8

photopheresis. A small number of patients have shown

a good response to combination treatment directed at
both humoral and cell-mediated autoimmunity. These
patients received oral prednisone, rituximab, and
dacli- zumab or basiliximab (both are nondepleting
mono- clonal antibody against CD25, the high affinity
IL-2 receptor of T cells). This appears to be a less toxic
way of downregulating both humoral and cellmediated autoimmunity, with promising early results.

PREVENTI
ON
Section 8

::
Disorders of Epidermal and DermalEpidermal Adhesion

There is no known intervention that may prevent the

development of PNP in a patient with a known lymphoid malignancy. Although there has been
individual case reports of PNP perhaps being
triggered by certain drugs, radiation therapy, or
cytokine administration, it is still not clear that any of
these treatments triggered the autoimmune disease,
and it appears more likely that the neoplasm itself
triggers the autoimmunity.

Full reference list available at www.DIGM8.com

DVD contains references and additional content
1. Anhalt GJ et al: Paraneoplastic pemphigus: An autoimmune mucocutaneous disease associated with neoplasia.
N Engl J Med 323:1729, 1990
3. Posner JB. Immunology of paraneoplastic syndromes:
Overview. Ann N Y Acad Sci 998:178, 2003
6. Nousari HC et al: Elevated levels of interleukin-6 in paraneoplastic pemphigus. J Invest Dermatol 112:396, 1999
13. Nousari HC et al: The mechanism of respiratory failure in
paraneoplastic pemphigus. N Engl J Med 340:1406, 1999
14. Kim SC et al: cDNA cloning of the 210-kDa paraneoplastic pemphigus antigen reveals that envoplakin is a component of the antigen complex. J Invest Dermatol 109:365,
1997
23. Borradori L et al: Anti-CD20 monoclonal antibody (rituximab) for refractory erosive stomatitis secondary to
CD20(+) follicular lymphoma-associated paraneoplastic
pemphigus. Arch Dermatol 137:269, 2001

Chapter 56 :: Bullous Pemphigoid

:: Donna A. Culton, Zhi Liu, & Luis A. Diaz
BULLOUS PEMPHIGOID AT A
GLANCE
Usually occurs in elderly patients.
Yearly mortality varies from 6% to 40%.
Pruritic urticarial lesions and tense large
blisters. Oral mucous membrane erosions in
minority of patients.
Skin pathology shows subepidermal blisters
with eosinophils.
Direct immunofluorescence shows
immunoglobulin (Ig) G and C3 at epidermal
basement membrane of perilesional skin,
indirect immunofluorescence shows IgG
antibasement membrane autoantibodies in
the serum.
The autoantigens BPAg1e and the
BP180 are proteins of the keratinocyte
hemidesmosome, a basal cellbasement
membrane adhesion structure.

608

KEY REFERENCES

Therapy includes topical and systemic

corticosteroids and immunosuppressives.

Bullous pemphigoid was originally classified as a

unique disease with distinctive clinical and histo1
logic features by Walter Lever in 1953. Its separation from pemphigus was important, because at the
time pemphigus vulgaris was often fatal, whereas
bullous pemphigoid had a comparatively good
prognosis. The separation of bullous pemphigoid
from pemphigus was confirmed and fully justified
by the characteristic immunopathologic features
of these diseases described approximately 12 years
2,3
later.

EPIDEMIOL
OGY
Bullous pemphigoid typically occurs in patients over
4
60 years of age, with a peak incidence in the 70s.
There are several reports of bullous pemphigoid in
58
infants and children, although this is rare. There
is no known ethnic, racial, or sexual predilection for
developing bullous pemphigoid. The incidence of
bullous pemphigoid is estimated to be 7 per million per
year in both France and Germany, and 14 per million
4,911
per year in Scotland.
A recent large cohort study
suggests that the incidence of bullous pemphigoid
may be as high as 43 per million per year in the
United
Kingdom with incidence increasing over the last sev-

