9
Vesiculobullous PA RT
Disorders
Chapter 52 :: Pemphigus
:: Aimee S. Payne & John R. Stanley
AT-A-GLANCE
■ Two major types: pemphigus vulgaris and
pemphigus foliaceus.
■ Pemphigus vulgaris: erosions on mucous
membranes and skin; flaccid blisters on skin.
■ Pemphigus foliaceus: crusted, scaly skin lesions.
■ Pemphigus vulgaris histology: suprabasal
acantholysis.
■ Pemphigus foliaceus histology: subcorneal
acantholysis.
■ Autoantigens are desmogleins, transmembrane
desmosomal adhesion molecules.
■ Diagnosis depends on histology showing
intraepidermal acantholysis, immunofluorescence
studies documenting the presence of cell surface
autoantibodies, either bound to patient skin or in
the serum, and/or enzyme-linked immunosorbent
assay showing anti-desmoglein antibodies
■ Therapy includes topical and systemic
corticosteroids, oral immunosuppressive agents,
intravenous immunoglobulin, and rituximab
(anti-CD20 monoclonal antibody).
INTRODUCTION
DEFINITIONS
The term pemphigus refers to a group of autoimmune
blistering diseases of skin and mucous membranes
that are characterized histologically by intraepi-
dermal blisters due to acantholysis (ie, separation
of epidermal cells from each other) and immuno-
pathologically by in vivo bound and circulating
Kang_CH052_p0909-0933.indd 909
immunoglobulin directed against the cell surface of
keratinocytes. The nosology of this group of diseases
is outlined in Table 52-1. Essentially, pemphigus can
be divided into 4 major types: vulgaris, foliaceus
(Table 52-2), paraneoplastic (Chap. 53), and IgA pem-
phigus (Chap. 57). In pemphigus vulgaris (PV), the
blister occurs in the deeper part of the epidermis, just
above the basal layer, and in pemphigus foliaceus
(PF), also called superficial pemphigus, the blister is in
the granular layer.
HISTORICAL PERSPECTIVE
The history of the discovery of pemphigus, and its
various forms, is covered in Walter Lever’s clas-
sic monograph Pemphigus and Pemphigoid.1 Both PV
and PF display a spectrum of disease. Various points
along these spectra have been given unique names,
but because the presentation of these diseases is fluid,
patients’ disease usually crosses these artificial desig-
nations over time. Thus, patients with PV may pres-
ent with more localized disease, one form of which is
called pemphigus vegetans of Hallopeau. This may become
slightly more extensive and may merge into pemphigus
vegetans of Neumann. Finally, with more severe disease,
full-blown PV may appear. Similarly, patients with PF
may present with more localized disease, represented
by pemphigus erythematosus. However, these patients
often go on to more widespread PF.
The discovery by Ernst Beutner and Robert Jor-
don in 1964 of circulating antibodies against the cell
surface of keratinocytes in the sera of patients with
PV pioneered our understanding that PV is a tissue-
specific autoimmune disease of skin and mucosa.2
Ultimately, their work led the way to the discoveries
of autoantibodies in other autoimmune bullous dis-
eases of the skin.
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 9 TABLE 52-1
Nosology and Differential Diagnosis of
Pemphigus
Pemphigus Subtypes
■ Pemphigus vulgaris
■ Pemphigus vegetans
■ Pemphigus foliaceus
■ Pemphigus erythematosus
■ Endemic pemphigus foliaceus (eg, fogo selvagem)
■ Immunoglobulin A (IgA) pemphigus
■ Subcorneal pustular dermatosis
■ Intraepidermal neutrophilic dermatosis
■ Paraneoplastic pemphigus
Part 9
Intraepidermal Blistering Diseases Without Autoantibodies
■ Familial benign pemphigus (Hailey-Hailey disease)
■ Bullous impetigo, staphylococcal scalded-skin syndrome
■ Blisters from herpes simplex and zoster
::
■ Allergic contact dermatitis (eg, rhus dermatitis)
Vesiculobullous Disorders
■ Epidermolysis bullosa simplex
■ Incontinentia pigmenti
Mouth Ulcers/Erosion Without Autoantibodies
■ Aphthous ulcers
■ Candidiasis
■ Lichen planus
■ Behçet disease
Subepidermal Blistering Diseases With Autoantibodies
■ Bullous pemphigoid
■ Herpes gestationis
■ Cicatricial pemphigoid
■ Epidermolysis bullosa acquisita
■ Linear IgA disease and chronic bullous disease of childhood
■ Dermatitis herpetiformis
■ Bullous lupus erythematosus
Subepidermal Blistering Diseases Without Autoantibodies
■ Erythema multiforme
■ Toxic epidermal necrolysis
■ Porphyria
■ Junctional or dystrophic epidermolysis bullosa
EPIDEMIOLOGY
INCIDENCE, PREVALENCE,
AND SEX RATIO
A few prospective and several retrospective surveys of
patients with pemphigus clearly indicate that the epi-
demiology of pemphigus is dependent on both the area
in the world that is studied and the ethnic population
in that area.3-11 PV is more common in Jews and prob-
ably in people of Mediterranean descent and from the
Middle East. This same ethnic predominance does not
exist for PF. Therefore, in areas where the Jewish, Mid-
dle Eastern, and Mediterranean population predomi-
nates, the ratio of PV to PF cases tends to be higher.
For example, in New York, Los Angeles, and Croatia,
the ratio of PV to PF cases is approximately 5:1; in Iran
the ratio is 12:1; whereas in Singapore it is 2:1 and in
910 Finland, it is only 0.5:1. Similarly, the incidence of pem-
phigus varies by region. In Jerusalem, the incidence of
Kang_CH052_p0909-0933.indd 910
PV has been estimated to be 1.6 per 100,000 people per
year and in Iran approximately 10.0 per 100,000 people
per year. In Europe, the incidences are lower, ranging
from a high of 0.7 PV cases per 100,000 person years
in the United Kingdom to 10-fold less, 0.5 to 1.0 per
million person years, in Finland, France, Germany, and
Switzerland. In Taiwan, the incidence is 4.7 per million
per year.
The prevalence and incidence of PF are also very
dependent on its location, as best exemplified by the
finding of endemic foci of PF in Brazil, Colombia, and
Tunisia. The first recognition of endemic PF was in
Brazil and is called fogo selvagem, which means “wild
fire” in Portuguese. It is a disease that is clinically, his-
tologically, and immunopathologically the same as
sporadic PF in any individual patient, but its epidemi-
ology is unique.12,13 Fogo selvagem is endemic in the
rural areas of Brazil, especially along inland riverbeds.
The prevalence in some well-studied Indian reserva-
tions in rural Brazil can be as high as 3.4%, with the
incidence up to 0.8 to 4.0 new cases per 1000 people
per year.13,14 On the reservation in Limao Verde, up to
55% of unaffected individuals have a low-level IgG1
antibody response against desmoglein 1, the PF auto-
antigen, which becomes an IgG4 response of higher
titer against a more pathogenic epitope in disease.13
Fogo selvagem occurs often in children and young
adults, unlike sporadic PF, which is a disease of mostly
middle-aged and older patients. Also unlike PF, fogo
selvagem occurs not infrequently in genetically related
family members, although it is not contagious. There
is no known racial or ethnic predominance, and any-
one moving into an endemic area may be susceptible
to disease. Furthermore, the urban development of
rural endemic areas of Brazil decreased the incidence
of disease (Fig. 52-1).
These epidemiologic associations suggest that an
environmental agent may trigger a low-level autoan-
tibody response that in some genetically susceptible
individuals becomes pathogenic against desmoglein 1
by intermolecular epitope spreading. With this theory
in mind, it is interesting that 40% to 80% of patients
from Brazil with the insect-borne diseases onchocercia-
sis, leishmaniasis, and Chagas disease have low-level
anti-desmoglein 1 antibodies, but patients with other
infectious diseases from Brazil rarely have such anti-
bodies.15 Subsequent studies have shown that IgG4 and
IgE antibodies from fogo selvagem patients recognize
salivary gland antigens from the sand fly Lutzomyia
longipalpis, the vector of leishmaniasis.16 The current
theory is that fogo selvagem may initiate with an IgE
response against the sand fly salivary antigen LJM11,
which cross-reacts with desmoglein 1 and then gener-
alizes to an IgG4 response.17,18 This fascinating disease
holds clues to understanding how this autoimmune
response is triggered.
The sex ratio of pemphigus in women versus men
ranges from 1.33 to 2.25.7,9,19-24 Notable outliers to
this estimate are the predominance of women (4:1)
in an endemic focus of PF in Tunisia,6 and a predom-
inance of men (19:1) in an endemic focus of PF in
Colombia.25
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Kang_CH052_p0909-0933.indd 911

