Seminar

Pemphigoid diseases
Enno Schmidt, Detlef Zillikens

Lancet 2013; 381: 320–332 Pemphigoid diseases are a group of well defined autoimmune disorders that are characterised by autoantibodies
Published Online against structural proteins of the dermal–epidermal junction and, clinically, by tense blisters and erosions on skin or
December 11, 2012 mucous membranes close to the skin surface. The most common of these diseases is bullous pemphigoid, which
http://dx.doi.org/10.1016/
mainly affects older people and the reported incidence of which in Europe has more than doubled in the past decade.
S0140-6736(12)61140-4
Prognosis and treatments vary substantially between the different disorders and, since clinical criteria are usually not
Department of Dermatology
(Prof E Schmidt MD, sufficient, direct immunofluorescence microscopy of a perilesional biopsy specimen or serological tests are needed
Prof D Zillikens MD) and for exact diagnosis. In eight pemphigoid diseases the target antigens have been identified molecularly, which has
Comprehensive Centre for allowed the development of standard diagnostic assays for detection of serum autoantibodies—some of which are
Inflammation Medicine
commercially available. In this Seminar we discuss the clinical range, diagnostic criteria, diagnostic assay systems,
(Prof E Schmidt), University of
Lübeck, Lübeck, Germany and treatment options for this group of diseases.
Correspondence to:
Prof Enno Schmidt, Department Introduction necessary. However, the different diseases cannot usually
of Dermatology, University of Pemphigoid diseases are characterised by the presence of be distinguished on clinical grounds alone, so an assess-
Lübeck, Ratzeburger Allee 160,
autoantibodies against distinct structural components of ment of skin-bound or mucous membrane-bound auto-
23538 Lübeck, Germany
[email protected] the dermal–epidermal junction (figure 1). Junction pro- antibodies and serum autoantibodies is needed.
teins link the cytoskeleton of the basal keratinocytes to In 1953, Lever4 differentiated pemphigoid diseases from
the extracellular matrix of the dermis. Binding of pemphigus clinically and histopathologically. He described
pemphigoid autoantibodies leads to the separation of intraepidermal split formation and loss of cell adherence
the epidermis and dermis by a complex, yet fairly well between keratinocytes (acantholysis) as hallmarks of
understood process. pemphigus, and coined the term pemphigoid for disorders
The pemphigoid diseases include eight disorders for characterised by subepidermal splitting. About 10 years
which the molecular target antigens have been identified later, Jordon and colleagues5 (including Lever) first
(table). In addition to the seven named diseases listed in described serum and skin-bound autoantibodies in
the table, a few patients have a pemphigoid disease that bullous pemphigoid. Since then, detection of skin-bound
is characterised by renal insufficiency and autoantibodies or epithelium-bound and serum autoantibodies have
against the α5 chain of type IV collagen.1 IgG and IgA become diagnostic cornerstones for pemphigoid diseases,
autoantibodies that target several not-fully-characterised alongside clinical characteristics (table).
antigens (including 105 kDa, 125 kDa, and 168 kDa
proteins) have also been detected in serum samples Bullous pemphigoid
from patients with pemphigoid disorders.2,3 Dermatitis Incidence
herpetiformis, another subepidermal immunobullous In a prospective study of bullous pemphigoid that
disease, is not regarded as a pemphigoid disorder since encompassed the entire Swiss population, the inves-
the autoantigen epidermal transglutaminase is not a tigators calculated an incidence of 12·1 new cases per
structural component of the dermal–epidermal junction. 1 million people per year.6 In Germany, Scotland, and
Pemphigoid diseases share some clinical characteristics, France, incidences of 13·4, 14, and 21·7 per 1 million people
such as tense blisters and erosions and, by contrast with per year, respectively, have been reported.7–9 A 2008 report10
pemphigus, a negative Nikolsky sign—ie, friction of non- from the UK calculated a higher incidence of 66 new
lesional skin does not lead to intraepidermal disruption cases per 1 million people per year, on the basis of a data
and visible erosion. The disorders are, however, hetero- registry established in general practice. In the UK,
geneous with respect to overall clinical presentation, target Germany, and France, incidence has increased sub-
antigens, and autoantibody isotype. Importantly, prognosis stantially (two to five times) in the past 10 years,7,9,10 a
and treatment can vary substantially, so exact diagnosis is finding that might be related to the increasing age of the
general population, the availability of more sensitive and
specific diagnostic assay systems, or both.
Search strategy and selection criteria Bullous pemphigoid mainly affects older people, with
We searched PubMed using the terms “pemphigoid”, “linear onset usually in the late 70s. Incidence rises substantially
IgA”, “herpes gestationis”, and “epidermolysis bullosa to 150–330 per 1 million people per year in people older
acquisita”. Our search covered articles published in English than 80 years.6–11 With the changing age structure of
between Jan 1, 2000, and May 31, 2012. We identified the European population, the incidence is likely to rise.
additional reports from the reference lists of selected articles. Bullous pemphigoid rarely occurs in individuals
Some important older publications are cited either directly or younger than 50 years (incidence <0·5 cases per
indirectly through review articles. 1 million people per year).6,7,10,11 Few cases in infants,
children, and adolescents have been reported, and

