Clinical Features and Diagnosis of Bullous Pemphigoid and Mucous Membrane Pemphigoid - UpToDate

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Clinical features and diagnosis of bullous pemphigoid and mucous

membrane pemphigoid
Author: Kristin M Leiferman, MD
Section Editor: John J Zone, MD
Deputy Editor: Abena O Ofori, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2019. | This topic last updated: Apr 15, 2019.
INTRODUCTION
Bullous pemphigoid and mucous membrane pemphigoid (MMP) are autoimmune blistering diseases that most commonly
arise in older adults. These disorders are characterized by subepithelial blister formation and the deposition of
immunoglobulins and complement within the epidermal and/or mucosal basement membrane zone.
Although both bullous pemphigoid and MMP may affect skin and mucosa, the classical clinical findings in bullous
pemphigoid are tense, fluid-filled bullae on skin whereas the prevailing clinical feature in MMP is mucosal involvement. In
MMP, inflamed and eroded mucosa is characteristic, involving any or all of the oral cavity, ocular conjunctiva, nose,
pharynx, larynx, esophagus, anus, and genital mucous membranes.
The clinical features and diagnosis of bullous pemphigoid and MMP will be reviewed here (algorithm 1). The
epidemiology, pathogenesis, and treatment of these disorders as well as greater detail on the ocular form of MMP (ocular
cicatricial pemphigoid) and other autoimmune blistering disorders are discussed separately. (See "Epidemiology and
pathogenesis of bullous pemphigoid and mucous membrane pemphigoid" and "Management and prognosis of bullous
pemphigoid" and "Management of mucous membrane pemphigoid" and "Ocular cicatricial pemphigoid" and "Dermatoses
of pregnancy", section on 'Pemphigoid gestationis' and "Pathogenesis, clinical manifestations, and diagnosis of
pemphigus".)
CLINICAL FEATURES
Bullous pemphigoid — A prodromal phase lasting weeks to months may precede the development of cutaneous bullae
in patients with bullous pemphigoid [1,2]. The prodromal phase may present with pruritic eczematous, papular, or
urticaria-like skin lesions (picture 1D) [3]. Some patients with bullous pemphigoid never develop blistering.
When blisters develop, the classical lesion is a 1 to 3 cm tense bulla on an erythematous, urticarial, or noninflammatory
base, and blisters may be numerous and widespread (picture 1A-C) [4]. Associated pruritus is common and can be
severe [5,6]. The tense quality of the bullae differentiates the lesions of bullous pemphigoid from the flaccid bullae of
pemphigus vulgaris (picture 2A) (see "Pathogenesis, clinical manifestations, and diagnosis of pemphigus") [1,7].
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Eventually, the bullae rupture, leaving moist erosions and crusts that resolve without scarring. When mainly erosions are
present, it may be difficult to clinically distinguish bullous pemphigoid and pemphigus (picture 2B).
The trunk, extremity flexures, and axillary and inguinal folds are common sites for cutaneous involvement (picture 3A-C)
[8]. Mucosal lesions are present in 10 to 30 percent of patients (picture 4) [1,2,4,9]. The oral mucosa is the most frequent
location of mucosal involvement; less frequently, bullous pemphigoid involves other mucosal sites, such as the larynx,
genitals, and anus [9]. Nail changes also may develop [10,11].
Localized forms of bullous pemphigoid occur and account for up to 30 percent of cases [12]. Examples include disease
limited to the lower legs (picture 1E) [12-16], anogenital region [17,18], peristomal skin [19,20], or sites of incidental or
iatrogenic trauma (eg, radiation therapy) [21-27]. Disease that begins in localized areas may remain localized or may
progress to generalized involvement [12,28].
Other reported clinical variants of bullous pemphigoid include eczematous, urticarial, and prurigo-like (pemphigoid
nodularis) presentations, as well as bullous pemphigoid presenting as pruritus without any primary skin lesions (pruritic
nonbullous pemphigoid, bullous pemphigoid as pruritus in older adults); in such cases, the diagnosis is based upon
consistent laboratory findings (see 'Laboratory tests' below) [2,29-31]. Rare variants include pemphigoid vegetans, which
manifests with verruciform plaques in intertriginous areas [32,33], dyshidrosiform pemphigoid, which occurs on palmar
and/or plantar skin (resembling dyshidrotic eczema) and often is hemorrhagic (picture 1F) [34,35], vesicular bullous
pemphigoid, in which lesions resemble dermatitis herpetiformis [36], and bullous pemphigoid occurring in association with
transient palmoplantar keratoderma [37].
Lichen planus pemphigoides is another rare variant of bullous pemphigoid. It is postulated that the cellular inflammatory
process that occurs at the basement membrane zone in lichen planus results in exposure of basement membrane zone
antigens leading to subsequent development of basement membrane zone antibodies [38]. Patients with lichen planus
pemphigoides typically present with bullae in sites of previously normal-appearing skin or mucosa. The bullae usually
appear weeks to months after the onset of lichen planus [3].
Mucous membrane pemphigoid — MMP represents a group of heterogeneous, chronic subepithelial blistering
disorders that primarily affect mucosal surfaces [39]. Historically, the term cicatricial pemphigoid also referred to these
disorders. Some authors also consider cases of linear IgA bullous dermatosis and epidermolysis bullosa acquisita that
primarily involve the mucous membranes as forms of MMP [39]. However, our approach is to view these diagnoses as
distinct entities. (See "Linear IgA bullous dermatosis" and "Epidermolysis bullosa acquisita".)
MMP typically presents as relapsing and remitting mucosal inflammation and erosions (picture 5A-C). The oral cavity is
the most common site of involvement, and cutaneous involvement also may be present. In a report that summarized the
sites of involvement in 457 patients with MMP, the frequency of affected sites was as follows [40]:
● Oral mucosa (85 percent)