TABLE 52-2
Pemphigus Subtypes and Variants
IMMUNOFLUORESCENCE
MUCOUS MEMBRANE DIRECT INDIRECT ELISA
CUTANEOUS FINDINGS INVOLVEMENT PATHOLOGY (NONQUANTITATIVE) (SEMIQUANTITATIVE) (QUANTITATIVE)
Pemphigus Flaccid blisters, typically sparing Oral and nasal mucous Suprabasal blister with acantholysis IgG bound to surface Monkey esophagus Desmogleins 1, 3
vulgaris palmoplantar surface membranes most “row of tombstones” appearance of keratinocytes substrate ideal (mucosal and skin
Large erosions are common commonly affected (intercellular pattern) IgG in cell surface involvement)
presentations Esophageal pattern Desmoglein
(+) Nikolsky sign Vulvar, cervical, vaginal 3 (mucosal
Ocular dominant)
Pemphigus Erosions develop excessive Oral involvement is Suprabasal acantholysis, with papillomatosis of the IgG on cell surface of IgG in cell surface Desmoglein 3,
vegetansa papillomatosis tissue and common∗ dermal papillae and downward growth of epidermal keratinocytes∗ pattern∗ sometimes
crusting; intertriginous areas, strands into the dermis; presence of hyperkeratosis and desmoglein 1
scalp, or face scale-crust; eosinophilic or neutrophilic intraepidermal
abscesses
Pemphigus Scaly, crusted lesions on Very rare Early lesions show eosinophilic spongiosis; histopathology IgG bound to surface Guinea pig esopha- Desmoglein 1
foliaceus erythematous base; demonstrates acantholysis below stratum corneum; of keratinocytes gus or human skin
seborrheic distribution epidermis beneath the granular layer remains intact; (intercellular pattern) substrate ideal
(face, scalp, upper trunk); subcorneal pustules containing neutrophils and IgG in intercellular
small flaccid blisters are acantholytic epidermal cells in the blister cavity pattern
transient primary lesions
Pemphigus Crusted lesions in seborrheic Rare Similar to pemphigus foliaceus IgG and C3 deposition Desmoglein 1†
erythematosusb distribution at granular basement
membrane zone,
IgG with intercellular
pattern
Endemic Similar to pemphigus foliaceus; Rare Similar to pemphigus foliaceus Similar to pemphigus Desmoglein 1
pemphigus characterized by burning foliaceus
foliaceus sensation, and exacerbation
(fogo selvagem)c on sun exposure
a
Variant of pemphigus vulgaris.
b
Variant of pemphigus foliaceus.
c
Similar to pemphigus foliaceus clinically, histologically, and serologically, however with distinct epidemiologic features.‡
∗
Ruoco V, Ruocco E, Caccavale S, et al. Pemphigus vegetans of the folds (intertriginous areas). Clin Dermatol. 2015;33(4):471-476.
†
Oktarina D, Poot A, Kramer D. The IgG “lupus-band” deposition pattern of pemphigus erythematosus. Association with the desogein 1 ectodomain as revealed by 3 cases. Arch Dermatol. 2012;148(10):1173-1178.
‡
Rocha-Alvares R, Ortega-Loayza A, Friedman H. Endemic pemphigus vulgaris. Arch Dermatol. 2007;143(7):895-899.
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911

9
Chapter 52 :: Pemphigus
 9

A B
Part 9

Figure 52-1 Pemphigus vulgaris. A, Flaccid blisters. (Used with permission from Lawrence Lieblich, MD.) B, Oral erosions.
::
Vesiculobullous Disorders

In certain patients, erosions have a tendency to

AGE OF ONSET develop excessive papillimatosis and crusting, referred
to as vegetating lesions (Fig. 52-3). This type of lesion
The average age of disease onset also varies by region. tends to occur more frequently in intertriginous areas,
In Turkey, Saudi Arabia, Tunisia, and Iran, the mean in the scalp, or on the face. Generally, the prognosis
age of onset is approximately 40 years.6,19,21,26 Studies in for these so-called pemphigus vegetans patients is
the United States, Europe, and Taiwan demonstrate an thought to be better, with milder disease and a higher
average age of onset between 50 and 70 years.5,6,9-11,20,22,27-29 chance of remission compared to typical PV patients.34
Pemphigus rarely occurs in children,30 except in regions Some ordinary PV lesions heal with a vegetating mor-
of endemic disease. phology and can remain for long periods of time in one
place. Thus, vegetating lesions seem to be one reactive
pattern of the skin to the autoimmune insult of PV.
CLINICAL FEATURES
PEMPHIGUS VULGARIS
CUTANEOUS FINDINGS
The skin lesions in PV can be pruritic or painful.
Exposure to ultraviolet radiation may exacerbate dis-
ease activity.31,32 The primary lesion of PV is a flaccid
blister, which may occur anywhere on the skin sur-
face, but typically not the palms and soles (Fig. 52-1A,
Table 52-2). Usually, the blister arises on normal-
appearing skin, but it may develop on erythematous
skin. Because PV blisters are fragile, the most com-
mon skin lesions observed in patients are erosions
resulting from broken blisters. These erosions are
often quite large, as they have a tendency to spread at
their periphery (Fig. 52-2).
A characteristic finding in pemphigus patients is
that erosions can be extended into visibly normal
skin by pulling the remnant of the blister wall or rub-
bing at the periphery of active lesions; additionally,
erosions can be induced in normal-appearing skin
distant from active lesions by pressure or mechani-
cal shear force. This phenomenon is known as the
Nikolsky sign.33 This sign helps differentiate pemphi-
gus from other blistering diseases of the skin such as
pemphigoid (Table 52-1); however, similar findings
also can be elicited in staphylococcal scalded skin Figure 52-2 Pemphigus vulgaris. Extensive erosions due to
912 syndrome, Stevens-Johnson syndrome, and toxic epi- blistering. Almost the entire back is denuded. Note intact,
dermal necrolysis. flaccid blisters at the lower border of eroded lesions.

