Republic of Iraq

Ministry of Higher Education

& Scientific Research
Mustansiriyah University
College of Dentistry

Pemphigus Vulgaris : review of literature

A Project Submitted to The College of Dentistry, Mustansiriyah University,

Department of oral pathology in Partial Fulfillment for the Bachelor Degree in
Dental Surgery

By
Nour Jan Kamel Abdel Kazem

Supervisor by
(Assist. Lec. Abeer salah salman)
B.D.S., M.Sc. (oral Pathology)

2024A.D 1445A.H
Supervisor Certification

I certify that this project was prepared by the fifth year student Nour Jan Kamel Abdel Kazem
under my supervision at College of Dentistry, Mustansiriyah University in Partial fulfillment
of graduation requirements for the Bachelor Degree in Dentistry

Signature:
Name of the supervisor: Assist. Lec. Abeer salah salman
Supervisor degree: B.D.S., M.Sc. in Oral pathology

Date: 2024
 Dedication

I dedicate the fruits of my efforts to my father, who did not spare anything. He had
the first credit after God in bringing me to this stage. I dedicate it to the kind person
in my life, who enlightened my path with her advice, gave me the strength and
determination to continue on my path, and was the reason for me to continue my
studies, to the one who taught me patience and diligence, to (my dear mother), and I
dedicate it to my family and teachers.
 Acknowledgement

Primarily I would like to thank the supreme power the Almighty God for everything
in my life, for being able to complete this project with success.

I would like to extend my sincere thanks to the Dean of the College of Dentistry. Al-
Mustansiriya University, Prof. Dr. Maha Jamal Abbas Al-Ani .

Many thanks are expressed for the help. Assist. Prof. Dr. Atheer Talib Head of
the Oral Pathology Department, gave me the opportunity to do this project.

Special thanks, gratitude and sincere appreciation to my supervisor Assist. Lec.

Abeer salah salman for her support and advice to completing this project .

Finally, I would like to express grateful thanks to the reason of success, to my loving
and caring family, my parents, my brothers and my sister for their encouragement
and support.

I.
 List of Contents

Subjects Page No.

Acknowledgement I
List of Contents II
List of Figures III
List of Abbreviations IV
Introduction 1
Chapter One: Review of literature 2
1.1 Epithelium 3
1.1.1 Oral epithelium 4
1.1.2 Cutaneous 5
1.2 Pemphigus Diseases 5
1.3 Pemphigus vulgaris 5
1.4 Epidemiology 5
1.5 Pathogenesis 6
1.5.1 Autoantibodies 6
1.5.2 Desmogleins 6
1.5.3 Desmosomal (non-desmoglein)targets. 6
1.6. Clinical features 7
1.6.1. Oral Pemphigus vulgaris 7
1.6.2. Cutaneous Pemphigus vulgaris 8
1.6.3. Ocular Pemphigus vulgaris 10
1.7. Clinical Examination 10
1.8. Laboratory diagnostic 11
1.8.1. Histopathological features 11
1.8.2. Immunofluorescence examination 12
1.9. Treatment 14
Chapter Two: Discussion 17
Chapter Three: conclusion and suggestion 19
References 20
 List of Figures

Figure Figure title Page

No. No.
1 The details of the cell layers of the 4
epithelium
2 Oral pemphigus vulgaris 8
3 Cutaneous pemphigus vulgaris 9
4 Moderate conjunctivitis of the right eye 10

5 Histopathological picture of pemphigus 11

vulgaris (10X)
6 Histopathological picture of pemphigus 12
vulgaris (40X)
7 Direct immunofluorescence of pemphigus 13
vulgaris (PV
 III
List of Abbreviations

Abbreviation Description
PV Pemphigus vulgaris
IgGs Immunoglobulins antibody
DSG1 Desmoglein1
DSG3 Desmoglein3
TJ Tight junction
PF Pemphigus foliaceus
DSC Desmocollin
DIF Direct Immunofluorescence
IDIF In Direct Immunofluorescence test
PG Plakoglobin
 IV