● Ocular conjunctiva (64 percent)
● Skin (24 percent)
● Pharynx (19 percent)
● External genitalia (17 percent)
● Nasal mucosa (15 percent)
● Larynx (8 percent)
● Anus (4 percent)
● Esophagus (4 percent)
In the oral cavity, the gingival and buccal mucosae are most commonly affected. Gingival disease usually manifests as a
desquamative or erosive gingivitis (picture 5A), and, in mild cases, may manifest only with gingival erythema and edema
[41]. The detection of intact vesicles or bullae on mucosa is uncommon. Compared with the mucosal lesions of
pemphigus (picture 2C), pain associated with oral MMP lesions is usually less intense [2].
Scarring is a common consequence of MMP that distinguishes this variant from mucosal involvement in bullous
pemphigoid, which typically does not scar. Reticulated, white striations representing mucosal fibrosis often are present at
sites of healed lesions, and functional limitations secondary to scarring may occur [2,41]. As examples, MMP involving
the ocular mucosa can lead to symblepharon, ankyloblepharon, and eventual blindness, and progressive laryngeal and
tracheal involvement can result in asphyxiation [41]. (See "Ocular cicatricial pemphigoid", section on 'Clinical
manifestations'.)
Cutaneous involvement in patients with MMP typically involves the scalp, face, or upper trunk. The bullous lesions
resemble those seen in bullous pemphigoid, but, similar to mucosal lesions of MMP, often heal with scarring.
ASSOCIATED DISORDERS
Patients with bullous pemphigoid often have multiple comorbidities [42,43]. In a case-control study that included 105
patients with bullous pemphigoid and 315 matched controls, patients with bullous pemphigoid were more likely to have
two or more other chronic diseases (84 versus 65 percent) [42].
Neurologic disorders — Associations between bullous pemphigoid and neurologic disorders have been reported in
several observational studies and case reports [43-55]. In a hospital-based prospective case-control study of 201 patients
with bullous pemphigoid and 345 matched controls, dementia, Parkinson's disease, and unipolar or bipolar disorder were
among the identified independent risk factors for this disease [46]. In addition, a population-based case-control study of
868 patients with bullous pemphigoid and more than 3400 controls found that patients with preexisting diagnoses of
dementia, Parkinson's disease, or stroke were significantly more likely to develop bullous pemphigoid [45]. Further, a
case-control study with more than 5000 patients with multiple sclerosis and over 26,000 controls supported an
association of bullous pemphigoid and this disease [56].
Homology between bullous pemphigoid antigens in the skin and neuronal antigens in the central nervous system has
been proposed as a cause for the observed link between bullous pemphigoid and neurologic disease, along with a
genetic predisposition [57-61]. However, further studies are necessary to explore the relationship between these
disorders. (See "Epidemiology and pathogenesis of bullous pemphigoid and mucous membrane pemphigoid", section on
'Epitope spreading'.)
Malignancy — MMP with antibodies directed against laminin 332 (previously known as laminin 5 and epiligrin) has been
associated with an increased risk for internal malignancy (figure 1). In a cohort of 35 patients with this type of MMP
(diagnosed with immunoprecipitation), 10 (29 percent) developed solid organ malignancies, 7 of which were diagnosed
within 14 months after a diagnosis of MMP [62]. Occurrences of non-Hodgkin lymphoma and cutaneous T cell lymphoma
have also been reported in individual patients with anti-laminin 332 MMP [63]. The pathophysiologic relationship of this
subtype of MMP to cancer is unknown. However, expression of laminin 332 has been detected in malignant cells, and
laminin 332 appears to be capable of promoting tumor cell growth, invasion, and metastasis [63,64].
The clinical manifestations of MMP in patients with laminin 332 antibodies are similar to the features of MMP with other
antibody profiles. Therefore, clinical examination cannot reliably distinguish anti-laminin 332 MMP from other forms of
MMP. Additional studies are necessary to confirm the findings of a retrospective study of 154 patients with MMP that
associated the detection of laminin 332 antibodies via a novel enzyme-linked immunosorbent assay (ELISA) with a
greater likelihood for severe disease [65].
Since diagnostic laboratory testing for laminin 332 antibodies is not commercially available, suspicion for laminin 332
primarily is based upon immunofluorescence microscopy findings. Although not exclusive to laminin 332 MMP, the
detection of antibodies bound to the dermal side of basement membrane zone-split (salt-split) skin suggests the
possibility of this diagnosis. (See 'Indirect immunofluorescence of serum' below.)
Until definitive testing for laminin 332 antibodies becomes available, we recommend that patients with MMP in whom
serum indirect immunofluorescence (IIF) studies reveal antibodies bound to the dermal side of basement membrane
zone-split skin undergo age and gender appropriate cancer screening. Additional evaluation for malignancy should be
performed as indicated based upon a review of symptoms, physical examination, and the results of age-appropriate
screening.
The relationship between bullous pemphigoid and malignancy is less clear. While some studies support an association,
others have failed to find a significant increase in malignancy risk, attributing occurrences of malignancy to age rather
than bullous pemphigoid [55,66,67]. Further study is necessary to confirm the findings of a systematic review and meta-
analysis of observational studies that did not find an association of bullous pemphigoid with malignancy overall but found
an association between bullous pemphigoid and hematologic malignancies [68]. In addition, the results of a cohort study
that found a disproportionate increase in risk for malignancy in young versus old individuals with bullous pemphigoid
need to be confirmed [66]. In our practice, we evaluate young and middle-aged patients with bullous pemphigoid for
underlying malignancy particularly when they present with severe or refractory disease, present with symptoms or signs
in organ systems other than skin, or if there is a family history of genetically associated malignancy.
DISEASE COURSE
Bullous pemphigoid is a chronic disorder characterized by exacerbations and remissions over the course of months to
years. However, in some patients the disease is self-limited, resulting in disease remissions within a few years. (See
"Management and prognosis of bullous pemphigoid", section on 'Prognosis'.)
In the absence of treatment, MMP is usually a chronic, progressive disease that results in functionally limiting or, in some
cases (such as those with airway involvement), life-threatening disease [41]. The clinical course and prognosis of ocular
MMP is reviewed in greater detail separately. (See "Ocular cicatricial pemphigoid", section on 'Clinical manifestations' and
"Ocular cicatricial pemphigoid", section on 'Prognosis and cessation of therapy'.)
DIAGNOSIS
Although clinical findings may strongly suggest bullous pemphigoid or MMP, other disorders present with similar
mucocutaneous lesions, and atypical presentations can occur (table 1) (see 'Differential diagnosis' below). Thus,
confirmation of the diagnosis requires the careful interpretation of both clinical and laboratory findings.
Clinical assessment — Clinical features that suggest bullous pemphigoid or MMP in patients over the age of 60 years
include:
● Blistering skin disease characterized by the presence of tense blisters and erosions that occur without another
identifiable cause
● Desquamative gingivitis or mucositis involving oral, ocular, nasal, genital, anal, pharyngeal, laryngeal, and/or
esophageal mucosae
● Unexplained pruritus, pruritic eczematous eruptions, or urticarial plaques
The possibility of bullous pemphigoid or MMP also should be considered in the evaluation of younger individuals
(including neonates, infants, and children) with suggestive symptoms in the absence of another identifiable cause (picture
1G) [69-71]. In patients with signs or symptoms of these disorders, laboratory assessment is indicated. (See
"Epidemiology and pathogenesis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Epidemiology'.)
Laboratory tests — The principal studies used in the evaluation of patients with lesions suspicious for bullous
pemphigoid or MMP include (table 2):
● A lesional skin biopsy from the edge of an intact blister (or other inflamed/affected tissue, urticarial or eczematous)
for hematoxylin and eosin (H&E) staining and a skin biopsy from a perilesional area for direct immunofluorescence
(DIF). DIF is considered the most sensitive test for the diagnosis of bullous pemphigoid. (See 'Skin biopsy' below and
"Approach to the patient with cutaneous blisters", section on 'Skin biopsy'.)
● A serum specimen for indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) testing to
detect circulating basement membrane zone antibodies. (See "Approach to the patient with cutaneous blisters",
section on 'Serologic tests'.)
Our approach — In patients with clinical findings suggestive of bullous pemphigoid or MMP, we begin the laboratory
assessment by obtaining both a lesional tissue specimen for routine (fixed tissue) histopathology and a perilesional
tissue specimen for DIF examinations. Bullous pemphigoid antigens may be sparse in distal anatomical locations;
therefore, when possible, choosing a proximal anatomical site for the perilesional DIF specimen is preferred. Obtaining a
lesional specimen often is difficult in MMP involving the mouth and vulva, because affected mucosa is friable and easily
erodes. When this occurs, perilesional tissue with intact epithelium should still be obtained for DIF.
Serologic studies provide additional information that is useful for diagnosis and management in most patients. IIF
performed on basement membrane zone-split skin substrate aids in distinguishing bullous pemphigoid from epidermolysis
bullosa acquisita and can identify patients with MMP who are at risk for malignancy-associated laminin 332 (epiligrin)
MMP. Because of its value, we perform serum testing (IIF and ELISA) in all patients with clinical, histopathologic, and/or
DIF findings consistent with bullous pemphigoid or MMP. (See 'Malignancy' above and 'Indirect immunofluorescence of
serum' below and "Epidermolysis bullosa acquisita", section on 'Diagnosis'.)
Routine inclusion of both DIF microscopy and IIF testing on human basement membrane zone-split skin in the evaluation
of suspected bullous pemphigoid may optimize early detection of the disease, especially in patients who present without
blisters. In an analysis of 1125 patients with suspected bullous pemphigoid, in which 343 received a pemphigoid
diagnosis, DIF was the most sensitive diagnostic test (sensitivity of 88.3 percent, 95% CI 84.5-91.3 percent and
specificity of 99.2 percent, 95% CI 98.3-99.7 percent), and IIF on human basement membrane zone-split (salt-split) skin
was less sensitive but highly specific (sensitivity of 77 percent, 95% CI 72.2-81.1 and specificity of 99.9 percent, 95% CI
99.3-100 percent) [72]. Based upon the study findings, the authors proposed achievement of at least two the following
three characteristics as minimal diagnostic criteria:
● Pruritus and/or predominant cutaneous blisters
● Linear immunoglobulin G (IgG) and/or C3 deposits by DIF on a skin biopsy specimen
● Positive epidermal (roof) side IgG staining by IIF basement membrane zone-split skin on a serum sample
In addition, serologic studies can be of value when DIF is negative in a patient with clinical and histopathologic findings
that are consistent with bullous pemphigoid or when it is not possible to obtain adequate biopsy tissue [73]. The
combination of IIF and ELISA serum testing is useful to support a clinical diagnosis of bullous pemphigoid [74].
An algorithm depicting our approach to the diagnosis of patients who present with skin lesions suspicious for bullous
pemphigoid and oral lesions suggestive of MMP is provided (algorithm 1).
Skin biopsy — Separate specimens are optimal for H&E (light microscopy of fixed tissue) and DIF because of
differences in the requirements for the preferred biopsy location and tissue handling. We typically obtain two 4 mm punch
biopsies. However, careful splitting of a 5 or 6 mm punch biopsy specimen or a shave biopsy specimen into lesional and
perilesional specimens is an additional option. If only one small specimen can be obtained, the preferred test to perform
is DIF. (See "Skin biopsy techniques", section on 'Punch biopsy' and "Approach to the patient with cutaneous blisters",
section on 'Skin biopsy'.)
Light microscopy of formalin-fixed tissue — Biopsies for histopathology (H&E staining) should be taken from
lesional skin, preferably of an intact vesicle or the edge of an intact bulla (table 2). The specimen should include the
blister edge and the immediately adjacent tissue. Care should be taken to avoid excessive torsion and crushing, which
may alter tissue cleavage planes and increase the difficulty of pathologic interpretation. Specimens obtained for H&E are
placed in formalin for processing.
Common histopathologic findings in cutaneous lesions of bullous pemphigoid include [1]:
● Eosinophilic spongiosis (particularly in early lesions) (picture 6)
● Subepidermal blister formation (often with numerous eosinophils within cleft) (picture 7)
● A superficial dermal inflammatory cell infiltrate of variable intensity with lymphocytes, eosinophils, and neutrophils
(picture 6)
Histopathologic examination of mucosal lesions of MMP shows epithelial-subepithelial cleavage and a mixed submucosal
inflammatory cell infiltrate composed of lymphocytes, histiocytes, neutrophils, and eosinophils [41]. Additional findings
may include plasma cell infiltration and subepidermal fibrosis; the latter is a finding consistent with the scarring nature of
MMP [41].
Direct immunofluorescence — Direct immunofluorescence (DIF) testing is a highly sensitive, supportive