Kang_CH052_p0909-0933.indd 912 03/12/18 8:59 am


A B
Figure 52-3 A, Crusted, vegetating lesions in pemphigus vulgaris. B, Extensive, vegetating lesions in intertriginous regions
in pemphigus vegetans-type pemphigus vulgaris.
Although hair loss is not a usual feature in pemphi-
gus, temporary hair loss can be seen in about 5% of
patients and can rarely be a presenting sign of disease.35
MUCOUS MEMBRANE LESIONS
The mucous membranes most often affected by PV are
those of the oropharyngeal cavity (Fig. 52-1B) and nasal
mucosa.36,37 Endoscopic evaluation revealed that 87% of
PV patients had ear, nose, or throat lesions, with involve-
ment of nasal mucosa, pharynx, and larynx being most
common at 76%, 66%, and 55%, respectively.38 Laryngeal
involvement was often asymptomatic. As with cutane-
ous lesions, intact blisters are rare. Oropharyngeal ero-
sions can be so painful that the patient is unable to eat
or drink. The inability to eat or drink adequately may
require inpatient hospitalization for disease control and
intravenous fluid and nutrient repletion.
In the majority of patients, painful mucous mem-
brane erosions are the presenting sign of PV and may
be the only sign for an average of 5 months before skin
lesions develop.3 However, the presenting symptoms
may vary; in a study from Croatia, painful oral lesions
were the presenting symptom in 32% of patients.23
Most of these patients progressed to a more general-
ized eruption in 5 months to 1 year; however, some had
oral lesions for more than 5 years before generalization.
On the other hand, in Tehran, 62% of patients presented
with oral lesions only.7 Skin involvement without
mucous membrane involvement in PV is less common,
accounting in one study for 11% of PV cases.39
GI tract involvement with PV has been described
in the esophagus, stomach, duodenum, and anus,
although only biopsies of the esophagus have proven
the lesions were due to suprabasal acantholysis.7,40,41
About 27% of PV patients demonstrate such PV his-
tology on blind biopsies of the esophagus.41 Further-
more, esophageal involvement may be asymptomatic
but may also lead to esophagitis dissecans, evidenced
by sloughing of esophageal casts.41,42 Involvement of
other mucous membranes can also occur, including
Kang_CH052_p0909-0933.indd 913
9
Chapter 52 :: Pemphigus
the vulvovaginal and ocular epithelia.43-46 Vulvar and
cervicovaginal lesions may be found in up to 51% of
women with active disease but these lesions may be
asymptomatic. Vulvar lesions are most common and
may cause severe burning with urination. Even with-
out obvious lesions, Pap smears may be positive in
women with pemphigus and the acantholytic cells
may be misinterpreted as indicative of cervical dys-
plasia.47,48 There is ocular involvement in about 16%
of PV patients, some with erosions of the conjunctiva,
but findings may be nonspecific.49 There are rare case
reports of corneal erosions in PV patients, but without
histologic confirmation of acantholysis.50
PEMPHIGUS FOLIACEUS
CUTANEOUS FINDINGS
The characteristic clinical lesions of PF are scaly,
crusted erosions, often on an erythematous base. In
more localized and early disease, these lesions are
usually well demarcated and scattered in a seborrheic
distribution, including the face, scalp, and upper trunk
(Fig. 52-4A, Table 52-2). The primary lesions of small
flaccid blisters are typically not found. Disease may
stay localized for years, or it may rapidly progress to
generalized involvement, resulting in an exfoliative
erythroderma (Fig. 52-4B). Like PV, PF may be exac-
erbated by ultraviolet radiation.32,51,52 Patients with PF
often complain of pain and burning in the skin lesions.
In contrast to patients with PV, those with PF very
rarely, if ever, have mucous membrane involvement,
even with widespread disease.
The colloquial term for Brazilian endemic pemphi-
gus, fogo selvagem (Portuguese for “wild fire”), takes
into account many of the clinical aspects of this dis-
ease: the burning feeling of the skin, the exacerbation
of disease by the sun, and the crusted lesions that make 913
the patients appear as if they had been burned.
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 9
A B
Figure 52-4 Pemphigus foliaceus. A. Scaly, crusted lesions on upper back. B. Exfoliative erythroderma due to confluent
Part 9
lesions.
::
PEMPHIGUS ERYTHEMATOSUS
Vesiculobullous Disorders
In 1926, Francis Senear and Barney Usher described
11 patients with features of a pemphigus-lupus ery-
thematosus overlap (Senear-Usher syndrome).53 Over
the next several decades, debate over whether these
patients had lupus erythematosus, pemphigus, sebor-
rheic dermatitis, or features of all 3 disorders contin-
ued, with Senear concluding that the disease is best
considered a variant of pemphigus, termed pemphigus
erythematosus.54 As these observations were made prior
to the development of immunofluorescence testing for
both pemphigus and lupus, the diagnosis was primar-
ily based on the clinical presentation: crusted erosions
in a seborrheic distribution, at times concurrent with
more lupuslike discoid lesions with “carpet-tack”
scale. Walter Lever noted that many patients initially
categorized as pemphigus erythematosus went on to
develop systemic lupus, or more widespread pemphi-
gus foliaceus, or even pemphigus vulgaris, in some
cases because of incorrect initial diagnosis. Therefore,
rather than perpetuate the use of one term for different
diseases, he proposed that pemphigus erythematosus
be used to describe a localized form of PF with better
prognosis.1 After the development of immunofluores-
cence and antinuclear antibody testing for pemphigus
and lupus, it was discovered that pemphigus erythe-
matosus patients demonstrate immunologic overlap
features; by definition, all demonstrate the cell sur-
face staining pattern classic for pemphigus, approxi-
mately 30% have positive antinuclear antibody titers,
and 80% have positive lupus band tests, although the
latter test is only positive in 20% to 40% of biopsies
on non–sun-exposed skin.55 Subsequent studies have
shown that the positive “lupus band” test in pemphi-
gus erythematosus patients is due to granular deposits
of IgG and cleaved desmoglein 1 ectodomain depos-
ited at the basement membrane zone, which is thought
to occur after ultraviolet light exposure.56 Thus,
because most patients with pemphigus erythema-
tosus do not develop systemic signs or symptoms of
lupus, and some may progress from localized disease
914 to generalized PF,57 the diagnosis of the pemphigus
Kang_CH052_p0909-0933.indd 914
erythematosus variant of PF is largely one of historic,
rather than clinical, significance.
NEONATAL PEMPHIGUS
Infants born to mothers with PV may display clinical,
histologic, and immunopathologic signs of pemphigus
vulgaris.58,59 The degree of involvement varies from none
to severe enough to result in a stillbirth. If the infant
survives, disease tends to remit as maternal antibody
is catabolized. Mothers with PF may also transmit their
autoantibodies to the fetus, but, as discussed in the sec-
tion “Pathophysiology of Acantholysis”, neonatal PF
occurs only rarely.60-62 Neonatal pemphigus should be
distinguished from PV and PF that occur in childhood,
which are similar to the autoimmune diseases seen in
adults.63
DRUG-INDUCED
PEMPHIGUS
Although there are sporadic case reports of pemphigus
associated with the use of several different drugs, the
association with penicillamine, and perhaps captopril,
is the most significant.64 The prevalence of pemphigus
in penicillamine users is estimated to be approximately
7%. PF (including pemphigus erythematosus) is more
common than PV in these penicillamine-treated
patients, although either may occur. The findings of
direct and indirect immunofluorescence are positive
in most of these patients. Three patients with drug-
induced PF and one with drug-induced PV have been
shown to have autoantibodies to the same molecules
involved in sporadic pemphigus, namely, desmo-
glein 1 and desmoglein 3, respectively.65 Therefore, by
immunofluorescence and immunochemical determi-
nations, these patients with drug-induced pemphigus
resemble those with sporadic disease.
03/12/18 8:59 am
 Both penicillamine and captopril contain sulfhydryl
groups that are postulated to interact with the sulfhy-
dryl groups in desmoglein 1, 3, or both, thereby caus-
ing pemphigus either by directly interfering with these
adhesion molecules66 or, alternatively, by modifying
them so that they become more antigenic. The use of
these drugs may also lead to a more generalized dys-
regulation of the immune response, as penicillamine
has been associated with the onset of several other
autoantibody-mediated diseases including myas-
thenia gravis,67 Goodpasture syndrome,68 and anti-
neutrophil cytoplasmic antibody vasculitis.69 Some,
but not all, patients with drug-induced pemphigus
go into remission after they stop taking the offending
drug.
Additionally, rare anecdotal reports have suggested
the association of dietary intake and pemphigus, pro-
posing the hypothesis that thiol-containing foods such
as garlic, leeks, and onions may precipitate disease.70,71
Some patients may note that certain foods aggravate
oral lesions, but it is unlikely that dietary intervention
alone will remit disease in most patients.
Interestingly, anecdotal case reports have reported
improvement of PV with cigarette smoking,72 as well
as with the cholinergic agonists pyridostigmine, car-
bachol, and pilocarpine.73,74 Studies suggest that acti-
vation of cholinergic receptors may regulate signaling
pathways modulated by PV IgG, thereby affecting cell
adhesion.75 These results are intriguing given the clini-
cal benefit of nicotine noted in other inflammatory dis-
eases, such as ulcerative colitis.76
ASSOCIATED DISEASES
Myasthenia gravis, thymoma, or both have been
associated with pemphigus.77-79 Approximately one-
half of thymoma-associated pemphigus cases are
vulgaris; one-half, foliaceus or erythematosus. Most
of these data, however, were reported before the rec-
ognition of paraneoplastic pemphigus as a distinct
entity. Therefore, although thymoma may clearly be
associated with PV and PF, it also may be associated
with paraneoplastic pemphigus (Chap. 53). Myasthe-
nia gravis is a tissue-specific autoantibody-mediated
disease leading to skeletal muscle weakness. Early
disease usually affects facial muscles, leading to
symptoms of dysarthria, dysphagia, ptosis, or dip-
lopia. Disease may then progress to affect the larger
muscles of the trunk and extremities, with potential
fatal complications from respiratory muscle involve-
ment. Thymoma, in contrast, is typically asymptom-
atic in adults. In children, thymomas are more likely
to be symptomatic with cough, chest pain, superior
vena cava syndrome, dysphagia, and/or hoarseness
from localized tumor encroachment. Myasthenia gra-
vis would be best evaluated by a neurologist, who
can complete a full neurologic examination and may
test for the presence of serum acetylcholine receptor
autoantibodies. The course of myasthenia gravis and
Kang_CH052_p0909-0933.indd 915
the course of pemphigus appear to be independent
of each other. Likewise, thymic abnormalities may
9
either precede or follow the onset of pemphigus.
Posteroanterior and lateral chest radiographs with or
without computed tomography follow-up can detect
most thymomas. Irradiation of the thymus or thymec-
tomy, although clearly beneficial for myasthenia gra-
vis, may or may not improve the pemphigus disease
activity.80
Recent epidemiologic studies have identified that
pemphigus vulgaris patients have a higher preva-
lence of autoimmune thyroid disease, rheumatoid
arthritis, and Type 1 diabetes compared with the
general population.81 Higher prevalences of these
Chapter 52 :: Pemphigus
autoimmune diseases are also observed in the fam-
ily members of PV patients, suggesting a common
genetic element that may underlie autoimmune
susceptibility.
ETIOLOGY AND
PATHOGENESIS
The discovery of pemphigus as an organ-specific, auto-
antibody-mediated disease of desmosomes highlights
the synergy between clinical care and basic science
research. The development of light microscopy and
electron microscopy allowed dermatologists to iden-
tify the morphology and immunopathology of disease.
Patient serum IgG served as a key reagent to help iden-
tify both the PF and PV antigens.82-84 The cloning and
characterization of the pemphigus antigens have sub-
sequently led to the development of enzyme-linked
immunosorbent assays (ELISAs) to improve the sen-
sitivity and specificity of disease diagnosis, and con-
tinued studies on pemphigus pathophysiology aim to
develop safer and effective therapies for these poten-
tially fatal diseases. A recent in-depth review discusses
these issues.85
PEMPHIGUS
AUTOANTIGENS
Pemphigus antigens are desmogleins, transmembrane
