Chapter 54. Pemphigus

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Fitzpatrick's Dermatology in General Medicine, 8e
Chapter 54. Pemphigus
Aimee S. Payne; John R. Stanley
Pemphigus: Introduction
Pemphigus 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.
Diagnosis depends on histology showing intraepidermal acantholysis and immunofluorescence studies documenting the presence of cell surface
autoantibodies, either bound to patient skin or in the serum.
Pemphigus vulgaris histology: suprabasal acantholysis.
Pemphigus foliaceus histology: subcorneal acantholysis.
Direct immunofluorescence shows immunoglobulin G (IgG) on the keratinocyte cell surface of the patient's skin; indirect immunofluorescence shows
IgG in patient serum that binds the cell surface of normal keratinocytes.
Autoantigens are desmogleins, transmembrane desmosomal adhesion molecules.
Therapy includes topical and systemic corticosteroids and immunosuppressive agents.
The term pemphigus refers to a group of autoimmune blistering diseases of skin and mucous membranes that are characterized histologically by
intraepidermal blisters due to acantholysis (i.e., separation of epidermal cells from each other) and immunopathologically by in vivo bound and
circulating immunoglobulin (Ig) directed against the cell surface of keratinocytes. The nosology of this group of diseases is outlined in Box 541.
Essentially, pemphigus can be divided into four major types: (1) vulgaris, (2) foliaceus, (3) paraneoplastic (see Chapter 55), and (4) IgA pemphigus (see
Chapter 54). 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.
Box 541 Differential Diagnosis of Pemphigus
PEMPHIGUS SUBTYPES
Pemphigus vulgaris
Pemphigus vegetans
Pemphigus foliaceus
Pemphigus erythematosus
Endemic pemphigus foliaceus (e.g., fogo selvagem)
Immunoglobulin A (IgA) pemphigus
Subcorneal pustular dermatosis
Intraepidermal neutrophilic dermatosis
Paraneoplastic pemphigus
INTRAEPIDERMAL BLISTERING DISEASES WITHOUT AUTOANTIBODIES
Familial benign pemphigus (Hailey–Hailey disease)
Bullous impetigo, staphylococcal scaldedskin syndrome
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Blisters from herpes simplex and zoster
Chapter 54. Pemphigus, Aimee S. Payne; John R. Stanley Page 1 / 28
Allergic contact dermatitis (e.g., rhus dermatitis)
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Epidermolysis bullosa simplex
Incontinentia pigmenti
circulating immunoglobulin (Ig) directed against the cell surface of keratinocytes. The nosology of this group of diseases is outlined in Box 541.
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Essentially, pemphigus can be divided into four major types: (1) vulgaris, (2) foliaceus, (3) paraneoplastic (see Chapter 55), and (4) IgA pemphigus (see
Chapter 54). 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.
Box 541 Differential Diagnosis of Pemphigus
PEMPHIGUS SUBTYPES
Pemphigus vulgaris
Pemphigus vegetans
Pemphigus foliaceus
Pemphigus erythematosus
Endemic pemphigus foliaceus (e.g., fogo selvagem)
Immunoglobulin A (IgA) pemphigus
Subcorneal pustular dermatosis
Intraepidermal neutrophilic dermatosis
Paraneoplastic pemphigus
INTRAEPIDERMAL BLISTERING DISEASES WITHOUT AUTOANTIBODIES
Familial benign pemphigus (Hailey–Hailey disease)
Bullous impetigo, staphylococcal scaldedskin syndrome
Blisters from herpes simplex and zoster
Allergic contact dermatitis (e.g., rhus dermatitis)
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
The history of the discovery of pemphigus, and its various forms, is covered in Walter Lever's classic 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 designations over time. Thus, patients with PV may present 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, fullblown PV may appear. Similarly, patients with PF may present with more localized
Chapter 54. Pemphigus, Aimee S. Payne; John R. Stanley
disease, represented by pemphigus erythematosus. However, these patients often go on to more widespread PF.
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The discovery by Ernst Beutner and Robert Jordon in 1964 of circulating antibodies against the cell surface of keratinocytes in the sera of patients with
2
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The history of the discovery of pemphigus, and its various forms, is covered in Walter Lever's classic 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 designations over time. Thus, patients with PV may present 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, fullblown 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 Jordon 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 tissuespecific autoimmune disease of skin and mucosa.2 Ultimately, their work led the way to the
discoveries of autoantibodies in other autoimmune bullous diseases of the skin.
Epidemiology
Incidence and Prevalence
A few prospective and several retrospective surveys of patients with pemphigus clearly indicate that the epidemiology of pemphigus is dependent on
both the area in the world that is studied as well as the ethnic population in that area.3–10 PV is more common in Jews and probably 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, Middle
Eastern, and Mediterranean population predominates, 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 Finland, it is only 0.5:1. Similarly,
the incidence of pemphigus varies by region. In Jerusalem, the incidence of 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. Elsewhere 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 tenfold less, 0.5–1.0 per million person years, in Finland, France, Germany, and Switzerland.
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, histologically, and immunopathologically the same as sporadic PF in any individual patient, but its epidemiology is unique.11,12 Fogo
selvagem is endemic in the rural areas of Brazil, especially along inland riverbeds. The geographic distribution of disease clustering is similar to that of
a black fly, Simulium nigrimanum, thought by natives to be a vector of this disease. A study of potential environmental risk factors has also implicated
the bite of this black fly, showing it to be significantly more frequent among those with the disease compared to an age, sex, and occupationmatched
control population with unrelated dermatoses.13 The prevalence on some wellstudied Indian reservations in rural Brazil can be as high as 3.4%, with
the incidence up to 0.8–4.0 new cases per 1,000 people per year.12,14 On the reservation in Limao Verde, up to 55% of unaffected individuals have a
lowlevel IgG1 antibody response against desmoglein 1, the PF autoantigen, which becomes an IgG4 response of higher titer against a more pathogenic
epitope in disease.12 These results suggest that some environmental agent (e.g., insects or other infectious disease agent) may trigger a lowlevel
autoantibody response that becomes pathogenic by intramolecular epitope spreading in genetically susceptible individuals. With this theory in mind,
it is interesting that 40%–80% of patients from Brazil with the insectborne diseases onchocerciasis, leishmania, and Chagas disease have lowlevel
antidesmoglein 1 antibodies, but patients with other infectious diseases from Brazil rarely have such antibodies.15
Fogo selvagem occurs often in children and young adults, unlike sporadic PF, which is a disease of mostly middleaged and older patients. Also unlike
PF, fogo selvagem occurs not infrequently in genetically related family members, although it is not contagious. This fact probably implies a common
exposure, as well as susceptibility. There is no known racial or ethnic predominance, and anyone moving into an endemic area may be susceptible to
disease. Again supporting the presence of an environmental trigger, the development of the rural endemic areas of Brazil decreased the incidence of
disease. Certainly, this fascinating disease holds clues to understanding how this autoimmune response is triggered.
