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Archives ong>ofong> Oral Sciences & Research

ORAL PEMPHIGUS VULGARIS – REPORT OF A CASE;

REVIEW ON ITS ETIOPATHOGENESIS

Sreeshyla HS * , Usha Hegde * , Vidya GD *

ABSTRACT

Vesiculobullous lesions and ulcerations are manifestations ong>ofong> numerous diseases. Autoimmune blistering conditions are

one such disease entities that produce these manifestations. Pemphigus Vulgaris is an autoimmune blistering disease,

though rare, can cause serious involvement ong>ofong> mucocutaneous tissues and even death. It characteristically involves

ong>oralong> mucosa more than the skin and in most ong>ofong> the ong>caseong>s, the ong>oralong> lesions precede cutaneous lesions. We ong>reportong> a ong>caseong> ong>ofong>

ong>oralong> ong>pemphigusong> ong>vulgarisong> and a brief ong>reviewong> ong>ofong> literature on its etiopathogenesis with emphasis on recent trends.

AOSR 2011;1(4):210-214.

Keywords: Pemphigus, Etiopathogenesis, Desmogleins, Nikolsky’s sign, Suprabasilar split, Tzanck cells.

* Department ong>ofong> Oral Pathology & Microbiology, JSS Dental College & Hospital, Mysore, India.

INTRODUCTION:

Pemphigus includes a group ong>ofong> autoimmune blistering

diseases ong>ofong> the skin and mucous membrane. It is characterized

histologically by intradermal blisters and immunologically

by circulating autoantibodies directed against the cell

surface ong>ofong> keratinocytes. The term Pemphigus is derived

from the Greek word “Pemphix”, meaning Bubble or Blister.

The three primary subsets ong>ofong> ong>pemphigusong> include Pemphigus

Vulgaris(PV), Pemphigus Foliaceous and Paraneoplastic

Pemphigus, with PV being the most common and important

variant. 1 The ong>oralong> lesions precede skin lesions in 50% ong>ofong>

ong>caseong>s. In cutaneous disease, concomitant ong>oralong> lesions are

encountered in 90% ong>ofong> the ong>caseong>s. 2 Pemphigus can be a life

threatening disease and hence its early diagnosis and

treatment is essential. If subtle ong>oralong> lesions ong>ofong> ong>pemphigusong> are

recognized early, treatment can be initiated to prevent

progression ong>ofong> blistering to other mucous membranes and

skin. 3

Fig 1 Large Irregular Area ong>ofong> Ulceration with

Erythematous Margins

CASE REPORT:

A 34 year old female patient presented with history ong>ofong>

ulceration and burning sensation on the left cheek mucosa

since 15 days. On clinical examination, a large irregular

area ong>ofong> ulceration with erythematous margins was seen on

left buccal mucosa. (Fig.1) Lesion on the lower lip showed

superficial eroded erythematous surface on the mucosal

side and the recent rupture ong>ofong> bullae could be appreciated.

(Fig.2) Similar lesions appearing as multiple small irregular

areas ong>ofong> erosion and erythema were seen on the posterior

palate and on dorsum ong>ofong> tongue. Nikolsky’s sign was

positive. No skin lesions were evident.

Histopathological examination revealed presence ong>ofong>

hyperplastic epithelium showing suprabasilar split. (Fig.3)

Fig 2 Superficial Eroded Erythematous Surface on the

Mucosal Side

Fig 3 Photomicrograhic Picture Showing Suprabasilar

Split (Arrow) With Spongiosis

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Oral ong>pemphigusong> ong>vulgarisong>- A ong>caseong> ong>reportong>

Acantholysis ong>ofong> the cells with loss ong>ofong> intercellular

attachment was appreciated. Spongiosis was noted in

the superficial layers ong>ofong> the epithelium. Presence ong>ofong> few

inflammatory cells was seen in the split. Chronic mixed

inflammatory infiltrate was noted in the connective tissue.

Based on the clinical and histopathological findings,

the ong>caseong> was diagnosed as Pemphigus Vulgaris and the

treatment was instituted with regular follow-up.

