712 CHA P T E R 16 Dermatologic Diseases

Direct Indirect immunopathologic features of the more important immune-

immunofluorescence immunofluorescence mediated mucocutaneous diseases is found in Table 16-3.
Apply Apply patient's
fluorescein-conjugated
anti-human Ig
serum, antibodies
bind to homologous
◆ PEMPHIGUS
antibodies structures
Patient's Section of The condition known as pemphigus represents four related
tissue monkey diseases of an autoimmune origin:
specimen esophagus 1. Pemphigus vulgaris
Wash off excess Wash off excess 2. Pemphigus vegetans
3. Pemphigus erythematosus
Apply
fluorescein-conjugated
4. Pemphigus foliaceus
anti-human Ig Only the first two of these affect the oral mucosa, and
antibodies the discussion is limited to pemphigus vulgaris. Pemphi-
View with UV gus vegetans is rare; most authorities now feel it represents
microscope
simply a variant of pemphigus vulgaris.
Pemphigus vulgaris is the most common of these disor-
Wash off excess ders (vulgaris is Latin for common). Even so, it is not seen
very often. The estimated incidence is one to five cases per
million people diagnosed each year in the general popula-
tion. Nevertheless, pemphigus vulgaris is an important con-
View with UV dition because, if untreated, it often results in the patient’s
microscope death. Furthermore, the oral lesions are often the first sign
of the disease, and they are the most difficult to resolve with
therapy. This has prompted the description of the oral
lesions as “the first to show, and the last to go.”
The blistering that typifies this disease is due to an abnor-
mal production, for unknown reasons, of autoantibodies
• Fig. 16-47 Immunofluorescence Techniques. Comparison of that are directed against the epidermal cell surface glycopro-
the techniques for direct and indirect immunofluorescence. The left
side depicts the direct immunofluorescent findings in cicatricial pem-
teins, desmoglein 3 and desmoglein 1. These desmogleins
phigoid, a disease that has autoantibodies directed toward the base- are components of desmosomes (structures that bond epi-
ment zone. The right side shows the indirect immunofluorescent thelial cells to each other), and the autoantibodies attach to
findings for pemphigus vulgaris, a disease that has autoantibodies these desmosomal components, effectively inhibiting the
directed toward the intercellular areas between the spinous cells of the molecular interaction that is responsible for adherence. As
epithelium. Ig, Immunoglobulin; UV, ultraviolet.

Normal structures Targeted structures

for immune-mediated
diseases

Pemphigus (desmoglein 3
of desmosome)

Desmosome

Basal cell layer

Hemidesmosome

Basement membrane Pemphigoid (various components

of BMZ or hemidesmosome)

Anchoring fibrils Epidermolysis bullosa acquisita

(type VII collagen of anchoring
Connective tissue
fibrils)

• Fig. 16-48 Epithelial Attachment Apparatus. Schematic diagram demonstrating targeted structures
in several immune-mediated diseases. BMZ, Basement membrane zone.
TABLE
16-3!
Chronic Vesiculoulcerative Diseases

Sex Histopathologic Direct Indirect

Condition Mean Age Predilection Clinical Features Features Immunofluorescence Immunofluorescence

Pemphigus vulgaris Fourth to sixth Equal Vesicles, erosions, and Intraepithelial clefting Positive intercellular Positive
decade ulcerations on any oral
mucosal or skin
surface
Paraneoplastic Sixth to seventh Equal Vesicles, erosions, and Subepithelial and Positive, intercellular Positive (rat bladder)
pemphigus decade ulcerations on any intraepithelial clefting and basement
mucosal or skin membrane zone
surface
Mucous membrane Sixth to seventh Female Primarily mucosal lesions Subepithelial clefting Positive, basement Negative
pemphigoid decade membrane zone
Bullous pemphigoid Seventh to eighth Equal Primarily skin lesions Subepithelial clefting Positive, basement Positive
decade membrane zone
Erythema multiforme Third to fourth Male Skin and mucosa Subepithelial edema and Nondiagnostic Negative
decade involved; target lesions perivascular
on skin inflammations
Lichen planus Fifth to sixth decade Female Oral and/or skin lesions; Hyperkeratosis, Fibrinogen, basement Negative
may or may not be saw-toothed rete membrane zone
erosive ridges, bandlike
infiltrate of
lymphocytes
CHAPTER 16 Dermatologic Diseases
713
714 CHA P T E R 16 Dermatologic Diseases