Sex Ratio
The sex ratio of pemphigus cases is difficult to estimate accurately due to the overall low incidence. Larger epidemiologic studies (i.e., those identifying
greater than 100 cases) have shown that the sex ratio of pemphigus in women versus men ranges from 1.33 or 2.25 to 1.7,9,16–20 Notable exceptions
are the predominance of women (4:1) in an endemic focus of PF in Tunisia,6 and a predominance of men (19:1) in an endemic focus of PF in
Colombia.21
Age of Onset
The average age of disease onset also varies by region. In Turkey, Saudi Arabia, Tunisia, and Iran, the mean age of onset is approximately 40
years.6,16,18,22 Studies in the United States and elsewhere in Europe demonstrate an average age of onset between 50 and 70
The sex ratio of pemphigus cases is difficult to estimate accurately due to the overall low incidence. Larger epidemiologic studies (i.e., those identifying
greater than 100 cases) have shown that the sex ratio of pemphigus in women versus men ranges from 1.33 or 2.25 to 1.7,9,16–20 Notable exceptions
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are the predominance of women (4:1) in an endemic focus of PF in Tunisia,6 and a predominance of men (19:1) in an endemic focus of PF in
Colombia.21
Age of Onset
The average age of disease onset also varies by region. In Turkey, Saudi Arabia, Tunisia, and Iran, the mean age of onset is approximately 40
years.6,16,18,22 Studies in the United States and elsewhere in Europe demonstrate an average age of onset between 50 and 70
years.5,6,9,10,17,19,23,24,25 Pemphigus rarely occurs in children,26 except in regions of endemic disease.
Etiology and Pathogenesis
The discovery of pemphigus as an organspecific, autoantibodymediated disease of desmosomes highlights the synergy between clinical care and
basic science research. The development of light microscopy and electron microscopy allowed dermatologists to identify the morphology and
immunopathology of disease. Patient serum IgG served as a key reagent to help identify both the PF and PV antigens.27–29 The cloning and
characterization of the pemphigus antigens have subsequently led to the development of enzymelinked immunosorbent assay (ELISA) tests to
improve the sensitivity and specificity of disease diagnosis, and continued studies on pemphigus pathophysiology aim to develop safer and effective
therapies for these potentially fatal diseases.
Pemphigus Autoantigens
Pemphigus antigens are desmogleins, transmembrane glycoproteins of desmosomes (celltocell adhesion structures, reviewed in Chapter 53).30,31
Desmogleins are part of the cadherin superfamily of calciumdependent cell adhesion molecules. The original members of this family (e.g., Ecadherin)
demonstrate homophilic adhesive interactions (binding between like molecules). Desmogleins similarly demonstrate homophilic binding but can also
participate in heterophilic adhesion by binding desmocollins, the other major transmembrane glycoprotein of desmosomes.32,33
The PF antigen (as well as the fogo selvagem antigen) is desmoglein 1, a 160kDa protein.27,28,34 The PV antigen is desmoglein 3, a 130kDa protein
that is 64% similar and 46% identical in amino acid sequence to desmoglein 1.29 All patients with PV have antidesmoglein 3 antibodies, and some of
these patients also have antidesmoglein 1 antibodies.35,36 Patients with mucosaldominant PV tend to have only antidesmoglein 3 antibodies,
whereas those with mucocutaneous disease usually have both antidesmoglein 3 and antidesmoglein 1 antibodies.37–39 PF patients typically have
antibodies against only desmoglein 1.
Several lines of evidence indicate that antidesmoglein 1 and 3 antibodies in pemphigus patients 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 clinically and histologically mimic the
corresponding type of pemphigus in patients.40–42 The antidesmoglein antibodies are responsible for blister formation in the passive transfer model,
since affinity purified antidesmoglein 1 and 3 autoantibodies cause PF and PV blisters, respectively, and adsorption of desmogleinreactive
autoantibodies from PF or PV IgG abrogates disease.43–46 Similar passive transfer “experiments” have been described in humans, where mothers
with even mild PV can pass IgG autoantibodies to the fetus, causing blistering oral and skin disease that resolves by approximately 6 months,
concurrent with the disappearance of maternal IgG from the circulation.47
Desmoglein 4, which is expressed in the developing hair cortex and the superficial epidermis, is a target of some pemphigus antibodies.48 However,
the antidesmoglein 4 antibodies in mucocutaneous PV and in PF have been shown to be a result of crossreactivity from desmoglein 1 autoantibodies,
and the desmoglein 4 reactivity has not been shown to be necessary or sufficient for acantholysis.49 Other cell surface molecules such as acetylcholine
receptors and Ecadherin have also been identified as immunologic targets of pemphigus autoantibodies, although their direct involvement in the
pathophysiology of pemphigus is similarly unclear.50,51
Electron Microscopy
Early ultrastructural studies of the blisters in PV and PF focused on the appearance of desmosomes, because these are the most prominent
celltocell adhesion junctions in stratified squamous epithelia (see Fig. 522 and Chapter 52). 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 Section
“Pathophysiology of Acantholysis.” However, conclusions from electron microscopy studies as to the mechanism of desmosome destruction have
varied. Several groups have proposed that the first pathologic event in pemphigus is intercellular widening of interdesmosomal cell membranes,
with intact desmosomal junctions. 52–55 Other studies have demonstrated halfsplit desmosomes without keratin tonofilament retraction, suggesting
that pemphigus autoantibodies directly interfere with the transadhesive interface of desmosomes, and that keratin retraction is secondary to the
loss of intercellular adhesion. Halfdesmosomes without tonofilament collapse have also been observed in a mouse model of PV.56,57 Others have
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Early ultrastructural studies of the blisters in PV and PF focused on the appearance of desmosomes, because these are the most prominent
celltocell adhesion junctions in stratified squamous epithelia (see Fig. 522 and Chapter 52). 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 Section
“Pathophysiology of Acantholysis.” However, conclusions from electron microscopy studies as to the mechanism of desmosome destruction have
varied. Several groups have proposed that the first pathologic event in pemphigus is intercellular widening of interdesmosomal cell membranes,
with intact desmosomal junctions.52–55 Other studies have demonstrated halfsplit desmosomes without keratin tonofilament retraction, suggesting
that pemphigus autoantibodies directly interfere with the transadhesive interface of desmosomes, and that keratin retraction is secondary to the
loss of intercellular adhesion. Halfdesmosomes without tonofilament collapse have also been observed in a mouse model of PV.56,57 Others have
proposed that keratin retraction is a primary pathogenic event in pemphigus, triggered by cellular signaling after PV autoantibody binding.58 As a
potential reconciliation of these findings, one study found that electron microscopic findings may differ depending on the site analyzed: in early
blisters, halfdesmosomes without keratin retraction are observed; in welldeveloped lesions, keratin retraction from halfdesmosomes occurs; and
in spongiotic nonblistered skin, intercellular widening with intact desmosomal junctions can be found, similar to electron microscopy findings in
other spongiotic epidermal diseases. The conclusion from these studies is that desmosomal splitting is a primary ultrastructural change of
acantholytic lesions in pemphigus.59 Currently, electron microscopy studies are not part of the clinical diagnostic workup for pemphigus.