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 Seminar

treatment responses in these patient groups do not

differ greatly from those in adults.12
Corneal layer

Mortality, risk factors, and associated diseases

Epidermis
1-year mortality for patients with bullous pemphigoid
ranges from 20% to 40%, which is about two to
Dermis
three times higher than that of age-matched and sex-
matched controls.9,10,13 Old age, widespread disease, a low
Karnofsky score, and, importantly, high doses of oral
corticosteroids are key risk factors for death.14,15 Patients
with bullous pemphigoid are also three times more likely Keratin
filaments Plectin
to develop pneumonia and pulmonary embolism than Cell
membrane
are matched controls.10
In the past 5 years, researchers have learned of an
Hemidesmosomal BP230
association between bullous pemphigoid and neuro- plaque
logical disorders. Between a third and half of all bullous
pemphigoid patients have neurological diseases (odds
ratios from 2·4 to 10·6).16–19 In particular, major cognitive α6
NC16A
impairment, Parkinson’s disease, stroke, epilepsy, and β4
domain
Lamina integrin
multiple sclerosis have been associated with bullous
lucida
pemphigoid in controlled studies.16–19 These findings are Laminin γ1 BP180
Laminin 332
especially intriguing since both bullous pemphigoid
target antigens, BP180 (also termed type XVII collagen,
COL17, or bullous pemphigoid antigen 2, BPAG2) and Lamina
BP230 (dystonin or BPAG1), are expressed in the central densa
nervous system. BP180 expression has been reported in Dermal
collagens
the cerebellum of rats and in autopsy samples of various
Type VII collagen
neuroanatomical regions of human brain,20,21 and the Sublamina
densa
antigen is predominantly seen in lipofuscin granules of
ageing, post-mitotic neurons.20 Mice with mutations in
the dystonin gene that encodes for various isoforms of Figure 1: Schematic diagram of the dermal–epidermal junction
BPAG1, including the epithelial isoform BP230, develop Only molecules that are targeted by autoantibodies in pemphigoid diseases are shown.
severe dystonia and sensory nerve degeneration.22
Investigators discovered an independent association of with urticarial plaques (figure 2). Blisters often arise on
bullous pemphigoid with psoriasis in a population-based the flexural aspects of the limbs and on the abdomen and
study based on data from the national health insurance can persist for several days, leaving erosions and crusts. In
database in Taiwan.17 Various autoimmune disorders and almost all patients, severe pruritus is present. Mild oral
cancer have also been linked with the disease. However, lesions develop in 10–20% of patients, but other mucosal
investigators of a case-control study23 did not report any areas are rarely affected.29 Before development of blisters,
increased risk for other autoimmune disorders and the disease is typically preceded for several weeks and
investigators of two case-control studies into bullous even months by a prodromal phase in which pruritus
pemphigoid and cancer risk reported no association24 or alone or in association with excoriated, eczematous, and
only a weak association with gastric cancer25 in Swedish papular or urticarial lesions occur (figure 2). In some
and Japanese cohorts, respectively, compared with age- patients, these non-bullous skin symptoms persist and are
matched controls. defined as several clinical variants—eg, prurigo-like,
Several triggers have been implicated in disease onset erythroderma-like, ecthyma gangrenosum-like, intertrigo-
in individual patients, including trauma, burns, radio- like, and toxic epidermolysis-like bullous pemphigoid.29
therapy, ultraviolet radiation, and vaccination—most Localised forms of the disease frequently affect the
frequently against infuenza.26,27 Investigators of two pretibial area. In 2011, an international panel of experts
studies reported weak but significant associations with defined outcome measures for clinical studies and
chronic use of spironolactone and phenothiazines with developed a clinical scoring system, the BP Disease Area
aliphatic side chains,19,28 so use of these drugs should be Index,30 to allow comparisons of clinical trials. This index
carefully assessed by prescribing physicians. will need further validation.

Clinical presentation Target antigens

Bullous pemphigoid typically presents with tense, mostly Two hemidesmosomal proteins, BP180 and BP230,
clear, blisters and erythema, frequently in conjunction have been identified as target antigens in bullous

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 Seminar

Autoantibody specificities (main Clinical signs First-line treatment

target antigens listed in the first line)
Bullous BP180 NC16A domain* Tense blisters and erosions Whole-body highly potent topical corticosteroids or oral
pemphigoid BP230* without predominant mucosal prednisolone at 0·5 mg per kg per day (level A)
involvement Possible effects have been attributed to azathioprine,
chlorambucil, dapsone, methotrexate, mycophenolic acid,
and tetracyclines (all level B)
Mucous BP180, laminin 332 Predominant mucosal Low-risk:‡ potent topical corticosteroids plus a tetracycline
membrane BP230,* α6β4 integrin, laminin 311,† involvement or dapsone (level C)
pemphigoid type VII collagen High-risk:‡ prednisolone 1·0–1·5 mg per kg per day (level B)
plus cyclophosphamide, azathioprine, or mycophenolic acid
(all level C)
Ocular: prednisolone 1·0–1·5 mg per kg per day (level C) plus
cyclophosphamide, dapsone, intravenous immunoglobulin,
mycophenolic acid (all level B)
Pemphigoid BP180 NC16A domain* Pregnancy or post-partum Potent topical corticosteroids plus cetirizine (level C)§
gestationis BP230* period
Linear IgA disease LAD-1, Tense blisters and erosions Dapsone or sulfapyridine (both level B) plus potent topical
BP230 (IgA reactivity) without predominant mucosal corticosteroids (level C)
involvement
Epidermolysis Type VII collagen* Mechanobullous and Oral corticosteroids (0·5–2·0 mg per kg per day, dependent
bullosa acquisita inflammatory variant on severity) plus colchicine or dapsone (level C)
Anti-laminin g1/ Laminin γ1 (p200 protein) Tense blisters and erosions As for bullous pemphigoid (level C)
anti-p200 without predominant mucosal
pemphigoid involvement
Lichen planus BP180 NC16A domain* Tense blisters that do not arise Therapy for lichen planus plus same treatment algorithm as
pemphigoides BP230* directly on lichen planus lesions for bullous pemphigoid (level C)

Treatment regimens are based on the scientific literature cited in the text and the authors’ own experience. Doses are detailed in the text. Recommendations are based on
different evidence levels: A=randomised controlled trials; B=poor-quality controlled trials and large case series; C=small case series, case reports, and expert opinion. Since no
international guidelines are available, these regimens and doses should be adapted to individual patients by physicians with experience in the treatment of pemphigoid
diseases. *Commercial detection systems are available for BP180 NC16A domain and BP230; a commercial detection system exists for type VII collagen, but has not been
approved by the US Food and Drug administration. †Laminin 311 shares the α3 chain with laminin 332 so is cotargeted. ‡Low-risk=mucosal lesions are limited to the mouth;
high-risk=any other mucosal site affected. §Not licensed during pregnancy and breastfeeding.