a result of this immunologic attack on the desmosomes, a

split develops within the epithelium, causing a blister to
form. Desmoglein 3 is preferentially expressed in the para-
basal region of the epidermis and oral epithelium, whereas
desmoglein 1 is found primarily in the superficial portion
of the epidermis, with minimal expression in oral epithe-
lium. Patients who have developed autoantibodies directed
against desmoglein 3, with or without desmoglein 1, will
histopathologically show intraepithelial clefting just above
the basal layer, and clinically oral mucosal blisters of
pemphigus vulgaris will form. Patients who develop auto-
antibodies directed against only desmoglein 1 will histo-
pathologically show superficial intraepithelial clefting of the
epidermis, but oral mucosa will not be affected. Clinically,
the fine scaly red lesions of pemphigus foliaceus or pemphi- • Fig. 16-49 Pemphigus Vulgaris. Multiple erosions of the left
buccal mucosa and soft palate.
gus erythematosus will be evident.
Occasionally, a pemphigus-like oral and cutaneous erup-
tion may occur in patients taking certain medications
(e.g., penicillamine, angiotensin-converting enzyme [ACE]
inhibitors, nonsteroidal antiinflammatory drugs [NSAIDs])
or in patients with malignancy, especially lymphoreticular
malignancies (so-called paraneoplastic pemphigus) (see
page 716). Similarly, a variety of other conditions may
produce chronic vesiculoulcerative or erosive lesions of the
oral mucosa, and these often need to be considered in the
differential diagnosis (see Table 16-3). In addition, a rare
genetic condition termed chronic benign familial pem-
phigus or Hailey-Hailey disease may have erosive cutane-
ous lesions, but oral involvement in that process appears to
be uncommon.
• Fig. 16-50 Pemphigus Vulgaris. Large, irregularly shaped ulcer-
Clinical Features ations involving the floor of the mouth and ventral tongue.

The initial manifestations of pemphigus vulgaris often

involve the oral mucosa, typically in adults. The average age
at diagnosis is 50 years, although rare cases may be seen in
childhood. No sex predilection is observed, and the condi-
tion seems to be more common in persons of Mediterra-
nean, South Asian, or Jewish heritage.
Patients usually complain of oral soreness, and examina-
tion shows superficial, ragged erosions and ulcerations dis-
tributed haphazardly on the oral mucosa (Figs. 16-49 to
16-52). Such lesions may affect virtually any oral mucosal
location, although the palate, labial mucosa, buccal mucosa,
ventral tongue, and gingivae are often involved. Patients
rarely report vesicle or bulla formation intraorally, and such
lesions can seldom be identified by the examining clinician,
probably because of early rupture of the thin, friable roof
• Fig. 16-51 Pemphigus Vulgaris. Multiple erosions affecting the
of the blisters. More than 50% of the patients have oral marginal gingiva.
mucosal lesions before the onset of cutaneous lesions, some-
times by as much as 1 year or more. Eventually, however,
nearly all patients have intraoral involvement. The skin lesions of pemphigus typically do not cause scarring and
lesions appear as flaccid vesicles and bullae (Fig. 16-53) that symblepharon formation (see page 719).
rupture quickly, usually within hours to a few days, leaving Without proper treatment, the oral and cutaneous
an erythematous, denuded surface. Infrequently ocular lesions tend to persist and progressively involve more surface
involvement may be seen, usually appearing as bilateral area. A characteristic feature of pemphigus vulgaris is that
conjunctivitis. Unlike cicatricial pemphigoid, the ocular a bulla can be induced on normal-appearing skin if
 CHAPTER 16 Dermatologic Diseases 715

• Fig. 16-52 Pemphigus Vulgaris. The patient, with a known diag- • Fig. 16-54 Pemphigus Vulgaris. Low-power photomicrograph of
nosis of pemphigus vulgaris, had been treated with immunosuppres- perilesional mucosa affected by pemphigus vulgaris. An intraepithelial
sive therapy. The oral erosions shown here were the only persistent cleft is located just above the basal cell layer.
manifestation of her disease.

• Fig. 16-55 Pemphigus Vulgaris. High-power photomicrograph

• Fig. 16-53 Pemphigus Vulgaris. This flaccid cutaneous bulla is showing rounded, acantholytic epithelial cells sitting within the intraepi-
characteristic of skin involvement. thelial cleft.

firm lateral pressure is exerted. This is called a positive With this procedure, antibodies (usually IgG or IgM) and
Nikolsky sign. complement components (usually C3) can be demonstrated
in the intercellular spaces between the epithelial cells (Fig.
Histopathologic Features 16-56) in almost all patients with this disease. Indirect
immunofluorescence is also typically positive in 80% to
Biopsy specimens of perilesional tissue show characteristic 90% of cases, demonstrating the presence of circulating
intraepithelial separation, which occurs just above the basal autoantibodies in the patient’s serum. Enzyme-linked
cell layer of the epithelium (Fig. 16-54). Sometimes the immunosorbent assays (ELISAs) have been developed to
entire superficial layers of the epithelium are stripped away, detect circulating autoantibodies as well.
leaving only the basal cells, which have been described as It is critical that perilesional tissue be obtained for both
resembling a “row of tombstones.” The cells of the spinous light microscopy and direct immunofluorescence to maxi-
layer of the surface epithelium typically appear to fall apart, mize the probability of a diagnostic sample. If ulcerated
a feature that has been termed acantholysis, and the loose mucosa is submitted for testing, then the results are often
cells tend to assume a rounded shape (Fig. 16-55). This inconclusive because of either a lack of an intact interface
feature of pemphigus vulgaris can be used in making a between the epithelium and connective tissue or a great deal
diagnosis based on the identification of these rounded cells of nonspecific inflammation.
(Tzanck cells) in an exfoliative cytologic preparation. A
mild-to-moderate chronic inflammatory cell infiltrate is Treatment and Prognosis
usually seen in the underlying connective tissue.
The diagnosis of pemphigus vulgaris should be con- A diagnosis of pemphigus vulgaris should be made as early
firmed by direct immunofluorescence examination of fresh in its course as possible because control is generally easier
perilesional tissue or tissue submitted in Michel’s solution. to achieve. Pemphigus is a systemic disease; therefore,
716 CHA P T E R 16 Dermatologic Diseases