Pathophysiology of Acantholysis
Unlike many other autoantibodymediated diseases, such as pemphigoid and epidermolysis bullosa acquisita, in which the constant region of the
antibody is required for blister formation to activate complement or bind antibody receptors on inflammatory cells, in pemphigus the variable region
of the antibody is sufficient to cause blisters in neonatal mice or human skin.42,60–62 For this reason a significant amount of research on disease
pathophysiology has focused on the epitopes bound by pathogenic autoantibodies, as these regions are likely critical for maintaining desmosomal cell
adhesion.
Epitope mapping studies have shown that pathogenic PV and PF autoantibodies bind calciumsensitive, conformational epitopes in the amino
terminal extracellular domains of desmogleins, whereas nonpathogenic antibodies tend to bind more membrane proximal extracellular
domains.63–66 The aminoterminal domains bound by pathogenic autoantibodies are the same domains that are predicted to form the key molecular
interactions for desmoglein intercellular adhesion, based on studies of cadherin ultrastructure.67,68 This evidence is the primary basis for the “steric
hindrance” hypothesis, which proposes that pathogenic antibodies directly interfere with desmoglein adhesive interactions, causing acantholysis.
Studies on cultured keratinocytes have indicated that loss of intercellular adhesion by pathogenic autoantibodies leads to internalization and
degradation of desmogleins,69–72 indicating that pemphigus antibody binding leads to loss of desmoglein function. If this is the case, then other
model systems with loss of desmoglein function should mimic pemphigus. Indeed, mice genetically deficient for desmoglein 3 demonstrate suprabasal
blisters in the oral mucosa histologically identical to PV patients.73 Additionally, cleavage of desmoglein 1 by staphylococcal exfoliative toxin (in
bullous impetigo or staphylococcal scalded skin syndrome) causes blisters histologically identical to those seen in PF patients.74
If inactivation of desmoglein isoforms results in blistering, 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 immunofluorescence? In PF, for example, the antidesmoglein 1 antibodies bind throughout the
epidermis and mucous membranes,75 yet blisters occur only in the superficial epidermis. This apparent paradox can be explained by desmoglein
compensation, as outlined in Fig. 541. The concept of desmoglein compensation originates in the assumption that autoantibodies against one
desmoglein isoform inactivate only that isoform and that another isoform coexpressed in the same area can compensate in adhesion.76–78
Desmoglein compensation explains why neonatal PF is so unusual, because even though the maternal antidesmoglein 1 antibodies cross the placenta,
in neonatal skin, but not in adult skin, desmoglein 3 is coexpressed with desmoglein 1 in the superficial epidermis, thereby providing protection
against the loss of desmoglein 1based adhesion.77,79 Desmoglein compensation also offers an explanation for the differing sites of blister formation
in PV and PF, both in regard to the histology (i.e., suprabasal or superficial), as well as the areas of involvement (mucosa and/or skin.)
Figure 541
against the loss of desmoglein 1based adhesion.77,79 Desmoglein compensation also offers an explanation for the differing sites of blister formation
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in PV and PF, both in regard to the histology (i.e., suprabasal or superficial), as well as the areas of involvement (mucosa and/or skin.)
Figure 541
Desmoglein (Dsg) compensation. Triangles represent the distribution of Dsg1 and 3 in skin and mucous membranes. AntiDsg1 antibodies in
pemphigus foliaceus cause acantholysis only in the superficial epidermis of skin. In the deep epidermis and in mucous membranes, Dsg3 compensates
for antibodyinduced loss of function of Dsg1. In early pemphigus vulgaris, antibodies are present only against Dsg3, 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 probably because antibodies diffuse from the dermis
and interfere first with the function of desmosomes at the base of the epidermis.
In potential challenge to the steric hindrance hypothesis, several studies have suggested that modulation of cell signaling pathways can prevent blister
formation after passive transfer of pemphigus IgG in the neonatal mouse model, including p38 mitogen activated protein kinase (MAPK) and ρ
GTPases, among others.80–82 Whether signaling is upstream or downstream of the loss of intercellular adhesion is controversial. Nevertheless, the
current general consensus is that desmosomal adhesion is a dynamic process that is perturbed by pemphigus autoantibodies. 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 Restriction 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 HLADR4 haplotype is predominant, whereas in other ethnic groups with PV, the
DQ1 allele is more common.83 However, the association with disease susceptibility 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, HLADR alleles are associated with PF.84 The protein chains encoded by these PV MHC II alleles vary from
those found in HLADR4 and DQ1 controls without disease by only a few amino acids.
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Genetic Restriction 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 HLADR4 haplotype is predominant, whereas in other ethnic groups with PV, the
DQ1 allele is more common.83 However, the association with disease susceptibility 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, HLADR alleles are associated with PF.84 The protein chains encoded by these PV MHC II alleles vary from
those found in HLADR4 and DQ1 controls without disease by only a few amino acids.
MHC class II alleles encode cell surface molecules that are necessary for antigen presentation to the immune system; therefore, it is hypothesized that
PVassociated MHC class II molecules allow presentation of desmoglein 3 peptides to T cells.85 Consistent with this hypothesis, certain peptides from
desmoglein 3, predicted to fit into the DRB1*0402 peptidebinding pocket, were found to stimulate T cells from patients.86
Other studies have confirmed that the immune response in pemphigus is restricted to certain desmoglein peptides and MHC class II alleles.87–89 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,85,90 indicating that Tcell reactivity to desmoglein 3 peptides is not sufficient for disease onset. The factor that may
determine who gets pemphigus and who does not has been proposed to be the presence of regulatory T cells that can suppress the autoimmune
response in those who do not.91
Cloning of antidesmoglein antibodies from PV and PF patients has indicated a marked restriction of antibody gene usage by the antidesmoglein
antibodies, most notably for the heavy chain variable region.61,62,92 These studies also show that pathogenic antibodies from different patients bind
at or near common epitopes on desmogleins and may share common idiotypes. In comparison to the restricted Bcell antibody variable region gene
usage, there is more heterogeneity of the Tcell receptor variable gene usage in pemphigus patients.90,93 If specific antibody or Tcell receptor gene
usage patterns are found to be shared among multiple pemphigus patients, these may serve as clinical markers for targeting diseasespecific immune
cell populations in pemphigus patients.
Clinical Findings
Pemphigus Vulgaris
Cutaneous Lesions
The skin lesions in PV can be pruritic or painful. Exposure to ultraviolet radiation may exacerbate disease activity.94,95 The primary lesion of PV is a
flaccid blister, which may occur anywhere on the skin surface, but typically not the palms and soles (Fig. 542). Usually, the blister arises on normal
appearing skin, but it may develop on erythematous skin. Because PV blisters are fragile, the most common 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. 543).
Figure 542
Pemphigus vulgaris. A . Flaccid blisters. (Used with permission from Lawrence Lieblich, MD.) B . Oral erosions.
Figure 543
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Pemphigus vulgaris. A . Flaccid blisters. (Used with permission from Lawrence Lieblich, MD.) B . Oral erosions.
Figure 543
Pemphigus vulgaris. Extensive erosions due to blistering. Almost the entire back is denuded. Note intact, flaccid blisters at the lower border of eroded
lesions.