e
r
a
l
y
e
a
r
s
.
1
2

ETIOLOGY
PATHOGENESIS

AND

IMMUNOPATHOLOGY

PATHOPHYSIOLOGY OF
SUBEPIDERMAL BLISTERING
Bullous pemphigoid is an autoimmune inflammatory
disease. The distinctive feature of bullous pemphigoid is the presence of circulating and tissue-bound
autoantibodies against BP180 and BP230. Anti-BP180
autoantibodies of various immunoglobulin isotypes
and IgG subclasses are present in bullous pemphigoid
4446
sera with IgG being predominant, followed by IgE.
Serum levels of anti-BP180-NC16A IgG and IgE correlate well with disease activity in bullous pemphigoid
24,26,40
patients.
Inflammatory cells are present in the
upper dermis and bullous cavity, including eosinophils
(the predominant cell type), neutrophils, lymphocytes,
and monocytes/macrophages. Both intact and degranulating eosinophils, neutrophils, and mast cells (MC)
4750
are found in the dermis.
Local activation of these
cells may occur via the multiple inflammatory media5159
tors present in the lesional skin and/or blister fluid.
Several proteinases are found in bullous pemphigoid
blister fluid, including plasmin, collagenase, elastase,
6067
and MMP-9,
which may play a crucial role in subepidermal blister formation by their ability to degrade
extracellular matrix proteins.
Both in vitro and in vivo data demonstrate that
autoantibodies, particularly those against BP180, are
pathogenic. In vitro studies using normal human
skin sections indicate that bullous pemphigoid IgG is
capable of generating dermalepidermal separation in
68,69
the presence of complement and leukocytes.
Early
attempts to demonstrate the pathogenicity of patient
autoantibodies by a passive transfer mouse model
were unsuccessful because bullous pemphigoid antiBP180-NC16A autoantibodies fail to cross-react with
70
the murine BP180. To overcome this difficulty, rabbit
antibodies were raised against the epitope on mouse
BP180. Passive transfer of these rabbit antibodies to
neonatal mice induces blisters that resemble some key

Bullous Pemphigoid

Immunofluorescence (IF) techniques demonstrate that

patients with bullous pemphigoid exhibit circulating and tissue-bound autoantibodies directed against
antigens of the cutaneous basement membrane zone
3
(BMZ). Immunoelectron microscopy studies localize
bullous pemphigoid antigens to the hemidesmosome,
an organelle that is important in anchoring the basal
13
cell to the underlying basement membrane. These
autoantibodies bind to both the intracellular plaque
of the hemidesmosome and the extracellular face of
the hemidesmosome. Bullous pemphigoid autoantibodies recognize two distinct antigens with molecular weights of 230 kDa and 180 kDa by immunoblot
14
analysis of human skin extracts. The 230-kDa mole1417
cule is termed BP230, BPAG1, or BPAG1e.
BPAG1e
belongs to a gene family that includes desmoplakin
I, a desmosomal plaque protein that is important in
anchoring keratin intermediate filaments to the des18,19
mosome.
By immunoelectron microscopy BPAG1e
is located in the intracellular plaque of the hemidesmosome, exactly where keratin intermediate filaments
20
insert. Analysis of BPAG1e-deficient mouse strains
generated by transgenic knockout technology further
demonstrates that the function of BPAG1e is to anchor
keratin intermediate filaments to the hemidesmo21
some. Mice lacking BPAG1e show fragility of basal
cells due to collapse of the keratin filament network,
but no epidermaldermal adhesion defect. Interestingly, an alternatively spliced form of BPAG1e (termed
BPAG1n) is expressed in neural tissue. BPAG1n sta22,23
bilizes the cytoskeleton of sensory neurons,
just
as BPAG1e stabilizes the cytoskeleton of epidermal
cells. The lack of dermalepidermal separation in the
BPAG1e-null mice indicates that pathogenic autoantibodies in bullous pemphigoid do not act simply by
inhibiting the function of BPAG1e.
The 180-kDa BP autoantigen is termed BP180, BPAG2,
2426
or type XVII collagen.
BP180 is a transmembrane
protein with an intracellular amino-terminal domain
and an extended carboxyl-terminal domain that spans
the lamina lucida and projects into the lamina densa of
2731
the basement membrane.
Its cytoplasmic domain
is located in the plaque of the hemidesmosome and
its extracellular domain is linked to anchoring fila-

::

BULLOUS PEMPHIGOID
ANTIGENS

Chapter 56

The hallmarks of bullous pemphigoid include the

presence of subepidermal blisters, lesional and perilesional polymorphonuclear cell infiltrates in the
upper dermis, and immunoglobulin (Ig) G autoantibodies and C3 bound to the dermal epidermal junction. Remarkable advances have been made in the last
decades characterizing the antigens as hemidesmosomal components and developing an animal model
that demonstrates the pathogenicity of bullous pemphigoid autoantibodies.

