Pemphigus

Pathogenesis, clinical manifestations, and diagnosis of pemphigus - UpToDate 11/05/22 15:36
Authors: Michael Hertl, MD, Cassian Sitaru, MD

Section Editor: John J Zone, MD
Deputy Editor: Abena O Ofori, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2022. | This topic last updated: Mar 05, 2020.
INTRODUCTION
Pemphigus is defined as a group of life-threatening blistering disorders characterized by

acantholysis (loss of keratinocyte to keratinocyte adhesion) that results in the formation of
intraepithelial blisters in mucous membranes and skin [1]. The process of acantholysis is
induced by the binding of circulating immunoglobulin G (IgG) autoantibodies to
intercellular adhesion molecules [1-3]. Patients with pemphigus develop mucosal erosions
and/or flaccid bullae, erosions, or pustules on skin.
The four major entities of the pemphigus group include pemphigus vulgaris, pemphigus
foliaceus, immunoglobulin A (IgA) pemphigus, and paraneoplastic pemphigus. The
different forms of pemphigus are distinguished by their clinical features, associated
autoantigens, and laboratory findings [4,5].
The pathogenesis, clinical features, and diagnosis of pemphigus will be discussed here. The
management of pemphigus and greater detail on paraneoplastic pemphigus are reviewed
separately. (See "Initial management of pemphigus vulgaris and pemphigus foliaceus" and
"Management of refractory pemphigus vulgaris and pemphigus foliaceus" and
"Paraneoplastic pemphigus".)
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CLASSIFICATION
Common features of the major types of pemphigus are reviewed briefly below. A broader
summary of the clinical and laboratory features of pemphigus is provided in the table (
table 1).
● Pemphigus vulgaris
• Key features – Mucosal or mucosal and cutaneous involvement, suprabasal

acantholytic blisters, autoantibodies against desmoglein 3 or both desmoglein 1
and desmoglein 3
• Clinical variants – Pemphigus vegetans, pemphigus herpetiformis
● Pemphigus foliaceus
• Key features – Cutaneous involvement only, subcorneal acantholytic blisters,

autoantibodies against desmoglein 1
• Clinical variants – Endemic pemphigus foliaceus (fogo selvagem), pemphigus

erythematosus (Senear-Usher syndrome), pemphigus herpetiformis
● Immunoglobulin A (IgA) pemphigus
• Subtypes – Subcorneal pustular dermatosis-type IgA pemphigus (distinct from

classic subcorneal pustular dermatosis [Sneddon-Wilkinson disease]),
intraepidermal neutrophilic IgA dermatosis
• Key features – Grouped vesicles or pustules and erythematous plaques with

crusts, subcorneal or intraepidermal acantholytic blisters, autoantibodies against
desmocollin 1 in subcorneal pustular dermatosis-type IgA pemphigus [6]
● Paraneoplastic pemphigus
• Key features – Extensive, intractable stomatitis and variable cutaneous findings

with multiform exanthems, associated neoplastic disease, suprabasal acantholytic
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blisters, autoantibodies against desmoplakins or other desmosomal antigens (see

"Paraneoplastic pemphigus")
EPIDEMIOLOGY
Pemphigus vulgaris, which represents the most common form of pemphigus, is a rare
disease. Although pemphigus vulgaris occurs worldwide, the frequency is influenced by
geographic location and ethnicity. Incidence rates between 0.1 and 0.5 per 100,000 people
per year have been reported most frequently; however, higher rates have been
documented in certain populations [7]. Individuals with Jewish ancestry (particularly
Ashkenazi Jews) and inhabitants of India, Southeast Europe, and the Middle East have the
greatest risk for pemphigus vulgaris [8].
In most geographic locations, pemphigus vulgaris is more common than pemphigus

foliaceus. However, in certain locations, such as North Africa, Turkey, and South America,
the prevalence of pemphigus foliaceus exceeds pemphigus vulgaris [9]. Endemic
pemphigus foliaceus (fogo selvagem) contributes to the higher rate of pemphigus foliaceus
in some of these countries. In an endemic region in the state of Mato Grosso do Sul in
Brazil, the prevalence of pemphigus foliaceus during the mid-1990s was around 3 percent
[10]. An endemic form of pemphigus vulgaris also has been reported in a small number of
patients residing in an endemic region of pemphigus foliaceus in Brazil [11].
Pemphigus usually occurs in adults, with an average age of onset of 40 to 60 years for
pemphigus vulgaris and nonendemic pemphigus foliaceus [12,13]. Pemphigus is rare in
children, with the exception of endemic pemphigus foliaceus, which frequently affects
children and young adults in endemic areas [14]. Neonatal pemphigus is a rare transient
form of pemphigus that occurs as a consequence of placental transmission of
autoantibodies to the fetus from a mother with the disease. (See 'Neonatal pemphigus'
below.)
Overall, the sex ratio for pemphigus vulgaris and pemphigus foliaceus appears to be
equivalent or close to equivalent [15]. However, a few studies have found large imbalances
in the sex distribution, such as a study that found a 4:1 ratio of females to males with
pemphigus foliaceus in Tunisia [16] and a study that found a 19:1 ratio of males to females
in an endemic location in Colombia [17].
Epidemiologic information on immunoglobulin A (IgA) pemphigus is sparse. The disorder

may occur at any age and may be slightly more common in females [6]. Paraneoplastic
pemphigus is rare. The disorder is most commonly seen in middle-aged adults, but may
also occur in children. (See "Paraneoplastic pemphigus", section on 'Epidemiology'.)
PATHOGENESIS
Overview — Intensive investigations to elucidate the pathogenesis of pemphigus have led