Introduction
Phemphigus illnesses are a collection of uncommon autoimmune bullous disorders that affect the skin and
mucous membranes. In central Europe, their annual incidence is estimated to be two new cases per million
inhabitants (Sivapathasundharam, 2016). They display chronic evolution, with significant morbidity and
death, and an important decrease in quality of life. They are caused by the development of pathogenic
autoantibodies (typically IgGs) directed against various desmosome proteins (desmogleins). The binding of
these autoantibodies to desmosome components disrupts intraepidermal adhesion, resulting in acantholysis and
the production of vesicles, blisters, and erosions on the skin and/or mucous membranes(Di Lernia et al.,
2020). Various forms of pemphigus have been recognised based on clinical and histological characteristics, as
well as the specific antigens against which autoantibodies are generated. The major forms are pemphigus
vulgaris (PV) and pemphigus foliaceus (PF), however in recent decades non- classical variants of pemphigus
have also been described: paraneoplastic pemphigus, pemphigus herpetiformis, and IgA pemphigus (Weinberg
et al., 1997, Davenport et al., 2001). Autoantibodies against desmosome components have long been
thought to be the primary cause of pemphigus pathogenesis. In addition to the significance of humoral
immunity, cellular immunity has been highlighted in the research.
PV is the most common clinical form of pemphigus, accounting for over 70% of patients; it is also the most
severe form of the disease (Gnepp and Bishop, 2020).

Aims of the study

1. To gain a better understanding of pemphigus vulgaris, its prevalence in both men and women, and the
most common place of occurrence.

2. To learn how to treat pemphigus vulgaris .

1
 Chapter One
Review of literature
Pemphigus vulgaris (PV)

1.1 Epithelium

The human body consists of four main components epithelial, connective, muscle and nervous tissue.
The epithelium is an avascular tissue that produces glands, secretory parts, and ducts. It is created from the
three embryonic germ layers: ectoderm, mesoderm and endoderm. It covers the external and internal surfaces of
the human body (Eurell and Frappier, 2013) .All human body epithelium is supported by underlying fibrous
connective tissue (Locke and Harris, 2009). It classified into several shapes based on the shape of the cells in
the surface layer into three types: squamous, cuboidal, and columnar. The outer surface cells may show certain
characteristics such as cilia and keratinization, which can be used to classify the epithelium (Pawlina and Ross,
2018). The functions of the epithelium are as follows:

1. Secretion: Epithelial cells located in specific locations in the human body, such as the digestive system,
vagina, salivary gland and skin, are specialized in secreting a group of chemical compounds such as sweat,
mucus, and enzymes (Carols Junqueira and Kelly, 2020).
2. Absorption: The lining epithelium found in a variety of internal organs, such as the kidneys, liver, and
digestive system, has the ability to absorb various substances and transport them to the underlying tissues
(Gartner, 2020).
3. Sensory: The sensory receptors of epithelium located in different parts of the human body such as the
tongue, ear, nasal cavity, eye, and skin receives and senses different external influence (Ovalle and Nahirney,
2020).
4. Protection: The epithelium protects the skin, oral cavity, respiratory system, digestive system, and
various tissues in the human body from harmful external influences such as chemical agents, microbial attacks,
and physical stress (Gunasegaran, 2020).

3
 1.1.1 Oral epithelium

The oral mucosa is made up of stratified squamous epithelium supported by the basement membrane and
connective tissue.
The oral epithelium is divided based on the presence of keratin into keratinizing and non-keratinizing
stratified squamous epithelium (Winning and Townsend, 2000). Keratinized epithelium is found in
areas exposed to mechanical activities during chewing, such as the palate and lip, while the floor of the
mouth and buccal mucosa, are lined by epithelium that has not been keratinized (Hand and Frank,
2014). The dorsum of the tongue contains keratinized and non-keratinized epithelium (Squier and
Kremer, 2001). The oral epithelium consists of three to four layers (Figure 1):
The basal layer, which lies above the basement membrane. Stratum spinosum. Which consists of larger
cells with a spiky look. The granular layer consists of cells with basal granules. A superficiallayer known
as the keratinocyte layer contains flat cells with a thick plasma membrane and a large accumulation of
keratin filaments (Markopoulos, 2010). The main function of the oral epithelium is to protect the
underlying layer Tissues from external aggressions such as bacterial toxins, toxic enzymes, and
carcinogens (Cruchley and Bergmeier, 2018).