diagnostic test for pemphigoid [72,73,75]. The procedure utilizes labeled antibodies to detect immunoglobulin binding and
complement deposits in tissue. DIF is a more sensitive test for the diagnosis of bullous pemphigoid than IIF or ELISA
tests [72,73]. (See "Approach to the patient with cutaneous blisters", section on 'Direct immunofluorescence'.)
In contrast to biopsy specimens for H&E histopathologic evaluation, biopsy specimens for DIF should be obtained from
perilesional, not lesional skin (table 2). For affected skin, this can be an erythematous or urticarial area adjacent to a
blister. For affected mucosa, in which tissue immediately adjacent to an erosion can be friable, a tissue specimen from
normal-appearing mucosa several millimeters away from the edge of a lesion can be obtained.
The tissue specimen for DIF should not be placed in formalin; rather, the specimen should be placed promptly in a
transport medium compatible with the performance of immunofluorescence studies, such as Michel's medium or Zeus
medium. Specimens for DIF should be transported promptly to an immunodermatology laboratory for receipt within seven
days of obtaining the specimen; transport medium does not preserve a specimen indefinitely. Some immunodermatology
laboratories will also accept specimens transported on normal saline-soaked gauze (provided they are received during
laboratory working hours within six hours of obtaining them; sooner is better) or specimens that are flash-frozen with
liquid nitrogen, remain frozen, and transported on dry ice (table 2). Specimens should not be immersed in saline solution
or solutions other than Michel's or Zeus medium.
The classical DIF findings in bullous pemphigoid and MMP include [41,73,75,76]:
● Bullous pemphigoid – Linear IgG and/or linear C3 staining along the basement membrane zone is present in
greater than 90 percent of cases (picture 8A-C); less intense linear basement membrane zone staining for IgM, IgA,
and/or IgE may be present.
● Mucous membrane pemphigoid – Linear IgG and/or linear IgA and/or linear C3 staining along the basement
membrane zone is detected in approximately 70 to 100 percent of cases. Repeat DIF testing on more than one
biopsy specimen may be of value for patients with suspected MMP who test negative; multiple or repeated biopsies
increase the sensitivity of DIF for the diagnosis of MMP [77]. Linear IgE basement membrane zone staining can be
detected in specimens from some patients [78].
A modified DIF technique has been described utilizing basement membrane zone-split perilesional skin or mucosa from
patients with suspected pemphigoid. Ideally, this allows for more precise localization of antibody binding within the
epithelial basement membrane zone of diseased tissue and, therefore, additional information for diagnosis. However, the
technique is infrequently utilized with DIF because of its technical difficulty. In particular, basement membrane zone
separation often is difficult with inflamed skin and frequently is impossible to perform on mucosal specimens. Performing
IIF with the patient's serum on basement membrane zone-split skin substrate is a more practical test. The diagnostic
value of IIF is reviewed below. (See 'Indirect immunofluorescence of serum' below.)
Additional clues for diagnosis may be provided by analysis of the linear pattern of basement membrane zone antibody
staining detected in DIF. Whereas an n-serrated pattern has been associated with bullous pemphigoid, MMP, anti-p200
pemphigoid, and linear IgA dermatosis (picture 8C), a u-serrated pattern has been described in epidermolysis bullosa
acquisita and bullous systemic lupus erythematosus (picture 9) [79,80]. A true linear pattern is commonly observed along
with the characteristic n-serrated and u-serrated patterns in all of these immunobullous diseases [79,80].
Indirect immunofluorescence of serum — Indirect immunofluorescence (IIF) testing is used to detect circulating
basement membrane zone antibodies in patients with pemphigoid (picture 10A). To perform this test, the patient's serum
is overlaid on an epithelial tissue substrate, incubated, and then stained for fluorescent detection of antibodies (table 2).
(See "Approach to the patient with cutaneous blisters", section on 'Indirect immunofluorescence'.)
Bullous pemphigoid — Various tissue substrates containing epithelial basement membrane zones have been
used to perform IIF in bullous pemphigoid. Monkey esophagus is a useful substrate because it can broadly categorize
immunobullous diseases based on antibody staining patterns. (See "Paraneoplastic pemphigus" and "Linear IgA bullous
dermatosis" and "Dermatitis herpetiformis" and "Pathogenesis, clinical manifestations, and diagnosis of pemphigus".)
Human skin (from cadavers or surgical waste) that is artificially split at the level of the lamina lucida (basement
membrane zone-split skin) using prolonged (48 to 72 hours) exposure to 1 M sodium chloride (salt-split skin) or short
(30 minutes) exposure to ethylenediaminetetraacetic acid (EDTA) is a useful substrate, particularly when basement
membrane zone antibodies are known. This is because of the value of the test for distinguishing between certain
subepithelial immunobullous diseases [74,81,82].
IIF with a basement membrane zone-split skin substrate aids in distinguishing between certain subepithelial
immunobullous diseases because the test allows for localization of antibody deposition within the basement membrane
zone. Specimens from patients with bullous pemphigoid typically demonstrate antibody deposition localized to the
epidermal side of basement membrane zone-split skin, whereas in specimens from patients with epidermolysis
bullosa acquisita, bullous lupus erythematosus, anti-laminin 332 pemphigoid, and anti-p200 pemphigoid, antibodies are
typically found on the dermal side (picture 10A-B). Combined epidermal-dermal staining patterns on basement membrane
zone-split skin also are found in bullous pemphigoid and bullous lupus erythematosus (picture 11).
IIF is a highly specific test for bullous pemphigoid [72,73]. In a retrospective study in which 313 patients with bullous
pemphigoid were compared with 488 controls, the specificities of IIF on rabbit esophagus, IIF on monkey esophagus, and
IIF on human salt-split skin for diagnosis were 96.5, 97.1, and 100 percent, respectively [73]. The sensitivities of these
tests for diagnosis were 73.2, 73.3, and 72 percent, respectively. DIF had a similar specificity, but was significantly more
sensitive. The specificity of DIF was 98 percent and the sensitivity of DIF was 90.8 percent.
Mucous membrane pemphigoid — In early studies of MMP, IIF was positive in fewer than one-third of patients
[41]. However, the use of human basement membrane zone-split skin and/or concentrated serum may increase the
likelihood of detecting circulating antibodies [41,81,83]. In one series of eight patients with MMP, IIF on basement
membrane zone-split skin was positive in 50 percent [81]. A larger series of 67 patients found that IIF on a basement
membrane zone-split skin substrate yielded positive antibodies in 84 percent of patients [83].
In MMP, basement membrane zone split skin IIF is particularly useful for recognizing patients at risk for malignancy-
associated laminin 332 (previously known as laminin 5 and epiligrin) MMP; in this condition, antibodies are found along
the dermal side of the split [84,85]. Specific testing to confirm a diagnosis of anti-laminin 332 MMP remains limited to
specialized centers and research settings [86]. (See 'Differential diagnosis' below.)
Antigen-specific serologic testing
Bullous pemphigoid — The identification of increased circulating IgG antibodies against bullous pemphigoid
antigen 180 (BP180) and bullous pemphigoid antigen 230 (BP230) in patients with bullous pemphigoid has led to the use
of adjunctive antigen-specific serologic testing for these basement membrane zone antigens in the diagnosis of this
disorder (figure 1). The most common technique used for this purpose is ELISA. (See "Epidemiology and pathogenesis of
bullous pemphigoid and mucous membrane pemphigoid", section on 'Bullous pemphigoid'.)
ELISAs for bullous pemphigoid antibodies are commercially available. This testing detects circulating IgG that reacts with
collagen type XVII or BP180 (specifically, the NC16A domain of BP180, which is the most common antigenic target and
which also has been known as bullous pemphigoid antigen 2 [BPAg2]) and with BP230 (specifically, fused antigenic
targets from the N-terminal domain, central rod domain, and C-terminal domain of human BP230 and which also is known
as bullous pemphigoid antigen 1 [BPAg1]).
ELISA for antibodies to the BP180 NC16A domain is useful for baseline information in the diagnosis of bullous
pemphigoid; studies have documented sensitivity and specificity of 72 to 90 percent and 90 to 99 percent, respectively
[73,82,87,88]. Since IgG BP180 NC16A antibody levels also correlate with disease activity [89], many clinicians (including
ourselves) utilize ELISA testing, not only to support the diagnosis of bullous pemphigoid, but also as a measure of the
response to therapy.
ELISA for BP230 antibodies is less likely to be positive in bullous pemphigoid than ELISA testing for BP180 antibodies
[73,82,90]. In a retrospective study that evaluated ELISA results in 190 patients with bullous pemphigoid, the sensitivity
and specificity of the assay for BP230 were 61 and 96 percent compared with 79 and 90 percent for BP180 [82].
Moreover, combined testing for BP180 and BP230 antibodies was only slightly more sensitive than BP180 alone; the