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
rubbing at the periphery of active lesions; additionally, erosions can be induced in normalappearing skin distant from active lesions by pressure or
mechanical shear force. This phenomenon is known as the Nikolsky sign.96 This sign helps differentiate pemphigus from other blistering diseases of
the skin such as pemphigoid (Box 541); however, similar findings can also be elicited in staphylococcal scalded skin syndrome, Stevens–Johnson
syndrome, and toxic epidermal necrolysis.
Vegetating Lesions
In certain patients, erosions have a tendency to develop excessive granulation tissue and crusting, referred to as vegetating lesions (Fig. 544). This
type of lesion tends to occur more frequently in intertriginous areas, in the scalp, or on the face (see Fig. 544A). Historically, patients presenting with
vegetating lesions have been split out into different disease designations: pemphigus vegetans of Hallopeau and pemphigus vegetans of Neumann.
However, the subsequent analysis of vegetating skin lesions by histology and immunofluorescence suggests that these cases are simply clinical
variants of PV.1,97 In the Hallopeau variant, vegetating and often pustular lesions are present from the outset of disease, are not preceded by bullae,
and favor flexural regions (see Fig. 544B). Generally, the prognosis for these patients is thought to be better, with milder disease and a higher chance
of remission compared to typical PV patients.98 In patients with the Neumann variant, ordinary PV erosions heal with papillomatous formations, with
prognosis related to the extent of disease activity. The vegetating type of response may also appear in certain lesions that tend to be resistant to
therapy and 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.
Figure 544
therapy and 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
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of PV.
Figure 544
A . Crusted, vegetating lesions in pemphigus vulgaris. B . Extensive, vegetating granulomatous lesions in pemphigus vegetans.
Mucous Membrane Lesions
The mucous membranes most often affected by PV are those of the oropharyngeal cavity (see Fig. 542B). As with cutaneous lesions, intact blisters are
rare. Oropharyngeal erosions 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 membrane 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.20 Most of these patients progressed to a more generalized 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.99
Gastrointestinal tract involvement with PV has been described in the esophagus, stomach, duodenum, and anus, although only biopsies of the
esophagus have been proven to be due to suprabasal acantholysis.7,100,101 Involvement of other mucous membranes can also occur, including the
vulvovaginal, nasal, laryngeal, and conjunctival mucosa.102–106 In women, cervicovaginal lesions may be found in up to 51% of patients with active
disease but these lesions may be asymptomatic. Even without obvious lesions, Pap smears may be positive in women with pemphigus and the
acantholytic cells may be misinterpreted as indicative of cervical dysplasia.107,108 There are rare case reports on corneal erosions in PV patients, but
no histologic confirmation of acantholysis.109
Pemphigus Foliaceus
Cutaneous Lesions
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. 545A). 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. 545B). Like PV, PF may be exacerbated by ultraviolet radiation.95,110,111 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.
Figure 545
Pemphigus foliaceus. A . Scaly, crusted lesions on upper back. B . Exfoliative erythroderma due to confluent lesions.

burning in the skin lesions. In contrast to patients with PV, those with PF very rarely, if ever, have mucous membrane involvement, even with
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widespread disease.
Figure 545
Pemphigus foliaceus. A . Scaly, crusted lesions on upper back. B . Exfoliative erythroderma due to confluent lesions.
The colloquial term for Brazilian endemic pemphigus, fogo selvagem (Portuguese for “wild fire”), takes into account many of the clinical aspects of this
disease: the burning feeling of the skin, the exacerbation of disease by the sun, and the crusted lesions that make the patients appear as if they had
been burned.
Pemphigus Erythematosus
In 1926, Francis Senear and Barney Usher described eleven patients with features of a pemphigus–lupus erythematosus overlap (Senear–Usher
syndrome).112 Over the next several decades, debate over whether these patients had lupus erythematosus, pemphigus, seborrheic dermatitis, or
features of all three disorders continued, with Senear concluding that the disease is best considered a variant of pemphigus, termed pemphigus
erythematosus.113 As these observations were made prior to the development of immunofluorescence testing for both pemphigus and lupus, the
diagnosis was primarily based on the clinical presentation: crusted erosions in a seborrheic distribution, at times concurrent with more lupuslike
discoid lesions with “carpettack” scale. Walter Lever noted that many patients initially categorized as pemphigus erythematosus went on to develop
systemic lupus, or more widespread PF, or even PV, in some cases due to 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 immunofluorescence and antinuclear antibody testing for pemphigus and lupus, it was discovered that pemphigus erythematosus
patients demonstrate immunologic overlap features; by definition all demonstrate the cell surface staining pattern classic for pemphigus,
approximately 30% have positive antinuclear antibody titers, and 80% have positive lupus band tests, although the latter test is only positive in 20%–
40% of biopsies on nonsunexposed skin.114 As most patients with pemphigus erythematosus do not develop systemic signs or symptoms of lupus,
and some may progress from localized disease to generalized PF,115 the diagnosis of pemphigus erythematosus 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 PV.47,116 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 Section “Pathophysiology of Acantholysis,” neonatal PF occurs only rarely.117–119
Neonatal pemphigus should be distinguished from PV and PF that occur in childhood, which are similar to the autoimmune diseases seen in adults.120
DrugInduced 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.121 The prevalence of pemphigus in penicillamine users is estimated to be approximately 7%. PF (including
pemphigus erythematosus) is more common than PV in these penicillaminetreated patients, although either may occur. The findings of direct and
indirect immunofluorescence are positive in most of these patients. Three patients with druginduced PF and one with druginduced PV have been
shown to have autoantibodies to the same molecules involved in sporadic pemphigus, namely, desmoglein 1 and desmoglein 3, respectively.122
Therefore, by immunofluorescence and immunochemical determinations, these patients with druginduced pemphigus resemble those with sporadic
disease.
Both penicillamine and captopril contain sulfhydryl groups that are postulated to interact with the sulfhydryl groups in desmoglein 1, 3, or both,
thereby causing pemphigus either by directly interfering with these adhesion molecules or, more likely, by modifying them so that they become more
antigenic. The use of these drugs may also lead to a more generalized dysregulation of the immune response, allowing production of other
autoantibodies such as those resulting in myasthenia gravis. Most, but not all, patients with druginduced pemphigus go into remission after they stop
pemphigus erythematosus) is more common than PV in these penicillaminetreated patients, although either may occur. The findings of direct and
indirect immunofluorescence are positive in most of these patients. Three patients with druginduced PF and one with druginduced PV have been
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shown to have autoantibodies to the same molecules involved in sporadic pemphigus, namely, desmoglein 1 and desmoglein 3, respectively.122
Therefore, by immunofluorescence and immunochemical determinations, these patients with druginduced pemphigus resemble those with sporadic
disease.
Both penicillamine and captopril contain sulfhydryl groups that are postulated to interact with the sulfhydryl groups in desmoglein 1, 3, or both,
thereby causing pemphigus either by directly interfering with these adhesion molecules or, more likely, by modifying them so that they become more
antigenic. The use of these drugs may also lead to a more generalized dysregulation of the immune response, allowing production of other
autoantibodies such as those resulting in myasthenia gravis. Most, but not all, patients with druginduced pemphigus go into remission after they stop
taking the offending drug.