Figure1: The details of the cell layers of the epithelium(Kumar, 2014).

4
1.1.2 Cutaneous
The cutaneous layer consists of the epithelium (epidermis), dermis (underlying connective tissue), and
appendages (hair, nails, and glands). (Kantakis, 2002).
Epithelial cells are called keratinocytes because they contribute to the production of keratin (Cropley,
2001).The main functions of the skin include sensitivity, thermoregulation, and a protective barrier
(Sahel et al., 2015) .

1.2 Pemphigus Diseases

Pemphigus is a group of chronic autoimmune diseases Characterized by a damage of epithelial cell adhesion,
which leads to formation of blisters and ulcers within the epithelial cell layer of the skinand the mucous
membrane ( Schmidt and Zillikens, 2013, Hsu et al.,2016, Kridin et al., 2017).

1.3 Pemphigus vulgaris

Pemphigus vulgaris is a severe form of pemphigus that disrupts

keratinocyte adhesion and causes blisters on the skin or mucosa. PV's immunological mechanism
involves producing autoantibodies against epithelial cell adhesion antigens in the cutaneous and mucosal
membranes (Bystryn and Rudolph, 2005; Sánchez-Pérez and García-Díez, 2005; Ingold and Khan,
2021).

1.4 Epidemiology
PV is the most common form of pemphigus (kridin et.al. , 2017). It mainly affects adults aged 50 to 60
. The global incidence of PV varies by area and ranges from 0.07 to 1.6 per 100,000 people (Bystryn
and Rudolph, 2005) but it was significantly higher in the Jewish-American population (Didona et al. ,
2019) . According to most epidemiological studies, PV frequency in females is higher than in males (
Brenner and Wohl, 2007,), however, some studies found that the male showed PV lesions more than
females (Alcaide-Martín et al., 2010).
5
1.5 Pathogenesis
1.5.1 Autoantibodies
The IgG autoantibodies is associated with the progression of the disease. It causes epithelium
breakages (Gnepp and Bishop, 2020). IgG4 predominates during the acute phase, while IgG1 is
associated with remission. IgM and IgE were found to be implicated in the aetiology of PV (Nagel et
al., 2010, Pan et al., 2011, Tsunoda et al., 2011).

1.5.2 Desmogleins

Epithelium forms blisters when autoantibodies target Desmoglein1(DSG1) and Desmoglein3