sensitivity and specificity of conjoint testing were 87 and 88 percent. Although this finding suggests that testing for BP230
should be reserved for patients who test negatively for BP180, immunodermatology laboratories, including ours, test for
antibodies to both antigens in diagnostic panels for bullous pemphigoid [82]. We have observed a subset of pemphigoid
patients who have strong epidermal pattern basement membrane zone IgG antibodies by IIF and relatively high levels of
IgG BP230 antibodies by ELISA, but normal IgG BP180 antibody levels. (See "Epidemiology and pathogenesis of bullous
pemphigoid and mucous membrane pemphigoid", section on 'Pathogenesis'.)
Also, in our experience, approximately 10 percent of patients with bullous pemphigoid demonstrate characteristic
epidermal pattern IgG basement membrane zone antibodies by IIF and normal levels of both IgG BP180 and IgG BP230
antibodies by ELISA. These patients likely have antibodies to epitopes of BP180 or BP230 that are not recognized by
commercial ELISA tests or may have antibodies to basement membrane zone antigens other than BP180 and BP230. In
support of this observation, a study of 51 patients with clinical, histopathologic, and DIF findings consistent with bullous
pemphigoid identified four patients (8 percent) in whom ELISA for BP180 NC16A was negative, three of whom also had
negative ELISA for BP230 [91]. Despite the negative ELISA for BP180, further analysis by immunoblot revealed strong
reactivity to BP180 epitopes outside of NC16A in all four patients. These findings support the use of both IIF and ELISA
to identify patients with bullous pemphigoid. In the study described, IIF on basement membrane zone-split skin was
positive in three of the four ELISA BP180-negative patients. The subset of patients in whom serum antibodies to the
BP180 NC16A domain are not detectable may have milder clinical manifestations (minimal to no erythema and less
severe erosions and blistering) compared with patients who have increased levels of these antibodies [92].
The potential value of combining serologic studies also was demonstrated in a retrospective study of 313 patients with
bullous pemphigoid and 488 controls that found that the sensitivity of a panel of serologic tests (IIF on rabbit esophagus,
IIF on monkey esophagus, IIF on human salt-split skin, BP180 ELISA, and BP230 ELISA) for the diagnosis of bullous
pemphigoid was 88.8 percent, a figure that closely approximated the sensitivity of DIF (90.8 percent) [73]. There was very
high correlation between the results obtained with IIF on rabbit esophagus and IIF on monkey esophagus, suggesting
that a similar sensitivity would have been obtained upon elimination of one of these tests. Lower sensitivities (59 to 76
percent) were detected for the individual serologic tests.
Of note, the detection of BP180 and/or BP230 antibodies in serum does not definitively confirm a diagnosis of bullous
pemphigoid. In one series of 337 people without bullous pemphigoid, 25 (7 percent) tested positively for one or both
autoantibodies via ELISA [93]. Correlation of ELISA findings with IIF and/or DIF will reduce the risk for misdiagnosis [1].
Other techniques that have been utilized for the detection of antibodies in bullous pemphigoid include immunoblotting and
immunoprecipitation. However, these tests are technically demanding and generally are not utilized in the clinical setting
[1,74].
Mucous membrane pemphigoid — MMP may present with autoantibodies directed against a variety of antigens,
including BP180, BP230, laminin 332 (previously known as epiligrin and laminin 5), alpha6beta4 integrin, and type VII
collagen (figure 1) [39,65,94-97]. However, limited sensitivity of ELISA testing for the diagnosis of MMP prevents the sole
use of such testing. Pooled data analysis in a systematic review of studies reporting autoantibody profiles of patients with
MMP who had positive immunoblot or immunoprecipitation to NC16A found the sensitivity and specificity of ELISA using
both NC16A and C-terminal epitope portions of BP180 to be 73 and 94 percent, respectively [97]. Among patients with
IgG reactivity against the C-terminal domain of BP180, the sensitivity and specificity of ELISA testing were 43 and 56
percent, respectively.
Antigen specific testing of serum for basement membrane zone antibodies other than BP180 and BP230 primarily is
performed in research laboratories, limiting the value of this testing mode in the MMP population. However, additional
tests may be available in the future. Further study is necessary to clarify whether the detection of salivary IgA and IgG
antibodies to BP180 NC16A by ELISA is a useful diagnostic biomarker for MMP [98]. (See "Epidemiology and
pathogenesis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Mucous membrane pemphigoid'.)
Other laboratory findings — Peripheral blood eosinophilia is common in patients with bullous pemphigoid but is not
a diagnostic finding [99,100]. Increased interleukin (IL)-5, a critical cytokine in eosinophil production and activation, has
been observed in peripheral blood and blister fluid in patients with bullous pemphigoid but has not been systematically
studied [101,102]; these observations may have new significance as eosinophil reduction/elimination therapies, including
monoclonal anti-IL-5, have become available. Increased serum IgE levels also are commonly found [103,104].
DIFFERENTIAL DIAGNOSIS
The clinical findings in bullous pemphigoid and MMP may resemble a variety of other diseases, including other variants of
pemphigoid and additional blistering or non-blistering diseases (table 1).
Other pemphigoid variants
Pemphigoid gestationis — Pemphigoid gestationis is an autoimmune subepidermal blistering disorder that develops
during pregnancy and the postpartum period. Patients typically develop intensely pruritic papules, urticarial plaques,
vesicles, and bullae that begin on the abdomen prior to spreading to other areas [105,106]. The face and mucous
membranes are usually spared.
Like bullous pemphigoid, patients with pemphigoid gestationis have circulating BP180 antibodies that are detected by
enzyme-linked immunosorbent assay (ELISA) [107]. On direct immunofluorescence (DIF), complement deposition
predominates at the basement membrane zone. Pemphigoid gestationis is discussed in greater detail elsewhere. (See
"Dermatoses of pregnancy", section on 'Pemphigoid gestationis'.)
Anti-p200 (laminin gamma-1) pemphigoid — Anti-p200 pemphigoid, also known as anti-laminin gamma-1
pemphigoid, is a variant of pemphigoid that is characterized by antibodies to a 200 kilodalton component of the dermal-
epidermal junction. Indirect immunofluorescence (IIF) on basement membrane zone-split skin demonstrates dermal
localization of basement membrane zone antibodies [108] (see 'Indirect immunofluorescence of serum' above). The
antigenic target in most cases is the gamma-1 subunit of laminin 311 (previously known as laminin 6).
Patients with this type of pemphigoid are usually younger than those with bullous pemphigoid, but present with similar
clinical features. In one series of 29 patients with this disorder, 25 patients were male, and the mean age of patients was
61 years [109]. Additionally, 14 patients had coexistent psoriasis. In another series of 12 patients, tense acral blisters and
mucosal involvement were characteristic clinical features along with pruritus, and none had psoriasis [110].
Specific testing to confirm the presence of antibodies to p200, or particularly to laminin gamma-1, remains limited to
specialized centers and research settings [111]. As a result, it is likely that patients with this form of pemphigoid are
diagnosed erroneously with bullous pemphigoid or epidermolysis bullosa acquisita based on DIF findings [110]. Anti-p200
pemphigoid is one of the few diagnoses indicated by IIF testing that detects serum immunoglobulin G (IgG) basement
membrane zone antibodies binding to the dermal side of split skin substrate, also including epidermolysis bullosa
acquisita, bullous lupus, and anti-laminin 332 pemphigoid. Techniques that have been used to specifically identify p200
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antibodies include immunoblot with human dermal extract, ELISA to laminin gamma-1, IIF on skin substrates deficient in
type VII collagen and laminin 332, and localization of collagen type IV to the floor of blistering skin [110,112].
Brunsting-Perry pemphigoid — Brunsting-Perry pemphigoid is a cicatricial (scarring) form of pemphigoid that most
commonly occurs in older men. Affected patients develop subepidermal blisters localized to the head or neck (picture 12).
A variety of basement membrane zone antibodies have been detected in this variant [113-115].
Other disorders — Examples of nonpemphigoid disorders in the differential diagnosis for patients with cutaneous lesions
are included below (table 1 and algorithm 1):
● Urticaria and eczematous dermatitis – The prodromal phase lesions of bullous pemphigoid may resemble the
erythematous and edematous plaques of urticaria or the erythematous papules or plaques of eczematous dermatitis.
Unlike true urticaria, the lesions of bullous pemphigoid are not transient. DIF studies of biopsy specimens are useful
for distinguishing both of these disorders from bullous pemphigoid. (See "New-onset urticaria" and "Atopic dermatitis
(eczema): Pathogenesis, clinical manifestations, and diagnosis".)
● Skin-predominant epidermolysis bullosa acquisita – Epidermolysis bullosa acquisita is a rare disorder