Additionally, rare anecdotal reports have suggested the association of dietary intake and pemphigus, proposing the hypothesis that thiolcontaining
foods such as garlic, leeks, and onions may precipitate disease.123,124 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,125 as well as with the cholinergic agonists
pyridostigmine, carbachol, and pilocarpine.126,127 Studies suggest that activation of cholinergic receptors may regulate signaling pathways
modulated by PV IgG, thereby affecting cell adhesion.128 These results are intriguing given the clinical benefit of nicotine noted in other inflammatory
diseases, such as ulcerative colitis.129
Associated Diseases
Myasthenia gravis, thymoma, or both have been associated with PV and PF.130 Approximately onehalf of associated pemphigus cases are vulgaris;
onehalf, foliaceus or erythematosus. Most of these data, however, were reported before the recognition of paraneoplastic pemphigus as a distinct
entity. Therefore, although thymoma may clearly be associated with PV and PF, it may also be associated with paraneoplastic pemphigus (see Chapter
55). Myasthenia gravis is a tissuespecific autoantibodymediated disease leading to skeletal muscle weakness. Early disease usually affects facial
muscles, leading to symptoms of dysarthria, dysphagia, ptosis, or diplopia. Disease may then progress to affect the larger muscles of the trunk and
extremities, with potential fatal complications from respiratory muscle involvement. Thymoma, in contrast, is typically asymptomatic 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 gravis 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 pemphigus appear to be independent of each other. Likewise, thymic
abnormalities may either precede or follow the onset of pemphigus. Thymic abnormalities include benign or malignant thymoma and thymic
hyperplasia. Posteroanterior and lateral chest radiographs with or without computerized tomography followup can detect most thymomas.
Irradiation of the thymus or thymectomy, although clearly beneficial for myasthenia gravis, may not improve the pemphigus disease activity. Although
this association is reported in at least 30 cases, the finding of thymoma or myasthenia gravis in a patient with PV or PF is still unusual.
Laboratory Tests
Diagnosis of pemphigus relies on skin biopsy of a fresh lesion for histology to determine the site of blister formation, as well as a confirmatory
immunochemical study to document the presence of skin autoantibodies, either by direct immunofluorescence of perilesional skin, or indirect
immunofluorescence or ELISA of patient serum.
Histology
The characteristic histopathologic finding in PV is a suprabasal blister with acantholysis (Fig. 546). Just above the basal cell layer, epidermal cells lose
their normal celltocell contacts and form a blister. Often, a few rounded up (acantholytic) keratinocytes 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 appear to be a “row of tombstones,”
symbolic of the potentially fatal prognosis of this disease. Usually, the upper epidermis (from one or two cell layers above the basal cells) remains
intact, as these cells maintain their cell adhesion. Pemphigus vegetans shows not only suprabasilar acantholysis, but also papillomatosis of the dermal
papillae and downward growth of epidermal stands into the dermis, with hyperkeratosis and scalecrust formation. In addition, pemphigus vegetans
lesions may show intraepidermal abscesses composed of eosinophils and/or neutrophils.131 Early PV lesions may show eosinophilic spongiosis.132
Figure 546
symbolic of the potentially fatal prognosis of this disease. Usually, the upper epidermis (from one or two cell layers above the basal cells) remains
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intact, as these cells maintain their cell adhesion. Pemphigus vegetans shows not only suprabasilar acantholysis, but also papillomatosis of the dermal
papillae and downward growth of epidermal stands into the dermis, with hyperkeratosis and scalecrust formation. In addition, pemphigus vegetans
lesions may show intraepidermal abscesses composed of eosinophils and/or neutrophils.131 Early PV lesions may show eosinophilic spongiosis.132
Figure 546
Histopathology of pemphigus vulgaris. Suprabasilar acantholysis. The row of tombstones.
The histopathology of early blisters in PF patients demonstrates acantholysis (loss of celltocell contact) just below the stratum corneum and in the
granular layer (Fig. 547A). The stratum corneum is often lost from the surface of these lesions. The deeper epidermis, below the granular layer,
remains intact. Another frequent finding is subcorneal pustules, with neutrophils and acantholytic epidermal cells in the blister cavity (Fig. 547B).
Histologic findings in PF are often indistinguishable from those seen in bullous impetigo/staphylococcal scalded skin syndrome, because blisters in
these latter diseases also result from dysfunction of desmoglein 1, in these cases due to proteolytic cleavage by staphylococcal exfoliative toxins.31
Therefore, immunochemical studies are essential to confirm a diagnosis of PF, as these would be negative in staphylococcalmediated skin blisters.
The site of blister formation in pemphigus erythematosus is identical to PF. As in PV lesions, very early PF lesions may show eosinophilic
spongiosis.132
Figure 547
Histopathology of pemphigus foliaceus. A . Acantholysis in the granular layer. B . Subcorneal pustule with acantholysis.
Immunofluorescence
The hallmark of pemphigus is the finding of IgG autoantibodies against the cell surface of keratinocytes. These autoantibodies were first discovered in
patients’ sera by indirect immunofluorescence techniques and soon thereafter were discovered by direct immunofluorescence of patients’ skin.133
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. 548A).134 This is a nonquantitative test (either negative or positive). The diagnosis of pemphigus should be
seriously questioned if the test result of direct immunofluorescence is negative. It is important that the biopsy for direct immunofluorescence be
performed on normalappearing perilesional skin, as the immune reactants can be difficult to detect in blistered 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 pattern.135
patients’ sera by indirect immunofluorescence techniques and soon thereafter were discovered by direct immunofluorescence of patients’ skin. 133
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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. 548A).134 This is a nonquantitative test (either negative or positive). The diagnosis of pemphigus should be
seriously questioned if the test result of direct immunofluorescence is negative. It is important that the biopsy for direct immunofluorescence be
performed on normalappearing perilesional skin, as the immune reactants can be difficult to detect in blistered 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 pattern.135
Figure 548
Immunofluorescence in pemphigus. A . Direct immunofluorescence for immunoglobulin G (IgG) of perilesional skin from a patient with pemphigus
vulgaris. Note cell surface staining throughout the epidermis. B . Indirect immunofluorescence with the serum from a patient with pemphigus foliaceus
on normal human skin. Note IgG on the cell surface throughout the epidermis.
Indirect Immunofluorescence
Indirect immunofluorescence is performed by incubating serial dilutions 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 major national
laboratories and can remain positive for 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
immunofluorescence, more than 80% of patients with pemphigus have circulating antiepithelial cell surface IgG (Fig. 548B).136 The substrate used to
detect pemphigus antibody binding in indirect immunofluorescence 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 detecting 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 epidermis, despite the different autoantigen profiles in these two diseases. Therefore, it is usually not possible to differentiate the two
diseases by the pattern of immunofluorescence. There is a positive, but imperfect, correlation between the titer of circulating anticell surface antibody
and the disease activity in PV and in PF.137 Although this correlation may hold in general, and although patients in remission often show serologic
remission with negative direct and indirect immunofluorescence findings,138,139 disease activity in individual patients does not necessarily correlate
with indirect immunofluorescence titer. Therefore, in the daytoday management of these patients, following disease activity is more important than
following antibody titer.