3234

ments.
The extracellular domain of BP180 contains
a series of 15 collagen regions interrupted by 16 non29
collagen sequence. The NC16A subdomain, adjacent
to the membrane-spanning region, harbors the major
35,36
autoantibody-reactive epitopes.
These features
make the BP180 antigen a prime target for pathogenic
autoantibodies. As discussed in Section Pathophysiology of Subepidermal Blistering, antibodies against
the NC16A domain are capable of inducing subepidermal blisters in mice. Moreover, an enzyme-linked
immunosorbent assay (ELISA) to measure antibodies
against the BP180 NC16A domain is both sensitive and
3739
specific for a diagnosis of bullous pemphigoid
and
40
its titers correlate with disease activity. Further evidence that BP180 mediates dermalepidermal adhesion comes from analysis of the gene defect in patients
with the junctional subepidermal blistering disease,
non-Herlitz junctional epidermolysis bullosa (JEBnH), previously known as generalized atrophic benign
epidermolysis bullosa. These patients have recessively
inherited mutations in the BP180 gene that result in a
4143
missing or dysfunctional protein.

609

Proposed mechanism of subepidermal blister formation in mouse model of BP

BK
1
7

Blistering

Ab binding

C activation C5a

-BP180 IgG

BP180

MC
C5aR
FcRI
FcRIII
3

Section 8

::
Disorders of Epidermal and DermalEpidermal Adhesion

610

NE, MMP-9,
plasmin, ROS

BMZ injury

MC activation

TFN, etc

6
PMN
activation

4
FcRIII

PMN recruitment

5
Fc-FcR
binding
PMN

Figure 56-1 Proposed mechanism of subepidermal blister formation in mouse model of BP. Subepidermal
blistering is an inflammatory process that involves the following steps: 1, anti-BP180 IgG binds to the pathogenic
epitope of BP180 antigen on the surface of basal keratinocytes (BK); 2, the molecular interaction between BP180
antigen and anti-BP180
IgG activates the classical pathway of the complement system (C); 3, C activation products C3a and C5a cause mast
cells (MC) to degranulate; 4, TNF- and other proinflammatory mediators released by MC recruit neutrophils (PMN); 5,
infiltrat- ing PMNs bind to the BP180anti-BP180 immune complex via the molecular interaction between Fc receptor III
(FcRIII) on neutrophils and the Fc domain of anti-BP180 IgG; 6, the interaction between Fc and FcRIII activates PMNs
to release neutrophil elastase (NE), gelatinase B (MMP-9), plasminogen activators (PAs), and reactive oxygen species
(ROS); 7, Proteo- lytic enzymes and ROS work together to degrade BP180 and other extracellular matrix proteins, leading
to subepidermal blistering.
features of human bullous pemphigoid, including in
situ deposition of rabbit IgG and mouse C3 at the
BMZ, dermalepidermal separation, and an
70
inflammatory
cell
infiltrate.
These
studies
demonstrate that experi- mental blistering in animals
requires activation of the classical pathway of the
complement system, mast cell degranulation, and
neutrophil infiltration (Fig.
7175
56-1).
A well-orchestrated proteolytic event occurs
during the disease progression. Plasmin activates proenzyme MMP-9 and activated MMP-9 then degrades
1-proteinase inhibitor, the physiological inhibitor of
neutrophil elastase. Unchecked neutrophil elastase
degrades BP180 and other extracellular matrix components, resulting in dermalepidermal junction separa7679
tion.
To directly test the pathogenicity of antiBP180
IgG autoantibodies from bullous pemphigoid patients,
humanized BP180 mouse strains were generated, in
which the human BP180 or NC16A domain replaces
80,81
the murine BP180 or corresponding domain.
These
humanized mice, upon injection with anti-BP180 IgG
from bullous pemphigoid patients, develop subepi80,81
dermal blisters.
Like the rabbit antimurine BP180
IgG-induced model, the humanized NC16A mouse
model of bullous pemphigoid also requires comple80
ment, MC, and neutrophils (Fig. 56-2).