Before the development of corticosteroid therapy, as

many as 60% to 90% of these patients died, primarily as a
result of infections and electrolyte imbalances. Even today,
the mortality rate associated with pemphigus vulgaris is in
the range of 5% to 10%, usually because of the complica-
tions of long-term systemic corticosteroid use.

◆ PARANEOPLASTIC PEMPHIGUS
(NEOPLASIA-INDUCED PEMPHIGUS;
PARANEOPLASTIC AUTOIMMUNE
MULTIORGAN SYNDROME)
• Fig. 16-56 Pemphigus Vulgaris. Photomicrograph depicting the
Paraneoplastic pemphigus is a rare vesiculobullous disor-
direct immunofluorescence pattern of pemphigus vulgaris. Immunore- der that affects patients who have a neoplasm, usually lym-
actants are deposited in the intercellular areas between the surface phoma or chronic lymphocytic leukemia. Approximately
epithelial cells, resulting in a “chicken wire” pattern. 250 cases have been documented. Although the precise
pathogenetic mechanisms are unknown, some evidence sug-
gests abnormal levels of the cytokine, interleukin-6 (IL-6),
could be produced by host lymphocytes in response to the
treatment consists primarily of systemic corticosteroids patient’s tumor. IL-6 may then be responsible for stimulat-
(usually prednisone), often in combination with other ing the abnormal production of antibodies directed against
immunosuppressive drugs (so-called steroid-sparing agents), antigens associated with the desmosomal complex and the
such as mycophenolate mofetil or azathioprine. Although basement membrane zone of the epithelium. In addition to
some clinicians have advocated the use of topical cortico- a variety of different antibodies that attack these epithelial
steroids in the management of oral lesions, the observed adherence structures, some investigators have described
improvement is undoubtedly because of the absorption of cutaneous and mucosal damage that appears to be mediated
the topical agents, resulting in a greater systemic dose. The by cytotoxic T lymphocytes in some cases of paraneoplastic
potential side effects associated with the long-term use of pemphigus. As a result of this multifaceted immunologic
systemic corticosteroids are significant and include the attack, the disease manifests in an array of clinical features,
following: histopathologic findings, and immunopathologic findings
• Diabetes mellitus that may be perplexing if the clinician is unfamiliar with
• Adrenal suppression this condition.
• Weight gain
• Osteoporosis Clinical Features
• Peptic ulcers
• Severe mood swings Patients typically have a history of a malignant lymph-
• Increased susceptibility to a wide range of infections oreticular neoplasm, or less commonly, a benign lymph-
Ideally, a physician with expertise in immunosuppressive oproliferative disorder such as angiofollicular lymph node
therapy should manage the patient. The most common hyperplasia (Castleman disease). In approximately one-
approach is to use relatively high doses of systemic cortico- third of reported cases, paraneoplastic pemphigus devel-
steroids initially to clear the lesions, and then attempt to oped before a neoplasm was identified, thus signaling the
maintain the patient on as low a dose of corticosteroids as presence of a tumor. The neoplastic disease may or may not
is necessary to control the condition. Often the clinician be under control at the time of onset of the paraneoplastic
can monitor the success of therapy by measuring the titers condition. Signs and symptoms of paraneoplastic pemphi-
of circulating autoantibodies using indirect immunofluores- gus usually begin suddenly and may appear polymorphous.
cence, because disease activity frequently correlates with the In some instances, multiple vesiculobullous lesions affect
abnormal antibody levels. The use of rituximab, a mono- the skin (Fig. 16-57) and oral mucosa. Palmar or plantar
clonal antibody that targets B-lymphocytes, represents bullae may be evident, a feature that is uncommon in pem-
another promising approach to managing this disease, as it phigus vulgaris. For other patients, skin lesions can appear
targets the cells responsible for producing the autoantibod- more papular and pruritic, similar to cutaneous lichen
ies that cause pemphigus. planus. The lips often show hemorrhagic crusting similar to
Pemphigus may undergo complete resolution, although that of erythema multiforme (Fig. 16-58). Oral mucosal
remissions and exacerbations are common. One study sug- involvement is an early, consistent feature of paraneoplastic
gested that up to 75% of patients will have disease resolu- pemphigus, and patients develop multiple areas of erythema
tion after 10 years of treatment, although most centers and diffuse, irregular ulceration (Fig. 16-59), affecting vir-
report a remission rate of approximately 30%. tually any oral mucosal surface. If the lesions remain
 CHAPTER 16 Dermatologic Diseases 717

• Fig. 16-57 Paraneoplastic Pemphigus. The bulla and crusted • Fig. 16-60 Paraneoplastic Pemphigus. Ocular involvement.
ulcerations on this patient’s arm are representative of the polymor-
phous cutaneous lesions.

