Download Pemphigoid diseases: Pathogenesis, diagnosis, and treatment

Autoimmunity, February 2012; 45(1): 55–70
q Informa UK, Ltd.
ISSN 0891-6934 print/1607-842X online
DOI: 10.3109/08916934.2011.606447
Pemphigoid diseases: Pathogenesis, diagnosis, and treatment
MICHAEL KASPERKIEWICZ1, DETLEF ZILLIKENS1, & ENNO SCHMIDT1,2
1
Department of Dermatology, University of Lübeck, Lübeck, Germany, and 2Comprehensive Center for Inflammation Medicine,
University of Lübeck, Lübeck, Germany
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(Submitted 25 June 2011; accepted 12 July 2011)
Abstract
Pemphigoid diseases (including bullous pemphigoid, mucous membrane pemphigoid, pemphigoid gestationis, linear IgA
dermatosis, lichen planus pemphigoides, and anti-p200 pemphigoid) are a subgroup of autoimmune bullous skin diseases
characterized by an autoantibody response toward structural components of the hemidesmosome resulting in subepidermal
blistering. By the use of different in vitro systems and experimental animal models, the pathogenic relevance of these
autoantibodies has been demonstrated. Recent advances in the understanding of autoantibody responses have led to novel
diagnostic tools and a more differentiated therapeutic approach for these disorders. This review covers the most recent
understanding of the pathophysiology, diagnosis, and treatment of this group of autoimmune diseases.
Keywords: Pemphigoid, skin, antibody, antigen
Introduction
The pemphigoid group of diseases is characterized by
subepidermal blisters due to autoantibody-induced
disruption of the components of the dermal –
epidermal anchoring complex. Pemphigoid diseases
include bullous pemphigoid (BP), mucous membrane
pemphigoid (MMP), pemphigoid gestationis (PG),
linear IgA dermatosis (LAD), lichen planus pemphigoides (LPP), and anti-p200 pemphigoid. In particular, disorders with anti-BP180 (type XVII collagen)
reactivity, including BP, PG, LAD, LPP, and a
subgroup of MMP may form a continuous spectrum
of subepidermal autoimmune blistering dermatoses.
BP is not only the most common disorder within
the pemphigoid group, but also represents the most
frequent autoimmune blistering disease in general
[1,2]. The incidence of BP has been estimated between
4.5 and 14 new cases/million/year in central Europe
[1 –5]. A higher incidence of 42.8/million/year has
recently been reported in Great Britain based on a
data registry established on the general practitioner
level [6]. Interestingly, in Germany and Great Britain,
it has been shown that the incidence of BP has
considerably increased within the last 10 years (2-fold
and 4.8-fold, respectively) [1,6]. This development
may be due to the increasing age of the general
population and/or an increased awareness leading to
further diagnostic steps. MMP and PG have been
identified as the second most frequent pemphigoid
diseases in central Europe with an incidence of two
new patients/million/year [1].
For the correct diagnosis of pemphigoid diseases,
the detection of tissue-bound and circulating autoantibodies is pivotal [7]. Although direct immunofluorescence (IF) microscopy differentiates pemphigus
from pemphigoid disorders, serological analyses are
necessary to separate pemphigoid diseases from each
other and from epidermolysis bullosa acquisita (EBA).
In fact, while direct IF microscopy is still the gold
standard for the diagnosis of pemphigoid diseases, in
the great majority of patients, diagnosis can be made
serologically today [7].
By indirect IF microscopy on 1 M NaCl-split
human skin, anti-laminin 332 MMP and anti-p200
pemphigoid can be distinguished from BP, LAD, PG,
and anti-BP180 MMP, but final diagnosis can only
be made by more sophisticated methods, i.e. use
of cell-derived or recombinant forms of the target
antigens (Figure 1). In recent years, various novel
detection systems for serum antibodies have been
Correspondence: M. Kasperkiewicz, Department of Dermatology,University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Tel: 0049-451-500-5844. Fax: 0049-451-500-5162. E-mail: [email protected]
56
M. Kasperkiewicz et al.
(a)
Disease
Main target antigens
Bullous pemphigoid
BP180, BP230
Mucous membrane
pemphigoid
BP180, BP230,
α6β4 integrin
Pemphigoid gestationis
BP180, BP230
Linear IgA dermatosis
BP180, BP230
Lichen planus
pemphigoides
BP180, BP230
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(b)
Disease
Main target antigens
Mucous membrane
pemphigoid
Laminin 332
Anti-p200
pemphigoid
Laminin γ1
Figure 1. Indirect IF microscopy on 1 M NaCl split human skin and main target autoantigens of pemphigoid diseases. Differentiation of
the diseases and target molecules is based on the binding pattern with either (a) epidermal or (b) dermal binding of circulating autoantibodies
on the artificial split.
developed, some of which are also commercially available. These now allow for a more accurate diagnosis,
which is becoming increasingly important to guide
treatment decisions, while our knowledge about the
therapeutic arsenal of these disorders has also
expanded. In this review, we focus on recent progress
in our understanding of the pathogenesis, diagnosis,
and treatment of the different pemphigoid diseases.