IgE anti-BP180 autoantibodies may also play a role

in blister formation. Human skin grafted onto
immune- deficient mice injected with an IgE
hybridoma to the extracellular portion of BP180 or
total IgE from bullous pemphigoid patients sera
82,83
exhibit histological dermal epidermal separation,
suggesting that anti-BP180
IgE antibodies may also participate in pathogenesis
of bullous pemphigoid through activating MC and
recruiting eosinophils.
Although animal model studies clearly show that
an inflammatory cascade is triggered by BP180specific antibodies and is essential for blister formation, direct interference of hemidesmosome-mediated
cellcell matrix adhesion by anti-BP180 autoantibodies
84
may be another disease mechanism. Involvement of
anti-BP230 autoantibodies in bullous pemphigoid blistering is also implicated in some animal model stud85,86
ies,
but direct evidence in humans is lacking.
In addition to the humoral response, bullous pemphigoid patients also mount a cell mediated autoimmune response. Autoreactive T and B lymphocytes
8789
recognize BP180.
These studies suggest that bullous pemphigoid is a T- and B-cell-dependent and
anti- body-mediated skin autoimmune disease. As in
most autoimmune diseases, the initial trigger for
induction

Humanized BP180NC16A mouse model of BP

NC16A

Collagen domains
hBP180

NC14A
mBP180
N

NC16A
hmBP180
N

Chapter 56

::

(a) Clinical

(b) lgG

(c) C3

(e) MC

(f) PMN

Bullous Pemphigoid

(d) DermalEpidermal

Separation

Figure 56-2 Humanized BP180NC16A mouse model of BP. A. Human BP180 (top panel) is a transmembrane
protein of basal keratinocytes. It contains a single transmembrane domain. The extracellular region is consisted of 15
interrupted collagen domains (yellow bars) and 16 noncollagen domains (black lines). The NC16A domain (red line)
harbors immuno- dominant epitopes recognized by BP autoantibodies. The extracellular region of mouse BP180
(middle panel) contains
13 collagen domains (blue bars) and 14 noncollagen domain (black lines). In humanized BP180NC16A mice, the mouse
BP180NC14A domain was replaced by the human NC16A domain (lower panel). B. Neonatal NC16A mice injected i.d.
with BP180NC16A-specific IgG autoantibodies developed clinical blistering (a). Direct IF showed BMZ deposition of
human IgG (b) and murine C3 (c). Histological sections of lesional skin showed dermalepidermal separation (d).
Examination of toluidine blue-stained skin sections revealed degranulating mast cells (MC) (e). Hematoxylin/Eosin (H/E)
staining showed infiltrating neutrophils (PMN) in the upper dermis (400 magnification) (f ). E = epidermis; D = dermis; V
= vesicle; arrows in panels bd = basal keratinocytes.

611

of autoreactive lymphocytes and autoantibody production in bullous pemphigoid remains unknown.

Several other subepidermal blistering diseases also
show autoimmune responses to BP180. These include
pemphigoid gestationis (or herpes gestationis), cicatricial pemphigoid (or mucous membrane pemphigoid),
linear IgA bullous dermatosis, and lichen planus pem90100
phigoid.
It is possible that they may share some
common immunopathological mechanisms with bullous pemphigoid.

CLINICAL
FINDINGS
Section 8

HISTORY

::
Disorders of Epidermal and DermalEpidermal Adhesion

Most cases of bullous pemphigoid occur sporadically

without any obvious precipitating factors. However,
there are several reports in which bullous pemphigoid appears to be triggered by ultraviolet (UV) light,
either UVB or following PUVA therapy, and radiation
101103
therapy.
Certain medications have also been associated with the development of bullous pemphigoid
including penicillamine, efalizumab, etanercept, and
104109
furosemide.

CUTANEOUS LESIONS
The classic form of bullous pemphigoid is
characterized by large, tense blisters arising on normal
110,111
skin or on an erythematous base (Fig. 56-3A).
These lesions are most commonly found on flexural
surfaces, the lower abdomen, and thighs, although
they may occur any- where. The bullae are typically
filled with serous fluid, but may be hemorrhagic. The
Nikolsky and Asboe Hansen signs are negative.
Eroded skin from ruptured blisters usually heals
spontaneously without scarring, although milia can
sometimes occur. Once the lesions heal they leave
hyperpigmented patches that may last for several
months. Pruritus may be intense in some patients, but
minimal in others.