(DSG3) proteins (Lazarova and Anhalt, 2003). Acantholysis is caused by autoantibodies binding to
desmogleins, however the specific process is unclear. The established hypotheses to explain acantholysis are that
cell adhesion is reduced by transmembrane signalling, direct interference with adhesion (steric hindrance), and
proteinase activation (Pan et al., 2011, Caldelari et al., 2001) .Desmogleins' extracellular domains contain five
ECs (EC1-5). The EC1 and EC2 domains include adhesive contact units, and pemphigus autoantibodies typically
target them (Boggon et al., 2002; Harrison et al., 2016).
1.5.3 Desmosomal (non-desmoglein)targets.
Researchers observed that deletion of the DSC 3 (Desmocollin) gene can result in PV-like lesions in mice. This
finding suggests that autoantibodies targeting DSC1(Desmocollin) may play an important role in PV
pathomechanism (Chen et al. 2008).
Autoantibodies to DSC are identified in less than 10% of PV cases. Further research is needed to determine the
relationship between the DSC(Desmocollin) and PV (Ishii et al., 2015; Mindorf et al., 2017). PG is
demonstrated to be targeted by antibodies in PV, resulting in dissociation from DSG. This is corroborated by
immunohistochemistry (IHC) studies in PV, which found that PG(Plakoglobin) staining was moved towards the
nucleus in compared to healthy controls.PG reduction reduces desmosome junction disorganisation associated
with c-myc and p38 MAPK accumulation due to loss of PG suppression action, which is thought to lead to
keratinocyte deadhesion (Bierkamp et al.,1999; Williamson et al., 2006; Egu et al., 2017).
6
1.6. Clinical features:
Pemphigus vulgaris lesions could arise in the mucosal membrane or on the skin. Almost all PV patients
develop oral mucosal lesions (Wojnarowska and Venning, 2010). In half of patients, oral involvement
was linked to lesions in cutaneous, nasal, anus, and ocular mucous membranes ( España et al., 2007;
Khezri et al., 2013; Harman et al., 2017). Cutaneous and other mucous membrane lesions develop
simultaneously or after oral lesions by days, weeks, or months (Baum et al., 2014).

1.6.1. Oral Pemphigus vulgaris

Pemphigus vulgaris can form anywhere in the oral cavity, with the most common sites being the buccal
mucosa, tongue, and gingiva (Mignogna et al., 2001). PV oral lesions begin with numerous vesicles
filled with clear fluid and may present with erythematous hallo. The oral blisters have a thin roof, making
them fragile and prone to rupture before they reach a large size. As a result, an unbroken blister at the
time of diagnosis is unusual (Shamim et al., 2008; Scully and Mignogna, 2008). When the vesicles
break out, they turn into ulcers and erosions with an uneven boundary. The ulcer may spread
peripherally, with phases of healing and recurrence (Mustafa et al., 2015).
Patients with oral PV experience discomfort ranging from mild to severe, causing difficulty
eating (Lagha et al., 2005).

7
 Figure2: Oral pemphigus vulgaris (Gupta et al., 2018)

1.6.2. Cutaneous Pemphigus vulgaris

PV cutaneous lesions can arise concurrently with oral lesions or after weeks or months. Lesions are either
localised or generalised, and they can appear anywhere on the skin. PV lesions are most commonly found
on the face, scalp, flexures, palms, soles, trunk, axilla, and inguinal region (Venugopal and Murrell,
2011, Porro et al., 2019). The cutaneous lesions begin as fragile blisters on normal or erythematous skin.
The skin blister was mostly filled with clear fluid, but pus or blood have also been reported in certain
cases. Skin lesions, like those in the oral cavity, are prone to rapture, but the blister has a longer life due
to the highly keratinized epidermis. When blisters rupture, they generate seeping or bleeding erosions or
ulcers that are later covered by a crust (Browning, 2018). The erosions' healing activity is restricted or
absent, and if it occurs, the erosion transforms into an excessively pigmented zone with no visible scar
(Melchionda and Harman, 2019).

Figure 3: Cutaneous pemphigus vulgaris

8
1.6.3. Ocular Pemphigus vulgaris

ocular involvement occurs in less than one-third of PV patients and often coincides with oral
lesions(Bhol et al., 2000). The symptoms of ocular PV vary by case, including conjunctivitis, bulbar and
palpebral conjunctiva erosion, and symblepharon. ( España et al. 2017) reported disturbances in visual
activity and photophobia.

Figure 4: Moderate conjunctivitis of the right eye

(Akhyani et al., 2014).