to wide acceptance of the theory that acantholysis induced by the binding of
autoantibodies to epithelial cell surface antigens leads to the clinical manifestations of
pemphigus [2,18,19]. This theory is supported by the consistent detection of intercellular
autoantibodies in perilesional tissue from patients with pemphigus ( picture 1A-B) (see
'Diagnosis' below). Experimental findings that offer further support include the following:
● In vitro studies have demonstrated that immunoglobulin G (IgG) autoantibodies from

patients with pemphigus vulgaris, pemphigus foliaceus, and immunoglobulin A (IgA)
pemphigus are capable of inducing loss of epidermal cohesion [20-23].
● In vivo studies have shown that the passive transfer of IgG autoantibodies from
patients with pemphigus vulgaris into neonatal mice induces blistering and erosions
with histologic, ultrastructural, and immunofluorescence features consistent with
pemphigus [24,25]. The blister-inducing potential of IgG autoantibodies in pemphigus
foliaceus and paraneoplastic pemphigus has been demonstrated in similar in vivo
mouse studies [26-28].
● Removal of pemphigus autoantibodies from serum from patients with pemphigus

vulgaris or pemphigus foliaceus via antigen-specific immunoadsorption prior to
injection into neonatal mice prevents blistering [29,30].
The molecular mechanisms through which binding of autoantibodies to epithelial cells

leads to acantholysis are still intensively debated. Several mechanisms for antibody-
mediated acantholysis have been proposed, including the induction of signal transduction
events that trigger cell separation and the inhibition of adhesive molecule function through
steric hindrance [2,31,32]. In particular, the theory of apoptolysis suggests that acantholysis
results from autoantibody-mediated induction of cellular signals that trigger enzymatic
cascades that lead to structural collapse of cells and cellular shrinkage [33].
Target antigens — Autoantibodies against a variety of epithelial cell surface antigens,

intracellular and transmembranous components of desmosomes, have been identified in
patients with pemphigus.
Pemphigus vulgaris and pemphigus foliaceus — Desmogleins, which are

transmembrane glycoproteins of the cadherin (calcium-dependent cell adhesion molecule)
family, are the antigens that have been most extensively studied in pemphigus vulgaris and
pemphigus foliaceus. Desmogleins are components of desmosomes, integral structures for
cell-to-cell adhesion ( figure 1).
IgG autoantibodies to desmogleins are consistently detected via enzyme-linked

immunosorbent assay (ELISA) in patients with pemphigus, and the expression of these
autoantibodies often correlates with the type of disease [34,35]. IgG autoantibodies against
desmoglein 3 are characteristic of mucosal pemphigus vulgaris, autoantibodies against
desmoglein 1 have been linked to pemphigus foliaceus, and autoantibodies to
desmoglein 1 and desmoglein 3 have been linked to mucocutaneous pemphigus
vulgaris. The amino-terminal portions of desmogleins appear to be the important epitopes
for pathogenicity as evidenced by studies that demonstrate that IgG directed against an
amino-terminal recombinant fraction of desmoglein 3 (EC1-2), but not the carboxy-terminal
portion, induce epithelial blistering when injected into neonatal mice or exposed to
cultured human skin [36,37]. IgG autoantibodies considered to be pathogenic are of the
IgG4 subclass [25,37-39].
In the 1990s, the desmoglein compensation theory was proposed as an explanation for
the observed correlation between the clinical features and autoantibody profiles of
pemphigus vulgaris and pemphigus foliaceus [40]. Although the theory is still widely cited,
subsequent data has raised questions about whether this concept sufficiently explains the
pathogenic mechanism of these diseases [41].
According to the desmoglein compensation theory, the correlation between clinical

findings and ELISA results reflects innate differences in desmoglein expression in the skin
and mucous membranes [40]. In the skin, desmoglein 1 is expressed most intensely in the
upper portions of the epidermis, whereas desmoglein 3 is more strongly expressed in the
basal and parabasal layers. In the mucous membranes, desmoglein 3 is present in
abundance throughout the epithelium. In contrast, the expression of desmoglein 1 is much
lower throughout the mucosal epithelium ( figure 2).
The interpretation of this theory as it relates to the clinical findings in pemphigus is as

follows:
● Patients with only autoantibodies against desmoglein 3 should have mucosal

dominant pemphigus vulgaris because in skin, desmoglein 1 compensates for the
loss of desmoglein 3. In the mucous membranes, the expression of desmoglein 1 is
insufficient for compensation.
● Patients with only autoantibodies against desmoglein 1 should have pemphigus

foliaceus (superficial skin blistering and no mucous membrane involvement) because
autoantibodies against desmoglein 1 result in separation of cells in the superficial
epithelium, but not in the deeper epithelium, where desmoglein 3 compensates well
for desmoglein 1 dysfunction. The mucous membranes are spared due to the high
levels of desmoglein 3 and the relatively low levels of desmoglein 1 expressed in
mucosa.
● Patients with both autoantibodies against desmoglein 1 and 3 should have