612

Nonbullous lesions are the first manifestation of bul112

lous pemphigoid in almost half of patients. Often,
urticarial type lesions precede the more classic tense
bullae, and patients may present with these lesions
early in the course of disease (Fig. 56-3B). The erythematous component in some bullous pemphigoid
patients may appear eczematoid, serpiginous, or targetoid with erythema multiforme-like lesions.
Mucous membrane lesions occur in approximately
10% of patients and are almost always limited to the
oral mucous membranes, particularly the buccal
110,113115
mucosa.
Intact oral mucosa blisters are rare,
with
erosions more commonly seen. The lesions heal without scarring and are fairly limited. Unlike erythema
multiforme, the vermillion border of the lips is rarely
involved. There are rare reports of esophageal involve116,117
ment.
The presence of scarring is more suggestive
of cicatricial pemphigoid as discussed in Chapter 57.
In addition to the more classic findings, unusual
118
clinical presentations can be seen. In these cases,
the diagnosis is confirmed by IF and ELISA studies. For example, localized bullous pemphigoid
often presents as tense bullae restricted to localized
areas of involvement, most commonly on the lower
119,120
legs.
Patients with localized disease have antibodies against the same pemphigoid antigens as
119121
patients with more generalized disease.
The
lesions may remain localized for years or progress to
generalized bullous pemphigoid. Childhood bullous
pemphigoid often presents as localized disease with
58,122
acral distribution being common.
Localized vulvar and perivulvar disease has also been described
123,124
in young girls.
Other reports of localized bullous
pemphigoid suggest that changes induced by radiation, trauma, or surgery (colostomy, urostomy, or skin
graft donor site) at a particular site may precipitate
125133
disease in these areas.
Other less common presentations include erythroderma, prurigo nodularis-like or vegetating lesions,
and dyshidrotic dermatitis-like lesions. Again, the
antibodies from these patients show typical IF localiza121,134142
tion and bind the pemphigoid antigens.

Figure 56-3 Bullous pemphigoid. A. Large, tense bullae and erythematous patches studded of small vesicles on
the thighs and lower legs. B. urticarial lesions of bullous pemphigoid with overlying tense vesicles and bullae in the
axilla.

In addition to atypical clinical presentations, bullous

pemphigoid may also coexist with other cutaneous
dis- eases. Lichen planus pemphigoides describes the
coex- istence of bullous pemphigoid and lichen planus
with
typical
clinical,
histologic,
and
143146
immunopathologic fea- tures of both diseases.
Lichen planus pemphigoi- des more often presents in
middle-aged patients (mean age of onset 3545 years
of age) and is more localized to the extremities with a
less severe clinical course when compared to classic
bullous pemphigoid. In rare instances, bullous
pemphigoid has also been reported to coexist with
147150
pemphigus.

The diagnosis of bullous pemphigoid is made based

upon clinical, histologic, and IF features as described
below. Other laboratory studies play a small supporting role. Approximately half of patients will have
elevated total serum IgE levels, which often correlate
with titers of bullous pemphigoid IgG autoantibod51,161,162
ies by IF and pruritus.
Approximately one-half
of patients have peripheral blood eosinophilia, which
162,163
does not correlate with serum IgE levels.

HISTOPATHOL
OGY
Biopsy of an early small vesicle is diagnostic with
histology revealing a subepidermal blister with a

superficial dermal infiltrate consisting of eosinophils,

neutrophils lymphocytes, and monocytes/macro110
phages (Fig. 56-4). The infiltrate ranges from intense
to sparse, but it characteristically contains some eosinophils, which may also be seen in the blister cavity.
The blister roof is usually viable without evidence of
necrosis. Histology of urticarial lesions may only show
a superficial dermal infiltrate of lymphocytes, monocytes/macrophages, and eosinophils with papillary
dermal edema. These urticarial lesions may also
display degranulating eosinophils at the dermal
epidermal junction, with early separation of individual
basal cells from the basement membrane and/or
164
eosinophilic spongiosis.

Bullous Pemphigoid

LABORATORY
TESTS

Figure 56-4 Histopathology of bullous pemphigoid.

Sub- epidermal blister with an inflammatory cell infiltrate
con- taining eosinophils in the superficial dermis (100
magni- fication).

::

Neurological disease is seen more frequently in bullous pemphigoid patients and it appears that patients
with neurological disease (especially those over
80 years of age) have a significantly higher risk of
developing bullous pemphigoid than those without
151153
neurological disease.
In rare instances, bullous
pemphigoid may be seen in association with acquired
hemophilia due to acquired Factor VIII inhibitor.
Cutaneous clinical manifestations include ecchymoses, hematomas, and hemorrhagic bullae in addition
to more systemic findings such as gastrointestinal
154156
bleeding.
There have been many case reports of bullous pemphigoid associated with malignancy. However, casecontrol studies suggest that there is no increase, or a
very small increase, in the frequency of malignancy
in bullous pemphigoid patients compared with age152,157159
matched controls.
There may be an increased
frequency of malignancy in bullous pemphigoid
patients with negative indirect IF studies as compared
113,160
with those with positive findings.
The perceived
association may be explained by the fact that both bullous pemphigoid and malignancy occur more commonly in elderly patients. While a thorough review of
systems and symptom-guided workup is indicated in
patients with a new diagnosis of bullous pemphigoid,
extensive screening for an asymptomatic malignancy
is not warranted.