Table: Autoantibody specificities, diagnostically relevant clinical signs, and first-line treatments of pemphigoid diseases

pemphigoid.31–33 BP180 is a 180 kDa transmembrane Clinical evidence consists of the association of disease
glycoprotein of about 1500 aminoacids that ultrastruc- activity with serum concentrations of IgG antibodies
turally spans the lamina lucida before kinking back from against the NC16A domain and other epitopes on the
the lamina densa into the lamina lucida (figure 1). The BP180 ectodomain.36,37,45–47 Fc receptor-independent effects
extracellular portion of the 16th non-collagenous (NC16A) have been shown in cultured human keratinocytes in
domain is the immunodominant region in bullous which incubation with BP180-specific antibodies resulted
pemphigoid.34 Most patients also raise IgG antibodies in reduced BP180 expression followed by cell detachment
against epitopes outside the NC16A domain.35–37 IgG and signal transduction events leading to the release of
reactivity with C-terminal epitopes seems to be associated interleukin 6 and interleukin 8 (figure 3).48–50 Fc receptor-
with mucosal involvement and severe skin disease, mediated effects are pivotal in blister formation, as has
whereas the intracellular domain is preferentially targeted been shown in vitro51,52 and in various animal models.53
at an early clinical stage.36,38 In addition to IgG reactivity, Most data were generated in neonatal mice in which the
IgA and IgE anti-BP180 antibodies are present in serum injection of rabbit antimurine BP180 antibodies dupli-
samples from most patients.39–42 cated major characteristics of the human disease.54 This
BP230 is a 230 kDa intracellular constituent of the model has shown the importance of complement acti-
hemidesmosomal plaque and belongs to the plakin vation at the dermal–epidermal junction, neutrophils,
family of proteins. As with BP180, B-cell epitopes are not macrophages, mast cells, and various proteases including
equally distributed on the molecule but preferentially neutrophil elastase, matrix metalloproteinase 9, plasmin,
localise to the globular C-terminal domain.37,43 In addition α1 proteinase inhibitor, and mast cell proteinase 4 for
to IgG reactivity, IgE antibodies against BP230 can be blister formation (figure 3).53,55
detected in the serum samples from most patients.44 The generation of transgenic mice that express human
BP180 in murine skin has allowed replication of the
Pathophysiology essential features of human disease.56–58 Subsequently,
Ample evidence exists for the pathogenic importance two active mouse models have been developed that have
of humoral and cellular autoimmunity against BP180. elucidated the role of autoreactive T cells. These are

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 Seminar

wild-type mice immunised with recombinant murine

A B
NC15A and Rag2–/–/COL17-humanised mice that
received splenocytes from wild-type mice that had been
immunised by grafting of human COL17-trangenic
mouse skin, both of which developed anti-BP180
antibodies and a blistering phenotype.59,60 Results of
work with the COL17-humanised mouse model61 showed
the importance of NC16A-reactive CD4 T cells and
accorded with evidence from previous in-vitro studies62,63
with human cells that showed a restriction of NC16A-
reactive CD4 T cells to the HLA-DQB1*0301 allele, which
has been identified as a susceptibility gene for bullous C D
pemphigoid. Patients cells with this allele preferentially
produce both Th1 and Th2 cytokines by contrast with
Th1-restricted controls.62,63 Raised cytokines and chemo-
e
kines such as interleukin 1β, interleukin 5, interleukin 6,
interleukin 8, interleukin 10, interleukin 15, tumour d
necrosis factor α, chemokine (c-c motif) ligand 2 (CCL2),
CCL5, CCL11, CCL13, and CCL18 have been reported in e
serum samples and blister fluids of bullous pemphigoid
d
patients, and some parallel disease activity.64 Although
we can speculate that these mediators orchestrate the Figure 2: Clinical and immunopathological characteristics of bullous pemphigoid
inflammatory reaction in the skin, no data for their Tense blisters and erosions on back and right arm (A) and eczematous lesions, erosions, and crusts on left arm and
flank (B) of patients with bullous pemphigoid. Direct immunofluorescence microscopy of a perilesional specimen
functional relevance are available.
reveals linear deposits of IgG at the dermal-epidermal junction (C). Histopathology of a lesional skin specimen shows
Evidence for the pathogenic role of IgE autoantibodies subepidermal splitting, a hallmark of all pemphigoid diseases, and a dense inflammatory infiltrate of eosinophils and
comes from clinical findings and two mouse models.65,66 neutrophils (D). The intact dermal–epidermal junction in D is indicated by a dotted line. e=epidermis. d=dermis.
IgE BP180 NC16A-specific antibodies are associated
with more severe forms of disease in people, and one dermal–epidermal splitting has been induced by 1 mol/L
corticosteroid-resistant patient responded very well to NaCl solution. This substrate also allows for differ-
omalizumab, which is a humanised monoclonal antibody entiation between different autoantibody specificities:
that inhibits IgE binding to its high-affinity receptor.40,41,67 antibodies to BP180 and BP230 bind to the roof of the
By contrast with BP180, the pathogenic relevance of artificial split (figure 4).71 Circulating antibodies against
autoantibodies against BP230 remains elusive: two BP180 NC16A and BP230 can be detected in serum
animal models that were intended for investigation of samples with commercially available ELISA systems
the relevance of antibodies to BP230 have been reported, (Euroimmun, Lübeck, Germany; MBL, Nagoya, Japan) in
but blisters were not,68 or not consistently,69 seen. Results 80–90% and 60–70% of cases, respectively.46,70,72,73 With the
of studies into the relation between serum anti-BP230 combined use of these two ELISA systems, diagnostic
autoantibodies and disease have been contradictory, with sensitivity is 90%.73–75 Use of various recombinant frag-
most reporting no association.37,45,70 However, since ments of BP180 and BP230 can allow detection of auto-
Bp230–/– mice, in addition to mild skin fragility, developed antibodies in serum samples from all patients.37
neurological defects with sensory neuron degeneration22 High serum concentrations of anti-BP180 NC16A
and with the known association between the disease antibodies at the time of discontinuation of corticosteroid
and neurological disorders,16–19 autoimmunity to BP230 treatment are associated with risk of relapse.76 The BP180
might contribute to more than only the skin phenotype NC16A ELISA, therefore, would seem to be useful for
in patients with bullous pemphigoid. guiding treatment decisions during the course of the
disease. Low serum concentrations of anti-BP180 or anti-
Diagnosis BP230 antibodies can also be seen in about 4% of
Diagnosis of bullous pemphigoid is based on a com- dermatological patients who do not have bullous pem-
bination of clinical criteria, direct immunofluorescence phigoid, especially in those with pruritic dermatoses.77,78
microscopy of a perilesional specimen, and serology In these patients, direct immunofluorescence micros-
(table). Direct immunofluorescence microscopy reveals copy is required to exclude bullous pemphigoid.
linear deposits of IgG or complement component 3 at Histopathology of a lesional biopsy can vary with the
the dermal–epidermal junction, sometimes combined clinical situation and typically shows subepidermal
with weaker linear IgA or IgE staining (figure 2). The splitting and a moderate to dense inflammatory infiltrate
most sensitive immunofluorescence microscopy sub- composed of lymphocytes, neutrophils, and, character-
strate for the screening of serum autoantibodies in istically, eosinophils. Histopathologically, bullous pem-
bullous pemphigoid is healthy human skin in which phigoid cannot be differentiated from other pemphigoid