mucocutaneous pemphigus vulgaris because dysfunction of both desmoglein 1 and
3 prevents the ability of these glycoproteins to compensate for one another, resulting
in a loss of cell-cell adhesion in both skin and mucous membranes.
However, it is likely that the pathogenesis of pemphigus is more complex than this model
predicts. Discordance between the clinical and serologic profiles (eg, patients with
pemphigus foliaceus who have autoantibodies against desmoglein 3, patients with pure
mucosal pemphigus vulgaris who have autoantibodies against desmoglein 1, and patients
with pemphigus who have neither autoantibodies against desmoglein 1 nor autoantibodies
against desmoglein 3) may occur in about one-third of cases [41,42]. This observation and
the knowledge that the presence of autoantibodies to both desmoglein 1 and desmoglein 3
does not result in complete dissolution of the epithelium suggest that other factors
contribute to the development of these diseases.
Autoantibodies against desmocollin 3 may contribute to pemphigus in some patients. Like

desmogleins, desmocollins are transmembrane glycoproteins found within desmosomes (
figure 1). Desmocollin 3-specific autoantibodies from patients with pemphigus have
induced loss of keratinocyte adhesion ex vivo and in experimental animals [43,44].
Moreover, a subset of patients with clinical features most consistent with pemphigus
herpetiformis or pemphigus vegetans and direct immunofluorescence findings consistent
with pemphigus who have autoantibodies against desmocollin but no autoantibodies
against desmoglein has been identified [45,46].
Additional autoantibodies detected in serum from patients with pemphigus include

autoantibodies against desmoglein 4, the acetylcholine receptor, pemphaxin, and others
[33,47-51]. Whether autoantibodies with any of these molecular specificities are pathogenic
in pemphigus vulgaris or pemphigus foliaceus remains to be determined.
IgA pemphigus — Unlike the other forms of pemphigus, which are characterized by IgG
autoantibodies targeting epithelial cell surface antigens, IgA pemphigus is characterized by
antikeratinocyte cell surface autoantibodies of the IgA class [52]. The target antigen in the
subcorneal pustular dermatosis type of IgA pemphigus is desmocollin 1, a
transmembrane glycoprotein within desmosomes [53-55].
In contrast, the targeted antigens in the intraepidermal neutrophilic dermatosis variant of

IgA pemphigus appear to be more heterogeneous. While autoantibodies against
desmogleins 1 and 3 have been reported in several patients [54,56-58], immunoelectron
microscopy studies suggest that IgA autoantibodies in these patients recognize an
unidentified non-desmosomal transmembranous protein [59]. Thus, a common
autoantigen remains elusive and the mechanism of blister formation in IgA pemphigus is
not fully understood [23].
Paraneoplastic pemphigus — Multiple autoantibodies have been detected in patients
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with paraneoplastic pemphigus. The target antigens for this variant are reviewed
separately. (See "Paraneoplastic pemphigus", section on 'Humoral immunity'.)
Contributing factors — As with many other autoimmune diseases, the precipitating

factors of pemphigus diseases are poorly understood. Both genetic and environmental
factors may influence the development of pemphigus [9].
Genetics — Multiple studies have evaluated the relationship between pemphigus vulgaris
and pemphigus foliaceus with human leukocyte antigen (HLA) class II alleles. Pemphigus
vulgaris is associated with DR4 and DR14, though the susceptibility gene differs dependent
upon ethnic origin. HLA-DRB1 0402 is associated with the disease in Ashkenazi Jews [60,61],
and DRB1 1401/04 and DQB1 0503 are associated pemphigus vulgaris in non-Jewish
patients of European or Asian descent [62-67]. Sporadic and endemic pemphigus foliaceus
are also associated with DR4, DR14, and DR1 alleles [9].
In contrast to pemphigus vulgaris, the association with HLA alleles in pemphigus foliaceus
is less restricted. DRB1 0402, 0403, 0404, 0406, 1401, 1402, 1406, and 0102 subtypes have
been detected at increased frequency in patients with pemphigus foliaceus, while DRB1
0301, 0701, 0801, 1101, 1104, and 1402 are negatively associated with this disease [68-71].
The involvement of genetic factors in susceptibility to pemphigus is further strengthened

by detection of low titers of desmoglein 3-specific autoantibodies in asymptomatic relatives
of patients with both pemphigus vulgaris and foliaceus [11,72]. In addition, a case-control
study found that compared with relatives of healthy controls, first-degree family members
of patients with pemphigus had an increased prevalence of autoimmune diseases [60]. The
findings of one study suggest that pemphigus vulgaris clusters with autoimmune thyroid
disease, rheumatoid arthritis, and type 1 diabetes in patients and their families [73].
Environment — While most cases of pemphigus foliaceus are idiopathic, environmental

factors appear to contribute in the development of endemic pemphigus foliaceus (fogo
selvagem) [47,74]. A black fly (Simulium nigrimanum) or other insects may serve as a vector
for the endemic form of this disease [75].
Ultraviolet radiation has been proposed as an exacerbating factor for pemphigus foliaceus
and pemphigus vulgaris [76-79], and pemphigus has been reported to develop following
burns or cutaneous electrical injury [80]. Viral infections, certain food compounds, ionizing
radiation, and pesticides have been suggested as additional stimuli for this disease [81-86].
Drug exposure — Pemphigus vulgaris and pemphigus foliaceus may be precipitated by

drugs. Thiol drugs, including penicillamine and captopril, are the most common inciting
agents [87]. In one series of 104 patients treated with penicillamine for at least six months,
7 percent developed pemphigus foliaceus [88]. Examples of additional drugs that have
been associated with pemphigus vulgaris or pemphigus foliaceus include penicillins,
cephalosporins, enalapril, rifampin, and nonsteroidal anti-inflammatory agents ( table 2)
[87,89,90].
Drug-induced biochemical and/or immunologic reactions may contribute to the