glycoproteins of desmosomes (cell-to-cell adhesion
structures, reviewed in Chap. 15).86,87 Desmogleins are
part of the cadherin superfamily of calcium-dependent
cell-adhesion molecules. The original members of this
family (eg, E-cadherin) demonstrate homophilic adhe-
sive interactions (binding between like molecules).
Desmogleins similarly demonstrate homophilic bind-
ing but likely participate in predominantly heterophilic
adhesion by binding desmocollins, the other major
transmembrane glycoprotein of desmosomes.88-90
The PF antigen (as well as the fogo selvagem anti-
gen) is desmoglein 1, a 160-kDa protein.82,83,91 The PV
antigen is desmoglein 3, a 130-kDa protein that is 64% 915
03/12/18 8:59 am
 9 similar and 46% identical in amino acid sequence
to desmoglein 1.84 All patients with PV have anti–
desmoglein 3 antibodies, and some of these patients
also have anti–desmoglein 1 antibodies.92,93 Patients
with mucosal-dominant PV tend to have only anti–
desmoglein 3 antibodies, whereas those with muco-
cutaneous disease usually have both anti–desmoglein
3 and anti–desmoglein 1 antibodies.94-96 PF patients
typically have antibodies against only desmoglein 1.
However, these rules are not true for every patient.97,98
IgG antibodies against another desmosomal cadherin,
desmocollin, can be found infrequently in PV, pemphi-
gus vegetans, and atypical pemphigus patients.99,100 Fur-
thermore, mice with a targeted deletion of desmocollin
Part 9
3 have PV-like skin lesions,101 and anti-desmocollin anti-
bodies can cause acantholysis in vitro.99,102
Other cell surface molecules such as acetylcholine
receptors and E-cadherin also have been identified as
::
immunologic targets of pemphigus serum, although
Vesiculobullous Disorders
their direct involvement in the pathophysiology of
pemphigus has not been well validated.103-106
ELECTRON MICROSCOPY
Early ultrastructural studies of the blisters in pemphi-
gus vulgaris and foliaceus focused on the appearance
of desmosomes, because these are the most promi-
nent cell-to-cell adhesion junctions in stratified squa-
mous epithelia (Chap. 15). Almost all studies confirm
that at various time points during acantholysis, the
desmosome is affected and ultimately destroyed,
consistent with the cell biologic data discussed in the
section below. However, conclusions from electron
microscopy studies as to the mechanism of desmo-
some destruction have varied. Several groups have
proposed that the first pathologic event in pemphigus
is intercellular widening of interdesmosomal cell mem-
branes, with intact desmosomal junctions.107-110 Other
studies have demonstrated half-split desmosomes
without keratin tonofilament retraction, suggesting
that pemphigus autoantibodies directly interfere with
the trans-adhesive interface of desmosomes, and that
keratin retraction is secondary to the loss of intercellu-
lar adhesion. Half-desmosomes without tonofilament
collapse also have been observed in a mouse model of
PV.111,112 Others have proposed that keratin retraction is
a primary pathogenic event in pemphigus, triggered
by cellular signaling after PV autoantibody binding.113
As a potential reconciliation of these findings, one study
found that electron microscopic findings may differ
depending on the site analyzed: in early blisters, half-
desmosomes without keratin retraction are observed; in
well-developed lesions, keratin retraction from half-des-
mosomes occurs; and in spongiotic non-blistered skin,
intercellular widening with intact desmosomal junc-
tions can be found, similar to electron microscopy find-
ings in other spongiotic epidermal diseases.114 Similarly,
large-scale electron microscopic maps (“nanotomy”)
916 have identified evidence of both half desmosomes and
smaller desmosomes in pemphigus patients,115 and
Kang_CH052_p0909-0933.indd 916
super-resolution microscopy indicates that desmo-
somes are smaller in PV patients,116 consistent with a
desmoglein nonassembly/desmosome depletion model
for pathogenesis as discussed below.
Currently, electron microscopy studies are not part
of the clinical diagnostic workup for pemphigus.
PATHOPHYSIOLOGY OF
ACANTHOLYSIS
Autoantibodies in pemphigus are pathogenic as sug-
gested by neonatal pemphigus, discussed above, in
which mothers with even mild PV can pass IgG auto-
antibodies to the fetus, causing blistering oral and skin
disease that resolves by approximately 6 months, con-
current with the disappearance of maternal IgG from
the circulation.58
Several lines of evidence indicate that it is the anti-
desmoglein 1 and 3 antibodies in pemphigus patients
who directly cause blisters and hence are the etiologic
agents of disease. Passive transfer of PV or PF IgG to
neonatal mice or human skin causes blisters that clini-
cally and histologically mimic the corresponding type
of pemphigus in patients.117-119 The anti-desmoglein
antibodies are responsible for blister formation in the
passive transfer model, because affinity purified anti-
desmoglein 1 and 3 autoantibodies cause PF and PV
blisters, respectively, and adsorption of desmoglein-
reactive autoantibodies from PF or PV IgG abrogates
disease.120-124 Finally, mice with a targeted deletion of the
desmoglein 3 gene have clinical and histologic lesions
similar to PV patients,125 suggesting that inactivation
of desmoglein 3 results in a PV-like blister. Similarly,
exfoliative toxin, the staphylococcus toxin that causes
blisters in bullous impetigo and staphylococcal scalded
skin syndrome, cleaves desmoglein 1 and results in a
blister with a histology similar or identical to PF.126
Unlike many other autoantibody-mediated dis-
eases, such as pemphigoid and epidermolysis bul-
losa acquisita, in which the constant region of the
antibody is required for blister formation to activate
complement or bind antibody receptors on inflam-
matory cells, in pemphigus the variable region of
the antibody is sufficient to cause blisters in neonatal
mice or human skin.119,127-129 Furthermore, IgG4, which
does not fix complement, has been shown to be both
pathogenic and the predominant IgG subclass in both
PF and PV.130-132 For this reason, a significant amount
of research on disease pathophysiology has focused
on the epitopes bound by pathogenic autoantibod-
ies, as these regions are likely critical for maintaining
desmosomal cell adhesion. Epitope mapping studies
have shown that pathogenic PV and PF autoantibodies
bind calcium-sensitive, conformational epitopes in the
amino terminal extracellular domains of desmogleins,
whereas nonpathogenic antibodies tend to bind more
membrane proximal extracellular domains.133-136 The
amino terminal domains bound by pathogenic auto-
antibodies are the same domains that are predicted
03/12/18 8:59 am
 to form the key molecular interactions for desmoglein
intercellular adhesion, based on studies of cadherin
ultrastructure.90,137,138 Furthermore, PV IgG have
been shown to directly inhibit desmoglein 3–mediated
trans-interactions by atomic force microscopy.139
Collectively, these data form the basis for the “steric
hindrance” hypothesis, which proposes that patho-
genic antibodies directly interfere with desmoglein
adhesive interactions, causing acantholysis.
Studies on cultured keratinocytes have indicated
that loss of intercellular adhesion by pathogenic auto-
antibodies leads to internalization and degradation of
desmogleins,140-143 thereby amplifying the loss of des-
moglein function. As discussed above, loss of desmo-
glein 3 and 1 function results in PV- and PF-like blisters
in model systems in which desmogleins are targeted
genetically or by enzyme cleavage.
If inactivation of desmoglein isoforms results in blis-
tering, then why do blisters in PV and PF have specific
tissue localizations that do not necessarily correlate
with the sites at which the antibodies bind by immuno-
fluorescence? In PF, for example, the anti–desmoglein 1
antibodies bind throughout the epidermis and mucous
membranes,144 yet blisters occur only in the superficial
epidermis. This apparent paradox can be explained
by desmoglein compensation, as outlined in Fig. 52-5.
The concept of desmoglein compensation originates
in the assumption that autoantibodies against one
desmoglein isoform inactivate only that isoform and
that another isoform co-expressed in the same area
can compensate in adhesion.145-147 Desmoglein com-
pensation explains why neonatal PF is so unusual,
because even though the maternal anti–desmoglein
1 antibodies cross the placenta, in neonatal skin, but
not in adult skin, desmoglein 3 is co-expressed with
desmoglein 1 in the superficial epidermis, thereby
providing protection against the loss of desmoglein
1-based adhesion.146,148 Desmoglein compensation also
offers an explanation for the differing sites of blister
formation in PV and PF, both in regard to the histology
(ie, suprabasal or superficial), as well as the areas of
involvement (mucosa and/or skin).
Further studies have suggested that perturbation
of cell signaling pathways can mediate and/or mod-
ulate blister formation in pemphigus. For example,
inhibition of the p38 mitogen activated protein kinase
(MAPK) pathway and activation of Rho GTPases,
among others, can prevent blister formation after pas-
sive transfer of pemphigus IgG in the neonatal mouse
model.149-151 The p38 MAPK pathway has been most
studied in this regard. It activates EGF receptor after
PV antibody binding, and blocking of this recep-
tor also blocks loss of cell adhesion.152 Although p38
activation may be secondary to loss of cell adhesion,
blocking it does decrease the degree of acantholysis,
suggesting that it would be a useful target in pemphi-
gus therapy.153,154 A more specific target in this path-
way, downstream of p38, is MAPK activated protein
kinase 2 (MK2), which also can be blocked to modu-
late pemphigus blister activity, especially spontaneous
blistering as opposed to blistering due to trauma (ie,
Nikolsky blistering).155 Finally, in vitro studies with
Kang_CH052_p0909-0933.indd 917
monoclonal anti-desmoglein 3 antibodies and human
pemphigus antibodies suggest that acantholysis is a
9
net result of both direct steric hindrance of pathogenic
monoclonal antibodies and polyclonal antibodies that
may not directly cause steric hindrance but that cause
internalization of desmogleins by crosslinking them.
This latter effect is dependent on MAPK signaling.156
The depletion of desmogleins by pemphigus anti-
bodies may lead to loss of desmogleins in desmosomes
resulting in smaller desmosomes and/or their defective
function in adhesion, a scenario referred to as the Dsg
nonassembly depletion hypothesis.115,140,141,157,158 Consistent
with this idea is the observation by direct immunofluo-
rescence of clustering of Dsgs in both PV and PF patients’
skin and that forced increased expression of Dsg3 can
Chapter 52 :: Pemphigus
prevent acantholysis by pemphigus antibodies.159
The current general consensus is that desmosomal
adhesion is a dynamic process that is perturbed by
pemphigus autoantibodies both directly and by sig-
naling pathways.160 Therefore, therapies that aim to
strengthen keratinocyte adhesion by modulation of
signaling pathways may have a beneficial effect on
pemphigus, regardless of whether cell signaling is a
primary pathologic cause of disease.
GENETIC
CHARACTERIZATION
OF THE PEMPHIGUS
IMMUNE RESPONSE
Compared to a matched population, patients with PV
have a markedly increased frequency of certain class
II major histocompatibility complex (MHC) antigens.
Among Ashkenazi Jews with PV, the serologically
defined HLA-DR4 haplotype is predominant, whereas
in other ethnic groups with PV, the DQ1 allele is more
common.161 However, the association with disease sus-
ceptibility becomes even more striking in an analysis
of these MHC alleles at a genetic level. Patients with
the DR4 serotype almost all have the unusual allele
DRB1∗0402, and patients with the DQ1 serotype almost
all have the rare allele DQB1∗0503. Similar, but less
restricted, HLA-DR alleles are associated with PF.162
The protein chains encoded by these PV MHC II alleles
vary from those found in HLA-DR4 and DQ1 controls
without disease by only a few amino acids. Other stud-
ies have confirmed that the immune response in pem-
phigus is restricted to certain desmoglein peptides and
MHC class II alleles.163-166
MHC class II alleles encode cell surface molecules
that are necessary for antigen presentation to the
immune system; therefore, it is hypothesized that PV-
associated MHC class II molecules facilitate presenta-
tion of desmoglein 3 peptides to T cells.167 Consistent
with this hypothesis, certain peptides from desmo-
glein 3, predicted to fit into the DRB1∗0402 peptide-
binding pocket, were found to stimulate T cells from
patients.168 More direct proof of the importance of the 917
03/12/18 8:59 am
 9 Desmoglein (DSG) compensation

