjunctiva, exural
generalized genital vegetations
Pemphigus Middle age Flexural Oral Vesicles, pustules, uncharacteristic Variable, may
vegetans erosions, vegetating Remit
plaques
Pemphigus Middle age Scalp, face, None Scaly papules, uncharacteristic Benign but
foliaceus chest, crusted Chronic
upper back, erosions,
rarely erythroderma
generalized
seborrhoeic
Endemic Children Head, neck, Uncommon Flaccid blisters, uncharacteristic Chronic
pemphigus young generalized erosions, verrucous mortality
foliaceus adults lesions, <10%
erythroderma
Pemphigus Uncommon moderate or severe Chronic
herpetiformis itching is characteristic indolent
IgA pemphigus Adults, Axillae, groins, Flaccid pustules itching is characteristic Chronic
Children face, annular in half of cases indolent
scalp, proximal or circinate
limbs conguration
Paraneo- Adults, Upper body, Severe Polymorphous, uncharacteristic Very poor
plastic Children palmoplantar mucositis bullae,
pemphigus erosions, target
lesions
 The distribution of different types of intraepidermal
autoimmune bullous dermatoses (pemphigus groop)
betheen 164 pacients

1%6%
13%

2%
4%

74%
Pemphigus vulgaris Pemphigus vegetans
Pemphigus foliaceus Pemphigus erythematosus
Pemphigus herpetiformis Paraneoplasic pemphigus

Machneva N. V. clinico-morphological and immunological aspects in early diagnostics and

treatment of an autoimmune bullous dermatoses of 2009 Moscow.286.
Pemphigus vulgaris
Pemphigus vegetans
Pemphigus foliaceus
Pemphigus eritematosus
Pemphigus herpetiformis
 IgA pemphigus

intraepidermal neutrophilic subcorneal pustular

type (IEN-type) dermatosistype (SPD-type)
Pemphigus paraneoplastic
Erythema
multiforme like
Bullous
pemphigoid like
Pemphigus
(vulgaris,
vegetans,
foliaceus -like
Graft-vs.-host
disease-like
Lichen planus
(bullous tipe)
like
Cicatricial
pemphigoid
like
Ig-A dermatite -
like
The sensitivity of clinical and histological findings for the
diagnosis of autoimmune bullous disease

Pacients Patients with Patients with

with bullous dermatitis
pemphigus pephigoid herpetiformis
(n = 70) (n = 59) (n = 12)

The sensitivity of
clinical findings 52,8 50,8 41,6
(%)

The sensitivity of
histological 78 52,5 50
findings (%)

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

Nikolsky Sign : Dislodging of epidermis by lateral finger

pressure in the vicinity of lesions, which leads to an erosion.
Shearing stresses on normal skin can cause new erosions to form
The expressivity of Nicolsky sign in autoimmune
bullous dermatoses.
Pemphigus vulgaris +
Pemphigus vegetans +
Pemphigus folliaceus ++
Pemphigus +++
erythematosus
Pemphigus herpetiformis -
Paraneoplastic +
pemphigus
Drug-indused pemphigus
IgA pemphigus IEN-type) ; SPD-type -
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)
The importance of various laboratory tests in
diagnostic of intraepidermal autoimmune
bullous dermatoss.
 The significance of Tzanck smear test in different types
of autoimune pemphiguses
Pemphigus vulgaris The presense of acantholytic cells (Tzanck cells)
is obligatory
Pemphigus Acantholytic cells (Tzanck cells). eozinophils
vegetans
Pemphgus foliaceus Acantholytic cells from new bullous lesions.
Pemphgus The presense of acantholytic cells (Tzanck cells)
erythematosus is not constant
Pemphigus As a rule acantholytic cells are absent
herpetiformis
Paraneoplastic The presense of acantholytic cells (Tzanck cells)
pemphigus is not constant
Drug- induced The presense of acantholytic cells (Tzanck cells)
pemphigus is not constant
IgA pemphigus Single acantholytic cells, neutroophils,
eozinophils
 The result of pathomorphological examination
in different types of autoimmune pemphiguses
Pemphigus vulgaris Acantholysis. Suprabazal blisters
Pemphigus vegetans Acantholysis. Suprabazal blisters. canthosis, infiltrate with
neutrophils/eoznophils
Pemphgus foliaceus Acantholysis.. Bullae in granular layer
Endemic pemphigus foliaceus Acantholysis.. Bullae in granular layer
fago selvagem
Pemphigus herpetiformis Eozinophilic spongiosis with minimal/absent acantholysis
Paraneoplastic pemphigus Lichenoid pattern.
In pemphigus-like type - intraepidermal cleavage with acantholysis,
or more rarely
In pemphigoid bullous-like type - subepidermal cleavage
with/without vacuolar degeneration of basal keratinocytes with
moderate mononuclear infiltrate on the basement
membrane.Keratinocyte necrolysis
Drug- induced pemphigus In the begining eozinophilic spongiosis, parakeratosis Lately
associated by acantholysis and suprabazal blisters similar to PV or
PF.
IgA pemphigus
subcorneal pustular dermatosistype (SPD- Sometimes acantholysis. Subcorneal blisters and pustules.
type
intraepidermal neutrophilictype (IEN-type) Sometimes acantholysis. Neutroophilic spongiosis
Pemphigus vulgaris IgA pemphigus
The sensitivity of clinical and histological findings for the
diagnosis of autoimmune bullous disease