characterized by subepidermal blister formation involving the skin and mucous membranes (picture 13). Unlike
bullous pemphigoid, IIF on basement membrane zone-split skin demonstrates serum antibody bound to the dermal
side of the split, and residual scarring and milia are common. Specific ELISA testing for antibodies to type VII
collagen is useful for making this diagnosis. (See "Epidermolysis bullosa acquisita".)
● Pemphigus – Pemphigus is a group of autoimmune blistering disorders characterized by autoantibodies directed

against epithelial cell surface antigens (also known as intercellular substance antigens). The flaccid nature of blisters
in pemphigus contrasts with the tense, subepidermal bullae in pemphigoid (picture 2A-C). DIF studies are essential
for diagnosis. Several pemphigus variants exist, including paraneoplastic pemphigus (picture 2D), which may show
basement membrane zone antibodies in addition to cell surface antibodies. (See "Paraneoplastic pemphigus" and
"Pathogenesis, clinical manifestations, and diagnosis of pemphigus".)
● Linear IgA bullous dermatosis – Linear IgA bullous dermatosis is an autoimmune subepithelial blistering disorder
that usually presents with annular and grouped tense vesicles arising on inflamed skin (picture 14). The skin lesions
often are described as resembling a cluster of jewels. Mucosal sites also may be affected. The DIF finding of linear
IgA antibody staining at the basement membrane zone in a perilesional skin biopsy specimen is essential for this
diagnosis. (See "Linear IgA bullous dermatosis".)
● Dermatitis herpetiformis – Intensely pruritic inflammatory papules, vesicles, or crusts with a predilection for the
elbows, knees, and buttocks are characteristic of dermatitis herpetiformis, another autoimmune subepidermal
blistering disorder (picture 15). The histopathologic finding of neutrophilic microabscesses in dermal papillary tips by
H&E and the immunohistopathologic detection of granular and/or fibrillar IgA deposits in the papillary dermis by DIF
are consistent with this diagnosis. (See "Dermatitis herpetiformis".)
● Bullous lupus erythematosus – Bullous systemic lupus erythematosus is a rare disorder. The development of
subepidermal blisters with neutrophilic infiltrates in a patient with systemic lupus erythematosus suggests this
disease. (See "Overview of cutaneous lupus erythematosus", section on 'Bullous cutaneous lupus erythematosus'.)
Mucosal lesions — Other causes of mucosal erosions that must be distinguished from those associated with MMP and
bullous pemphigoid include pemphigus variants (picture 2C-D), linear IgA bullous dermatosis or epidermolysis bullosa
acquisita with mucosal involvement, oral and genital mucosal lichen planus (picture 16A-B), erythema multiforme (picture
17A-B), Stevens-Johnson syndrome (picture 18), HIV-associated mucosal lesions, Behçet syndrome, and aphthous
ulcers (picture 19) [39]. (See "Paraneoplastic pemphigus" and "Linear IgA bullous dermatosis" and "Epidermolysis bullosa
acquisita" and "Oral lichen planus: Pathogenesis, clinical features, and diagnosis" and "Erythema multiforme:
Pathogenesis, clinical features, and diagnosis" and "Stevens-Johnson syndrome and toxic epidermal necrolysis:
Pathogenesis, clinical manifestations, and diagnosis" and "Clinical manifestations and diagnosis of Behçet syndrome"
and "Oral lesions", section on 'Erosions and ulcerations' and "Pathogenesis, clinical manifestations, and diagnosis of
pemphigus".)
The differential diagnosis for ocular involvement is reviewed separately. (See "Ocular cicatricial pemphigoid", section on
'Differential diagnosis'.)
SUMMARY AND RECOMMENDATIONS
● Bullous pemphigoid and mucous membrane pemphigoid (MMP) are uncommon autoimmune subepithelial blistering
disorders that affect skin and mucous membranes. (See 'Clinical features' above.)
● Features of bullous pemphigoid
• The onset of blistering lesions in bullous pemphigoid is frequently preceded by a prodromal phase characterized
by pruritic inflammatory plaques that resemble eczematous dermatitis or urticaria. Once the bullous phase
develops, patients exhibit multiple tense 1 to 3 cm bullae as well as erosions and crusts at sites of ruptured
bullae (picture 1A-G, 3A-C). The lesions of bullous pemphigoid usually heal without scarring. (See 'Bullous
pemphigoid' above.)
• The trunk and extremities are typically involved in bullous pemphigoid; localized presentations also may occur.
Mucosal disease is present in 10 to 30 percent of patients (picture 4). (See 'Bullous pemphigoid' above.)
● Features of MMP
• MMP most commonly presents as desquamative gingivitis or erosions of the oral mucosa. Other potential sites
of mucosal involvement include the ocular conjunctiva, skin, pharynx, genitalia, nasal mucosa, larynx, anus, and
esophagus (picture 5A-C). (See 'Mucous membrane pemphigoid' above and "Ocular cicatricial pemphigoid",
section on 'Clinical manifestations'.)
• Unlike bullous pemphigoid, lesions of MMP tend to scar. Scarring may result in serious functional impairment.
(See 'Mucous membrane pemphigoid' above.)
• Patients with the anti-laminin 332 (previously known as anti-laminin 5 or anti-epiligrin) form of MMP have an
increased risk for internal malignancy. An evaluation for associated malignancy should be performed in patients
with immunohistopathologic findings that suggest this disorder. Specific testing for antibodies against laminin
332 is not yet widely available. (See 'Malignancy' above.)
● Diagnosis
• The evaluation of patients with clinical findings suggestive of bullous pemphigoid or MMP begins with obtaining
skin or mucous membrane biopsy specimens from both lesional tissue for H&E (light microscopic
histopathology) and perilesional tissue for direct immunofluorescence (DIF) (algorithm 1). DIF is highly sensitive
for the diagnosis and demonstrates characteristic basement membrane zone antibody localization in almost all
patients with bullous pemphigoid and the majority of patients with MMP (picture 8A-C). (See 'Skin biopsy'
above.)
• Serologic studies to detect circulating basement membrane zone antibodies by indirect immunofluorescence
(IIF) and enzyme-linked immunoassay (ELISA) also are useful for the diagnosis of bullous pemphigoid. Both DIF
and serologic studies should be performed as part of the diagnostic evaluation (picture 10A and algorithm 1).
(See 'Indirect immunofluorescence of serum' above and 'Antigen-specific serologic testing' above.)
• The differential diagnosis of bullous pemphigoid and MMP is broad (table 1). The possibility of other pemphigoid
disorders, other blistering disorders, and nonbullous diseases must be considered. (See 'Differential diagnosis'
above.)
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are negative using the BP180 enzyme-linked immunosorbant assay. J Am Acad Dermatol 2013; 68:395.
92. Nakama K, Koga H, Ishii N, et al. Clinical and Immunological Profiles of 14 Patients With Bullous Pemphigoid
Without IgG Autoantibodies to the BP180 NC16A Domain. JAMA Dermatol 2018; 154:347.
93. Wieland CN, Comfere NI, Gibson LE, et al. Anti-bullous pemphigoid 180 and 230 antibodies in a sample of
unaffected subjects. Arch Dermatol 2010; 146:21.
94. Rashid KA, Gürcan HM, Ahmed AR. Antigen specificity in subsets of mucous membrane pemphigoid. J Invest
Dermatol 2006; 126:2631.
95. Chan LS, Majmudar AA, Tran HH, et al. Laminin-6 and laminin-5 are recognized by autoantibodies in a subset of
cicatricial pemphigoid. J Invest Dermatol 1997; 108:848.
96. Lazarova Z, Yee C, Lazar J, Yancey KB. IgG autoantibodies in patients with anti-epiligrin cicatricial pemphigoid
recognize the G domain of the laminin 5 alpha-subunit. Clin Immunol 2001; 101:100.
97. Amber KT, Bloom R, Hertl M. A systematic review with pooled analysis of clinical presentation and
immunodiagnostic testing in mucous membrane pemphigoid: association of anti-laminin-332 IgG with
oropharyngeal involvement and the usefulness of ELISA. J Eur Acad Dermatol Venereol 2016; 30:72.