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 Seminar

Proteases

CC C C ROS
6
C C C C C CC C C C C C C
1 2 C C C C C
Neutrophils
IL-6, IL-8 Chemokines, 5
proteases
Eosinophils MMP-9
3
Chemokines
α1-PI

4
Mast cells T cell
NE

BP180 and DEJ

Macrophages

Figure 3: Hypothetical sequence of events leading to blister formation in bullous pemphigoid

Binding of autoantibodies to BP180 initiates Fc receptor-independent events leading to the release of interleukin 6 (IL-6) and IL-8 from basal keratinocytes (1).
Complement is activated (2) at the dermal–epidermal junction (DEJ) and mast cells degranulate (3). Complement activation and chemokine gradients result in the
infiltration of inflammatory cells into the upper dermis (4). Secretion of inflammatory mediators further increases the inflammatory reaction before granulocytes at
the DEJ release proteases (insert) and reactive oxygen species (ROS) (5) that ultimately induce dermal–epidermal splitting (6). As shown in the neonatal mouse model
of bullous pemphigoid, matrix metalloproteinase 9 (MMP-9) secreted from neutrophils cleaves (green arrow) α1-proteinase inhibitor (α1-PI) to remove neutrophil
elastase (NE) inhibition (red bar). Both MMP-9 and NE also directly degrade proteins of the DEJ including BP180 (insert).

Bullous pemphigoid Mucous membrane pemphigoid

Mucous membrane pemphigoid Laminin 332
Pemphigoid gestationis Anti-p200 pemphigoid
Linear IgA disease Laminin γ1
Lichen ruber pemphigoides Epidermolysis bullosa
acquisita
BP180 α6β4 integrin Type VII collagen
BP230

Figure 4: Indirect immunofluorescence microscopy of 1 mol/L NaCl-split human skin

Indirect immunofluorescence microscopy on salt-split skin is used as a practical test for serum autoantibodies in pemphigoid diseases. Antibodies against BP180,
BP230, and α6β4 integrin bind along the top of the artificial split (left), whereas antibodies to laminin 332, laminin γ1/p200 antigen, and type VII collagen label the
bottom (right). The specific disorders and the corresponding target antigens are shown.

diseases such as anti-laminin 332 mucous membrane In a landmark study, Joly and colleagues14 showed in
pemphigoid and anti-p200/anti-laminin γ1 pemphig- patients with moderate disease that clobetasol propionate
oid.79,80 Knowledge of the histopathological range of 0·05% ointment (40 g per day, tapered over 12 months)
bullous pemphigoid allows histopathologists to use was as effective and safe as oral prednisolone at 0·5 mg
direct immunofluorescence microscopy and appropriate per day. In a subsequent study,82 lower dose clobetasol
serological analysis to obtain a definite diagnosis. propionate (10–30 g, tapered over 4 months) did not
differ in the time to achieve disease control compared
Treatment with the more intensive topical regimen and was
Only ten controlled, prospective studies into treatment associated with fewer severe adverse events (including
of bullous pemphigoid have been reported: several death), but more relapses, in patients with moderate
trials of oral corticosteroids, two studies of long-term disease. In patients with widespread disease (defined as
whole-body use of potent topical corticosteroids, two >10 bullae per day), treatment with oral prednisolone at
studies of azathioprine, two studies of plasmapheresis, an initial dose of 1·0 mg per kg of per day resulted in
one of mycophenolate mofetil, and one of nicotinamide substantially more frequent severe adverse events than
plus tetraycline.81 were seen with high-dose topical corticosteroids.14