Pemphigus foliaceus
Skin Mucous membrane

anti-Dsg1

1 3 3
Part 9
::
Vesiculobullous Disorders

Pemphigus vulgaris
Skin Mucous membrane

anti-Dsg3
only

1 3 3

Skin Mucous membrane

anti-Dsg3 1
+
anti-Dsg1

1 3 3

Figure 52-5 Desmoglein (Dsg) compensation. Triangles represent the distribution of Dsg1 and Dsg3 in skin and mucous
membranes. Anti-Dsg1 antibodies in pemphigus foliaceus cause acantholysis only in the superficial epidermis of skin.
In the deep epidermis and in mucous membranes, Dsg3 compensates for antibody-induced loss of function of Dsg1. In
mucosal pemphigus vulgaris, antibodies against Dsg3 are predominant, which cause blisters only in the deep mucous
membrane where Dsg3 is present without compensatory Dsg1. However, in mucocutaneous pemphigus, antibodies
against both Dsg1 and Dsg3 are present, and blisters form in both mucous membrane and skin. The blister is deep prob-
ably because antibodies diffuse from the dermis and interfere first with the function of desmosomes at the base of the
918 epidermis.

Kang_CH052_p0909-0933.indd 918 03/12/18 8:59 am

 DRB1∗0402 allele comes from a study of a human-
ized HLA-transgenic mouse for this allele in which
presentation of the immunodominant Dsg3 peptides
to human T cells results in production of pemphigus
antibodies and the epidermal pathology of PV.169
Expression of Dsg3 in the thymus, mediated by the
Aire transcription factor, promotes tolerance of CD4
T cells to stimulation by Dsg3.170 An unexpected
observation was that T cells of normal people with
the DRB1∗0402 or DQB1∗0503 respond just as well as
those of pemphigus patients to the same desmoglein 3
peptides,167,171 indicating that T-cell reactivity to desmo-
glein 3 peptides is not sufficient for disease onset. Dsg-
specific CD4+ T cells provide help to simulate anti-Dsg
B cells to produce antibodies.172 In this context, CD4+
T follicular helper cells are thought to be particularly
important. Concordantly, there are increased T follicu-
lar helper cells with their associated cytokine, IL-27, in
PV patients.173 Another factor that may determine who
gets pemphigus and who does not has been proposed
to be the presence of regulatory T cells that can sup-
press the autoimmune response in those who do not.174
Likely, multiple factors prevent T-cell Dsg responsive-
ness and subsequent help for B-cell anti-Dsg antibody
production.
Cloning of anti-desmoglein B-cell repertoires from
PV and PF patients has elucidated the diversity of the
antibody variable region genes contributing to the
pemphigus immune response.128,129,175 Shared VH1-46
gene usage has been identified in anti-Dsg3 B cells
among PV patients, probably because antibodies using
this gene require few or no mutations to bind Dsg3,
which may favor the selection of VH1-46 B cells early in
the autoimmune response.176 However, multiple other
VH genes have been identified in anti-Dsg3 antibod-
ies among PV patients that are more highly mutated
and may not be shared,128,177-179 although anti-Dsg anti-
bodies from different PV patients have been shown to
bind at or near common epitopes on desmoglein 3.177
Analysis of anti-Dsg1 IgG B-cell repertoires in fogo sel-
vagem patients has identified enrichment for VH3-23
heavy chain gene usage, as well as IGKV1D-39 light
chain gene usage, with evidence of shared mutations
as well as an increased number of somatic mutations in
the antigen-binding regions of Dsg1-reactive antibod-
ies, suggesting antigen-driven selective pressure.180
Cross-reactivity in the B-cell repertoire to foreign
and self-antigen has been proposed as a mechanism
for the onset of autoimmunity in both PV and PF. In
addition to the autoantibody cross-reactivity to LJM11
sand fly antigen and Dsg1 discussed previously,16 Dsg3
autoantibodies in PV have been shown to cross-react
with rotavirus VP6 coat protein, and VH1-46 mAbs
that both induce suprabasal blisters and inhibit rotavi-
rus infectivity have been identified.176 Unmutated IgM
VH1-46 B cells have a propensity to bind both rotavi-
rus VP6 coat protein,181 as well as the PV autoantigen
Dsg3.176 However, cross-reactivity to VP6 and Dsg3 in
the IgG compartment is rare because of the differing
nature of somatic mutations that confer VP6 versus
Dsg3 reactivity, thus preventing the onset of pemphi-
gus after rotavirus exposure.
Kang_CH052_p0909-0933.indd 919
To produce anti-Dsg autoantibodies, B cells must
lose tolerance to Dsg, which is a self-antigen. Studies
9
of cloned anti-Dsg B cells have shown that through-
out the course of PV, over the years, the same clones
of anti-Dsg B cells persist and new ones generally are
not produced.182 These data suggest that some event
causes a time-limited loss of tolerance of B cells to Dsg,
and if these B-cell clones can be completely eliminated,
patients might be cured, thus explaining the rationale
for B-cell depletion therapy in pemphigus.
DIAGNOSIS
Diagnosis of pemphigus relies on skin biopsy of a fresh
Chapter 52 :: Pemphigus
lesion for histology to determine the site of blister for-
mation, as well as a confirmatory immunochemical
study to document the presence of skin autoantibod-
ies, either by direct immunofluorescence of perile-
sional skin, or indirect immunofluorescence or ELISA
of patient serum.
LABORATORY TESTING
IMMUNOFLUORESCENCE
The hallmark of pemphigus is the finding of immuno-
globulin G (IgG) autoantibodies against the cell sur-
face of keratinocytes. These autoantibodies were first
discovered in patients’ sera by indirect immunofluo-
rescence techniques and soon thereafter were discov-
ered by direct immunofluorescence of patients’ skin.183
Direct Immunofluorescence: Essentially all
patients with active PV or PF have a positive finding on
a direct immunofluorescence study, which tests for IgG
bound to the cell surface of keratinocytes in perilesional
skin (Fig. 52-6A, Table 52-2).184 This is a non-quantitative
test (either negative or positive). The diagnosis of pem-
phigus should be seriously questioned if the test result
of direct immunofluorescence is negative. It is impor-
tant that the biopsy for direct immunofluorescence be
performed on normal-appearing perilesional skin, as
the immune reactants can be difficult to detect in blis-
tered inflamed epidermis (leading to a false negative
result). In some cases of pemphigus erythematosus, IgG
and C3 are deposited at the basement membrane zone
of erythematous facial skin, in addition to the epidermal
cell surface IgG, representing a positive lupus band test
in addition to the typical pemphigus intercellular pat-
tern.185 In at least some cases, this band may be the result
of UV-induced cleavage of Dsg1 with its accumulation
at the basement membrane.56
Indirect Immunofluorescence: Indirect immu-
nofluorescence is performed by incubating serial dilu-
tions of patients’ sera with epithelial substrates. It is
reported as a semiquantitative titer (indicating the last
dilution at which the serum demonstrates a positive
cell surface staining pattern). The test is offered by most 919
major national laboratories and can remain positive for
03/12/18 8:59 am
 9