98. Ali S, Kelly C, Challacombe SJ, et al. Salivary IgA and IgG antibodies to bullous pemphigoid 180 noncollagenous
domain 16a as diagnostic biomarkers in mucous membrane pemphigoid. Br J Dermatol 2016; 174:1022.
99. Kulthanan K, Chularojanamontri L, Tuchinda P, et al. Prevalence and clinical features of Thai patients with bullous
pemphigoid. Asian Pac J Allergy Immunol 2011; 29:66.
100. Bushkell LL, Jordon RE. Bullous pemphigoid: a cause of peripheral blood eosinophilia. J Am Acad Dermatol 1983;
8:648.
101. Borrego L, Maynard B, Peterson EA, et al. Deposition of eosinophil granule proteins precedes blister formation in
bullous pemphigoid. Comparison with neutrophil and mast cell granule proteins. Am J Pathol 1996; 148:897.
102. D'Auria L, Pietravalle M, Mastroianni A, et al. IL-5 levels in the serum and blister fluid of patients with bullous
pemphigoid: correlations with eosinophil cationic protein, RANTES, IgE and disease severity. Arch Dermatol Res
1998; 290:25.
103. Arbesman CE, Wypych JI, Reisman RE, Beutner EH. IgE levels in sera of patients with pemphigus or bullous
pemphigoid. Arch Dermatol 1974; 110:378.
104. Freire PC, Muñoz CH, Stingl G. IgE autoreactivity in bullous pemphigoid: eosinophils and mast cells as major
targets of pathogenic immune reactants. Br J Dermatol 2017; 177:1644.
105. Ambros-Rudolph CM, Black MM. From prurigo gestationis Besnier to atopic eruption of pregnancy: the confusing
nosology of the less well-defined dermatoses of pregnancy has been largely clarified. Clin Dermatol 2006; 24:545.
106. Ambros-Rudolph CM, Müllegger RR, Vaughan-Jones SA, et al. The specific dermatoses of pregnancy revisited and
reclassified: results of a retrospective two-center study on 505 pregnant patients. J Am Acad Dermatol 2006;
54:395.
107. Giudice GJ, Wilske KC, Anhalt GJ, et al. Development of an ELISA to detect anti-BP180 autoantibodies in bullous
pemphigoid and herpes gestationis. J Invest Dermatol 1994; 102:878.
108. Zillikens D, Kawahara Y, Ishiko A, et al. A novel subepidermal blistering disease with autoantibodies to a 200-kDa
antigen of the basement membrane zone. J Invest Dermatol 1996; 106:1333.
109. Dilling A, Rose C, Hashimoto T, et al. Anti-p200 pemphigoid: a novel autoimmune subepidermal blistering disease.
J Dermatol 2007; 34:1.
110. Meijer JM, Diercks GF, Schmidt E, et al. Laboratory Diagnosis and Clinical Profile of Anti-p200 Pemphigoid. JAMA
Dermatol 2016; 152:897.
111. Groth S, Recke A, Vafia K, et al. Development of a simple enzyme-linked immunosorbent assay for the detection of
autoantibodies in anti-p200 pemphigoid. Br J Dermatol 2011; 164:76.
112. García-Díez I, Martínez-Escala ME, Ishii N, et al. Usefulness of a Simple Immunohistochemical Staining Technique
to Differentiate Anti-p200 Pemphigoid From Other Autoimmune Blistering Diseases: A Report of 2 Cases. Actas
Dermosifiliogr 2017; 108:e1.
113. Martín JM, Pinazo I, Molina I, et al. Cicatricial pemphigoid of the Brunsting-Perry type. Int J Dermatol 2009; 48:293.
114. Jedlickova H, Niedermeier A, Zgažarová S, Hertl M. Brunsting-Perry pemphigoid of the scalp with antibodies
against laminin 332. Dermatology 2011; 222:193.
115. Fukuda S, Tsuruta D, Uchiyama M, et al. Brunsting-Perry type pemphigoid with IgG autoantibodies to laminin-332,
BP230 and desmoplakins I/II. Br J Dermatol 2011; 165:433.
Topic 16176 Version 15.0
GRAPHICS
Diagnostic evaluation of patients with suspected bullous pemphigoid or mucous membrane pemphigoid
BP: bullous pemphigoid; MMP: mucous membrane pemphigoid; DIF: direct immunofluorescence; IIF: indirect immunofluorescence; BMZ: basement
membrane zone; ELISA: enzyme-linked immunosorbent assay; IgG: immunoglobulin G; IgA: immunoglobulin A; EBA: epidermolysis bullosa acquisita; SLE:
systemic lupus erythematosus.
* Clinical features that indicate BP or MMP include tense blisters and erosions without another identifiable cause and unexplained, pruritic, eczematous
eruptions or urticarial plaques, mucositis, or desquamative gingivitis.
¶ The preferred biopsy site for histopathology includes a blister edge and adjacent tissue. Skin biopsy specimens for DIF testing should be taken from an
erythematous or urticarial area adjacent to a blister (ie, perilesional skin). Mucosal specimens for DIF should be taken several millimeters away from the
edge of a lesion. DIF is considered the gold standard test for the diagnosis of BP and MMP and should be performed whenever feasible. If biopsy cannot be
performed on a patient with suspected BP or MMP, we recommend obtaining serum for IIF testing on human BMZ-split skin substrate and BP180 and BP230
ELISA. The combination of these tests can be useful for supporting a clinical diagnosis.
Δ Common histopathologic findings in BP include eosinophilic spongiosis, subepidermal blister formation, and a superficial dermal inflammatory cell infiltrate
with lymphocytes, eosinophils, and neutrophils. Common findings in MMP include subepithelial separation and a mixed submucosal inflammatory cell
infiltrate with lymphocytes, histiocytes, neutrophils, and eosinophils. DIF findings in BP specimens include linear IgG and/or linear C3 localization along the
BMZ. DIF findings of MMP include linear IgG and/or linear IgA and/or linear C3 staining along the BMZ.
◊ The term "human basement membrane zone-split skin" is interchangeable with "human salt-split skin."
§ Additional biopsy specimens for DIF testing increase the sensitivity of DIF for the diagnosis of MMP and may be of value for patients with suspected MMP.
¥ Antibody deposition on the "roof" is also referred to as an "epidermal pattern." Antibody deposition on the "floor" is also referred to as a "dermal pattern."
‡ EBA may not be distinguishable from bullous SLE with this testing (similar IIF and IgG collagen VII ELISA findings could be found in either). Refer to †
footnote.
† Refer to UpToDate content on the diagnosis of EBA, anti-p200 pemphigoid, bullous SLE, and anti-laminin 332 pemphigoid for information on the diagnostic
evaluation of these diseases. Laboratory testing to confirm anti-laminin 332 MMP and anti-p200 pemphigoid is not widely available.
** Clinical correlation is needed because up to 7% of individuals unaffected by pemphigoid, including patients with other immunobullous diseases, have
increased IgG BP180 and/or IgG BP230 antibody levels by ELISA.
¶¶ Diagnostic possibilities include seronegative BP/MMP, BP/MMP with BMZ antibodies to targets other than BP180 and BP230, EBA, bullous SLE, and other
blistering diseases. Review of IIF findings on monkey esophagus and collagen VII ELISA may be helpful. Negative IIF on human skin but IIF on monkey
esophagus showing IgG BMZ deposition may occur in BP/MMP with BMZ antibodies to targets other than BP180 and BP230, EBA, bullous SLE, anti-p200
pemphigoid, or anti-laminin 332 MMP. Positive collagen VII ELISA supports a diagnosis of EBA or bullous SLE. Refer to UpToDate content for information on
the diagnostic evaluation of these diseases.
ΔΔ BP180 and BP230 ELISA can be negative in patients with BP or MMP. The sensitivity of serum testing is lower for MMP than for BP. In particular, MMP
may be associated with autoantibodies to BMZ antigens other than BP180 and BP230.
Graphic 120171 Version 2.0
Eczematous lesions in bullous pemphigoid
Eczematous and erythematous, urticarial plaques with eroded blisters and excoriations on
posterior trunk and extremity skin.
Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.
Tense blisters in bullous pemphigoid
Multiple tense bullae on inflamed skin.
Bullous pemphigoid
Multiple tense bullae on skin with one eroded blister base.
Bullous pemphigoid
Arm skin with tense bullae arising on urticarial plaques and eroded blister bases.
Pemphigus vulgaris
Flaccid bullae and erosions on the skin of a patient with pemphigus vulgaris.
Pemphigus vulgaris
Multiple erosions on the trunk skin of this patient with pemphigus vulgaris.
Bullous pemphigoid
Multiple erythematous plaques, bullae, erosions, and crusts on the trunk and extremity
skin.
Bullous pemphigoid
Multiple tense bullae arising on erythematous plaques, ruptured bullae, and