DISCUSSION:

Pemphigus ong>vulgarisong> is a chronic autoimmune mucocutaneous

disease that frequently appears first in the

ong>oralong> cavity and can progress to involve other sites.

The ong>reportong>ed incidence is 0.1-0.5 ong>caseong>s per 100,000

individuals worldwide per year. Its gender distribution

is generally ong>reportong>ed to be equal but few studies have

shown it to be slightly predominant in women. It

primarily manifests in adults during 5th or 6th decade

ong>ofong> life. Juvenile ong>caseong>s have been ong>reportong>ed, but are

rare. 3-5 It has been documented in all races and ethnic

groups. 3 Increased risk is seen among certain ethnic

groups such as Ashkenzain Jews, in persons ong>ofong>

Mediterranean and South Asian origin. 5,6

Pemphigus ong>vulgarisong> presents as flaccid, thin walled

vesicles and/or bullae, that usually rupture to leave

an area ong>ofong> erosion and ulceration. 3,5 Various mucosal

surfaces such as ong>oralong>, ocular, nasal, pharyngeal, laryngeal,

upper respiratory and anogenital mucous membranes

can be involved. Usually ong>oralong> lesions appear before the

skin lesions and may be more persistent than skin

lesions. 5 The disease shows positive Nikolsky’s sign

but is not specific for PV. 3-7 During active stage ong>ofong>

the lesion, when lateral pressure is applied on the blister

or perilesional skin or normal appearing skin, it results

in removal ong>ofong> upper layer ong>ofong> epidermis known as

Nikolsky's sign. Two types ong>ofong> Nikolsky's sign are

described – wet Nikolsky's sign in which after separation

ong>ofong> epidermis the base ong>ofong> skin is moist, glistening,

and exudative, and the dry Nikolsky's sign, if the

base ong>ofong> eroded skin is relatively dry. Active disease is

readily appreciated by presence ong>ofong> a wet Nikolsky's

sign, while a dry Nikolsky's sign indicates reepithelization

beneath a remnant blister top. The same

phenomenon can be appreciated in the mucous membrane

also. In the biopsy taken after eliciting Nikolsky’s sign

(by applying tangential pressure to a given area), the

histopathological changes at different levels ong>ofong> epithelium

helps in diagnosing the variants ong>ofong> ong>pemphigusong>. If the

changes are seen immediately above the basal layer,

it is PV, and if it is seen anywhere within the epithelial

layers, it is diagnosed as Pemphigus foliaceous. 8

In the present ong>caseong>, although the clinical picture

presented was classic ong>ofong> ong>pemphigusong>, the age ong>ofong> occurrence

was 3rd decade, slightly lower age group than its usual

presentation ong>ofong> 5th-6th decade. The histopathological

findings helped us in arriving at the ong>vulgarisong> variant ong>ofong>

ong>pemphigusong> in this ong>caseong>.

ETIOLOGY AND PATHOGENESIS:

The possible etiological factors that have been proposed

in PV include drugs, diet, viruses, certain autoimmune

disorders such as rheumatoid arthritis, myasthenia gravis,

lupus erythematoses, pernicious anemia, low levels ong>ofong>

smoking, pregnancy and high exposure to pesticides. 4-7

HLA complex may be responsible in part for the

pathogenesis ong>ofong> PV especially in certain ethnic groups. 3,6

Epithelial cells, the keratinocytes are anchored to one

another and to the underlying connective tissue by a

number ong>ofong> adhesive mechanisms. Desmosomes form

the predominant component ong>ofong> interepithelial cell

adhesion. 5 These desmosomes function both as an

adhesive complex and as cell surface attachment site for

the keratin intermediate filaments ong>ofong> the cytoskeleton.