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Prospective, controlled, multicentre trials with dapsone symblepharon, trichiasis, neovascularisation, and, finally,
and doxycycline are currently being analysed and recruited blindness (figure 5).92
for, respectively. Larger, uncontrolled studies of chloram- The disease is usually bilateral within 2 years of onset.
bucil (prospective), dapsone, and methotrexate (both When it is confined to the conjunctivae (about 20% of
retrospective) have also been reported.83–86 patients) the term ocular pemphigoid is used.87,89 All
A 2010 Cochrane review81 summarised the available data patients should be seen by an ophthalmologist, who can
for treatment of bullous pemphigoid: and concluded that identify subtle changes by slit-lamp examination. In
very potent topical steroids are effective and safe, but their patients without initial ocular involvement, the annual
use in widespread disease might be limited by side-effects risk for developing eye lesions is 5% over the first 5 years.89
and practical issues; initial doses of prednisolone greater Notably, since a solid cancer is present in about 30% of
than 0·75 mg per kg per day do not give additional benefit, patients with anti-laminin 332 mucous membrane
and doses lower than 0·75 mg can be adequate and reduce pemphigoid, a thorough tumour search should be done
the incidence and severity of adverse reactions; and the in patients with this subset of the disease.93
effectiveness of adjuvant treatments to corticosteroids Six target antigens associated with the clinical pheno-
needs further validation. type of mucous membrane pemphigoid have been
Most clinicians treat localised and mild disease with characterised molecularly: BP180 (in about 75% of
topical corticosteroids alone (level C; evidence levels are patients),94,95 BP230 (25%; usually in conjunction with
defined in the table) and moderate and widespread disease BP180 reactivity), laminin 332 (formerly called laminin 5
with topical corticosteroids or oral prednisolone at 0·5 mg or epiligrin; 25%),96 both subunits of α6β4 integrin, and
per kg per day (level A; table).14 Possible effects have also type VII collagen (figure 1, table). By contrast with
been attributed to azathioprine, chlorambucil, dapsone, bullous pemphigoid, C-terminal epitopes on BP180 are
methotrexate, mycophenolic acid, and tetracyclines (all predominantly recognised; the NC16A domain is
level B). In refractory patients, plasmapheresis, high-dose targeted by about 50% of BP180-reactive serum
intravenous immunoglobulin (both level B), immuno- samples.94,95,97 Laminin 332 is a heterotrimer consisting of
adsorption, or rituximab (both level C) can be added. α3, β3, and γ2 chains. In almost all patients with anti-
laminin 332 reactivity, the α3 chain is targeted.98
Mucous membrane pemphigoid Autoantibodies to α6 integrin have been described in
An international consensus conference87 has defined patients with oral lesions, and reactivity against
mucous membrane pemphigoid as immunobullous β4 integrin is associated with ocular involvement.94,99
disease with autoantibodies against components of the The pathogenic relevance of autoantibodies in mucous
dermal–epidermal junction and predominant mucosal membrane pemphigoid has been shown both in vitro and
involvement. Previously, the term cicatricial pemphigoid in vivo. Antibodies against laminin 332 induced non-
was used synonymously for mucous membrane inflammatory subepidermal blisters when injected into
pemphigoid. Now, cicatricial pemphigoid refers only to mice or human skin grafted onto immunocompromised
the rare clinical variant in which mucous membranes are mice.100,101 By contrast with bullous pemphigoid, antigen-
not predominantly affected and skin lesions heal with binding fragments of anti-laminin 332 antibodies are also
scarring.87 Incidence of mucous membrane pemphigoid pathogenic, and complement activation and mast cells
has been estimated at 1·3 and 2·0 per 1 million people are not necessary for blister formation in mice.102
per year in France and Germany, respectively.7,88 The Antibodies to α6β4 integrin induce separation along the
disease arises earlier than does bullous pemphigoid, with dermal–epidermal junction in organ cultures.103,104 Since
a mean age of onset between 60 and 65 years.89,90 An scarring is the major pathogenic process in conjunctival
association with HLA-DQB1*0301 has been reported.91 disease, fibrosis has been intensively studied in biopsy
Clinically, mucous membrane pemphigoid is a chronic specimens and cultured conjunctival fibroblasts. Various
and progressive disease that most frequently affects the profibrotic factors have been identified, including serpin
oral cavity (85% of patients), followed by conjunctivae h1 (heat shock protein 47), connective tissue growth
(65%), skin (25–30%), nasal cavity (20–40%), anogenital factor, transforming growth factor β, interleukin 4,
area (20%), pharynx (20%), larynx (5–10%), and interleukin 5, and interleukin 13.105,106
oesophagus (5–15%) (table, figure 5).87,89,90 Clinical severity Diagnosis of mucous membrane pemphigoid is based
is highly variable and can range from subtle oral lesions on predominant mucosal lesions and direct immuno-
and conjunctival injection to pervasive, very painful fluorescence microscopy of a perilesional specimen that,
mucosal involvement and devastating oesophageal and indistinguishable from bullous pemphigoid, shows
conjunctival disease.87,89,90 At all affected body sites lesions deposition of IgG, complement component 3, and, in
tend to heal with scarring, though in oral lesions some patients, IgA along the dermal–epidermal junction.
re-epithelialisation without scarring can occur. Ocular In ocular disease, detection of autoantibodies in this way
lesions usually start unilaterally with subtle symptoms can be unsuccessful in up to 20% of cases.89 By indirect
such as burning, dryness, and a sensation of foreign immunofluorescence microscopy on salt-split skin, epi-
body, and can proceed to scar formation causing dermal or dermal staining of the artificial split can be seen