Chapter 56

DISEASE ASSOCIATIONS

ELECTRON MICROSCOPY
Ultrastructural studies demonstrate that early blister formation in bullous pemphigoid occurs in the
lamina lucida, between the basal cell membrane
165
and the lamina densa (Fig. 56-5A and 56-5B). In
areas of blister formation, there is loss of anchoring
filaments and hemidesmosomes. Degranulation of
eosinophils,
neutrophils,
and MC
in
the
lesional/
perilesional skin has also been observed by electron
49
microscopy.

SPECIAL TESTS
Direct IF of perilesional skin shows linear IgG (usually
IgG1 and IgG4, although all IgG subclasses and IgE
have been reported) and C3 along the basement mem2,3,113,162,166
brane.
In approximately 70% of patients,
there are circulating IgG and IgE autoantibodies that
bind the BMZ on normal human skin or monkey
45,113,162,163,166169
esophagus by indirect IF.
Using 1 M
NaCl split skin, which separates the epidermis from
the dermis at the lamina lucida, an even higher
percentage of patients will have detectable circulating
170,171
anti-BMZ autoantibod- ies.
In addition to being
more sensitive, the other

613

Indirect IF

Immuno-EM

Section 8

::

Disorders of Epidermal and DermalEpidermal Adhesion

Figure 56-5 A. Indirect immunofluorescence of

bullous
pemphigoid serum shows a linear pattern of immunoglobulin G binding to the epidermal dermal junction of
normal skin. B. Binding of bullous pemphigoid
antibod- ies to human basal cell hemidesmosomes as
described by Mutasim et al: J Invest Dermatol 84:4753, 1985. A small rectangle of linear indirect IF staining
and the arrow depicts the immunolocalization of the
reactive antibodies to the hemidesmosome (white
asterisks).

advantage of the 1 M NaCl-split skin substrate is that

bullous pemphigoid antibodies bind the roof of the
artificially induced blister (i.e., the bottom of the basal
cells). This finding differentiates bullous pemphigoid
antibodies from epidermolysis bullosa acquisita (EBA)
autoantibodies, which bind the base or the floor of the
split skin (i.e., dermal side; Figs. 56-6A and 56-6B). In

contrast to pemphigus, in bullous pemphigoid the

indirect IF antibody titer does not usually correlate
172
with disease extent or activity.
Recently, ELISA techniques have proven to be useful
in both clinical and research settings for the detection
of circulating antigen specific IgG and IgE antibodies. Commercial kits are available for detection of both
BP-180 (NC16A and total) and BP-230 IgG antibodies.
A sensitivity of 89% and specificity of 98% when used
with appropriate cutoff values are reported with these
37
assays. As many as 75% of patients also have antigen
specific IgE with anti-BP180 and anti-BP230 IgE anti44,46,168,173176
bodies detectable by IF and ELISA.
Those
patients with anti-BP180 IgE antibodies may have a
174
more severe form of disease. Antigen specific IgE
anti- bodies may account for the early urticarial type
lesions and likely play a role in recruiting eosinophils
82,173
to skin lesions.
Recent studies have shown that approximately 7%
of the normal population has anti-BP180 antibodies
detectable by ELISA in the absence of clinical and histologic features of disease without age or gender predilection. The predictive relevance of these circulating
antibodies in healthy individuals is unknown as longterm follow-up is not available. However, this finding underscores the importance of using the ELISA
in appropriate clinical settings and not as a screening
177
tool in patients who lack other features of disease.