EnzymeLinked Immunosorbent Assay
For diagnosis of disease, antigenspecific 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.35,140 Additionally, ELISAs are easier to perform and less subjective
than immunofluorescence, and may replace the latter as the preferred first diagnostic test for pemphigus, although currently some major national
laboratories do not offer desmoglein ELISA. These assays use desmogleins 1 and 3 bound to plates, which are then incubated with patient sera and
developed with antihuman IgG reagents (Fig. 549). As an advantage over indirect immunofluorescence, ELISAs can help differentiate between PV and
PF due to the different autoantigen profiles in these two diseases.35,140,141,142 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 involvement, and is positive for only desmoglein
143–145 A small minority of PF
1 in PF. PV has rarely evolved into PF, and vice versa, as determined by clinical, histologic, and immunochemical criteria.
patients may also demonstrate autoantibodies to desmoglein 3146; therefore, diagnosis should be made based on the clinical–serologic correlation.
Additionally, some patients (e.g., those with bullous pemphigoid) may demonstrate a low level of antidesmoglein 3 autoantibodies,140 which are
For diagnosis of disease, antigenspecific 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.35,140 Additionally, ELISAs are easier to perform and less subjective
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than immunofluorescence, and may replace the latter as the preferred first diagnostic test for pemphigus, although currently some major national
laboratories do not offer desmoglein ELISA. These assays use desmogleins 1 and 3 bound to plates, which are then incubated with patient sera and
developed with antihuman IgG reagents (Fig. 549). As an advantage over indirect immunofluorescence, ELISAs can help differentiate between PV and
PF due to the different autoantigen profiles in these two diseases.35,140,141,142 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 involvement, and is positive for only desmoglein
1 in PF. PV has rarely evolved into PF, and vice versa, as determined by clinical, histologic, and immunochemical criteria.143–145 A small minority of PF
patients may also demonstrate autoantibodies to desmoglein 3146; therefore, diagnosis should be made based on the clinical–serologic correlation.
Additionally, some patients (e.g., those with bullous pemphigoid) may demonstrate a low level of antidesmoglein 3 autoantibodies,140 which are
detectable due to 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 negative, the latter presumably due to formation of nonpathogenic bystander autoantibodies after epidermal damage. As with
indirect immunofluorescence, the correlation of ELISA index value with disease activity is not perfect. In making treatment decisions, a negative result
on desmoglein 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.
Figure 549
Enzymelinked immunosorbent assay (ELISA) for desmoglein 3. AntiDsg3 antibodies (αDsg3) from pemphigus serum binds Dsg3 on the ELISA plate;
irrelevant antibodies, that do not bind, are washed off. The plate is then incubated with horseradish peroxidase (HRP) conjugated antihuman IgG,
which binds the antiDsg3 IgG that is on the plate. HRP is an enzyme that turns a clear substrate blue and the amount of color, read on
spectrophotometer, correlates with the amount of pemphigus (i.e., antiDsg3) antibody in the patient's serum.
Prognosis and Clinical Course
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 patients with concurrent
medical problems; however, in other patients its prognosis, without therapy, was much better than PV.147,148
The systemic administration of glucocorticoids and the use of immunosuppressive therapy have dramatically improved the prognosis for patients with
pemphigus; however, pemphigus is still a disease associated with a significant morbidity and mortality.149,150 In the United States, the annual
mortality rate from pemphigus (ageadjusted to the standard population) is estimated to be 0.023 deaths per 100,000.151 A study in the United
Kingdom showed that the risk of death in PV patients is 3.3 times greater than for controls.9 Infection is often the cause of death, and by causing the
immunosuppression necessary in the treatment of active disease, therapy is frequently a contributing factor.152 With glucocorticoid and
immunosuppressive 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, two patients (5%) died of sepsis and 17%, after an average of 18 months of therapy,
went into a complete and longlasting (>4 years, average, thought to be permanent) remission requiring no further therapy.153 Another 37% of
patients achieved remission but relapsed at times after therapy was stopped; most of these also eventually achieved longlasting remissions. The
The systemic administration of glucocorticoids and the use of immunosuppressive therapy have dramatically improved the prognosis for patients with
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pemphigus; however, pemphigus is still a disease associated with a significant morbidity and mortality.149,150 In the United States, the annual
mortality rate from pemphigus (ageadjusted to the standard population) is estimated to be 0.023 deaths per 100,000.151 A study in the United
Kingdom showed that the risk of death in PV patients is 3.3 times greater than for controls.9 Infection is often the cause of death, and by causing the
immunosuppression necessary in the treatment of active disease, therapy is frequently a contributing factor.152 With glucocorticoid and
immunosuppressive 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, two patients (5%) died of sepsis and 17%, after an average of 18 months of therapy,
went into a complete and longlasting (>4 years, average, thought to be permanent) remission requiring no further therapy.153 Another 37% of
patients achieved remission but relapsed at times after therapy was stopped; most of these also eventually achieved longlasting remissions. The
remainder of patients required continual therapy. In a group of 159 patients with PV from Croatia, only approximately 12% went into longterm
remission after therapy with glucocorticoids and immunosuppressives, but most relapsed.20 In a study from Tehran of 1,206 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 In some small
studies, higher percentages of patients were reported to go into complete remission (see below). With the advent of rituximab therapy, complete
remission in pemphigus may become more common.
Treatment
Despite the potentially fatal prognosis, there are currently no FDAapproved treatments. Approach to therapy of pemphigus varies widely, even among
experts.154 It is generally agreed that PV, even if initially limited in extent, should be treated at its onset, because it will ultimately generalize 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.155 Because PF may be localized for many years, and the prognosis without systemic therapy may be good, patients with this type
of pemphigus do not necessarily require treatment with systemic 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.
Recently, a consensus statement on disease definitions and endpoints was proposed by an international committee of pemphigus experts.156
Additionally, clinical instruments have been developed for tracking disease activity.157,158 The standardization of disease definitions and activity
scoring will facilitate future clinical trials for pemphigus.
Corticosteroids
The systemic administration of glucocorticoids, usually prednisone, is the mainstay of therapy for pemphigus. Before adjuvant immunosuppressive
therapy was available, very high initial doses of prednisone (>2.0 mg/kg/day) were used for treatment, although such regimens have retrospectively
been associated with significant morbidity and mortality from therapy.152,159,160 In many patients the disease can be brought under control with a
0.5–1.0 mg/kg/day 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.161,162 For patients who do not initially respond or
worsen, splitting the dose using a twice or three times daily schedule may achieve disease control. The full systemic dose of glucocorticoids has been
defined in the consensus guidelines as 1.5 mg/kg/day of prednisone equivalent for 3 weeks. Therefore, patients whose total daily prednisone dose
exceeds approximately 100 mg should be considered for adjunctive treatments, discussed below. Some experts still recommend controlling initial
refractive disease with escalating doses of prednisone (increasing by 50% every 1 to 2 weeks until disease control or prohibitive side effects occur),
with total daily doses as high as 240 mg.148,163
Once disease activity is controlled, tapering prednisone to as low a dose as possible should be the goal. Minimal therapy is defined as 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
glucocorticoid 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 of 10 mg or higher, adjunctive immunosuppressive agents should be
considered.