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dependent on the target antigen (figure 4). By contrast with detection of serum antilaminin 332 IgG, immuno-
bullous pemphigoid, serum samples from patients with precipitation with radiolabelled human keratinocytes is the
mucous membrane pemphigoid contain anti-dermal– most sensitive method, whereas immunoblotting with
epidermal junction reactivity at low titres (usually 1:10–1:40) extracellular matrix of cultured human keratinocytes
and in a low percentage of patients (50–80%).95,107 seems to be the most practical alternative.108 In suspected
IgA autoantibodies can be detected in about 60% of ocular mucous membrane pemphigoid with negative
serum samples,42,94,95,107 and a combined IgA and IgG direct immunofluorescence microscopy of a conjunctival
reactivity is associated with more severe disease than with specimen, we recommend additional oral biopsy and
IgG autoantibodies alone.94,107 Various recombinant frag- serological analysis.
ments and the cell-derived soluble ectodomain of BP180 Treatment of mucous membrane pemphigoid is
(linear IgA dermatosis antigen, LAD-1) have been used to challenging for three reasons: only two small, controlled
detect anti-BP180 autoantibodies.42,94,95 Immunoblotting therapeutic trials have been done in patients with ocular
with bovine gingivae lysate allows detection of α6β4 disease; clinical response to immunosuppression in
integrin-specific antibodies.99 Serum samples that are patients with severe disease, particularly those with ocular
unreactive with indirect immunofluorescence microscopy lesions, is poor; and conjunctival fibrosis is irreversible
on salt-split skin or that show dermal binding should be and, unlike other pemphigoid diseases, causes permanent
tested for laminin-332 reactivity, since reactivity with damage when treatment is delayed or ineffective.87,109,110 In
laminin 332 is associated with malignant disease. On the low-risk patients (lesions are limited to the mouth, with or
basis of comparison of six different methods for the without skin involvement), potent topical corticosteroids
in combination with a tetracycline or dapsone might
A B suffice (level C; table). In unresponsive patients, oral
prednisolone (0·5 mg per kg per day) can be added, then
azathioprine or mycophenolic acid (level C).87 For high-
risk patients (any other mucosal site affected) with severe
disease or rapid progression, prednisolone (1·0–1·5 mg
per kg per day) plus cyclophosphamide (1–2 mg per kg per
day orally or 500–1000 mg intravenously every 3–4 weeks)
is recommended (level C; table).87 Alternatively, pred-
nisolone can be combined with mycophenolic acid or, in
mild disease, with dapsone (both level C).87,110,111
In patients with ocular disease, cyclophosphamide (2 mg
C D per kg per day), dapsone (in mild disease), mycophenolic
acid, and intravenous immunoglobulin have had
favourable results in combination with prednisolone at
1·0–1·5 mg per kg per day (level B; table).87,109–112 In
oesophageal and severe or rapidly progressive conjunctival
disease, the risk of use of fairly high doses of prednisolone
(1·0–1·5 mg per kg per day), which frequently causes
severe adverse events, should be weighed against the high
risk of scarring, since fibrosis continues for some time
even when the inflammatory reaction has been stopped. In
E F
refractory patients with mucous membrane pemphigoid,
intravenous immunoglobulin and the anti-CD20 anti-
body rituximab have both been used successfully (both
level B).112,113 For the assessment and treatment of ocular
disease, ophthalmological consultations are necessary.
Ophthalmological care, including topical and surgical
treatment, has been reviewed by Saw and Dart92 and by
Foster and Sainz De La Maza.105

Pemphigoid gestationis
Figure 5: Clinical characteristics of other pemphigoid diseases Pemphigoid gestationis, previously known as herpes
Erosions and fibrinous plaques in the oral cavity (A), haemorrhagic crusts on and scar-related miniaturisation of gestationis, is a pregnancy-associated immunobullous
nasal orifices (B), and conjunctival injection, symblepharon, erosions, and yellow crusts (C) in a patient with disease with autoantibodies against BP180 NC16A. An
mucous membrane pemphigoid. Wheel-like plaques on the abdomen (D) of a patient with pemphigoid
annual incidence of between 0·5 and 2·0 cases per
gestationis. Annular erythematous plaques (E) with blistering along the edges (the so-called string-of-pearls sign)
in a patient with linear IgA disease. Vesicles, erosions, atrophic erythematous plaques, and milia on the extensor 1 million people has been reported in France, Germany,
surfaces of the left hand (F) of a patient with epidermolysis bullosa acquisita. and Kuwait.7,88,114 A much higher incidence than in these