development of acantholysis in drug-induced pemphigus. Potential mechanisms include
effects on enzymes that mediate keratinocyte aggregation, direct interference through
binding to molecules involved in cell adhesion, and stimulation of neoantigen formation
[89].
Direct immunofluorescence (DIF) and indirect immunofluorescence (IIF) studies are

negative in some patients with drug-induced pemphigus. In a series of six patients with this
disorder, DIF was negative in one patient and IIF was negative in two patients [90]. ELISA
was positive for desmoglein 1 or desmoglein 3 in all patients in this series.
Diet — Dietary factors including garlic, leek, onion, black pepper, red chili pepper, red
wine, and tea have been implicated as inducers of pemphigus vulgaris and pemphigus
foliaceus based on concise case reports. However, the existing evidence does not support a
strong link between diet as an environmental factor and pemphigus [85].
CLINICAL FEATURES
Pemphigus vulgaris — Almost all patients with pemphigus vulgaris develop mucosal
involvement. The oral cavity is the most common site of mucosal lesions and often
represents the initial site of disease [91]. Mucous membranes at other sites are also often
affected, including the conjunctiva, nose, esophagus, vulva, vagina, cervix, and anus [92-
94]. In women with cervical involvement, the histologic findings of pemphigus vulgaris may
be mistaken for cervical dysplasia in Papanicolaou (Pap) smears [95].
Since mucosal blisters erode quickly, erosions are often the only clinical findings (
picture 2A-C). The buccal mucosa and palatine mucosa are the most common sites for
lesion development in the oral cavity [96].
The pain associated with mucosal involvement of pemphigus vulgaris can be severe. Oral
pain is often augmented by chewing and swallowing, which may result in poor
alimentation, weight loss, and malnutrition.
Most patients also develop cutaneous involvement manifesting as flaccid blisters on

normal-appearing or erythematous skin ( picture 3A-B). The blisters rupture easily,
resulting in painful erosions that bleed easily ( picture 3B-D). Pruritus usually is absent.
Although any cutaneous site may be affected, the palms and soles are usually spared. The
Nikolsky sign (induction of blistering via mechanical pressure at the edge of a blister or on
normal skin) often can be elicited [97]. (See "Approach to the patient with cutaneous
blisters", section on 'Nikolsky sign'.)
Rarely, mucous membrane involvement is not observed despite the presence of circulating
autoantibodies to both desmoglein 1 and desmoglein 3 [98-100]. The term "cutaneous-type
pemphigus vulgaris" is used to refer to this presentation of the disease. (See 'Target
antigens' above.)
Other uncommon clinical presentations of pemphigus vulgaris include:
● Pemphigus vegetans – Patients with pemphigus vegetans present with vegetating

plaques composed of excessive granulation tissue and crusting ( picture 4). The
intertriginous areas, scalp, and face are the most common sites for these lesions. Two
clinical presentations of pemphigus vegetans have been described [101]. In
pemphigus vegetans of Neumann, vegetating plaques evolve from typical
pemphigus vulgaris lesions. Pemphigus vegetans of Hallopeau is a milder form of
pemphigus vegetans in which the vegetating plaques are not preceded by bullae.
Lesions of pemphigus vegetans of Hallopeau usually are found in intertriginous areas.
● Pemphigus herpetiformis – Pemphigus herpetiformis (also known as herpetiform
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pemphigus) is a term that describes pemphigus vulgaris or pemphigus foliaceus that

manifests with urticarial plaques and cutaneous vesicles arranged in a herpetiform or
annular pattern ( picture 5) [1,102-105]. Pruritus is frequently present. Mucosal
involvement is uncommon.
The clinical features of drug-induced pemphigus vulgaris are similar to idiopathic disease.
Pemphigus foliaceus — Pemphigus foliaceus is a superficial variant of pemphigus that

presents with cutaneous lesions. The mucous membranes are typically spared [1].
Pemphigus foliaceus usually develops in a seborrheic distribution. The scalp, face, and
trunk are common sites of involvement. The skin lesions usually consist of small, scattered
superficial blisters that rapidly evolve into scaly, crusted erosions ( picture 6A-C). The
Nikolsky sign often is present [13]. The skin lesions may remain localized or may coalesce to
cover large areas of skin. Occasionally, pemphigus foliaceus progresses to involve the
entire skin surface as an exfoliative erythroderma [12].
Pain or burning sensations frequently accompany the cutaneous lesions. Systemic

symptoms are usually absent.
Clinical variants of pemphigus foliaceus include:
● Endemic pemphigus foliaceus (fogo selvagem) – Endemic pemphigus foliaceus

presents with clinical features that are similar to the idiopathic form of the disease
[13]. An environmental trigger is believed to account for this variant of the disease.
(See 'Epidemiology' above.)
● Pemphigus erythematosus (Senear-Usher syndrome) – This term pemphigus

erythematosus is used to describe pemphigus foliaceus localized to the malar region
of the face ( picture 7) [12]. Historically, the term was used to refer to patients who
exhibited immunofluorescence findings consistent with pemphigus as well as
laboratory features of systemic lupus erythematosus. However, the term is no longer
used in this manner.
The clinical manifestations of drug-induced pemphigus foliaceus are similar to idiopathic

disease.
IgA pemphigus — Both the subcorneal pustular dermatosis and intraepidermal