• Fig. 16-61 Paraneoplastic Pemphigus. This medium-power

photomicrograph shows both intraepithelial and subepithelial clefting.
• Fig. 16-58 Paraneoplastic Pemphigus. Crusted, hemorrhagic lip
lesions may be mistaken for erythema multiforme or herpes simplex
infection.
develops, similar to that seen with cicatricial pemphigoid
(Fig. 16-60). The anogenital, nasopharyngeal, esophageal,
and respiratory tract mucosa may also be involved. Involve-
ment of the bronchiolar mucosa is particularly significant
because the lining epithelium sloughs and occludes the
bronchiolar lumina and the alveoli of the lung, resulting in
a condition known as bronchiolitis obliterans.

Histopathologic Features
The features of paraneoplastic pemphigus on light micro-
scopic examination may be as diverse as the clinical features.
In most cases, a lichenoid mucositis is seen, usually with
subepithelial clefting (like pemphigoid) or intraepithelial
clefting (like pemphigus) (Fig. 16-61).
• Fig. 16-59 Paraneoplastic Pemphigus. These diffuse oral ulcer- Direct immunofluorescence studies may show a weakly
ations are quite painful. positive deposition of immunoreactants (IgG and comple-
ment) in the intercellular zones of the epithelium and/or a
untreated, then they persist and worsen. Some patients may linear deposition of immunoreactants at the basement
develop only oropharyngeal lesions, without cutaneous membrane zone. Although antibodies directed against
involvement. desmoglein 1 and 3, as well as the bullous pemphigoid
Other mucosal surfaces are also commonly affected, with antigens are often produced, antibodies directed against the
70% of patients having involvement of the conjunctival plakin family of desmosomal components are more com-
mucosa. In this area, a cicatrizing (scarring) conjunctivitis monly identified and are more specific for paraneoplastic
718 CHA P T E R 16 Dermatologic Diseases

pemphigus. ELISA or immunoblotting techniques are used gus. The prognosis and microscopic features of pemphi-
to confirm the presence of antibodies directed against peri- goid, however, are very different.
plakin or envoplakin specifically. If these tests are not avail- Although a variety of terms have been used over the
able, then indirect immunofluorescence can be conducted decades to designate this condition, a group of experts from
using a transitional type of epithelium (e.g., rat urinary both medicine and dentistry met in 1999 and came to an
bladder mucosa) as the substrate due to its rich expression agreement that mucous membrane pemphigoid would be
of plakins. This technique shows a fairly specific pattern of the most appropriate name for the disease. Cicatricial pem-
antibody localization to the intercellular areas of the epithe- phigoid, another commonly used name for this process, is
lium. Examples of paraneoplastic pemphigus that show only derived from the word cicatrix, meaning scar. When the
a lichenoid reaction with no demonstrable autoantibody conjunctival mucosa is affected, the scarring that results is
production have infrequently been described. the most significant aspect of this disorder because it invari-
ably results in blindness unless the condition is recognized
Treatment and Prognosis and treated. Interestingly, the oral lesions seldom exhibit
this tendency for scar formation.
Paraneoplastic pemphigus is often a very serious condition
with a high morbidity and mortality rate, with some series Clinical Features
having a mortality rate of 90%. For the infrequent cases
associated with a benign lymphoproliferative condition, Mucous membrane pemphigoid usually affects older adults,
surgical removal of the tumor may result in regression of with an average age of 50 to 60 years at the onset of disease.
the paraneoplastic pemphigus. For those cases associated Females are affected more frequently than males by a 2 : 1
with malignancy, treatment usually consists of systemic ratio. Oral lesions are seen in most patients, but other sites,
prednisone combined with cyclosporine. Cyclophospha- such as conjunctival, nasal, esophageal, laryngeal, and
mide, another immunosuppressive agent, may be added to vaginal mucosa, as well as the skin (Fig. 16-62), may be
this regimen, although other immunosuppressive and involved.
immune-modulating drugs are also being evaluated. As with The oral lesions of pemphigoid begin as either vesicles or
pemphigus vulgaris, the skin lesions usually respond more bullae that may occasionally be identified clinically (Fig.
quickly to treatment than the oral lesions. Unfortunately, 16-63). In contrast, patients with pemphigus rarely display
although the immunosuppressive therapy often manages to such blisters. The most likely explanation for this difference
control the autoimmune disease, this immunosuppression is that the pemphigoid blister forms in a subepithelial loca-
often seems to trigger a reactivation of the malignant neo- tion, producing a thicker, stronger roof than the intraepi-
plasm. Thus a high mortality rate is seen, with patients thelial, acantholytic pemphigus blister. Eventually, the oral
succumbing to complications of the vesiculobullous lesions, blisters rupture, leaving large, superficial, ulcerated, and
complications of immune suppressive therapy, respiratory denuded areas of mucosa (Fig. 16-64). The ulcerated lesions
failure due to bronchiolitis obliterans, or progression of are usually painful and persist for weeks to months if
malignant disease. Occasionally, long-term survivors are untreated.
reported, but these seem to be in the minority. As more of Often this process is seen diffusely throughout the
these patients are identified, therapeutic strategies can be mouth, but it may be limited to certain areas, especially
better evaluated and modified for optimal care in the future. the gingiva (Fig. 16-65). Gingival involvement produces a
clinical reaction pattern termed desquamative gingivitis
◆ MUCOUS MEMBRANE PEMPHIGOID
(CICATRICIAL PEMPHIGOID; BENIGN
MUCOUS MEMBRANE PEMPHIGOID)
Evidence has accumulated to suggest that mucous mem-
brane pemphigoid represents a group of chronic, blister-
ing, mucocutaneous autoimmune diseases in which
tissue-bound autoantibodies are directed against one or
more components of the basement membrane. As such, this
condition has a heterogeneous origin, with autoantibodies
being produced against any one of a variety of basement
membrane components, all of which produce similar clini-
cal manifestations. The precise prevalence is unknown, but
most authors believe that it is at least twice as common as
• Fig. 16-62 Mucous Membrane Pemphigoid. Although cutane-
pemphigus vulgaris. ous lesions are not common, tense bullae such as these may develop
The term pemphigoid is used because clinically it often on the skin of 20% of affected patients. (Courtesy of Dr. Charles
appears similar (the meaning of the -oid suffix) to pemphi- Camisa.)
 CHAPTER 16 Dermatologic Diseases 719