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countries was noted in two English tertiary referral centres, and Kuwait.7,88,114,123 Higher incidences than in these
with the disease reportedly occurring in 4·2% of preg- countries have been noted in some African countries
nancies.115 Pemphigoid gestationis usually occurs in the (Mali, South Africa, Uganda) and in Malaysia.3 Linear IgA
second or third trimester, and in about 10% of patients disease is the most common pemphigoid disorder in
within 4 weeks after birth.115,116 Typically, pruritic erythe- children and has two peaks of onset—before the age of
matous papules and plaques, erythema multiforme-like 5 years and after the age of 60 years.124 The disease is
changes, eczematous lesions, or papulovesicles arise associated with HLA-B8, HLA-CW7, and HLA-DR3.3
around the umbilicus and then spread over the abdomen Individual lesions are similar in children and adults,
and thighs (figure 5); frank blistering is not always present. and include urticarial plaques, erosions, and blisters,
The clinical course is fairly benign, with an average frequently in an ring-shaped pattern with blistering
duration of 4–6 months. In less than 5% of patients, the along the edge of lesions, forming the so-called string-of-
disease persists and converts to bullous pemphigoid.116,117 pearls sign (figure 5). Mucosal involvement is common
Pemphigoid gestationis recurs in more than 90% of (about 70% of patients), generally with oral erosions and
cases when there is an additional pregnancy.116 A slightly ulcers; nasal crusting and genital lesions can also occur.124
increased risk for prematurity and small-for-gestational- In children, the face and perineal area are more often
age babies has been reported and transient skin lesions affected and lesions arise more abruptly than in adults,
in newborn babies have been seen in individual cases.117 in whom trunk and limbs are predominantly affected.3
The disease is strongly associated with maternal Linear IgA disease can be triggered by various drugs,
HLA-DR3 and HLA-DR4.117 most frequently vancomycin, followed by non-steroidal
The major target antigen is BP180,34,118 which is anti-inflammatory drugs.3 The disease has a fairly benign
expressed in the amniotic membrane and its shed course, with less severe relapses compared with the
ectodomain is a physiological constituent of the amniotic original presentation within 5 years.
fluid. Diagnosis is made by direct immunofluorescence The major target antigen is BP180. Serum samples
microscopy of a perilesional biopsy, with deposits of from most patients react with a 97 kDa extracellular
complement component 3, and, to a lesser extent, IgG fragment of BP180 in skin extract and with LAD-1, the
seen along the dermal–epidermal junction. Circulating 120 kDa shed ectodomain of BP180 from cultured
complement-fixing antibodies are an immunopatho- keratinocytes.125,126 The 97 kDa protein is an N-terminal
logical hallmark of pemphigoid gestationis and are seen portion of LAD-1. The BP180 NC16A domain is the target
along the dermal–epidermal junction by indirect in only 20% of patients.127 Since most serum samples
immunofluorescence microscopy on human skin after from linear IgA disease patients, in addition to IgA anti-
preincubation with a complement source. This finding is BP180 antibodies, contain IgG antibodies against BP180,
attributable to the strong complement-fixing properties of and IgA anti-BP180 antibodies can be detected in serum
the predominant IgG1 and IgG3 anti-BP180 NC16A anti- samples of most bullous pemphigoid patients, the two
bodies.119 The BP180 NC16A ELISA detects serum diseases could be regarded as different ends of a
autoantibodies in more than 90% of patients.120 As in continuous range.39 Researchers have investigated the
bullous pemphigoid, the NC16A domain contains the pathogenic role of autoantibodies in linear IgA disease
major pathogenic sites—preadsorption of serum samples by injecting monoclonal IgA antibodies against the
with peptides covering the N-terminal portion of this BP180 ectodomain in human skin grafted onto SCID
domain abolished their split-inducing potential in vitro.121 mice.128 Subepidermal splitting was seen in some mice by
Most patients will be adequately controlled with potent histopathology, but none showed clinical disease.
or highly potent topical corticosteroids in combination Although patients’ age and clinical presentation is
with H1-receptor antagonists such as cetirizine (table). If generally suggestive of linear IgA disease, diagnosis is
not sufficient, oral prednisolone can be added at an initial made on the basis of a combination of clinical appear-
dose of 0·25–0·5 mg per kg per day (level C). In a study ance, linear deposition of IgA at the dermal–epidermal
in 61 patients, use of oral prednisolone had no effect on junction by direct immunofluorescence microscopy of a
adverse pregnancy outcomes.122 perilesional skin or mucous membrane biopsy, detection
of IgA serum antibodies by indirect immunofluorescence
Linear IgA disease microscopy on human salt-split skin (figure 4), and IgA
Linear IgA disease is named for its main immuno- reactivity against BP180 (table). No prospective controlled
pathological feature, which is the linear binding of IgA at clinical trials or larger case series have been reported for
the dermal–epidermal junction. Some overlap is seen treatment. Patients usually respond well to therapy. First-
with bullous pemphigoid (patients with dual IgG and IgA line treatment is dapsone (level B), which can be used in
deposition along the junction), with mucous membrane combination with topical glucocorticosteroids (table).129
pemphigoid (patients with predominant mucosal Sulfapyridine (also level B) is an alternative to dapsone.
involvement), and IgA epidermolysis bullosa acquisita. Some patients might need concomitant low-dose pred-
Incidences between 0·25 and 1·0 per 1 million people per nisolone (0·25–0·5 mg per kg per day) to suppress blister
year have been reported in central Europe, Singapore, formation, and erythromycin, colchicine, flucloxacillin,

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 Seminar

intravenous immunoglobulin, azathioprine, myco- collagen antibodies—different tissue extracts or the