A B
Part 9

Figure 52-6 Immunofluorescence in pemphigus. A, Direct immunofluorescence for immunoglobulin G (IgG) of perile-
sional skin from a patient with pemphigus vulgaris. Cell surface staining is observed throughout the epidermis with a
slight basal predominance. B, Indirect immunofluorescence with the serum from a patient with pemphigus foliaceus on
::

normal human skin. IgG is observed on the cell surface throughout the epidermis with a slight superficial predominance.
Vesiculobullous Disorders

weeks to months after healing of skin lesions, making
it a good diagnostic test if a patient should present
with no active skin lesions, for example due to empiric
treatment with prednisone by a referring physician.
Depending on the substrate used for indirect immu-
nofluorescence, more than 80% of patients with pem-
phigus have circulating anti–epithelial cell surface IgG
(Fig. 52-6B, Table 52-2).186 The substrate used to detect
pemphigus antibody binding in indirect immunofluo-
rescence greatly influences the sensitivity of the test.
In general, monkey esophagus is more sensitive for
detecting PV antibodies, and guinea pig esophagus
or normal human skin is a superior substrate for detect-
ing PF antibodies. Patients with early localized disease
and those in remission are most likely to have negative
findings on an indirect immunofluorescence test; for
these patients, the increased sensitivity of ELISA may
help in diagnosis (see below).
Patients with PV and PF usually display similar direct
and indirect immunofluorescence findings with IgG on
the cell surface of epidermal cells throughout the epi-
dermis, despite the different autoantigen profiles in
these 2 diseases. Therefore, it is usually not possible to
differentiate the 2 diseases by the pattern of immuno-
fluorescence. There is a positive, but imperfect, corre-
lation between the titer of circulating anti–cell surface
antibody and the disease activity in PV and in PF.187
Although this correlation may hold in general, and
although patients in remission often show serologic
remission with negative direct and indirect immuno-
fluorescence findings,188,189 disease activity in individual
patients does not necessarily correlate with indirect
immunofluorescence titer. Therefore, in the day-to-day
management of these patients, following disease activ-
ity is more important than following antibody titer.
ENZYME-LINKED
IMMUNOSORBENT ASSAY
920 For diagnosis of disease, antigen-specific ELISAs
have been shown to be more sensitive and specific
than immunofluorescence, and their titer correlates
better than that of indirect immunofluorescence with
disease activity.92,190,191 Additionally, ELISAs are easier
to perform and less subjective than immunofluores-
cence, and have for many physicians replaced the
latter as the preferred first diagnostic test for pemphi-
gus (Table 52-2). These assays use desmogleins 1 and
3 bound to plates, which are then incubated with
patient sera and developed with anti-human IgG
reagents (Fig. 52-7). As an advantage over indirect
Enzyme-linked immunosorbent assay (ELISA)
for desmoglein 3
Irrelevant antibodies
α Dsg3
Dsg3
HRP-anti-human IgG
HRP-substrate
Figure 52-7 Enzyme-linked immunosorbent assay (ELISA)
for desmoglein 3. Anti-Dsg3 antibodies (αDsg3) from
pemphigus serum binds Dsg3 on the ELISA plate; irrel-
evant antibodies, that do not bind, are washed off. The
plate is then incubated with horseradish peroxidase (HRP)
conjugated anti-human IgG, which binds the anti-Dsg3
IgG that is on the plate. HRP is an enzyme that turns a clear
substrate blue, and the amount of color, read on spectro-
photometer, correlates with the amount of pemphigus
(ie, anti-Dsg3) antibody in the patient’s serum.