• Fig. 16-63 Mucous Membrane Pemphigoid. One or more intra- • Fig. 16-66 Mucous Membrane Pemphigoid. Although the earli-
oral vesicles, as seen on the soft palate, may be detected in patients est ocular changes are difficult to identify, patients with ocular involve-
with cicatricial pemphigoid. Usually, ulcerations of the oral mucosa are ment may show adhesions (symblepharons) between the bulbar and
also present. palpebral conjunctivae before severe ocular damage occurs.

• Fig. 16-64 Mucous Membrane Pemphigoid. Large, irregular oral • Fig. 16-67 Mucous Membrane Pemphigoid. The disease has
ulcerations characterize the lesions after the initial bullae rupture. caused the upper eyelid of this patient to turn inward (entropion),
resulting in the eyelashes rubbing against the eye itself (trichiasis). Also
note the obliteration of the lower fornix of the eye.

(see page 148). This pattern may also be seen in other condi-
tions, such as erosive lichen planus or, much less fre-
quently, pemphigus vulgaris.
The most significant complication of mucous membrane
pemphigoid, however, is ocular involvement. Although
exact figures are not available, up to 25% of patients with
oral lesions may eventually develop ocular disease. One eye
may be affected before the other. The earliest change is
subconjunctival fibrosis, which usually can be detected by
an ophthalmologist using slit-lamp microscopic examina-
tion. As the disease progresses, the conjunctiva becomes
inflamed and eroded. Attempts at healing lead to scarring
• Fig. 16-65 Mucous Membrane Pemphigoid. Often the gingival between the bulbar (lining the globe of the eye) and
tissues are the only affected site, resulting in a clinical pattern known
palpebral (lining the inner surface of the eyelid) conjuncti-
as desquamative gingivitis. Such a pattern may also be seen with
lichen planus and pemphigus vulgaris. vae. Adhesions called symblepharons result (Fig. 16-66).
Without treatment the inflammatory changes become more
severe, although conjunctival vesicle formation is rarely seen
(Fig. 16-67). Scarring can ultimately cause the eyelids to
720 CHA P T E R 16 Dermatologic Diseases

• Fig. 16-68 Mucous Membrane Pemphigoid. A patient with • Fig. 16-70 Mucous Membrane Pemphigoid. Medium-power
ocular involvement shows severe conjunctival inflammation. An oph- photomicrograph of perilesional tissue shows characteristic subepithe-
thalmologist removed the lower eyelashes because of trichiasis associ- lial clefting.
ated with entropion.

• Fig. 16-71 Mucous Membrane Pemphigoid. Direct immunofluo-

• Fig. 16-69 Mucous Membrane Pemphigoid. In this patient, the rescence studies show a deposition of immunoreactants at the base-
ocular involvement has resulted in nearly complete scarring between ment membrane zone of the epithelium. (Courtesy of Dr. Ronald
the conjunctival mucosa and the eyelids themselves, producing Grimwood.)
blindness.