They contain a series ong>ofong> proteins such as desmogleins and

desmocollins - glycoproteins ong>ofong> cadherin supergene

family which link to cytokeratins via desmoplakins and

plakoglobin. 8 Desmogleins forming the desmosomal

component are ong>ofong> different types - desmoglein1 (Dsg1),

desmoglein2 (Dsg2) and desmoglein3 (Dsg3). 8 (Table 1)

Oral epithelial desmosomal components differ somewhat

from those ong>ofong> the skin. While both Dsg1 and Dsg3

are expressed in the skin, only Dsg3 is preferentially

expressed in the ong>oralong> cavity. This has consequences in

terms ong>ofong> disease manifestations as well as antibody

detection. 8

Basic pathology in PV lies in the production ong>ofong>

autoantibodies against desmosomal components resulting

in epithelial cell separation called acantholysis. The

main antigen is Dsg3, but 50% ong>ofong> patients also have

autoantibodies to Dsg1 and the frequency may differ with

race as they are found in significantly greater propotion

ong>ofong> patients ong>ofong> Indian origin than with white Northern

Europeans. 6 The propotion ong>ofong> Dsg1 and Dsg3 antibodies

appear to be related to the clinical severity ong>ofong> PV.

As explained by desmoglein compensation hypothesis,

PV ong>ofong> skin is associated with the simultaneous presence

ong>ofong> anti-Dsg3 and anti-Dsg1, while those with only

Dsg3 antibodies have ong>oralong> lesions predominantly. 3,5,6,10

Thus depending on the type ong>ofong> antigen affected there

are two phenotypes ong>ofong> PV, mucosal-dominant showing

only Dsg3 antibodies and mucocutaneous with both

Dsg1 and Dsg3 antibodies (Table 2). Shift from one

type to other can occur over time. 5,10 The autoantibodies

are ong>ofong> IgG class. In active PV they are predominantly

IgG4 and are IgG1 during remission. 9 Although

complement mainly C3 can act as an antibody causing

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Sreeshyla HS et al.

Chromosomal

location

Table 1. Expression ong>ofong> different chromosomal components 8

Dsg1 Dsg2 Dsg3

18q12.1 18q12.1 18q12.1-q12.2

Gene expression DSG1 DSG2 DSG3

Expression site Suprabasal layers All layers ong>ofong> epithelium and

heart

Table 2. Disease condition and antigen distribution 5

Lower layers ong>ofong> epidermis & high in

stratified squamous epithelium

Disease condition

Mucosal predominant PV

Mucocutaneous type PV

Pemphigus foliaceous

Paraneoplastic ong>pemphigusong>

acantholysis, it is not always pathogenic. However, it may

elicit an influx ong>ofong> PMNs. 3 The classic histologic feature

seen in PV is the acantholysis ong>ofong> epithelial cells with

characteristic suprabasilar split. 1,3,5 Localization ong>ofong> this

split in PV can be explained by the pattern ong>ofong> distribution

ong>ofong> antibodies, the desmoglein compensation hypothesis.

In skin, Dsg1 is expressed largely in the upper levels ong>ofong>

epidermis, where as Dsg3 in lower levels in small amounts

and hence an anti-Dsg1 induces a split below the granular

layer. In ong>oralong> mucosa, Dsg1 is present only at upper levels,

but Dsg3 at all levels ong>ofong> the epithelium and hence, anti-Dsg3

rather than anti-Dsg1 induces the split that is suprabasal

in nature. 10 The precise mechanism underlying acantholysis

is still debated. One ong>ofong> the mechanism suggested

includes activation ong>ofong> proteases. 3,5,8,10,11 (Fig 4) Other

investigations have shown that plasminogen activators

Antigens

High titers ong>ofong> Dsg3

Dsg3, Dsg1, possibly Dsg4

Dsg1

Dsg3, Dsg1, plakoglobin family

and proteolytic enzymes are not essential for acantholysis

and on contrary they support the contention that the

antibodies in PV may cause dysjunction ong>ofong> contiguous

keratinocytes by sterically interfering with intercellular

adhesion mechanism. 2,11 Recent studies have shown

that acantholysis and spongiosis occur due to the loss ong>ofong>

syndecan 1 expression, a heparin sulphate which is present

on the membrane ong>ofong> keratinocytes, which functions in

intercellular adhesion. In spongiosis, desmosomal stretching

occurs prior to cell separation, while in acantholysis, cell

separation occurs without stretching. 12 A new ong>pemphigusong>

antigen, Dsg4, has recently been discovered and implicated

in the pathogenesis ong>ofong> PV. Besides IgG, IgA antibodies

against Dsg3 also have been identified. It is rare however,

to find ong>oralong> lesions in IgA ong>pemphigusong>. 5

Fig 4: Intracellular Mechanism ong>ofong> Acantholysis 5,6,9,10

Binding ong>ofong> PV IgG to Dsg3 ong>ofong> keratinocyte cell surface

Activation ong>ofong> phospholipase C

Increase in inositol 1, 4, 5-triphosphate (IP3) & diacyl glycerol (DAG)