DIFFERENTIAL
DIAGNOSIS
The differential diagnosis for bullous pemphigoid
includes other blistering diseases, such as linear IgA
disease, dermatitis herpetiformis, erythema multiforme, EBA, and pemphigus. Histology and IF can
easily distinguish bullous pemphigoid from these diseases (Box 56-1). Distinguishing bullous pemphigoid
from EBA and cicatricial pemphigoid may be difficult
115,178
as histology and direct IF may be identical.
EBA
can usually be distinguished from bullous pemphi-

A
B

614

Figure 56-6 Indirect immunofluorescence on normal skin previously incubated in 1 M NaCl to induce a split through
the lamina lucida of the dermalepidermal junction. A. IgG antibodies from bullous pemphigoid serum binds to the
roof of the artificial blister (hemidesmosomes). B. IgG antibodies from epidermolysis bullosa acquisita (EBA) serum
binds to the floor of the split (collagen VII of anchoring fibers).

BOx 56-1 DIFFERENTIAL DIAGNOSIS

OF BuLLOuS PEMPHIGOID
SUBEPIDERMAL BLISTERING
DISEASES WITH
AUTOANTIBODIES
Pemphigoid gestationis
Cicatricial pemphigoid
Epidermolysis bullosa acquisita (EBA)
Linear immunoglobulin A disease
Dermatitis herpetiformis
Bullous lupus erythematosus, described as an EBA
phenotype

Pemphigus
INTRAEPIDERMAL BLISTERING
DISEASES WITHOUT
AUTOANTIBODIES
Allergic contact dermatitis (e.g., rhus dermatitis)
Bullous impetigo, staphylococcal scalded-skin
syndrome
Friction blisters Hailey
Hailey disease
Incontinentia pigmenti

goid by indirect or direct IF on salt-split skin as stated

179
above.
Confirmation of EBA may be accomplished
by ELISA assays using type VII collagen, the EBA
antigen (discussed in Chapter 60). Immunoelectron
microscopy also distinguishes these diseases because
the IgG in EBA is below the lamina densa on the
anchoring fibrils (type VII collagen), whereas the IgG
in bullous pemphigoid is closely associated with the
180
basal cell hemidesmosomes.
As opposed to bullous pemphigoid, cicatricial
pemphigoid usually presents with mucosal lesions
predominantly, if not exclusively (see Chapter 57).
Cicatricial pemphigoid is characterized by desquamative gingivitis as well as inflammation and scarring of
conjunctiva. If there is blistering of the skin, it may be
transient and may result in scarring. Large, tense blisters, which are characteristic of bullous pemphigoid,
are usually not seen in cicatricial pemphigoid.

COMPLICATIONS
Complications in untreated patients include skin
infection developing within denuded bullae, dehy-

Bullous pemphigoid is characterized by a waxing and

waning course with occasional spontaneous remission
in the absence of treatment. Localized disease often
resolves spontaneously, but spontaneous remission
can even occur in patients with more generalized disease. For example, prior to the availability of systemic
corticosteroids, Lever reported that 8 of 30 adults with
bullous pemphigoid went into remission after approximately 15 months (range, 338 months) of active dis110
ease. In treated patients, the length of disease ranges
from 9 weeks to 17 years with a median treatment
period of 2 years and 50% remission rates in patients
181
followed for at least 3 years. Clinical remission with
reversion of direct and indirect IF to negative has been
noted in patients, even those with severe generalized
disease, treated with oral corticosteroids alone or with
162,182
azathioprine.
High ELISA titers and, to a lesser
degree, positive direct IF at the time of therapy cessation has been associated with a high risk of relapse
182
within the first year following cessation of therapy.
At least one of these tests should be performed before
therapy is discontinued.
Old age, poor general health, and the presence
of anti-BP180 antibodies have been associated with
183186
a poor prognosis.
Early mortality rates in
110
untreated patients were reported to be 25%. Newer
studies have shown the 1-year mortality of patients
with bullous pemphigoid to be between 19% and
40% in Europe, but lower (less than 6%12%) in the
12,183185,187190
United States.
The factors underlying
this discrepancy in mortality rates between Europe
and the United States are not clear. While mortality rates remain relatively low in the United States,
recent studies have confirmed a slow steady increase
in mortality over the last 24 years in the United
191
States.

Bullous Pemphigoid

INTRAEPIDERMAL BLISTERING
DISEASES WITH
AUTOANTIBODIES

PROGNOSIS/CLINICAL
COURSE

::

Erythema multiforme and toxic epidermal necrolysis

Porphyria
Epidermolysis bullosa (genodermatoses)

Chapter 56

SUBEPIDERMAL BLISTERING
DISEASES WITHOUT
AUTOANTIBODIES

dration, electrolyte imbalance, and possibly death

from sepsis.