Histopathologic Features
turn inward (entropion). This causes the eyelashes to rub
against the cornea and globe (trichiasis) (Fig. 16-68). The Biopsy of perilesional mucosa shows a split between the
scarring closes off the openings of the lacrimal glands as surface epithelium and the underlying connective tissue in
well, and with the loss of tears, the eye becomes extremely the region of the basement membrane (Fig. 16-70). A mild
dry. The cornea then produces keratin as a protective mech- chronic inflammatory cell infiltrate is present in the super-
anism; however, keratin is an opaque material, and blind- ficial submucosa.
ness ensues. End-stage ocular involvement may also be Direct immunofluorescence studies of perilesional
characterized by adhesions between the upper and lower mucosa show a continuous linear band of immunoreactants
eyelids themselves (Fig. 16-69). at the basement membrane zone in nearly 90% of affected
Other mucosal sites may also be involved and cause patients (Fig. 16-71). The immune deposits consist primar-
considerable difficulty for the patient. In females, the vaginal ily of IgG and C3, although IgA and IgM may also be
mucosal lesions may cause considerable pain during attempts identified. One study has suggested that, when IgG and IgA
at intercourse (dyspareunia). deposits are found in the same patient, the disease may be
Laryngeal lesions, which are fairly uncommon, may be more severe. All of these immunoreactants may play a role
especially significant because of the possibility of airway in the pathogenesis of the subepithelial vesicle formation by
obstruction by the bullae that are formed. Patients who weakening the attachment of the basement membrane
experience a sudden change in vocalization or who have through a variety of mechanisms, including complement
difficulty breathing should undergo examination with activation with recruitment of inflammatory cells, particu-
laryngoscopy. larly neutrophils.
 CHAPTER 16 Dermatologic Diseases 721

Indirect immunofluorescence is positive in only 5% to

25% of these patients, indicating a relatively consistent lack
of readily detectable circulating autoantibodies. One type
of mucous membrane pemphigoid produces low levels of
circulating autoantibodies to epiligrin (laminin-5), a com-
ponent of the basement membrane. Antiepiligrin mucous
membrane pemphigoid seems to have more widespread
involvement, affecting oral, nasal, ocular, and laryngeal
mucosa, compared with other forms of mucous membrane
pemphigoid. In contrast, another group of investigators has
shown that pemphigoid patients with only oral mucosal
involvement have circulating autoantibodies to α6 integrin,
a component of the hemidesmosome.
For an accurate diagnosis, perilesional tissue—rather
than the ulcerated lesion itself—should be obtained. Often • Fig. 16-72 Angina Bullosa Hemorrhagica. Hemorrhagic blisters
on the soft palate in a patient who regularly used a corticosteroid
the epithelium in the area of the lesion is so loosely attached inhaler. (Courtesy of Dr. Peter Lyu.)
that it strips off as the clinician attempts to perform the
biopsy. Such tissue is not usually adequate for diagnostic
purposes because the interface between the epithelium and
connective tissue is no longer intact (although some inves-
tigators have shown positive immunofluorescence with this bullosa acquisita (“acquisita” means “acquired”) because of
tissue). its clinical resemblance to the inherited condition, dystro-
Other relatively rare conditions can mimic pemphigoid phic epidermolysis bullosa. Unlike the inherited disorder,
histopathologically. These include linear IgA bullous der- epidermolysis bullosa acquisita typically affects middle-aged
matosis, angina bullosa hemorrhagica, and epidermoly- or older adults.
sis bullosa acquisita. Oral lesions are present in nearly 50% of the cases,
although such lesions are uncommon in the absence of
Linear IgA Bullous Dermatosis cutaneous lesions. To distinguish epidermolysis bullosa
Linear IgA bullous dermatosis, as the name indicates, is acquisita from other immunobullous diseases with subepi-
characterized by the linear deposition of only IgA along the thelial clefting, a special technique is performed. A sample
basement membrane zone. Even though some cases of of the patient’s perilesional skin is incubated in a concen-
mucous membrane pemphigoid may have IgA antibodies, trated salt solution; this causes the epithelium to separate
linear IgA bullous dermatosis predominantly affects the skin from the connective tissue, forming an artificially induced
and, therefore, can usually be distinguished from mucous bulla. Immunohistochemical evaluation shows deposition
membrane pemphigoid on a clinical basis. of IgG autoantibodies on the floor (connective tissue side)
of the bulla where type VII collagen resides. This finding is
Angina Bullosa Hemorrhagica in contrast to that of most forms of mucous membrane
Angina bullosa hemorrhagica is a rare, poorly characterized pemphigoid, in which the autoantibodies are usually local-
oral mucosal disorder that exhibits variably painful, ized to the roof of the induced blister.
blood-filled vesicles or bullae, usually affecting the soft
palate of middle-aged or older adults (Fig. 16-72). The Treatment and Prognosis
blisters typically rupture spontaneously and heal without
scarring. A subepithelial cleft is noted microscopically. Once the diagnosis of mucous membrane pemphigoid has
No hematologic or immunopathologic abnormalities have been established by light microscopy and direct immuno-
been detected, and although the cause is unknown, fluorescence, the patient should be referred to an ophthal-
many patients have a history of trauma or corticosteroid mologist who is familiar with the ocular lesions of this
inhaler use. condition for a baseline examination of the conjunctivae.
This should be done whether or not the patient is experienc-
Epidermolysis Bullosa Acquisita ing ocular complaints. In addition, if the patient is
Epidermolysis bullosa acquisita is an immunologically experiencing symptoms at other anatomic sites, then the
mediated condition characterized by autoantibodies directed appropriate specialist should be consulted.
against type VII collagen, the principal component of the Because this condition is characterized by heterogeneous
anchoring fibrils. The anchoring fibrils play an important pathogenetic mechanisms, it is not surprising that treat-
role in bonding the epithelium to the underlying connective ments advocated over the years have been varied. In fact,
tissue. As a result, their immunologic destruction leads to there is no single good therapy for every patient; treatment
the formation of bullous lesions of the skin and mucosa must be individualized, depending on lesional distribution,
with minimal trauma. The disease was named epidermolysis disease activity, and therapeutic response. Perhaps as the
722 CHA P T E R 16 Dermatologic Diseases