Pacients Patients with Patients with

with bullous dermatitis
pemphigus pephigoid herpetiformis
(n = 70) (n = 59) (n = 12)

The sensitivity of
clinical findings 52,8 50,8 41,6
(%)

The sensitivity of
histological 78 52,5 50
findings (%)

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
 The intraepidermal immunobullous diseases:
immunopathology and immunogenetics.
Disease1 Direct IMF Isotype Target antigens Epitopes Location

Pemphigus Intercellular IgG (few IgM, Desmoglein 3, Amino-terminal of Desmosome

Vulgaris IgA) sometimes extracellular
desmoglein 1 domain
desmocollins
Pemphigus Intercellular IgG (few IgM, Desmoglein 3, Desmosome
vegetans IgA) sometimes
desmoglein 1
desmocollins
Pemphigus Intercellular IgG Desmoglein 1, Amino-terminal of Desmosome
foliaceus sometimes extracellular
desmocollins domain
Endemic Intercellular IgG Desmoglein 1, Amino-terminal of Desmosome
pemphigus sometimes extracellular
foliaceus desmocollins domain
Pemphigus Intercellular IgG desmocollin-
herpetiformis 1(Dsc-1)
IgA pemphigus Intercellular IgA desmocollin

Paraneo-plastic Intercellular and IgG Plakins Various Desmosomes, BMZ;

pemphigus subepidermal (desmoplakin, stratied, simple and
envoplakin transitional epithelia
BP230,
periplakin)
 The level of circulate antibodies evaluated
by ELISA in autoimmune bullous diseases
Ab anti Ab anti Ab anti Ab anti Ab anti-
DSG 1 DSG 3 BP 180 BP 230 tisular
transglutami
nase
PF 91.6% 0% - - -

PV with lesions 9% 81.8% - - -

on the oral
mucosa

PV with cutaneo- 68% 89% - - -

mucous lesions

Bullous - - 89.6% 52% -

pemphigoid

Dermatitis - - - - 72.7%
herpetiformis
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.
 Diagnostic criteria for pemphigus vulgaris
(Yehuda Shoenfeld et al 2008)

(Diagnostic criteria in Autoimmune diseases Yehuda Shoenfeld, Ricard

Cervera, M.Eric Gershwin 2008)
Major clinical and laboratory findings in pemphigus group.

pemphigus vulgaris. pemphigus foliaceus

IgA pemphigus paraneoplastic pemphigus

 CONCLUSIONS
1. In spite of the fact that the pemphigus vulgaris remains the
most widespread type among all types of a pemphigus,
sensitivity of clinical and morphological features isn't so
high because several new pemphigus types have been
recently described.
2. Nikolskys sign is a well -known clinical sign classically
associated with the pemphigus group of disorders but also
occurring in other autoimmune dermatologic conditions.
The lack of standardization regarding how exactly to elicit
the sign has limited its usefulness, but it remains an
interesting sign to observe and interpret.
3. Confirmation of the diagnosis of an autoimmune
pemphigus with definition of concrete type is possible only
at complex laboratory research where the direct
immunofluorescence microscopy has paramount value.
4. The algorithm of early diagnostics of autoimmune
pemphigus provides the standardized approach with use of
diagnostic criteria.