1.7. Clinical Examination.

Nikolsky signs are one of the clinical techniques used to diagnose PV. This technique is thought to share
clinical characteristics with pemphigus, staphylococcal scalded skin syndrome, and toxic epidermal
necrolysis (Sachdev, 2003). Nikolsky's signs involve exerting firm sliding pressure with a thumb or
finger to the afflicted epithelium. This causes the upper layers of epidermis to separate from the lower
layers. Physicians must examine two variations of the Nikolsky sign (I, II) to identify whether they are
positive in PV patients (Kneisel and Hertl, 2011, Maity et al., 2020). To validate the direct Nikolsky
sign (I), apply light pressure to normal- looking skin or mucosa. A positive test results in the formation of
a blister (van Gijn and Gijselhart, 2011, Endo et al., 2018). The indirect Nikolsky sign (II) assesses
the ability to split the epithelium through gentle pressure on an intact blister. Positive results occur
when the blister expands beyond its original size due to fluid spreading under the perilesional epithelium
away from the location of pressure (Bolognia et al., 2014, Bagchi et al., 2019).

10
1.8. Laboratory diagnostic

1.8.1. Histopathological features

The blister must remain intact to validate the PV diagnosis. Because blisters rupture rapidly and readily,
the intact blister should be excised within 24 hours after its formation, or a new blister should be formed
by placing slight pressure on the normal seeming surface in contact with the previously produced ulcer
(Di Lernia et al., 2020). The microscopic image of an undamaged PV blister should show clefts inside
the epithelial layer, immediately above the basal cell layer (Femiano et al., 2002; Venugopal and
Murrell, 2011, Kilic, 2018). The epithelium's gap could be filled with clear fluid, a few inflammatory
cells, and a few epithelial cell sheets (Gnepp and Bishop, 2020). The basal cell layer remains intact
when the cells lose their later connection, while the hemidesmosomes maintain the basal cell's integrity.
The connective tissue exhibits signs of inflammation, such as increased vascularity and inflammatory cell
infiltration. In general, the inflammatory reactions range from mild to moderate (Sivapathasundharam,
2016).

Figure 5 : Histopathological picture of pemphigus vulgaris (10X) (Gnepp and Bishop, 2020)

11
 Figure 6: Histopathological picture of pemphigus vulgaris (40X)
(Gnepp and Bishop, 2020)

1.8.2. Immunofluorescence examination

Direct Immunofluorescence (DIF) is a one-step process that involves applying

fluorescently tagged antibodies to an epithelium sample (Porro et al., 2019). This test
assesses the presence of immunoreactants in the patient's tissues. DIF testing should be
utilised to confirm the diagnosis of PV (Popescu et al., 2019). Direct
immunofluorescence imaging of PV Reveals intercellular attachment of IgG and/or C3
inside the epithelial layers, with a fluorescent pattern resembling a chicken wire fence or a
honeycomb (Aoki et al., 2010, Neville and Damm, 2015).

12
 Figure 7: Direct immunofluorescence of pemphigus vulgaris (PV)

The indirect immunofluorescence test (IDIF) detects the presence of circulating antibodies in serum
(Chhabra et al., 2012). This procedure includes placing a patient serum with PV on a slide loaded with a
mucosal structure, often a monkey esophagus (Sezin et al., 2014). In the mucosa, autoantibodies attack
the target antigen. Fluorescent antihuman immunoglobulin was then added to the slide, interacting with
its targets (autoantibodies) and producing a fluorescent image. Intercellular compounds in PV patients
can be recognised using a fluorescent microscope. Positive results for anti-epithelial IgG class antibodies
range from 75% to 100% in PV patients (Porro et al., 2019). Pathogenic Abs in serum are debatable in
terms of their significance, as well as their relationship to illness severity and response to therapy
(Kridin and Bergman, 2018). Depicted the stages for both direct and indirect
immunofluorescent methods.