various forms of pemphigoid are better defined immuno- ◆ BULLOUS PEMPHIGOID

pathologically, more specific, directed therapy can be
devised. Bullous pemphigoid is the most common of the autoim-
mune blistering conditions, occurring at an estimated
Topical Agents rate of ten cases per million population per year. The
If only oral lesions are present, sometimes the disease can disease is characterized by the production of autoantibodies
be controlled with application of one of the more potent directed against components of the basement membrane.
topical corticosteroids to the lesions several times each day. In many respects, bullous pemphigoid resembles mucous
Once control is achieved, the applications can be discontin- membrane pemphigoid, but most investigators note
ued, although the lesions are certain to flare up again. that there are enough differences to consider these diseases
Sometimes alternate-day application prevents such exacer- as distinct but related entities. One significant difference
bations of disease activity. is that the clinical course in patients with bullous pemphi-
Patients with only gingival lesions often benefit from goid is usually characterized by periods of remission fol-
good oral hygiene measures, which can help to decrease the lowed by relapse, whereas the course in patients with
severity of the lesions and reduce the amount of topical mucous membrane pemphigoid is usually protracted and
corticosteroids required. As an additional aid in treating progressive.
gingival lesions, a flexible mouth guard may be fabricated
to use as a carrier for the corticosteroid medication. Clinical Features
Systemic Agents Bullous pemphigoid typically develops in older people;
If topical corticosteroids are unsuccessful, systemic treat- most patients are between 75 and 80 years of age. No
ments are available. Dapsone, which is a sulfa drug deriva- sex or racial predilection is generally reported, although
tive, can be used to treat patients with mild-to-moderate one group of investigators noted that men are overrepre-
involvement by mucous membrane pemphigoid. Systemic sented in this disease by a 2 : 1 margin when one corrects
treatment with dapsone typically has fewer serious side for the skewing of the aging population toward the female
effects when compared to systemic corticosteroid therapy, gender. Pruritus is often an early symptom. This is followed
for example. by the development of multiple, tense bullae on either
Some centers report good results with dapsone, but normal or erythematous skin (Fig. 16-73). These lesions
others observe that a minority of patients respond ade- eventually rupture after several days, causing a superficial
quately. Contraindications to its use include glucose- crust to form. Eventually, healing takes place without
6-phosphate dehydrogenase deficiency or allergy to sulfa scarring.
drugs. Oral mucosal involvement is uncommon, with approxi-
Another alternative systemic therapy that may be used mately 10% to 20% of patients being affected. The oral
for patients with less severe disease is tetracycline or mino- lesions, like the skin lesions, begin as bullae, but they tend
cycline and niacinamide (nicotinamide). Systemic daily to rupture sooner, probably as a result of the constant low-
divided doses of 0.5 to 2.0 g of each drug have been reported grade trauma to which the oral mucosa is subjected. Large,
(in open-label trials) to be effective in controlling mucous shallow ulcerations with smooth, distinct margins are
membrane pemphigoid. Double-blind, placebo-controlled present after the bullae rupture (Fig. 16-74).
studies on larger groups of patients should be done to
confirm this form of therapy, however.
For more severely affected patients with mucous
membrane pemphigoid, corticosteroids plus other
immunosuppressive/immune modulating agents, (such as,
rituximab, mycophenolate mofetil, or cyclophosphamide)
may be used. This type of aggressive treatment is often
indicated in the presence of advancing ocular disease, but
it must be realized that many of these patients are older and
may have preexisting medical conditions that may preclude
aggressive immune suppression. Some studies have sug-
gested that treatment with intravenous (IV) human immu-
noglobulin (which is very expensive) may be more effective
in managing ocular lesions of pemphigoid than systemic
corticosteroid therapy. Attempts at surgical correction of
any symblepharons that might have formed must be done
when the disease is under control or quiescent; otherwise, • Fig. 16-73 Bullous Pemphigoid. Cutaneous vesiculobullous
the manipulation often induces an acute flare of the ocular lesions of the heel. The bullae eventually rupture, leaving hemorrhagic
lesions. crusted areas.
 CHAPTER 16 Dermatologic Diseases 723