IP3 mediated release ong>ofong> intracellular stores

Activation ong>ofong> Protein kinase C/ Plasminogen

Increased in intracellular calcium

Phosphorylation ong>ofong> Dsg3 by Kinase

Dsg3 dissociates from plakoglobin

Depletion ong>ofong> Dsg3 from desmosomes

Loss ong>ofong> cell cell adhesion

Acantholysis

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Oral ong>pemphigusong> ong>vulgarisong>- A ong>caseong> ong>reportong>

Recent findings that antibodies from PV serum can

induce blisters even in Dsg3 deficient mice has shed

light on the presence ong>ofong> other autoantigens - the

nondesmoglein antigens that could possibly have

a pathological role in PV. Keratinocytes express a

unique cholinergic receptor that binds to both nicotinic

and muscarinic agonists which can act as an antigen.

Newly recognized antigens, α9 acetylcholine receptor

and pemphaxin, a keratinocyte PV autoantigen with

annexin homology are among several acetylcholine

receptor autoantigens in PV. 6,10

Discovery ong>ofong> non-desmoglein antibodies and few

other recent findings such as - binding ong>ofong> PV IgGs

not restricted to desmosomes, production ong>ofong> anti-Dsg

antibodies may follow rather than precede acantholysis,

Dsg1 and Dsg3 antibodies not unique to Pemphigus,

but can be present in the disease free relatives and

healthy subjects and an increase in the titer ong>ofong> the

antibodies seems to follow, rather than precede the

onset ong>ofong> clinical disease, contradicts the original

desmoglien compensation hypothesis. Currently a

multiple hit hypothesis has been proposed. According

to this hypothesis multiple hits by both Dsg and non-

Dsg autoantibodies are required to cause acantholysis

in ong>pemphigusong>. The proposed autoantigens are adhesion

molecules such as- Dsg1, Dsg2, Dsg3, desmocollins,

plakoglobin, collagen XVII/BP180 and the receptor

molecules such as- α3 AChR, α9 AChR, pemphaxin

and other annexins, FcεRIα. More recently,

autoantibodies to envoplakin and/or periplakin have

been detected in some PV patients. 10,13

The classic histologic feature seen in PV is acantholysis

which is the loss ong>ofong> cell to cell contact in the

epithelial cell layers. Development ong>ofong> intercellular

edema within the epithelial layers, dissolution ong>ofong> the

intercellular bridges and the widening ong>ofong> intercellular

spaces, lead to separation between the cells and the

formation ong>ofong> blisters just above the basal cell layer.

Hence, the split is characteristically suprabasilar and

the basal cells remain tightly attached to the basal

lamina producing tombstone appearance. 1,3,5 Presence

ong>ofong> Tzanck cells which are free floating, rounded

acantholytic epithelial cells will be found within the

vesicle. 3 They can be demonstrated cytologically by

Tzanck test. The vesicular fluid and the connective

tissue may show scant inflammatory cell infiltration. 1

Spongiosis and acantholysis ong>ofong> the adjacent epithelium

can occur. 12

Direct immunong>ofong>luroscence (DIF) demonstrates

homogenous epithelial cell surface staining particularly

in the intercellular spaces, with IgG and possibly also

IgA, IgM, C3, C1 properdin and properdin factor B.