neutrophilic immunoglobulin A (IgA) dermatosis types of IgA pemphigus are characterized
by the subacute development of vesicles that evolve into pustules [6]. The vesicles and
pustules are usually, but not always, accompanied by erythematous plaques. A
herpetiform, annular, or circinate pattern may be present [6,55,96].
The trunk and proximal extremities are common sites for involvement. The scalp,
postauricular skin, and intertriginous areas are less common sites for lesion development
[6,55,106]. Pruritus may or may not be present. Mucous membranes are usually spared.
The subcorneal pustular dermatosis type of IgA pemphigus is clinically similar to classic
subcorneal pustular dermatosis (Sneddon-Wilkinson disease). Immunofluorescence studies
are necessary to distinguish these diseases. (See "Neutrophilic dermatoses", section on
'Subcorneal pustular dermatosis' and 'IgA pemphigus' below.)
Paraneoplastic pemphigus — Paraneoplastic pemphigus (also known as paraneoplastic

autoimmune multiorgan syndrome) is an autoimmune multi-organ syndrome associated
with neoplastic disease [27]. Typically, patients suffer from severe and acute mucosal
involvement with extensive, intractable stomatitis ( picture 8A-C). The cutaneous
manifestations are variable, and include blisters, erosions, and lichenoid lesions that may
resemble other autoimmune blistering diseases, erythema multiforme, graft versus host
disease, or lichen planus ( picture 9A-B). Life-threatening pulmonary involvement
consistent with bronchiolitis obliterans also may be seen [107]. (See "Paraneoplastic
pemphigus", section on 'Clinical manifestations'.)
Neonatal pemphigus — Neonatal pemphigus is a rare transient condition in which

neonates develop blisters due to placental transmission of autoantibodies from a mother
with pemphigus. Neonatal pemphigus vulgaris occurs more frequently than neonatal
pemphigus foliaceus [108,109]. The clinical, histologic, and direct immunofluorescence
findings of neonatal pemphigus are consistent with pemphigus. Indirect
immunofluorescence has been positive in the majority of reported cases [108]. The disease
manifestations usually resolve within three weeks.
COMORBIDITIES
Cross-sectional studies have found increased prevalence rates for other disorders in
patients with pemphigus, including hematologic malignancies, solid malignancies
(esophageal and laryngeal cancer), other autoimmune diseases (Sjögren syndrome,
systemic lupus erythematosus, and alopecia areata), psoriasis, and neurologic diseases
(dementia, Parkinson disease, and epilepsy) [110-113]. Further studies are necessary to
firmly establish the clinical relevance of these findings.
Although an increased prevalence of malignancy in patients with pemphigus has been

reported, malignancy is uncommon overall [110,114]. A cross-sectional study of 1985
patients with pemphigus vulgaris or pemphigus foliaceus and 9874 matched controls
found modest increases in the prevalence rates of chronic leukemia (0.9 versus 0.4 percent,
odds ratio [OR] 2.1, 95% CI 1.2-3.6), multiple myeloma (0.8 versus 0.4 percent, OR 2.2, 95%
CI 1.2-3.9), and non-Hodgkin lymphoma (1.8 versus 1.2 percent, OR 1.5, 95% CI 1.0-2.2)
among pemphigus patients [114]. Paraneoplastic pemphigus, a very rare obligate
paraneoplastic disease, is a distinct subtype of pemphigus that occurs only in association
with malignancy and is reviewed separately. (See "Paraneoplastic pemphigus".)
DIAGNOSIS
The diagnosis of pemphigus is made through the assessment of clinical, histologic,

immunopathologic, and serologic findings ( table 1). Even in cases in which the clinical
findings strongly suggest pemphigus, laboratory investigations to confirm the diagnosis
are indicated since other disorders may present with similar clinical findings. (See
'Differential diagnosis' below.)
Pemphigus vulgaris and pemphigus foliaceus — In addition to a complete examination

of cutaneous and mucosal surfaces, the clinical assessment should include a review of the
patient's medications since clinical and laboratory studies cannot reliably distinguish
between idiopathic pemphigus and drug-induced pemphigus. In addition, patients who
may have pemphigus vulgaris should be questioned about ocular symptoms, hoarseness,
dysphagia, dysuria, and dyspareunia to evaluate for symptoms suggestive of extraoral

mucus membrane involvement. (See 'Drug exposure' above and 'Clinical features' above.)
Our standard laboratory work-up for patients with clinical findings suggestive of
pemphigus vulgaris or foliaceus includes:
● A lesional skin or mucosal biopsy for routine hematoxylin and eosin (H&E) staining
● A perilesional skin or mucosal biopsy for direct immunofluorescence (DIF)
● Serum collection for enzyme-linked immunosorbent assay (ELISA) and indirect

immunofluorescence (IIF)
Histopathology — The biopsy for routine histologic examination should be taken from an
early lesion. The biopsy should be placed at the edge of a blister or erosion. A 4 mm punch
biopsy is usually sufficient. (See "Approach to the patient with cutaneous blisters", section
on 'Skin biopsy'.)
The characteristic findings in pemphigus vulgaris include ( picture 10):
● Intraepithelial cleavage with acantholysis (detached keratinocytes) primarily localized

to the suprabasal region
● Retention of basal keratinocytes along the basement membrane zone, resulting in an

appearance that resembles a "row of tombstones"
● Sparse inflammatory infiltrate in the dermis with eosinophils
In the pemphigus vegetans variant of pemphigus vulgaris, the suprabasal cleavage is