Interestingly, prednisone can control blistering within days, at a time when the autoantibody titer would be unchanged. A possible explanation is that
prednisone may increase the synthesis of desmogleins or other cell adhesion molecules or change their posttranscriptional processing to prolong
their halflife.164 If pemphigus IgG depletes desmosomes of desmogleins, then prednisone could counteract this effect.
Topical corticosteroids may be used as monotherapy in mild forms of disease, or as adjunctive therapy to help heal new lesions. Patients with mucosal
disease may benefit from the use of glucocorticoid elixirs as a swish and spit or 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.
Immunosuppressive Agents
Interestingly, prednisone can control blistering within days, at a time when the autoantibody titer would be unchanged. A possible explanation is that
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prednisone may increase the synthesis of desmogleins or other cell adhesion molecules or change their posttranscriptional processing to prolong
their halflife.164 If pemphigus IgG depletes desmosomes of desmogleins, then prednisone could counteract this effect.
Topical corticosteroids may be used as monotherapy in mild forms of disease, or as adjunctive therapy to help heal new lesions. Patients with mucosal
disease may benefit from the use of glucocorticoid elixirs as a swish and spit or 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.
Immunosuppressive Agents
When greater than minimal doses of glucocorticoids are required for disease control, or if there are contraindications to oral glucocorticoids, other
immunosuppressive agents are used for pemphigus therapy. In many cases, treatment regimens often begin with an immunosuppressive agent and
prednisone simultaneously. Prospective randomized studies have shown that immunosuppressive agents such as mycophenolate mofetil,
azathioprine, and cyclophosphamide have a steroidsparing effect; retrospective studies suggest decreased mortality with use of adjuvants plus
steroids compared to steroids alone.147,165,166
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, gastrointestinal ulcer disease, high blood pressure, diabetes, glaucoma, cataracts, osteoporosis, and
infection. The decision to use immunosuppressive agents, particularly in young patients, must also take into account the potential incidence of
malignancies that might be associated with the longterm use of these drugs, as well as the risks of infertility (for cyclophosphamide) and
teratogenicity (for mycophenolate mofetil, azathioprine, and cyclophosphamide, which are all pregnancy category D).
Azathioprine
Azathioprine has historically been considered as a firstline immunosuppressive agent for pemphigus, with clinical remission rates of approximately
50% in retrospective studies.139,167 In a prospective randomized trial of high dose methylprednisolone (2.0 mg/kg/day) plus azathioprine (2.0
mg/kg/day), 72% of patients achieved clinical remission within a mean of 74 days, although 33% experienced significant adverse effects of therapy,
including hyperglycemia, dizziness, abnormal liver enzyme tests, and infection.165
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. 89% of Caucasians demonstrate normal to high levels of TPMT,
11% are intermediate, and 0.3% are deficient for TPMT, the latter group representing those who do not tolerate azathioprine therapy.168 Additionally,
1%–2% of Caucasians may have “super high” levels of TPMT, which is correlated with both treatment resistance as well as increased hepatotoxicity
from excessive metabolite production.169 Altogether, it is estimated that 5% of patients will be azathioprine intolerant, although the genotype–
phenotype correlation is imperfect.170
In patients with normal TPMT levels, the consensus dosing regimen that defines treatment failure is 2.5 mg/kg/day for 12 weeks.156 From a practical
standpoint however, not all laboratories offer TPMT testing. Additionally, since patients with normal levels of TPMT may also experience azathioprine
toxicity, it is reasonable to start all patients at a lower dose (e.g., 50–100 mg daily) and titrate upward until clinical remission, the target dose of 2.5
mg/kg/day, or unacceptable side effects result. Frequent blood and liver monitoring should continue, particularly over the first 8–12 weeks when
delayed toxicity from the accumulation of metabolites may emerge.
Mycophenolate Mofetil
Mycophenolate mofetil is also considered to be a firstline immunosuppressive agent for pemphigus. In 2006, the FDA granted orphan drug status to
mycophenolate mofetil for the treatment of PV, thereby increasing the feasibility of a new drug approval. Typical doses range from 30–40 mg/kg/day
dosed twice daily (2.0–3.0 g/day), although certain patients such as the elderly may achieve disease control with doses as low as 1.0 g/day.
In case series, mycophenolate mofetil has been shown to have a rapid effect in lowering pemphigus antibody titers and decreasing disease activity,
even in patients whose disease is unresponsive to azathioprine.171,172 A prospective randomized trial comparing methyprednisolone (2.0 mg/kg/day)
with azathioprine (2.0 mg/kg/day) or mycophenolate mofetil (2.0 g/day) 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.165 19% of patients experienced significant side
effects of mycophenolate mofetil therapy, compared to 33% in the azathioprine group. None of these differences was statistically significant. Another
prospective randomized study indicated that azathioprine was significantly more effective than mycophenolate mofetil as a steroid sparing agent,
although this study compared a full dose of azathioprine (2.5 mg/kg/day) to a partial dose of mycophenolate mofetil (2.0 g/day).166 Caution with use
of mycophenolate mofetil is warranted, as fatal infection and sepsis occurred in 2%–5% of transplant patients receiving mycophenolate mofetil, and
increased risk of infection with or reactivation of cytomegalovirus, herpes zoster, atypical mycobacteria, tuberculosis, and John Cunningham (JC) virus
(in progressive multifocal leukoencephalopathy) have been noted in postmarketing surveillance.173 Interestingly, mycophenolate mofetil may offer
even in patients whose disease is unresponsive to azathioprine.171,172 A prospective randomized trial comparing methyprednisolone (2.0 mg/kg/day)
with azathioprine (2.0 mg/kg/day) or mycophenolate mofetil (2.0 g/day) in pemphigus patients showed 72% in the azathioprine group and 95% in the
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mycophenolate mofetil group went in clinical remission in a mean of 74 and 91 days, respectively.165 19% of patients experienced significant side
effects of mycophenolate mofetil therapy, compared to 33% in the azathioprine group. None of these differences was statistically significant. Another
prospective randomized study indicated that azathioprine was significantly more effective than mycophenolate mofetil as a steroid sparing agent,
although this study compared a full dose of azathioprine (2.5 mg/kg/day) to a partial dose of mycophenolate mofetil (2.0 g/day).166 Caution with use
of mycophenolate mofetil is warranted, as fatal infection and sepsis occurred in 2%–5% of transplant patients receiving mycophenolate mofetil, and
increased risk of infection with or reactivation of cytomegalovirus, herpes zoster, atypical mycobacteria, tuberculosis, and John Cunningham (JC) virus
(in progressive multifocal leukoencephalopathy) have been noted in postmarketing surveillance.173 Interestingly, mycophenolate mofetil may offer
protection against Pneumocystis carinii infection.174
Cyclophosphamide
Cyclophosphamide, although more toxic than azathioprine or mycophenolate mofetil, is thought to be very effective in controlling severe disease, with
one report of 19 of 23 patients with pemphigus achieving complete remission in a median time of 8.5 months.175 A variety of small case series have
evaluated different cyclophosphamide regimens for pemphigus, including daily oral therapy (1.1–2.5 mg/kg/day), daily oral therapy (50 mg) with
intermittent highdose intravenous dexamethasone and cyclophosphamide, and immunoablative intravenous cyclophosphamide.167,175–179 All
methods were effective in the shortterm, although none were curative. Significant side effects, including hematuria, infection, and transitional cell
carcinoma of the bladder, were observed with higher dose regimens, although one study using a lower daily dose of cyclophosphamide (1.1–1.5
mg/kg/day) did not report a significantly different safety profile compared with other immunosuppressive agents. Together with the risk of infertility,
cyclophosphamide is not generally considered a firstline agent in the treatment of PV.