Bullous pemphigoid
Pathogenesis
Two hemidesmosomal proteins, the 230 kDa protein
(BP230 or BPAG1), and 180 kDa antigen (BP180,
BPAG2, or type XVII collagen) have been identified
as the major antigenic targets of BP autoantibodies
[8–10]. BP230 is an intracellular plakin protein member
showing homology with plectin and desmoplakins I
and II and promotes the association of hemidesmosomes with keratin intermediate filaments [11–13].
In contrast, BP180 is a transmembrane protein with a
type II orientation that spans the lamina lucida and
projects into the lamina densa of the epidermal basal
membrane zone (BMZ). The extracellular region
consists of 15 collagen domains separated from one
another by noncollagen sequences [14,15].
The noncollagenous 16A domain (NC16A),
located at the membrane-proximal region of BP180,
is considered to harbor major pathogenically relevant
epitopes in BP and is recognized by autoantibodies in
80 – 90% of BP patients [16 –19]. The importance of
anti-BP180 NC16A reactivity is further highlighted
by the observation that serum levels of BP180
NC16A-specific antibodies correlate with the disease
activity in BP patients [20].
In addition, it was reported that autoantibodies
preferentially recognize the phosphorylated BP180
ectodomain [21,22]. Recent studies have identified
the presence of memory B cells specific for the NC16A
domain, which can be induced in vitro to synthesize
autoantibodies [23]. These cells belong to the shortlived plasma blast population [24]. The BP180
NC16A-specific autoantibodies are not only of the
IgG isotype (mainly IgG1 and IgG4 subclasses), but
also of the IgE class [25 –27]. In fact, patients with
BP frequently have IgE autoantibodies binding to the
NC16A domain of BP180 [28].
The presence of IgE autoantibodies has recently
been correlated with a severe form of BP, and BP
patients, positive for IgE anti-BP180 antibodies,
required longer duration for remission, higher dosage
of prednisolone, and more intensive therapies for
remission [29]. Interestingly, one study showed that a
recombinant NC16A fusion protein degranulated
basophils opsonized with IgE from patients with BP
[30], further supporting the pathophysiological role
of IgE antibodies in BP. In addition, other antigenic
sites exist on both the extracellular and intracellular
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Update on pemphigoid
domain of BP180, which are recognized by IgE and
IgG autoantibodies in BP patients [16 –18,31 – 34].
BP patients also exhibit significant reactivity with
BP230, which is thought not to be involved in the
initiation of the inflammatory response in BP due to
its intracellular localization [8,35 –40]. Currently, it is
unclear whether anti-BP230 autoantibodies in BP
patients directly contribute to blister formation or
whether they are just a result of keratinocyte injury
and determinant spreading of the autoimmune
response. Very recently, two retrospective studies with
a large series of 138 and 190 patients with active BP,
respectively, have determined the outcome of BP230
autoantibody detection using commercial enzymelinked immunosorbent assays (ELISAs) [39,40].
In the first-mentioned study, 59% of patients had a
positive BP230 ELISA result and 86% had a positive
BP180 ELISA result, while only 5% had anti-BP230
autoantibodies without anti-BP180 autoantibodies
[39]. In the second study, anti-BP230 and antiBP180 antibodies were detected in 61 and 79% of BP
patients serum samples, respectively, while 8% had
anti-BP230 autoantibodies without anti-BP180 autoantibodies [40]. Although the study by Charneux et al.
found no relationship between a positive BP230
ELISA result and disease extent or presence of
mucosal involvement [39], with regard to this specific
finding, the study by Roussel et al. [40] showed the
opposite finding. Two other studies suggested that
anti-BP230 antibodies may be preferentially associated with localized types of BP [37,38].
In contrast to the humoral immune response, the
cellular immune response has been less widely studied
in human BP. Autoreactive T and B cells are almost
constantly found in BP patients. These cells react with
the same regions of BP180 and BP230 that are
recognized by IgG autoantibodies. The differential
epitope recognition of BP180 seems to be associated
with distinct clinical severity: T- and B-cell reactivity
against the NH2-terminal portion of the BP180
ectodomain is associated with severe BP, while the
central portion is more frequently recognized in
patients with limited disease.