Indirect immunong>ofong>luroscenc (IIF) demonstrates the

circulating antibodies. The quantification ong>ofong> serum titers

with IIF is useful to observe disease progression over

time and to evaluate therapeutic interventions. 1,5

Systemic corticosteroids remain the mainstay ong>ofong> the

treatment. However, certain alternative and new drugs

are also available. Monitoring the specificity and titre

ong>ofong> antibodies along with the clinical features may be

useful in determining the degree ong>ofong> immunosuppression

needed. Improving ong>oralong> hygiene, minimizing irritation

ong>ofong> the lesion and local immunosuppressive treatment is

necessary to improve ong>oralong> care ong>ofong> the patient. 3,5,6

Pemphigus is a chronic disease with periods ong>ofong>

exacerbation and remission, even when patients are on

treatment. Thus it becomes opt to define the criterias

that aid in measuring the activity ong>ofong> the disease. It has

been suggested that the activity in ong>pemphigusong> can be

defined by certain criterias such as presence ong>ofong> new

blisters, spontaneous peripheral extension ong>ofong> existing

blisters, positive Nikolsky's sign on lesion, perilesional,

or normal appearing skin, demonstration ong>ofong> circulating

antibodies against cell adhesion molecules and/or

non-desmoglein protein antigen, and presence ong>ofong> IgG

antibodies in epidermis demonstrated by DIF, even in

clinically normal appearing skin. 9

Numerous scoring systems such as PAS (Pemphigus

Activity Score), PAAS (Pemphigus Area and Activity

Score), PDAI (Pemphigus Disease Area Index), ABSIS

(Autoimmune Bullous Skin Disorder Intensity Score)

etc. for assessing the disease activity and therapeutic

response in ong>pemphigusong> have been described in the

literature. An independent scoring system has been

devised for ong>oralong> ong>pemphigusong> by Saraswat et al. This

scoring system considers the site, extent and severity ong>ofong>

the lesion, which is measured by assessing the degree

ong>ofong> discomfort during eating/drinking different food

items. 14

Prognostic variables for ong>pemphigusong> ong>vulgarisong> include

localization ong>ofong> the initial lesions as well as diagnosis

and treatment ong>ofong> ong>oralong> lesions before the onset ong>ofong> skin

disease. 11 Various short term, long term and drug

related complications ong>ofong> the disease include fluid loss,

risk ong>ofong> infection-ocular, respiratory, liver, skin and

urinary tract infections, septicemia, osteoporosis, CNS

toxicity, chemically induced diabetes mellitus, muscle

wasting, gastric ulceration, bleeding etc. 11

CONCLUSION:

Being a serious disease it becomes very important to

diagnose PV at an early stage when it is limited to ong>oralong>

cavity. It requires careful assessment and correlation

ong>ofong> the clinical appearance, histological features and

immunong>ofong>luroscence findings. The role ong>ofong> desmogleins

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Sreeshyla HS et al.

in the pathogenesis ong>ofong> ong>pemphigusong> although well

established, is questionable presently with the recent

findings. It requires further studies to throw light on

the role ong>ofong> non-desmogliens in the pathogenesis

ong>ofong> ong>pemphigusong>, either alone or in association with

desmogliens.

REFERENCES:

1. Rajendran R, Shivapathasundharam. Shafer’s Textbook

ong>ofong> Oral Pathology. 5th edition. Elsevier publications.

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8. Scully C, Bagan JV, Black M et al.

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9. Vaishnani JB, Bosamiya SS. Pemphigus: Active or

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10. Kalish RS. Pemphigus ong>vulgarisong>: the other half ong>ofong>

the story. J. Clinical Invest 2000;106: 1433-1435.

11. Sciubba JJ. Autoimmune aspects ong>ofong> ong>pemphigusong>

ong>vulgarisong> and mucosal pemphigoid. Adv Dent Res

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12. Leena VB, Manjunath GV, Sunila A. Clinicopathological

study ong>ofong> 22 ong>caseong>s ong>ofong> ong>pemphigusong>. J Clinical

Diagnostic Research 2010;4: 2446-2451.

13. Dmochowski M, Nguyen VT. Pemphigus: An unfolding

story. Letters to the editor. J Invest Dermatol 2001;117:

990-995.

14. Grover S. Scoring systems in ong>pemphigusong>. Indian

J Dermatol 2011;56: 145-149.

CORRESPONDENCE :

Dr. Vidya G.D

915, 1st main, 1st cross

I block, R K Nagar, Mysore-22

Ph.No.+91 9036296736

Email – sreeshylahs@gmail.com

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