Kang_CH052_p0909-0933.indd 920 03/12/18 8:59 am

 immunofluorescence, ELISAs can help differentiate
between PV and PF because of the different autoanti-
gen profiles in these 2 diseases.92,190 In most cases, ELISA
is positive for desmoglein 3 (but not desmoglein 1) in
mucosal PV, is positive for both desmogleins 3 and 1 in
PV with both mucosal and significant skin involve-
ment, and is positive for only desmoglein 1 in PF. PV
has rarely evolved into PF, and vice versa, as deter-
mined by clinical, histologic, and immunochemical
criteria.192-194 A small minority of PF patients may also
demonstrate autoantibodies to desmoglein 3195; there-
fore, diagnosis should be made based on the clinical-
serologic correlation. Additionally, some patients (eg,
those with bullous pemphigoid) may demonstrate
a low level of anti–desmoglein 3 autoantibodies,190
which are detectable because of the high sensitivity
of the ELISA. Therefore, a result in the indeterminate
range should be interpreted carefully, as this may
represent a true positive or a false positive, the latter
presumably because of formation of nonpathogenic
bystander autoantibodies after epidermal damage. As
with indirect immunofluorescence, the correlation of
ELISA index value with disease activity is not perfect.
For example, although ELISA titers correlate with clin-
ical activity, patients in clinical remission (often still
on corticosteroid therapy) whose titers have dropped
from peak values may still have positive results.196 In
making treatment decisions, a negative result on des-
moglein ELISA is more helpful than a positive result,
as a patient with the former is more likely to achieve
remission off immunosuppressives, whereas a patient
with the latter may or may not. In other words, disease
activity is the mainstay for determining treatment.
PATHOLOGY
The characteristic histopathologic finding in PV is
a suprabasal blister with acantholysis (Fig. 52-8,
Table 52-2). Just above the basal cell layer, epidermal
cells lose their normal cell-to-cell contacts and form a
blister. Often, a few rounded up (acantholytic) kera-
tinocytes are in the blister cavity. The basal cells stay
attached to the basement membrane, but may lose
the contact with their neighbors; as a result, they may
Figure 52-8 Histopathology of pemphigus vulgaris.
Suprabasal acantholysis. The row of tombstones.
Kang_CH052_p0909-0933.indd 921
appear to be a “row of tombstones,” symbolic of the
potentially fatal prognosis of this disease. Usually,
9
the upper epidermis (from 1 or 2 cell layers above the
basal cells) remains intact, as these cells maintain their
cell adhesion. Pemphigus vegetans shows not only
suprabasal acantholysis but also papillomatosis of the
dermal papillae and downward growth of epidermal
stands into the dermis, with hyperkeratosis and scale-
crust formation. In addition, pemphigus vegetans
lesions may show intraepidermal abscesses composed
of eosinophils and/or neutrophils.197 Early PV lesions
may show eosinophilic spongiosis.198
The histopathology of early blisters in PF patients
demonstrates acantholysis (loss of cell-to-cell contact)
Chapter 52 :: Pemphigus
just below the stratum corneum and in the granular
layer (Fig. 52-9A). The stratum corneum is often lost
from the surface of these lesions. The deeper epider-
mis, below the granular layer, remains intact. Another
frequent finding is subcorneal pustules, with neutro-
phils and acantholytic epidermal cells in the blister
cavity (Fig. 52-9B). Histologic findings in PF are often
indistinguishable from those seen in bullous impe-
tigo/staphylococcal scalded skin syndrome, because
blisters in these latter diseases also result from dys-
function of desmoglein 1, in these cases due to proteo-
lytic cleavage by Staphylococcal exfoliative toxins.87
Therefore, immunochemical studies are essential to
confirm a diagnosis of PF, as these would be negative
in Staphylococcal-mediated skin blisters. The site of
A
Figure 52-9 Histopathology of pemphigus foliaceus. A,
Acantholysis in the granular layer. B, Subcorneal pustule 921
with acantholysis.
03/12/18 8:59 am
 9 blister formation in pemphigus erythematosus is iden-
tical to PF. As in PV lesions, very early PF lesions may
show eosinophilic spongiosis.198
DIFFERENTIAL DIAGNOSIS
See Table 52-1.
CLINICAL COURSE AND
PROGNOSIS
Part 9
Before the advent of glucocorticoid therapy, PV was
almost invariably fatal due to severe blistering of the
skin and mucous membranes, leading to malnutrition,
dehydration, and sepsis. PF was fatal in approximately
::
60% of patients. PF was almost always fatal in elderly
Vesiculobullous Disorders
patients with concurrent medical problems; however,
in other patients, its prognosis, without therapy, was
much better than PV.199,200
The systemic administration of glucocorticoids and
the use of immunosuppressive therapy have dramati-
cally improved the prognosis for patients with pemphi-
gus; however, pemphigus is still a disease associated
with a significant morbidity and mortality.201,202 In the
United States, the annual mortality rate from pemphi-
gus (age-adjusted to the standard population) is esti-
mated to be 0.023 deaths per 100,000.203 The inpatient
mortality from pemphigus has been estimated at 1.6%
to 3.2%, with increased mortality likely due to numer-
ous comorbid health conditions.79 The risk of death in
pemphigus vulgaris patients is 2.36 to 3.3 times greater
than for controls in the United Kingdom and Taiwan.9,11
Infection is often the cause of death, and by causing
the immunosuppression necessary in the treatment
of active disease, therapy is frequently a contribut-
ing factor.11,204 With glucocorticoid and oral immuno-
suppressive therapy, the mortality (from disease or
therapy) of PV patients followed from 4 to 10 years
is approximately 10% or less, whereas that of PF is
probably even less. In a study of 40 patients with PV, 2
patients (5%) died of sepsis and 17%, after an average
of 18 months of therapy, went into a complete and long-
lasting (>4 years, average, thought to be permanent)
remission requiring no further therapy.205 Another 37%
of patients achieved remission but relapsed at times
after therapy was stopped; most of these also eventu-
ally achieved long-lasting remissions. The remainder
of patients required continual therapy. In a group of
159 patients with PV from Croatia, only approximately
12% went into long-term remission after therapy with
glucocorticoids and immunosuppressives, but most
relapsed.23 In a study from Tehran of 1206 pemphigus
patients seen over 20 years, 6.2% of PV and 0.2% of PF
patients died, mostly of septicemia; only 9.3% were in
complete remission without therapy.7 Another study
showed that; with the use of corticosteroids, about
50% of patients went into at least transient complete
922 remission off therapy after a mean of 3 years.206 Immu-
nosuppressive adjuvant therapy may reduce the risk
Kang_CH052_p0909-0933.indd 922
of relapse.207 With the advent of rituximab therapy,
complete remission in pemphigus has become more
common and is quicker to achieve. Approximately
50-90% of PV patients go into remission off all other
immunosuppressive therapy, after 1 or more courses of
rituximab.208 Similar remission rates are found in PF.209
MANAGEMENT
Several consensus guidelines for pemphigus disease
therapy have been published.211-214 It is generally agreed
that PV, even if initially limited in extent, should be
treated at its onset, because it will ultimately general-
ize and the prognosis without therapy is very poor. In
addition, it is probably easier to control early disease
than widespread disease, and mortality may be higher
if therapy is delayed.215 Because PF may be localized
for many years, and the prognosis without systemic
therapy may be good, patients with this type of pem-
phigus do not necessarily require treatment with sys-
temic therapy; the use of topical corticosteroids may
suffice. When the disease is active and widespread,
however, the therapy for PF is, in general, similar to
that for PV.
A consensus statement on disease definitions and
endpoints was proposed by an international com-
mittee of pemphigus experts.216 Additionally, clinical
instruments have been developed for tracking dis-
ease activity that have been shown to be reliable and
valid.217,218 The standardization of disease definitions
and activity scoring will facilitate future clinical trials
for pemphigus.
There has been a tremendous advance in the arma-
mentarium of therapies for pemphigus since the time
before the development of glucocorticoids when PV
was a fatal disease. Thanks to these advances, the “row
of tombstones” seen in the pathology of PV no longer
alludes to its prognosis for most patients.
CORTICOSTEROIDS
The systemic administration of glucocorticoids, usually
prednisone, remains the mainstay of therapy for pem-
phigus. Before adjuvant immunosuppressive therapy
was available, very high initial doses of prednisone
(>2.0 mg/kg/d) were used for treatment, although such
regimens have retrospectively been associated with sig-
nificant morbidity and mortality from therapy.204,219,220 The
full systemic dose of glucocorticoids has been defined in
the consensus guidelines as 1.5 mg/kg/d of prednisone
equivalent for 2 to 3 weeks.216 However, many patients
can be brought under control with a 0.5- to 1.0-mg/kg/d
single daily dose, especially if used in combination
with adjunctive immunosuppressive therapy, which is
thought to result in fewer complications and decreased
mortality as compared to higher-dose glucocorticoid
regimens.221,222 For patients who do not initially respond
or worsen, splitting the dose using a twice- or 3-times-
daily schedule may achieve disease control.
03/12/18 8:59 am
 Once disease activity is controlled, tapering pred-
nisone to as low a dose as possible should be the
goal. Minimal therapy is defined as 5 to 10 mg daily
of prednisone equivalent. Although there are no set
guidelines, if disease activity can be fully controlled
on minimal-dose prednisone or lower, then glucocor-
ticoid monotherapy may be feasible depending on the
patient’s other comorbidities and contraindications
to alternative immunosuppressive agents. If patients
have continued relapses, with daily prednisone doses
approaching or exceeding 5 to 10 mg, adjunctive
immunosuppressive agents are warranted.
Interestingly, prednisone can control blistering
within days, at a time when the autoantibody titer
would be unchanged. A possible explanation is that
prednisone increases the synthesis of desmogleins or
other cell-adhesion molecules or change their posttran-
scriptional processing to prolong their half-life.223,224 If
pemphigus IgG depletes desmosomes of desmogleins,
as discussed above, then prednisone could counteract
this effect.
Topical corticosteroids may be used as monotherapy
in mild forms of disease, especially PF, or as adjunctive
therapy to help heal new lesions. Patients with muco-
sal disease may benefit from the use of glucocorticoid
elixirs as a swish and spit for dental trays to help apply
class I corticosteroid gels or ointments to the gingiva.
Additionally, class I-IV corticosteroids can be used as
topical therapy to help resolve new blisters, even in
patients on systemic glucocorticoids.
RITUXIMAB
A very effective therapy for pemphigus, even in cases
refractory to standard immunosuppressive therapy, is
a monoclonal anti-CD20 antibody, rituximab, which
was approved by the FDA for therapy of pemphigus
vulgaris in 2018. Rituximab targets B cells, the precur-
sors of antibody-producing plasmablasts. The B cell
also acts to process autoantigen and present it to T cells
that provide “help” in stimulating the autoantibody
response.225 Rituximab is infused intravenously at a
dose of 1000 mg on day 1 and day 15. A maintenance
dose of 500 mg can be infused at 12 months and every
6 months thereafter based on clinical evaluation, or a
1000 mg dose if clinical relapse occurs. A pivotal clini-
cal trial comparing first line rituximab therapy plus
short-term prednisone (0.5-1.0 mg/kg/day) to high
dose (1.5 mg/kg/day) prednisone alone for moderate
to severe pemphigus showed superior rates of com-
plete remission off prednisone in the rituximab-treated
group (89% versus 34%), although maintenance dos-
ing appears to be required to prevent disease relapse.
Although not the FDA-approved dose, a lymphoma
dose regimen of 375 mg/m2 once weekly for four
weeks has also been evaluated in a prospective clinical
trial.226 A single cycle of rituximab using the lymphoma
dose has been shown to be effective even in relapsed
and refractory pemphigus, with 86% of patients expe-
riencing complete healing of skin lesions on or off
Kang_CH052_p0909-0933.indd 923
prednisone.226 Approximately 80% of patients relapse
and require additional therapy to regain disease
9
control,209 but with repeat cycles of rituximab and/or
additional prednisone therapy after clinical relapse,
48% of PV and PF patients, including those with previ-
ously refractory disease, are ultimately able to achieve
complete remission off prednisone. Disease activity
usually begins to remit within 3 months of rituximab
infusion; with first-line rituximab therapy, the median
time to complete remission off steroids is 9 months.
Rituximab has also been shown to be an effective ther-
apy for children with refractory pemphigus.227-229
Therapy with rituximab, as with other immunosup-
pressive treatments, has significant risks.230 37% of
Chapter 52 :: Pemphigus
PV patients treated with rituximab plus prednisone
experienced treatment-related infections, similar to the
rate (42%) observed in patients treated with high-dose
prednisone alone. Grade 3 or higher infectious adverse
events requiring hospitalization were observed in 8%
of rituximab and prednisone-treated patients, com-
pared to 3% treated with prednisone alone. Fatal infec-
tions with rituximab and prednisone therapy have
been observed with chronic rituximab therapy, includ-
ing sepsis, Pneumocystis pneumonia, reactivation of
hepatitis B, and JC virus infection reactivation causing
progressive multifocal leukoencephalopathy.209,231-233 In
addition, 56% of PV patients treated with rituximab
develop anti-drug antibodies. Although the clinical sig-
nificance of this immunogenicity is currently unclear,
one PV patient was reported to develop neutralizing
anti-chimeric antibodies to rituximab, associated with
infusion reactions and lack of clinical efficacy.234
ORAL
IMMUNOSUPPRESSIVE
AGENTS
As rituximab is not accessible to all pemphigus patients,
many experts still use oral immunosuppressive ther-
apy, usually with, but also without, prednisone, from
the beginning of therapy. Certainly, when continued
doses of glucocorticoids greater than 5 to 10 mg are
required for disease control, or if there are contraindi-
cations to or intolerable side effects from oral gluco-
corticoids, adjunctive immunosuppressive agents are
used for pemphigus therapy. Prospective randomized
studies have shown that immunosuppressive agents
such as mycophenolate mofetil and azathioprine have
a steroid-sparing effect; retrospective studies suggest
decreased mortality with use of adjuvants plus ste-
roids compared to steroids alone.199,235-238
Because patients may die from complications of
therapy, it is important to monitor all patients closely
for potential side effects, such as blood count, liver and
kidney laboratory abnormalities, GI ulcer disease, high
blood pressure, diabetes, glaucoma, cataracts, osteoporo-
sis, and infection. The decision to use immunosuppres-
sive agents, particularly in young patients, must also take 923
into account the potential incidence of malignancies that
03/12/18 8:59 am
 9 might be associated with the long-term use of these drugs,
as well as the risks of teratogenicity (for mycophenolate
mofetil, azathioprine, and methotrexate). Use of myco-
phenolate in women of child-bearing potential requires
counseling and monitoring regarding pregnancy.
AZATHIOPRINE
Azathioprine is an effective adjunctive immunosup-
pressive agent for pemphigus, with clinical remis-
sion rates of approximately 50% in retrospective
studies.189,229 In a prospective randomized trial of
high-dose methylprednisolone (2.0 mg/kg/d) plus
azathioprine (2.0 mg/kg/d), 72% of patients achieved
Part 9
even in patients whose disease is unresponsive to
azathioprine.244,245 A prospective randomized trial com-
paring methylprednisolone (2 mg/kg/d) with azathio-
prine (2 mg/kg/d) or mycophenolate mofetil (2.0 g/d)
in pemphigus patients showed 72% in the azathioprine
group and 95% in the mycophenolate mofetil group
went in clinical remission in a mean of 74 and 91 days,
respectively.235 Nineteen percent of patients experi-
enced significant side effects of mycophenolate mofetil
therapy, compared to 33% in the azathioprine group.
None of these differences were statistically significant.
Another trial showed that mycophenolate mofetil
adjuvant therapy decreased the time to initial response
and increased the duration of response to therapy and

tended to decrease prednisone dosage, although the

clinical remission within a mean of 74 days, although
latter was not statistically significant.238 A prospec-
33% experienced significant adverse effects of therapy,
tive randomized study indicated that azathioprine
including hyperglycemia, dizziness, abnormal liver
was significantly more effective than mycophenolate
::

enzyme tests, and infection.235

mofetil as a steroid-sparing agent, although this study
Vesiculobullous Disorders