accompanied by hyperkeratosis, papillomatosis, and prominent acanthosis with downward
proliferation of the rete ridges [115]. Eosinophils may be present within the areas of
cleavage.
The characteristic findings of pemphigus foliaceus include ( picture 11) [115]:
● Intraepithelial cleavage with acantholysis beneath the stratum corneum or within the
granular layer; neutrophils within the blister cavity are occasionally seen
● Mixed inflammatory infiltrate in the superficial dermis with eosinophils and

neutrophils; eosinophils may be more prevalent in drug-induced pemphigus foliaceus
Direct immunofluorescence — Unlike the biopsy for routine histologic examination, the
biopsy for DIF should be taken from normal-appearing perilesional skin or mucosa. The
biopsy should not be placed in formalin. (See "Approach to the patient with cutaneous
blisters", section on 'Direct immunofluorescence'.)
Both pemphigus vulgaris and pemphigus foliaceus demonstrate intercellular deposition of

immunoglobulin G (IgG) on DIF ( picture 1A-B). Although some cases of pemphigus
foliaceus demonstrate deposition of IgG that is primarily distributed in upper levels of the
epidermis ( picture 1B), DIF cannot be used to reliably distinguish between these
diseases.
Essentially all patients with idiopathic pemphigus vulgaris or pemphigus foliaceus have
positive DIF results. Thus, if DIF is negative, the diagnosis should be questioned. In
contrast, negative DIF studies may occur in patients with drug-induced pemphigus (see
'Drug exposure' above) [87,90]. Occasionally, intercellular deposition of antibodies occurs in
other diseases (eg, spongiotic dermatitis, burns, toxic epidermal necrolysis, systemic lupus
erythematosus, or lichen planus) [96].
Serology — IIF and ELISA are serologic studies that can detect circulating autoantibodies
that bind epithelial cell surface antigens. In patients with positive DIF results, these tests
are used to further support the diagnosis of pemphigus.
Indirect immunofluorescence — More than 80 percent of patients with pemphigus

vulgaris or pemphigus foliaceus have circulating antibodies detectable by IIF [101]. The
substrate used influences the test sensitivity [101]. Monkey esophagus is the preferred
substrate for the diagnosis of pemphigus vulgaris. In contrast, normal human skin and
guinea pig esophagus are the most sensitive substrates for the diagnosis of pemphigus
foliaceus. In both disorders, IgG deposits are found intercellularly ( picture 12). IIF cannot
be used to distinguish between these diseases. (See "Approach to the patient with
cutaneous blisters", section on 'Indirect immunofluorescence'.)
Enzyme-linked immunosorbent assay — ELISA for IgG antibodies to desmoglein 1
and desmoglein 3 is commercially available. ELISA is more sensitive and specific than IIF for
the diagnosis of pemphigus vulgaris and pemphigus foliaceus [101]. The sensitivity of ELISA
exceeds 90 percent [12].
In addition, since desmoglein antibody levels often fall in the setting of clinical
improvement, ELISA may aid with monitoring disease activity and the response to
treatment [116-118]. In a retrospective study that assessed the predictive values of
pemphigus autoantibodies in patients with pemphigus vulgaris and pemphigus foliaceus,
desmoglein 1 autoantibodies were more closely correlated with the disease course than
desmoglein 3 autoantibodies [117]. Desmoglein 3 antibody levels remained high during
disease remissions in some patients with mucosal pemphigus vulgaris. In patients with
pemphigus vulgaris, levels of IgE antibodies to desmoglein 3 may also correlate with
disease activity [119]. (See "Initial management of pemphigus vulgaris and pemphigus
foliaceus" and "Management of refractory pemphigus vulgaris and pemphigus foliaceus".)
Other — Additional serologic tests that may be used for the diagnosis of pemphigus
vulgaris and pemphigus foliaceus include immunoblotting and immunoprecipitation.
However, these tests are more difficult to perform than IIF and ELISA. Thus, they are
infrequently used in the clinical setting.
Aside from the detection of pemphigus antibodies in serum, pemphigus is not associated
with specific laboratory abnormalities. Other laboratory abnormalities may occur related to
complications of the disease or its treatment.
IgA pemphigus — Similar to other forms of pemphigus, the diagnosis of immunoglobulin

A (IgA) pemphigus is based upon the combined assessment of clinical and laboratory
findings. The standard laboratory workup consists of histologic examination, DIF, and IIF.
Typical histologic findings of IgA pemphigus include [6,115]:
● Intraepidermal clefts and pustules located in a subcorneal location (subcorneal

pustular dermatosis-type IgA pemphigus) or in the entire or mid-epidermis
(intraepithelial neutrophilic dermatosis)
● Slight or absent acantholysis
● Mixed inflammatory infiltrate in the dermis
DIF microscopy of perilesional skin reveals intercellular IgA deposition within the epidermis
that is occasionally more pronounced in the upper epidermis. Weaker intercellular deposits
of IgG and/or C3 may also be present [6,55]. IIF on monkey esophagus demonstrating
intercellular deposits of IgA offers further support for the diagnosis. However, IIF on
monkey esophagus is positive in less than or equal to 50 percent of patients [6,55]. IIF on
human skin may demonstrate intercellular antibody deposition more frequently; in one
series of patients with IgA pemphigus, IIF of normal human skin showed intercellular
deposition of IgA in 31 of 48 patients (65 percent) [55].
Other studies that have been utilized to identify circulating IgA pemphigus desmocollin
autoantibodies include immunoblotting [120], ELISA using recombinant desmocollin
[55,106], and immunofluorescence molecular assay using desmocollin-transfected COS-7
cells [53,55]. The availability of these studies is limited to specialized centers and research
settings.
Although autoantibodies against desmocollin 1 appear to be strongly associated with the