Dapsone
In a case series and randomized doubleblind trial, dapsone demonstrated a trend toward efficacy as a steroidsparing drug in maintenance phase PV,
although these results were not statistically significant.180,181 Dapsone may be used in conjunction with other immunosuppressive agents,
particularly rituximab (discussed below), where it offers the additional benefit of Pneumocystis pneumonia prophylaxis.
Additional Therapies
There are additional therapies that can be used when the more standard treatments, discussed previously, are not effective.
Rituximab
A very effective therapy for pemphigus that is refractory to more standard therapy is a monoclonal antiCD20 antibody rituximab, approved for therapy
of Bcell malignancies. In pemphigus patients, this monoclonal antibody presumably targets B cells, the precursors of antibodyproducing plasma
cells. The B cell also acts to process autoantigen and present it to T cells that provide “help” in stimulating the autoantibody response.182 Rituximab is
infused intravenously at a dose of 375 mg/m2 once weekly for 4 weeks. Alternatively, the rheumatoid arthritis dosing regimen can be used (1,000 mg
intravenously on day 1 and day 15). The course can be repeated in approximately 6 months for patients with more refractory disease, although a single
cycle of rituximab has been shown to be highly effective, with 86% of patients experiencing complete remission lasting 34 months or greater.183
Disease activity usually begins to remit within 1–2 months after the course of therapy. Some experts consider rituximab the therapy of choice for severe
pemphigus uncontrolled by corticosteroids and azathioprine or mycophenolate mofetil or who have contraindications to corticosteroids.183,184
However, fatal infections with rituximab therapy have been observed, including Pneumocystis pneumonia, reactivation of hepatitis B, and JC virus
infection or reactivation causing progressive multifocal leukoencephalopathy.185–188 Although these complications are rare, some experts
recommend Pneumocystis prophylaxis for 1 year following rituximab infusion.
Intravenous Immunoglobulin
Another method of decreasing serum autoantibodies is the intravenous use of γglobulin (IVIg) in high doses. IVIg is thought to function by saturating
circulating neonatal Fc receptor, thereby increasing catabolism of the patient's serum antibodies, which include the pathogenic
autoantibodies.189–191 It may be useful as adjuvant therapy in those pemphigus patients whose condition does not respond to more conventional
therapy.192,193 A multicenter, randomized, placebocontrolled, double blind study has confirmed its efficacy in pemphigus,194 but it is expensive and
probably requires continued infusions for maintenance of remission. There can also be significant side effects with this therapy, including stroke,
deep venous thrombosis, and renal failure with sucrosecontaining formulations.195 Some centers will use IVIg to establish initial control of blistering
in severely affected patients because it does not increase risk of infection as much as corticosteroids and immunosuppressants. IVIg has also been
used in combination with rituximab,196 although it is unclear whether the combination is safer or more effective compared to either alone.
Another method of decreasing serum autoantibodies is the intravenous use of γglobulin (IVIg) in high doses. IVIg is thought to function by saturating
circulating neonatal Fc receptor, thereby increasing catabolism of the patient's serum antibodies, which include the pathogenic Access Provided by:
autoantibodies.189–191 It may be useful as adjuvant therapy in those pemphigus patients whose condition does not respond to more conventional
therapy.192,193 A multicenter, randomized, placebocontrolled, double blind study has confirmed its efficacy in pemphigus,194 but it is expensive and
probably requires continued infusions for maintenance of remission. There can also be significant side effects with this therapy, including stroke,
deep venous thrombosis, and renal failure with sucrosecontaining formulations.195 Some centers will use IVIg to establish initial control of blistering
in severely affected patients because it does not increase risk of infection as much as corticosteroids and immunosuppressants. IVIg has also been
used in combination with rituximab,196 although it is unclear whether the combination is safer or more effective compared to either alone.
Plasmapheresis
Plasmapheresis is sometimes used for severe pemphigus, or for pemphigus that is unresponsive to a combination of prednisone and
immunosuppressive agents. Although one controlled study found it to be ineffective,197 other studies have found that it both reduces serum levels of
pemphigus autoantibodies and controls disease activity.198 Plasmapheresis plus intravenous pulse therapy with cyclophosphamide has been
reported to result in remissions of PV.199 For maximum effectiveness, it is probably necessary to perform plasmapheresis on patients taking
immunosuppressive agents to prevent the antibodyrebound phenomenon that can follow the removal of IgG. Protein A immunoadsorption, which
removes IgG selectively from plasma, has also been used.200
Pulsed Intravenous HighDose Glucocorticoids
Intravenous, pulse administration of methylprednisolone, 250–1,000 mg given over approximately 3 hours daily for 4–5 consecutive days, can result in
longterm remissions and decrease the total dose of glucocorticoids necessary to control disease.201 Although the purpose of this therapy is to
decrease the incidence of complications of longterm steroid use, it can result in all the usual glucocorticoid complications, as well as cardiac
arrhythmias with sudden death, and its use is controversial.202 Furthermore, a controlled trial found that adjuvant oral dexamethasone pulse therapy
in addition to standard therapy with prednisolone and azathioprine for PV is not beneficial.203 It may be that simply giving divided lower doses of
prednisone could accomplish the same result with fewer side effects.
All in all, there has been a tremendous advance in the armamentarium 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.
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Chapter 54. Pemphigus

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Pemphigus vulgaris. A . Flaccid blisters. (Used with permission from Lawrence Lieblich, MD.) B . Oral erosions.

Pemphigus foliaceus. A . Scaly, crusted lesions on upper back. B . Exfoliative erythroderma due to confluent lesions.

Pemphigus foliaceus. A . Scaly, crusted lesions on upper back. B . Exfoliative erythroderma due to confluent lesions.

Histopathology of pemphigus foliaceus. A . Acantholysis in the granular layer. B . Subcorneal pustule with acantholysis.

188. Teichmann LL et al: Fatal Pneumocystis pneumonia following rituximab administration for rheumatoid arthritis. Rheumatology 4 7:1256, 2008

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