phenolic acid, and immunoadsorption have been used in recombinant NC1 domain can be applied by immuno-
unresponsive patients (all level C).129 blotting or ELISA.132,137 Two highly sensitive and specific
assays have been commercialised, using the recombinant
Epidermolysis bullosa acquisita NC1 and NC2 domains by ELISA and NC1 domain-
Epidermolysis bullosa acquisita is a clinically hetero- expressing cells by indirect immunofluorescence micros-
geneous disease characterised by autoantibodies against copy.144,145 In a subgroup of less than 10% of patients,
type VII collagen. Incidence reportedly ranges between autoantibodies are restricted to the IgA isotype—these
0·2 and 0·5 new cases per 1 million people per year.7,88,123 patients tend to display the inflammatory phenotype.133
The disease is associated with HLA-DR2—notably the Treatment of epidermolysis bullosa acquisita is chal-
DRB1*15:03 allele—and African descent.130 Clinically, lenging. No controlled prospective trials have been
epidermolysis bullosa acquisita can either be the classic reported and disease activity is difficult to suppress.110 The
form or an inflammatory variant.131,132 The classic mechano- mainstay is systemic corticosteroids (0·5–2·0 mg per kg
bullous form presents with tense blisters and skin fragility per day, dependent on disease severity) in combination
preferentially localised to the extensor skin surfaces at with colchicine or dapsone (level C; table). For refractory
trauma-prone areas. Lesions usually heal with scarring patients or severe cases, cyclosporine, azathioprine, myco-
and milia formation (figure 5); hyperpigmentation and phenolate mofetil, plasmapheresis, immunoadsorption,
hypopigmentation are common. Nail loss and oesophageal intravenous immunoglobulin, and rituximab can be
stenosis can also occur.131 The inflammatory subtype can added (all level C).
resemble bullous pemphigoid or mucous membrane
pemphigoid.128 In both subtypes, mucous membranes are Anti-p200/anti-laminin γ1 pemphigoid and
affected in about half of patients.133 lichen planus pemphigoides
The mucous membrane pemphigoid variant of Both anti-p200 pemphigoid and lichen planus pemphi-
epidermolysis bullosa acquisita can also be classified as goides are rare, with fewer than 100 reported cases of
mucous membrane pemphigoid.87 In about 20% of each worldwide. Anti-p200 pemphigoid clinically mimics
patients with epidermolysis bullosa acquisita, concomitant bullous pemphigoid, although patients tend to be
inflammatory bowel disease has been reported.134 The younger and concurrent psoriasis is seen in about a third
autoantigen is homotrimeric type VII collagen, a of cases.146,147 Serum samples from 90% of patients react
constituent of the anchoring fibrils (figure 1).135,136 The with laminin γ1.148 Diagnosis is made by detection of
N-terminal 145 kDa NC1 domain is the immunodominant autoantibodies against the 200 kDa protein of the
region and is recognised in almost all serum samples.137 dermal–epidermal junction by immunoblotting with
Anti-type VII collagen antibodies injected into mice extract of dermis or against the C-terminus of laminin γ1
elicit skin lesions resembling those in patients.138,139 The by immunoblotting or ELISA.147,149 Anti-p200/anti-laminin
disease can also be induced in mice by immunisation γ1 pemphigoid is very probably underdiagnosed because
with a portion of the murine NC1 domain.140 In these of low availability of the diagnostic assays. It is often
models, neutrophils were identified as major effector classified as bullous pemphigoid, although patients tend
cells that are recruited and activated via the FcγIV to be younger and usually respond more rapidly to
receptor after interaction with skin-bound autoanti- treatment;146 treatment is the same as for bullous
bodies.141 The glycolisation of type VII collagen-specific pemphigoid (level C; table).
antibodies is essential for this interaction.142 The Lichen planus pemphigoides always arises in
manipulation of neutrophil activation and autoantibody conjunction with lichen planus. The main target antigen
glycolisation might open novel therapeutic avenues. is BP180. By contrast with bullous pemphigoid, the
Diagnosis is based on linear deposits of IgG, IgA, and disease affects fairly young patients (mean age of onset
complement component 3 at the dermal–epidermal junc- 40–50 years), mainly arises on the limbs, and preferentially
tion by direct immunofluorescence microscopy of a targets C-terminal epitopes in the immunodominant
perilesional skin or mucous membrane biopsy. By contrast NC16A domain. The disease tends to be less severe than
with all other pemphigoid diseases, Ig labels the dermal– bullous pemphigoid.150 Diagnosis is made on the basis of
epidermal junction in a u-serrated pattern—ie, in the presence of tense blisters outside lichen planus
upstanding arms of the sublamina densa zone between lesions, detection of linear deposits of IgG or complement
the rootlets of the basal keratinocytes.143 In all other component 3 at the dermal–epidermal junction by direct
pemphigoid disorders, an n-serrated pattern is seen. immunofluorescence microscopy of a perilesional biopsy,
Serration pattern analysis is of particular importance in and detection of circulating IgG antibodies against BP180
epidermolysis bullosa acquisita, since only 40–60% of NC16A (table). Therapy for lichen planus is necessary to
serum samples react by indirect immunofluorescence avoid further stimulation of the anti-dermal–epidermal
microscopy on salt-split skin, labelling the dermal side of junction autoimmune process. Simultaneous treatment
the artificial split (figure 4).132,133 Serologically, epidermolysis for pemphigoid lesions should follow the same algorithm
bullosa acquisita is diagnosed by detection of anti-type VII as for bullous pemphigoid (level C; table).

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Contributors 19 Bastuji-Garin S, Joly P, Lemordant P, et al. Risk factors for bullous

Both authors reviewed the scientific literature, interpreted the data, and pemphigoid in the elderly: a prospective case-control study.
wrote the report. ES prepared the figures. J Invest Dermatol 2011; 131: 637–43.
20 Seppanen A, Miettinen R, Alafuzoff I. Neuronal collagen XVII is
Conflicts of interest localized to lipofuscin granules. Neuroreport 2010; 21: 1090–94.
Both authors received honoraria for lectures from Roche and Fresenius 21 Claudepierre T, Manglapus MK, Marengi N, et al. Collagen XVII
Medical Care. We have received funding for research and development and BPAG1 expression in the retina: evidence for an anchoring
projects from Euroimmun (both authors), Fresenius Medical Care (DZ), complex in the central nervous system. J Comp Neurol 2005;
Biotest (DZ), and Novartis (ES). Neither author has had, within the past 487: 190–203.
3 years, any stocks, shares, or equity in a relevant company, nor a 22 Guo L, Degenstein L, Dowling J, et al. Gene targeting of BPAG1:
contract of employment or named position on a company board. abnormalities in mechanical strength and cell migration in
stratified epithelia and neurologic degeneration. Cell 1995;
Acknowledgments
81: 233–43.
We acknowledge those researchers whose contributions we have not
23 Taylor G, Venning V, Wojnarowska F, Welch K. Bullous pemphigoid
cited directly, but, because of space limitations, through review articles.
and autoimmunity. J Am Acad Dermatol 1993; 29: 181–84.
This work was supported by the German Research Foundation
24 Lindelof B, Islam N, Eklund G, Arfors L. Pemphigoid and cancer.
Excellence Cluster—Inflammation at Interfaces (EXC 306/1).
Arch Dermatol 1990; 126: 66–68.
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