subcorneal pustular dermatosis type of IgA pemphigus, autoantibodies to desmogleins
may be present in other patients with IgA pemphigus [54,55]. In one series of 22 patients
with IgA pemphigus, ELISA tests for IgA autoantibodies against desmoglein 1 or
desmoglein 3 were positive in three patients and one patient, respectively [54]. The patients
with desmoglein autoantibodies had either the intraepidermal neutrophilic type of IgA
pemphigus or a presentation that had clinical and pathologic features of pemphigus
foliaceus. None of the 10 patients with subcorneal pustular dermatosis-type IgA
pemphigus had autoantibodies against these desmogleins, but all 10 had serum samples
that reacted with desmocollin 1 expressing COS-7 cells.
Paraneoplastic pemphigus — Similar to other forms of pemphigus, the diagnosis of

paraneoplastic pemphigus involves review of clinical, histologic, immunopathologic, and
serologic findings. The diagnosis of paraneoplastic pemphigus vulgaris is reviewed
separately. (See "Paraneoplastic pemphigus", section on 'Diagnosis'.)
DIFFERENTIAL DIAGNOSIS
Multiple mucocutaneous blistering diseases share clinical features with the different forms
of pemphigus ( table 3). In all forms of pemphigus, laboratory investigations, particularly
immunopathologic tests, usually easily distinguish pemphigus from other diseases.
● Pemphigus vulgaris – Cutaneous involvement in pemphigus vulgaris must be

distinguished from other autoimmune blistering diseases. The morphology of
cutaneous blisters in pemphigus vulgaris can be helpful for narrowing the differential
diagnosis. The flaccid blisters often seen in pemphigus vulgaris contrast with the
tense blisters that are frequently seen in association with subepithelial blistering
diseases, such as bullous pemphigoid, linear immunoglobulin A (IgA) bullous
dermatosis, and epidermolysis bullosa acquisita ( picture 13A-C and algorithm 1).
(See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane
pemphigoid" and "Clinical features and diagnosis of bullous pemphigoid and mucous
membrane pemphigoid", section on 'Clinical features of bullous pemphigoid' and
"Linear IgA bullous dermatosis", section on 'Clinical manifestations' and
"Epidermolysis bullosa acquisita", section on 'Clinical manifestations'.)
Mucosal lesions pemphigus vulgaris can resemble other blistering or erosive

disorders of the mucous membranes. As examples, the possibility of other pemphigus
variants, mucous membrane pemphigoid, mucosal linear IgA bullous dermatosis or
epidermolysis bullosa acquisita, erythema multiforme, and Stevens-Johnson
syndrome should be considered. (See "Approach to the patient with cutaneous
blisters", section on 'Mucous membrane involvement'.)
● Pemphigus foliaceus – The lesions of pemphigus foliaceus may resemble other

inflammatory disorders, such as seborrheic dermatitis ( picture 14), impetigo,
subacute cutaneous lupus erythematosus ( picture 15A-B), IgA pemphigus, and the
non-IgA pemphigus form of subcorneal pustular dermatosis ( picture 16A-B). (See
"Neutrophilic dermatoses", section on 'Subcorneal pustular dermatosis'.)
● IgA pemphigus – The differential diagnosis of IgA pemphigus overlaps with

pemphigus foliaceus. In addition, disorders that may present with grouped vesicular
lesions or pustules, such as dermatitis herpetiformis ( picture 17), bullous impetigo,

linear IgA bullous dermatosis ( picture 13B), and pustular psoriasis ( picture 18A-B
) should be considered.
● Paraneoplastic pemphigus – The differential diagnosis of paraneoplastic pemphigus

is reviewed separately. (See "Paraneoplastic pemphigus", section on 'Differential
diagnosis'.)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Pemphigus".)
SUMMARY AND RECOMMENDATIONS
● Pemphigus comprises a group of autoimmune blistering diseases that are

characterized by histologic acantholysis (loss of cell-to-cell adhesion) and mucosal
and/or cutaneous blistering. The four major types of pemphigus are pemphigus
vulgaris, pemphigus foliaceus, immunoglobulin A (IgA) pemphigus, and
paraneoplastic pemphigus ( table 1). (See 'Classification' above.)
● Pemphigus is rare. Pemphigus vulgaris is the most common form of pemphigus.

However, in certain areas, particularly in locations where an endemic form of
pemphigus foliaceus occurs, pemphigus foliaceus is more prevalent. (See
'Epidemiology' above.)
● The intraepidermal blistering observed in pemphigus occurs due to an immune

response that results in the deposition of autoantibodies against epidermal cell
surface antigens within the epithelium of mucous membranes or skin. The
mechanism through which acantholysis occurs is not fully understood. (See
'Pathogenesis' above.)
● Pemphigus vulgaris generally is a more severe disease than pemphigus foliaceus.
Patients with pemphigus vulgaris usually present with widespread mucocutaneous

blisters and erosions ( picture 2A-B, 3A-D). Cutaneous blistering in pemphigus
foliaceus tends to occur in a seborrheic distribution ( picture 6A-C). Compared with
pemphigus vulgaris, blistering in pemphigus foliaceus is more superficial. (See
'Clinical features' above.)
● Vesicles, pustules, and crusts on skin are common features of IgA pemphigus. The
skin lesions may appear in an annular, circinate, or herpetiform distribution. (See 'IgA
pemphigus' above.)
● The diagnosis of pemphigus is based upon the recognition of consistent clinical,