TREATME
NT
Treatment of bullous pemphigoid depends greatly on
the extent of disease. Localized bullous pemphigoid
often can be treated successfully with topical cortico162,166,192
steroids alone (Box 56-2).
Topical tacrolimus
has also been reported to be useful in a few cases of
192196
local- ized pemphigoid.
More extensive disease is usually treated with oral
192,197,198
prednisone.
Despite the lack of randomized
controlled trials, oral prednisone remains the mainstay of therapy. Some recent studies suggest that
potent topical steroids, such as clobetasol proprionate cream 0.05% applied twice daily, are also effective
in both moderate and severe bullous pemphigoid
189
and may be safer than oral prednisone. Thus, these
patients received a daily dose of 40 g of clobetasol
propionate that was applied twice daily to the entire
surface of the body until 15 days after control of the

615

BOx 56-2 TREATMENTS FOR BuLLOuS

PEMPHIGOID
CORTICOSTEROIDS
High potency topical steroids
Prednisone
OTHER IMMUNOSUPPRESSIVE AGENTS
Azathioprine
Mycophenolate mofetil
Others: methotrexate, cyclophosphamide

Section 8

MODULATORS OF ANTIBODY
LEVELS Intravenous -globulin
Plasmapheresis

::

OTHER

Disorders of Epidermal and DermalEpidermal Adhesion

616

Tetracycline or erythromycin and nicotinamide

Dapsone
Topical tacrolimus

disease had been attained. High-potency topical

treatment did result in significant systemic absorption and therefore may act via local and systemic
199
effects. Such topical therapy can be expensive and
difficult to apply, which may prove prohibitive in
many patients.
In elderly patients, the complications of systemic
glucocorticoid therapy (such as osteoporosis, diabetes, and immunosuppression) may be especially
200
severe. Therefore, it is important to try to minimize
the total dose and duration of therapy with oral glucocorticoids. Starting doses of prednisone of 0.751.0
mg/kg/day or even less may be adequate for
201
disease control. In addition, immunosuppressive
agents such as azathioprine, mycophenylate mofetil,
and
methotrexate
(and
less
often
cyclophosphamide) are often used in conjunction
with prednisone for their potential steroid-sparing
192,198,202209
effects,
although very few controlled trials
have addressed this com-

mon approach to therapy. High-dose pulse

therapy with intravenous methylprednisolone also
has been reported to be effective in rapidly
controlling active blister formation in bullous
210
pemphigoid.
Once the development of blisters
has been arrested and the erythema has subsided, a
careful tapering of the prednisone
is
recommended. A weekly lowering of 5 mg to
reach 30 mg is commonly used. Lower- ing this
dose must be done according to the clinical response
of the patient. The majority of patients may be
controlled with small amounts of prednisone and
immunosuppressive drugs. Sulfones may be effective in a minority of patients. Dapsone and sulfapyridine have been reported to control disease activity
198,211213
in 15%44% of bullous pemphigoid patients.
Reports have described successful treatment of
some bullous pemphigoid patients with tetracycline
and nic- otinamide or variations on this theme, such as
eryth- romycin and nicotinamide or tetracycline
214216
alone.
In small numbers of patients, other therapies reported
217
to be effective include plasmapheresis, intravenous
218220
205,207,221
immunoglobulins,
methotrexate,
lefluno222
223
mide, and chlorambucil.

KEY REFERENCES
Full reference list available at www.DIGM8.com
DVD contains references and additional content
19. Stanley JR et al: Isolation of complementary DNA for
bullous pemphigoid antigen by use of patients autoantibodies. J Clin Invest 82(6):1864, 1988
28. Diaz LA et al: Isolation of a human epidermal cDNA
corresponding to the 180-kD autoantigen recognized by
bullous pemphigoid and herpes gestationis sera. Immunolocalization of this protein to the hemidesmosome. J
Clin Invest 86(4):1088, 1990
75. Liu Z: Bullous pemphigoid: Using animal models to
study the immunopathology. J Investig Dermatol Symp
Proc 9(1):41, 2004
165. Lever WF: Pemphigus and pemphigoid. A review of the
advances made since 1964. J Am Acad Dermatol 1(1):2,
1979
167. Beutner EH, Jordon RE, Chorzelski TP: The immunopathology of pemphigus and bullous pemphigoid. J Invest
Dermatol 51(2):63, 1968
197. Patton T, Korman NJ: Bullous pemphigoid treatment
review. Expert Opin Pharmacother 7(17):2403, 2006