13
1.9. Treatment

Untreated, Pemphigus vulgaris can lead to fatality rates ranging from 60 to 90%. Sepsis, electrolyte or
water imbalances, poor temperature regulation, and heart or renal failure are all possible complications
(Bystryn and Rudolph, 2005). Systemic corticosteroids and adjuvant therapies have reduced the
mortality rate of PV patients to approximately 10%. The major goal of treatment in PV patients is to
suppress the immune system and prevent pathogen development. Clinically, a considerable drop in
pathogens in patients' skin and serum indicates the termination of fresh vesicle formation and the
preservation of remission (Kridin, 2018). Pemphigus vulgaris management consists of four phases:
illness control, consolidation, remission induction, and remission maintenance (Murrell et al., 2008;
Gregoriou et al., 2015).
1.Disease control (phase one) is the period of time between the start of treatment and when new lesions
cease forming and old lesions begin to heal. At this moment, the consolidation phase begins.
2.The end of the consolidation (phase two) is defined as no new blisters or erosions appearing for at least
14 days and 20% of existing lesions healing. Following consolidation, the remission induction phase will
begin, with physicians aiming to sustain the remission with a gradually lowering therapeutic dose.
3.Pemphigus vulgaris patients (phase three) are considered to be in complete remission if they have not
developed a new lesion while receiving a minimum dose of medication for at least 60 days.
4.Off-therapy remission (phase 4) is defined as the absence of new lesions for 60 days after stopping all
therapies.
There are no standardised guidelines for treating PV patients. Systemic corticosteroids are crucial for
achieving and maintaining remission. Adjuvant medicines have slow onset than corticosteroids and are
mostly used to sustain remission. Adjuvant medications are widely used in conjunction with
corticosteroids to boost effectiveness while decreasing maintenance corticosteroid dosage, resulting in
corticosteroid side effects (Yeh et al., 2005; Hertl et al., 2015).
Treat with systemic corticosteroids, with or without other immunosuppressive therapies (eg, rituximab),
IV immune globulin, or plasma exchange. Systemic corticotherapy is necessary in the treatment of PV,
the starting dose is 1-2 mg/kg/day. Corticoid decrease must begin after complete cutaneous remission
and 1-2 weeks of no new lesions. The dose is reduced by 10mg/week until 30mg/day is attained, after
which the reduction should be 5-10 mg/month, resulting in a dose of 10 mg/day. Withdrawal from this
dose occurs at a rate of 2.5 mg every 1-2 months, depending on the disease's clinical course. After one
year of modest daily doses on alternate days, treatment may be discontinued if no new lesions appear.
The medications mentioned above are only a small portion of the options for PV control that are now
available. The more important solutions have been described in terms of their ease of use and
accessibility in our country; nevertheless, in the not too distant future, we hope to be able to provide
photodynamic therapy and specialised plasmapheresis, among other therapeutic possibilities.

15
Chapter two
Discussion
Discussion:
Pemphigus vulgaris is a mucocutaneous disorder that impacts both the mucous membrane
and the skin. PV diagnosis is based on both clinical and lesion biopsy examinations. Most
PV lesions begin in the lining of the oral cavity. About half of patients with pemphigus
vulgaris have only oral lesions. Use Nikolsky and Asboe-Hansen signs to help clinically
differentiate pemphigus vulgaris from other bullous disorders. Confirm the diagnosis by
immunofluorescence testing of skin samples.
 17

Chapter Three
Conclusions and Suggestions
In conclusion, managing pemphigus vulgaris requires a comprehensive approach that involves
collaboration between healthcare providers, including dermatologists, immunologists, and dentists. The
primary goal of treatment is to control the disease activity, prevent flare-ups, and minimize
complications .

Suggestions for individuals with pemphigus vulgaris include:

1. Strict adherence to prescribed medications, including corticosteroids, immunosuppressants, and other

medications as advised by healthcare providers.
2. Regular monitoring and follow-up appointments with healthcare providers to assess disease activity
and adjust treatment as needed.
3. Practice good oral hygiene, including using a soft-bristled toothbrush and gentle toothpaste to prevent
irritation and injuries to the mouth.
4. Manage stress levels through relaxation techniques, mindfulness, and other stress-reduction strategies
to help prevent flare-ups.
5. Monitor for signs of infection, such as fever, redness, swelling, or increased pain, and seek medical
attention promptly if any occur.

By implementing these suggestions and working closely with healthcare providers, individuals with
pemphigus vulgaris can better manage their condition and improve their quality of life.
 19

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