erosions in and around skin of the axilla.
Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights

reserved.
Bullous pemphigoid
Inflammatory plaques, bullae, erosions, crusts, and postinflammatory

hyperpigmentation on trunk skin.

reserved.
Bullous pemphigoid
Multiple erosions on the oral mucosa in this patient with bullous pemphigoid.
Bullous pemphigoid
Tense bullae on the anterior tibial and ankle skin.
Dyshidrosiform bullous pemphigoid
Multiple eroded blisters with hemorrhagic bases on the palmar surface of the hands.
Mucous membrane pemphigoid
Desquamative gingivitis with edema and hemorrhage in this patient with mucous
membrane pemphigoid.
Irregular erosions and a blister on the mucosal surface of the lip.
Mucosal erosions on the gingiva and palate.
Pemphigus vulgaris - oral lesions
Multiple erosions on the palate in a patient with pemphigus vulgaris.

reserved.
The epidermal basement membrane zone
Differential diagnosis of mucocutaneous lesions in pemphigoid disorders
Aphthous stomatitis
Behçet syndrome
Bullous impetigo
Bullous lupus erythematosus
Bullous mastocytosis
Bullous morphea
Bullous mycosis fungoides
Chronic eczema
Contact dermatitis
Dermatitis herpetiformis
Drug-induced bullous disorder
Epidermolysis bullosa acquisita
Erythema multiforme
HIV-associated mucosal lesions
Hypereosinophilic syndromes
Incontinentia pigmenti (blistering stage)
Lichen planus
Linear IgA bullous dermatosis
Pemphigoid (herpes) gestationis
Pemphigus
Porphyria and pseudoporphyria
Pruritus, generalized (various etiologies)
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Urticaria
Viral infection
Herpes simplex virus
Varicella-zoster virus
Others
Wells' syndrome
IgA: immunoglobulin A.
Bullous pemphigoid in childhood
Multiple tense bullae, inflammatory plaques, erosions, and crusts on the skin of
this child with bullous pemphigoid.

reserved.
Diagnostic pemphigoid testing
Test Specimen Site Procedure Transport
Histopathology (H&E) Skin or mucous membrane Lesional or part lesional At least 4 mm punch In formalin to a
biopsy* dermatopathology
Specimen should laboratory
contain intact
epidermis/epithelium,
basement membrane
zone, and upper
dermis/subepithelium
Avoid torsion and
crushing to prevent
separation artifact
Direct immunofluorescence Skin or mucous membrane Perilesional At least 4 mm punch In Michel's or Zeus
For cutaneous biopsy* medium to an
lesions, an Specimen should immunodermatology
erythematous or contain intact laboratory ¶
urticarial area next to epidermis/epithelium,
a blister from a basement membrane
proximal anatomical zone, and upper
location is ideal dermis/subepithelium
For mucous Avoid torsion and
membrane lesions, crushing to prevent
avoid areas of separation artifact
scarring; normal-
appearing
epithelium since
perilesional tissue
may be friable
Indirect Serum Peripheral blood Serum separated from at In serum tube to an

immunofluorescence and least 5 mL of blood immunodermatology
ELISA obtained by venipuncture laboratory
(red top, no
anticoagulant); send
serum separated from
clot Δ
If questions about specimen site selection or acceptable specimen handling conditions, contact an immunodermatology laboratory.
H&E: hematoxylin and eosin; ELISA: enzyme-linked immunosorbent assay.

* An alternative to two biopsies, one each for H&E and direct immunofluorescence, as indicated above, is to obtain one 5 or 6 mm punch biopsy or one
deep shave biopsy specimen that contains both lesional and perilesional tissue. The specimen is split into two pieces with a scalpel. Care should be
taken to avoid disrupting the epidermis or crushing the specimen during splitting. The lesional portion is placed in formalin for H&E histology, and the
perilesional portion is placed in Michel's or Zeus transport medium for direct immunofluorescence.
¶ Some immunodermatology laboratories will accept tissue on saline-saturated gauze if it is transported to the laboratory within six hours (the sooner
the better and to be received during working hours) and will also accept tissue specimens flash frozen in liquid nitrogen and transported on dry ice.
Δ The serum can be separated without a centrifuge by allowing whole blood to clot in a tube for a half hour to two hours. The serum on top of the
clotted blood is then carefully transferred into a serum tube with a disposable pipette and sent to an immunodermatology laboratory. Alternatively,
some immunodermatology laboratories accept whole blood if it is transported to the laboratory promptly (within six hours).
Bullous pemphigoid
This hematoxylin and eosin stain of a skin tissue biopsy specimen from an early lesion of
bullous pemphigoid demonstrates epidermal spongiosis, eosinophils within the epidermis,
and a mixed perivascular cellular infiltrate in the upper dermis.
Reproduced with permission from: Leiferman KM, Peters MS. Eosinophils in cutaneous diseases.
In: Fitzpatrick's Dermatology in General Medicine, 8th ed, Goldsmith L, Katz S, Gilchrest B, et
al (Eds), McGraw-Hill, New York 2012. Copyright © 2012 McGraw-Hill Companies, Inc.
Bullous pemphigoid
This hematoxylin and eosin stain of a skin tissue biopsy specimen from the edge
of an established lesion of bullous pemphigoid demonstrates a subepidermal
blister with an edematous papillary dermis as its base. The roof of the blister
consists of the intact epidermis, including the stratum basalis. Eosinophil-rich
inflammatory cells, fibrin, and tissue fluid fill the blister.
Reproduced with permission from: Rubin E, Farber JL. Pathology, 3rd ed, Lippincott
Williams & Wilkins, Philadelphia 1999. Copyright ©1999 Lippincott Williams & Wilkins.
Linear IgG basement membrane zone antibody staining in

bullous pemphigoid by direct immunofluorescence microscopy
Direct immunofluorescence microscopy of perilesional skin from a patient with bullous

pemphigoid reveals characteristic linear IgG basement membrane zone staining.
Courtesy of Kristin M Leiferman, MD, Immunodermatology Laboratory, Department of