In contrast, combined T- and B-cell response against
the COOH- and NH2-terminal globular domains of
BP230 was found in less than 50% [41]. The response
to the BP180 ectodomain is restricted by certain HLA
class II alleles, such as the DQb1*0301 allele [42,43].
Autoreactive T cells in BP patients produce a Th1/Th2
mixed cytokine profile. We and others have detected
elevated levels of IL-1b, IL-2, IL-4, IL-5, IL-6, IL-8,
IL-10, IL-15, IL-16, eotaxin, MCP-4, tumor necrosis
factor a (TNFa), and CCL18 in the sera and/or blister
fluids of BP patients [44 –55].
Serum levels of TNFa, IL-6, IL-8, IL-15, and
CCL18 correlated with patients’ disease activity [47–
49,54], pointing to a pathological relevance of these
mediators. The observation that Th2-type cytokines
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are important in human BP is supported by the
increased frequency of cutaneous lymphocyte-associated antigen-positive IL-4- and IL-13-producing cells
in the peripheral blood [56]. Furthermore, analysis of
cell subsets with immunoregulatory functions in
BP patients has shown that while the number of
circulating CD4 þ CD25 þ FOXP3 þ regulatory T
cells, natural killer T cells, and natural killer cells are
normal, gd T cells are reduced in BP patients [57,58].
Our knowledge about the functionally relevant
pathogenic mechanisms in BP is based on in vitro
studies using cultured human keratinocytes, ex vivo
studies using cryosections of human skin as well as
various mouse models [59,60]. When cultured human
keratinocytes were treated with anti-BP180 IgG, doseand time-dependent increases of both mRNA and
protein levels of IL-6 and IL-8 were observed,
pointing to a signal-transducing event via BP180
[61]. In the same model, decreased expression of
BP180 and weakening of keratinocyte attachment in
response to anti-BP180 IgG were seen [62].
Using cryosections of human skin, BP patients’ sera
were shown to generate dermal –epidermal separation
when co-incubated with leukocytes and complement
from healthy volunteers [63]. Characterizing the
specificity of pathogenically relevant autoantibodies,
we were later able to demonstrate that IgG antibodies
to human BP180, purified from sera of BP patients
and from rabbits immunized against recombinant
human BP180, induce dermal– epidermal separation
in this model. This effect was shown to be mediated by
binding of autoantibodies to the NC16A domain of
human BP180 and to be dependent on the Fc portion
of autoantibodies [64].
Passive transfer of rabbit IgG, raised against the
murine homolog of the human BP180 NC16A
domain, into neonatal wild-type mice produced
clinical, histologic, and immunopathologic alterations
like those seen in patients with BP [65]. In this model,
blister formation is dependent on the activation of
complement, degranulation of mast cells, and recruitment of neutrophils [65 –68].
Blister fluid and lesional/perilesional biopsies from
BP patients have been shown to contain high levels of
proteolytic enzymes, including neutrophil elastase
(NE), cathepsin G, collagenase, plasminogen activators, plasmin, matrix metalloproteinase-2 (MMP-2,
gelatinase A), MMP-9 (gelatinase B), and MMP-13
[69 – 77]. These enzymes, particularly the neutrophiland eosinophil-derived MMP-9 and NE, are secreted
into the extracellular space upon cell activation
and are thought to proteolytically degrade various
extracellular matrix proteins, including the extracellular domain of BP180 [76,78,79]. Mice genetically
deficient in NE or MMP-9 have been shown to be
resistant to experimental BP [80,81].
An interaction between MMP-9, NE, and the
plasminogen/plasmin system was demonstrated to
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M. Kasperkiewicz et al.
occur during proteolytic events in experimental BP: in
the early stages of blistering, MMP-9 is mainly
activated by plasmin, which is formed from plasminogen by tissue plasminogen activator (tPA) and/or
urokinase plasminogen activator (uPA) [82]. Furthermore, an elevated expression and release of tPA from
normal human keratinocytes upon stimulation with
antibodies to human BP180 has been reported [83].
In addition to plasmin, the mast cell-specific serine
protease MCP-4 (chymase) is also able to activate
MMP-9 [84]. Activated MMP-9 is believed to
proteolytically inactivate a1-proteinase inhibitor, the
physiological inhibitor of NE, which allows unrestrained activity of NE [85]. These findings demonstrate that loss of cell-matrix adhesion within the
dermal-epidermal junction (DEJ) is directly mediated
by proteinases released by inflammatory cells.