consists of systemic immunosuppressive therapy. Moderate

daily doses of systemic prednisone usually control the con-
dition, after which alternate-day therapy may be given to
reduce the risk of corticosteroid complications. If the lesions
do not respond to prednisone alone, then another immu-
nosuppressive agent (such as, azathioprine, methotrexate, or
mycophenolate mofetil) may be added to the regimen.
Dapsone, a sulfa derivative, may be used as an alternative
therapeutic agent, and tetracycline and niacinamide therapy
is reported to be effective for some patients. The more
severe, resistant cases require prednisone combined with
cyclophosphamide; however, this regimen has the potential
for significant side effects.
• Fig. 16-74 Bullous Pemphigoid. These oral lesions appear as
The prognosis is generally good with respect to control
large, shallow ulcerations involving the soft palate. of the skin lesions, with many patients experiencing remis-
sion. Recent reports based on a relatively large series of
Histopathologic Features bullous pemphigoid patients have suggested that problems
frequently develop due to the immunosuppressive therapy
Microscopic examination of tissue obtained from the used in this older adult population. Mortality rates that are
perilesional margin of a bulla shows separation of the epi- three times that of an age- and sex-matched control popula-
thelium from the connective tissue at the basement mem- tion may be seen, with approximately 20% of patients
brane zone, resulting in a subepithelial separation. Modest expiring 1 year after diagnosis.
numbers of both acute and chronic inflammatory cells are
typically seen in the lesional area, and the presence of eosin- ◆ ERYTHEMA MULTIFORME
ophils within the bulla itself is characteristic.
Direct immunofluorescence studies show a continuous Erythema multiforme is a blistering, ulcerative mucocuta-
linear band of immunoreactants, usually IgG and C3, local- neous condition of uncertain etiopathogenesis. This is prob-
ized to the basement membrane zone in 90% to 100% of ably an immunologically mediated process, although the
affected patients. These antibodies bind to proteins associ- cause is poorly understood. In about 50% of the cases, the
ated with hemidesmosomes, structures that bind the basal clinician can identify an apparent precipitating cause,
cell layer of the epithelium to the basement membrane and usually a preceding infection, such as herpes simplex
the underlying connective tissue. These proteins have been or Mycoplasma pneumoniae, or less commonly, exposure
designated as bullous pemphigoid antigens (BP180 and to any one of a variety of drugs and medications, particu-
BP230), and immunoelectron microscopy has demon- larly antibiotics or analgesics. These agents may trigger
strated the localization of BP180 to the upper portion of the immunologic derangement that produces the disease.
the lamina lucida of the basement membrane. Sophisticated techniques in molecular biology have demon-
In addition to the tissue-bound autoantibodies, 50% to strated the presence of herpes simplex DNA in patients with
90% of the patients also have circulating autoantibodies in recurrent erythema multiforme, thus supporting the concept
the serum, producing an indirect immunofluorescent of an immunologic precipitating event. Interestingly, direct
pattern that is identical to that of the direct immunofluo- and indirect immunofluorescence studies are nonspecific
rescence. Unlike pemphigus vulgaris, the antibody titers and are not really very useful diagnostically except to rule
seen in bullous pemphigoid do not appear to correlate with out other vesiculobullous diseases.
disease activity. The antibodies alone do not appear to be For many years it was thought that erythema multiforme
capable of inducing bullae in this disease. Instead, binding exhibited a spectrum of severity, ranging from erythema
of the antibodies to the basement membrane initiates the multiforme minor through erythema multiforme major
complement cascade, which in turn results in degranulation (traditionally thought to be synonymous with Stevens-
of mast cells, with recruitment of neutrophils and eosino- Johnson syndrome) and toxic epidermal necrolysis (Lyell
phils to the area. The damage to the basement membrane disease). Most authorities currently feel that erythema mul-
is thought to be mediated by elastases and matrix metallo- tiforme minor and major may represent a distinctly differ-
proteinases released by these inflammatory cells. ent process from the latter two conditions. Therefore,
Stevens-Johnson syndrome and toxic epidermal necrolysis
Treatment and Prognosis will be discussed separately in the next section.

Treatment of patients with mild or localized bullous pem- Clinical Features

phigoid consists of application of one of the stronger topical
corticosteroid preparations. Management of the patient Erythema multiforme typically has an acute onset and
with moderate-to-severe, widespread bullous pemphigoid usually affects young adults in their 20s or 30s, with a slight