Dermatology, University of Utah, Salt Lake City, Utah.
Linear C3 basement membrane zone antibody staining in bullous

pemphigoid by direct immunofluorescence microscopy
Direct immunofluorescence microscopy of perilesional skin from a patient with bullous

pemphigoid reveals characteristic linear C3 basement membrane zone staining.
Courtesy of Kristin M Leiferman, MD, Immunodermatology Laboratory, Department of Dermatology,

University of Utah, Salt Lake City, Utah.
N-serrated pattern of IgG basement membrane zone antibody staining

in bullous pemphigoid by direct immunofluorescence microscopy
The positive direct immunofluorescence staining along the basement membrane zone in this section
of a perilesional skin specimen demonstrates what is described as an n-serrated linear pattern
interspersed with segments of true linear IgG basement membrane zone antibody reactivity. This
pattern is associated with bullous pemphigoid, mucous membrane pemphigoid, anti-laminin gamma-1
pemphigoid, and linear IgA bullous dermatosis.

U-serrated IgG basement membrane zone antibody staining in

epidermolysis bullosa acquisita by direct immunofluorescence
microscopy
The positive direct immunofluorescence staining along the basement membrane zone in this section
of a perilesional skin specimen demonstrates what is described as a u-serrated linear pattern
interspersed with segments of true linear IgG basement membrane zone antibody reactivity. This
pattern is characteristically thicker than the n-serrated patter in bullous pemphigoid and is associated
with epidermolysis bullosa acquisita and bullous systemic lupus erythematosus.
IgG: immunoglobulin G.

Serum IgG basement membrane zone antibodies localizing to

the epidermal side of split skin substrate in bullous pemphigoid
by indirect immunofluorescence microscopy
Linear IgG antibody staining on the epidermal side of basement membrane zone-split
skin substrate characteristic of bullous pemphigoid. This pattern also is referred to as
staining the roof of the blister.

Serum IgG basement membrane zone antibodies localizing to

the dermal side of split skin substrate in epidermolysis bullosa
acquisita by indirect immunofluorescence microscopy
Linear IgG antibody staining on the dermal side of basement membrane zone-split skin
substrate characteristic of epidermolysis bullosa acquisita. This pattern also is referred to
as staining the floor of the blister, and may be found in bullous lupus erythematosus and
two subsets of pemphigoid, namely, anti-laminin 332 and anti-laminin gamma-1
pemphigoid.

Serum IgG basement membrane zone antibodies showing combined

epidermal-dermal staining on split skin substrate in bullous pemphigoid
by indirect immunofluorescence microscopy
Linear IgG antibody staining in a combined pattern, epidermal-dermal, on basement membrane zone-
split skin substrate characteristic of bullous pemphigoid and, rarely, bullous lupus erythematosus.
This pattern also is referred to as staining the roof and floor of the blister.

Brunsting-Perry pemphigoid
Erosions leading to scarring on scalp skin.
Epidermolysis bullosa acquisita
Tense bullae, erosions, and crusts on skin of a patient with epidermolysis bullosa
acquisita.
Paraneoplastic pemphigus
An erosive mucositis in a patient with paraneoplastic pemphigus associated with

Castleman's tumor; mucous membrane and cutaneous lesions cleared with
tumor removal.
Copyright © Chris Ha, MD, Dermatlas; http://www.dermatlas.org.
Linear IgA bullous dermatosis
Tense bullae, erosions, and crusts, often in a pattern described as "clusters of jewels" or
"strings of pearls," on skin of a patient with linear IgA bullous dermatosis.
IgA: immunoglobulin A.
Dermatitis herpetiformis
Vesicles, bullae, erosions, and crusts on elbow skin.
Oral lichen planus
Erythema and erosions on the gingiva in a patient with oral lichen planus.

reserved.
Vulvar erosive lichen planus
Erythema and erosions on the vulvar labial mucosa in a patient with erosive
lichen planus.
Reproduced with permission from Ridley CM, Neill SM (Eds), The Vulva, 2nd ed,
Blackwell Science, Oxford 1999. Copyright © 1999 Blackwell Science.
http://www.blackwell-science.com.
Erythema multiforme
Mucosal erosions and crusts on the lips of a patient with erythema multiforme.

reserved.
Erythema multiforme
Hemorrhagic crusting and mucosal erosions involving the lips and tongue in a
patient with erythema multiforme.

reserved.
Mucosal changes in Stevens-Johnson syndrome/toxic

epidermal necrolysis
Changes similar to those observed in SJS/TEN can be observed also in erythema

multiforme majus.
SJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysis.
Aphthous ulcers
Round, yellow-gray ulcers are present on the oral mucosa.

reserved.
Contributor Disclosures
Kristin M Leiferman, MD Employment: University of Utah Department of Dermatology, Co-Director Immunodermatology Laboratory
[Pemphigoid (Immunoassays performed for the diagnosis of immunobullous diseases)]. John J Zone, MD Nothing to disclose Abena
O Ofori, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through
a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced
content is required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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Clinical features and diagnosis of bullous pemphigoid and mucous

● Oral mucosa (85 percent)

● Unexplained pruritus, pruritic eczematous eruptions, or urticarial plaques

● Pruritus and/or predominant cutaneous blisters

● Linear immunoglobulin G (IgG) and/or C3 deposits by DIF on a skin biopsy specimen

Common histopathologic findings in cutaneous lesions of bullous pemphigoid include [1]:

● Eosinophilic spongiosis (particularly in early lesions) (picture 6)

Direct immunofluorescence — Direct immunofluorescence (DIF) testing is a highly sensitive, supportive

Antigen-specific serologic testing

Other pemphigoid variants

● Skin-predominant epidermolysis bullosa acquisita – Epidermolysis bullosa acquisita is a rare disorder

● Pemphigus – Pemphigus is a group of autoimmune blistering disorders characterized by autoantibodies directed

SUMMARY AND RECOMMENDATIONS

● Features of bullous pemphigoid

Use of UpToDate is subject to the Subscription and License Agreement.

3. Kasperkiewicz M, Zillikens D, Schmidt E. Pemphigoid diseases: pathogenesis, diagnosis, and treatment.

10. Benmously-Mlika R, Hammami-Ghorbel H, Mokhtar I. Onychomadesis during bullous pemphigoid. J Am Acad

Topic 16176 Version 15.0

Graphic 120171 Version 2.0

Eczematous lesions in bullous pemphigoid

Graphic 80385 Version 6.0

Tense blisters in bullous pemphigoid

Multiple tense bullae on inflamed skin.

Graphic 54541 Version 6.0

Multiple tense bullae on skin with one eroded blister base.

Graphic 70352 Version 6.0

Graphic 79112 Version 6.0

Graphic 53425 Version 7.0

Graphic 63170 Version 5.0

Graphic 72866 Version 5.0

Multiple tense bullae arising on erythematous plaques, ruptured bullae, and

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights

Graphic 78910 Version 3.0

Inflammatory plaques, bullae, erosions, crusts, and postinflammatory

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights

Graphic 59590 Version 5.0

Graphic 66179 Version 6.0

Tense bullae on the anterior tibial and ankle skin.

Graphic 71249 Version 6.0

Dyshidrosiform bullous pemphigoid

Graphic 50357 Version 5.0

Mucous membrane pemphigoid

Graphic 73874 Version 6.0

Mucous membrane pemphigoid

Irregular erosions and a blister on the mucosal surface of the lip.

Graphic 52208 Version 5.0

Mucous membrane pemphigoid

Mucosal erosions on the gingiva and palate.

Graphic 63997 Version 6.0

Pemphigus vulgaris - oral lesions

Multiple erosions on the palate in a patient with pemphigus vulgaris.

Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights

Graphic 57924 Version 6.0

The epidermal basement membrane zone

Graphic 67891 Version 3.0

Differential diagnosis of mucocutaneous lesions in pemphigoid disorders

Bullous lupus erythematosus

Bullous mycosis fungoides

Drug-induced bullous disorder

Epidermolysis bullosa acquisita

HIV-associated mucosal lesions