Azathioprine is a prodrug, which is converted to

active mercaptopurine, thioguanine, and thioinosine
metabolites, in part by thiopurine methyltransferase
(TPMT), an enzyme whose levels can vary widely in the
population. Overall, 89% of whites demonstrate nor-
mal to high levels of TPMT, 11% are intermediate, and
0.3% are deficient for TPMT, the latter group represent-
ing those who do not tolerate azathioprine therapy.240
Additionally, 1% to 2% of whites may have “super high”
levels of TPMT, which is correlated with both treatment
resistance and increased hepatotoxicity from excessive
metabolite production.241 Azathioprine toxicity has
also been associated with genetic polymorphisms in
nucleotide triphosphate diphosphatase (NUDT15), par-
ticularly in Asian populations, and inosine triphosphate
pyrophosphatase (ITPA).242 Altogether, it is estimated
that approximately 5% of patients will be azathioprine
intolerant.243
In patients with normal TPMT levels, the consen-
sus dosing regimen that defines treatment failure is
2.5 mg/kg/d for 12 weeks.216 From a practical stand-
point, however, not all laboratories offer TPMT test-
ing. Additionally, because patients with normal levels
of TPMT may also experience azathioprine toxicity, it
is reasonable to start all patients at a lower dose (eg,
50 to 100 mg daily) and titrate upward until clinical
remission, the target dose of 2.5 mg/kg/d, or unac-
ceptable side effects result. Frequent blood and liver
monitoring should continue, particularly over the first
8 to 12 weeks when delayed toxicity from the accumu-
lation of metabolites may emerge.
MYCOPHENOLATE MOFETIL
Mycophenolate mofetil is also an effective steroid-
sparing agent for pemphigus. Typical doses range
from 30 to 40 mg/kg/d (maximum dose 3 g/d) dosed
twice daily (2.0 to 3.0 g/d), although certain patients
such as the elderly may achieve disease control with
doses as low as 1.0 g/d.
In case series, mycophenolate mofetil has been
924 shown to have a rapid effect in lowering pemphi-
gus antibody titers and decreasing disease activity,
compared a full dose of azathioprine (2.5 mg/kg/d)
to a partial dose of mycophenolate mofetil (2.0 g/d).224
Mycophenolate mofetil also has been reported to be an
effective therapy for pediatric PV.246
Caution with use of mycophenolate mofetil is war-
ranted, as fatal infection and sepsis occurred in 2% to
5% of transplant patients receiving mycophenolate
mofetil, and increased risk of infection with or reac-
tivation of cytomegalovirus, herpes zoster, atypical
mycobacteria, tuberculosis, and JC virus (in progres-
sive multifocal leukoencephalopathy) have been noted
in postmarketing surveillance.247 Interestingly, myco-
phenolate mofetil may offer protection against Pneu-
mocystis carinii infection.248
METHOTREXATE
Once-a-week use of methotrexate is another option
for an immunosuppressive therapy in pemphigus,
although it is not used as frequently as azathioprine or
mycophenolate mofetil.249
INTRAVENOUS
IMMUNOGLOBULIN
Another method of decreasing serum autoantibod-
ies is the intravenous use of γ-globulin (IVIg) in high
doses. IVIg is thought to function by saturating neo-
natal Fc receptor, thereby increasing catabolism of the
patient’s serum antibodies, which include the patho-
genic autoantibodies.250-252 It may be useful as adjuvant
therapy in those pemphigus patients whose condition
does not respond to more conventional therapy.253,254 A
multicenter, randomized, placebo-controlled, double
blind study has confirmed its efficacy in pemphigus,255
but it is expensive and probably requires continued
infusions for maintenance of remission. There also can
be significant side effects with this therapy, includ-
ing stroke, deep venous thrombosis, and aseptic
meningitis.256 Some centers will use IVIg to establish

Kang_CH052_p0909-0933.indd 924 03/12/18 8:59 am

 initial control of blistering in severely affected patients
because it does not increase the risk of infection as do
corticosteroids and immunosuppressants. IVIg also
has been used in combination with rituximab,257,258
although it is unclear whether the combination is safer
or more effective compared to either alone.
OTHER THERAPIES
There are additional therapies that can be used as
adjuncts to standard treatments, or have historically
been used for severe or refractory cases of pemphigus.
Cyclophosphamide, although more toxic than aza-
thioprine, mycophenolate mofetil, or rituximab, is
thought to be very effective in controlling severe dis-
ease, with one report of 19 of 23 patients with pem-
phigus achieving complete remission in a median
time of 8.5 months.259 A variety of small case series
have evaluated different cyclophosphamide regi-
mens for pemphigus, including daily oral therapy
(1.1-2.5 mg/kg/d), daily oral therapy (50 mg) with
intermittent high-dose intravenous dexametha-
sone and cyclophosphamide, and immunoablative
intravenous cyclophosphamide.239,260-263 All methods
were effective in the short term, although none were
curative. Significant side effects, including hematu-
ria, infection, and transitional cell carcinoma of the
bladder, were observed with higher dose regimens,
although one study using a lower daily dose of cyclo-
phosphamide (1.0-1.5 mg/kg/d) did not report a sig-
nificantly different safety profile compared with other
immunosuppressive agents. Together with the risk of
infertility, cyclophosphamide is not considered a first-
line steroid-sparing agent in the treatment of PV.
In a case series and randomized double-blind trial,
dapsone demonstrated a trend toward efficacy as a ste-
roid-sparing drug in maintenance phase PV, although
these results were not statistically significant.264,265 Dap-
sone may be used in conjunction with other immuno-
suppressive agents, particularly rituximab, where it
offers the additional benefit of Pneumocystis pneumo-
nia prophylaxis.
Plasmapheresis is sometimes used for severe pem-
phigus, or for pemphigus that is unresponsive to a
combination of prednisone and immunosuppressive
agents. Although one controlled study found it to be
ineffective,266 other studies have found that it both
reduces serum levels of pemphigus autoantibodies
and controls disease activity.267 Plasmapheresis plus
intravenous pulse therapy with cyclophosphamide has
been reported to result in remissions of PV.268 For maxi-
mum effectiveness, it is necessary to have patients take
immunosuppressive agents to prevent the antibody-
rebound phenomenon that can follow the removal of
IgG. Protein A immunoadsorption, which removes
IgG selectively from plasma, also has been used.269
Intravenous, pulse administration of methylpred-
nisolone 250 to 1000 mg given over approximately
3 hours daily for 4 to 5 consecutive days, can result
in long-term remissions and decrease the total dose
Kang_CH052_p0909-0933.indd 925
of glucocorticoids necessary to control disease.270
Although the purpose of this therapy is to decrease the
9
incidence of complications of long-term steroid use, it
can result in all the usual glucocorticoid complications,
as well as cardiac arrhythmias with sudden death, and
its use is controversial.271 Furthermore, a controlled
trial found that adjuvant oral dexamethasone pulse
therapy in addition to standard therapy with predniso-
lone and azathioprine for PV is not beneficial.272 It may
be that simply giving divided lower doses of predni-
sone could accomplish the same result with fewer side
effects.
Chapter 52 :: Pemphigus
PERSPECTIVES FOR FUTURE
THERAPEUTIC STRATEGIES
Given the well-defined nature of disease in pemphigus
and unmet need for safe and effective therapies, clinical
trials in pemphigus are increasing. As discussed above,
inhibitory anti-chimeric antibodies can cause resis-
tance to rituximab. Fc gamma receptor polymorphisms,
which can cause decreased antibody-dependent cel-
lular cytotoxic killing of B lymphocytes after rituximab
therapy, also have been proposed as a cause of rituximab
resistance,273-276 although these polymorphisms may not
always correlate with therapeutic outcome in patients
with B-cell cancers.277,278 Newer, fully humanized or gly-
coengineered anti-CD20 antibodies may be useful in
these situations279,280, although none are currently in clini-
cal development for pemphigus. PRN1008, an oral cova-
lent inhibitor of the Bruton tyrosine kinase (Btk) required
for mature peripheral B cell survival, has entered Phase 2
trials for pemphigus (NCT02704429). The successful clin-
ical development of these B cell–targeted therapies may
offer novel strategies for pemphigus treatment in the
future.
Agents that block the neonatal Fc receptor (FcRn)
have also recently entered clinical trials in pemphigus,
including SYNT001 (NCT03075904) and ARGX-113
(NCT03334058). FcRn maintains the serum half-life of
IgG and regulates cross-presentation of immune com-
plexes, among other immune functions. Additionally,
a phase 1 study (NCT03239470) has been initiated to
evaluate the safety and preliminary efficacy of ex vivo
expansion and infusion of autologous polyclonal
regulatory T cells, which are hypothesized to restore
immune tolerance in pemphigus patients. Finally, a
novel approach to targeted therapy for pemphigus,
called chimeric autoantibody receptor T cell or CAAR-
T therapy, has demonstrated preclinical efficacy in
experimental PV models.281 CAAR-T therapy uses the
disease autoantigen, Dsg3, as part of a chimeric immu-
noreceptor to program a patient’s own T cells to spe-
cifically kill Dsg-specific B cells, and offers the hope
of a potentially lasting remission of disease without
generalized immune suppression due to the poten-
tial for long-term CAART cell engraftment. Efforts are
underway to determine the clinical efficacy of CAAR-T 925
technology in pemphigus patients.
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