histologic, and direct immunofluorescence (DIF) findings, as well as the detection of
circulating immunoglobulin G (IgG) and IgA autoantibodies against cell surface
antigens in serum ( table 1). Laboratory studies are useful for distinguishing
pemphigus from other blistering and erosive diseases. Our standard laboratory work-
up for patients with clinical findings suggestive of pemphigus vulgaris or foliaceus
includes (see 'Diagnosis' above):
• A lesional skin or mucosal biopsy for routine hematoxylin and eosin (H&E) staining
• A perilesional skin or mucosal biopsy for DIF
• Serum collection for detection of autoantibodies by enzyme-linked

immunosorbent assay (ELISA) and indirect immunofluorescence (IIF)
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Pathogenesis, clinical manifestations, and diagnosis of pemphigus - UpToDate 11/05/22 15:36

Authors: Michael Hertl, MD, Cassian Sitaru, MD

Pemphigus is defined as a group of life-threatening blistering disorders characterized by

• Key features – Mucosal or mucosal and cutaneous involvement, suprabasal

• Clinical variants – Pemphigus vegetans, pemphigus herpetiformis

• Key features – Cutaneous involvement only, subcorneal acantholytic blisters,

• Clinical variants – Endemic pemphigus foliaceus (fogo selvagem), pemphigus

● Immunoglobulin A (IgA) pemphigus

• Subtypes – Subcorneal pustular dermatosis-type IgA pemphigus (distinct from

• Key features – Grouped vesicles or pustules and erythematous plaques with

• Key features – Extensive, intractable stomatitis and variable cutaneous findings

blisters, autoantibodies against desmoplakins or other desmosomal antigens (see

In most geographic locations, pemphigus vulgaris is more common than pemphigus

Epidemiologic information on immunoglobulin A (IgA) pemphigus is sparse. The disorder

Overview — Intensive investigations to elucidate the pathogenesis of pemphigus have led

● In vitro studies have demonstrated that immunoglobulin G (IgG) autoantibodies from

● Removal of pemphigus autoantibodies from serum from patients with pemphigus

The molecular mechanisms through which binding of autoantibodies to epithelial cells

Target antigens — Autoantibodies against a variety of epithelial cell surface antigens,

Pemphigus vulgaris and pemphigus foliaceus — Desmogleins, which are

IgG autoantibodies to desmogleins are consistently detected via enzyme-linked

According to the desmoglein compensation theory, the correlation between clinical

The interpretation of this theory as it relates to the clinical findings in pemphigus is as

● Patients with only autoantibodies against desmoglein 3 should have mucosal

● Patients with only autoantibodies against desmoglein 1 should have pemphigus

● Patients with both autoantibodies against desmoglein 1 and 3 should have

Autoantibodies against desmocollin 3 may contribute to pemphigus in some patients. Like

Additional autoantibodies detected in serum from patients with pemphigus include

In contrast, the targeted antigens in the intraepidermal neutrophilic dermatosis variant of

Paraneoplastic pemphigus — Multiple autoantibodies have been detected in patients

Contributing factors — As with many other autoimmune diseases, the precipitating

The involvement of genetic factors in susceptibility to pemphigus is further strengthened

Environment — While most cases of pemphigus foliaceus are idiopathic, environmental

Drug exposure — Pemphigus vulgaris and pemphigus foliaceus may be precipitated by

Drug-induced biochemical and/or immunologic reactions may contribute to the

Direct immunofluorescence (DIF) and indirect immunofluorescence (IIF) studies are

be mistaken for cervical dysplasia in Papanicolaou (Pap) smears [95].

Most patients also develop cutaneous involvement manifesting as flaccid blisters on

Other uncommon clinical presentations of pemphigus vulgaris include:

● Pemphigus vegetans – Patients with pemphigus vegetans present with vegetating

● Pemphigus herpetiformis – Pemphigus herpetiformis (also known as herpetiform

pemphigus) is a term that describes pemphigus vulgaris or pemphigus foliaceus that

Pemphigus foliaceus — Pemphigus foliaceus is a superficial variant of pemphigus that

Pain or burning sensations frequently accompany the cutaneous lesions. Systemic

Clinical variants of pemphigus foliaceus include:

● Endemic pemphigus foliaceus (fogo selvagem) – Endemic pemphigus foliaceus

● Pemphigus erythematosus (Senear-Usher syndrome) – This term pemphigus

The clinical manifestations of drug-induced pemphigus foliaceus are similar to idiopathic

IgA pemphigus — Both the subcorneal pustular dermatosis and intraepidermal

Paraneoplastic pemphigus — Paraneoplastic pemphigus (also known as paraneoplastic

Neonatal pemphigus — Neonatal pemphigus is a rare transient condition in which

Although an increased prevalence of malignancy in patients with pemphigus has been

The diagnosis of pemphigus is made through the assessment of clinical, histologic,

Pemphigus vulgaris and pemphigus foliaceus — In addition to a complete examination

dysphagia, dysuria, and dyspareunia to evaluate for symptoms suggestive of extraoral

● A perilesional skin or mucosal biopsy for direct immunofluorescence (DIF)

● Serum collection for enzyme-linked immunosorbent assay (ELISA) and indirect

The characteristic findings in pemphigus vulgaris include ( picture 10):

● Intraepithelial cleavage with acantholysis (detached keratinocytes) primarily localized

● Retention of basal keratinocytes along the basement membrane zone, resulting in an