In a first attempt to explore the functional relevance
of human anti-BP180 antibodies reacting with the
human target antigen, human skin was transplanted
onto Severe Combined Immunodeficiency (SCID)
mice. The injection of BP IgG into the transplant did,
however, not result in blister formation within the
observation period of 48 h [86]. Recently, additional
“humanized” mouse models have been established.
Olasz et al. generated a novel transgenic mouse
expressing human BP180 in murine epidermal BMZ
by the use of a keratin 14 promoter construct. They
showed that wild-type or MHC I2/2 , but not MHC
II2/2 , mice grafted with transgenic skin elicited IgG
that bound human epidermal BMZ and BP180.
Transgenic grafts on wild-type mice developed
neutrophil-rich leukocyte infiltrates and subepidermal
blisters [87]. Nishie et al. [88] used the same BP180
transgenic mice to rescue the blistering phenotype
of BP1802/2 mice by backcrossing experiments.
Clinical, histological, and immunopathologic features
of BP were achieved by passive transfer of IgG from
patients or IgG1 monoclonal antibodies against
humanized BP180 NC16A into these BP180-humanized mice [88,89]. To show that pathogenic antiBP180 autoantibodies act in combination with key
innate immune system players also in the humanized
BP mouse model, Liu et al. generated a humanized
mouse strain, in which murine BP180 NC14A was
replaced by the homologous human BP180 NC16A
epitope [90]. These BP180 humanized mice pretreated with mast cell activation blocker or depleted of
complement or neutrophils become resistant to BP
after passive transfer of human BP autoantibodies.
More recently, an active mouse model for BP has been
developed by transferring splenocytes from wild-type
mice that had been immunized by grafting of human
BP180-transgenic mouse skin onto Rag-22/2 /BP180humanized mice. The recipient mice produced
anti-human BP180 IgG antibodies in vivo and
developed blisters and erosions corresponding
to clinical, histological, and immunopathological
features of BP [91].
In two other mouse models, the pathogenic effect of
IgE anti-BP180 antibodies has been elucidated,
demonstrating that an IgE hybridoma to LABD97
antigen or purified IgE from BP patients was able to
induce BP-characteristic inflammatory skin changes
and partly subepidermal blistering in human skin
grafts on nude mice [92,93].
Diagnosis
Clinically, BP is characterized by tense blisters predominantly on flexural aspects of the limbs and abdomen
and associated with severe itching (Figure 2a). BP
typically affects the elderly with an average age at
diagnosis between 75 and 81 years [1,2,94,95]. Before
blisters arise, BP is typically preceded by a prodromal,
non-bullous stage, in which excoriated, eczematous,
papular, and/or urticarial lesions are found that may
persist for several weeks or even months.
Light microscopy of lesional skin from patients with
BP typically demonstrates a subepidermal blister with
an eosinophil- and/or neutrophil-rich leukocytic
infiltrate within the papillary dermis and along the
epidermal BMZ (Figure 2b). By direct IF microscopy
of perilesional skin linear deposits of IgG and/or C3
can be found at the epidermal BMZ (Figure 2c).
In approximately 80% of the cases, patient IgG
autoantibodies react with the epidermal side of 1 M
NaCl split human skin by indirect IF microscopy
(Figure 2d) [96].
Based on the finding that NC16A is the immunodominant region of BP180 [17,18], two highly specific
and sensitive BP180 NC16A-specific ELISAs for
detection of circulating autoantibodies in BP have
been commercialized [19,97]. When these assays are
combined with other detection systems, including
those using BP180 fragments outside the NC16A
domain and BP230, the sensitivity of these tests can be
increased to even 100% [38,41,98,99]. In contrast to
serum levels of antibodies to BP230, BP180 NC16Aspecific autoantibodies correlate closely with disease
activity and may thus be not only of diagnostic use, but
also allow the monitoring of circulating autoantibody
levels during the course of the disease, helping to
guide treatment decisions [19,20,36].
BP must be differentiated from pemphigus and
other subepidermal blistering autoimmune dermatoses, including EBA and dermatitis herpetiformis.
In contrast to BP, blister formation in pemphigus
results from intraepithelial cell separation and shows
an intercellular pattern of IgG between keratinocytes.
Differentiation of BP especially from EBA, anti-p200
pemphigoid, and MMP, however, presents a more
difficult task. The mechanobullous, non-inflammatory form of EBA is characterized by the appearance
of skin fragility and tense blisters at anatomic
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Update on pemphigoid
59
Figure 2. Clinical, histologic, and immunopathologic findings in BP as representative pemphigoid disease. (a) Tense blisters and erosion on
erythematous base on the leg. (b) Histophathology of lesional skin demonstrating a subepidermal blister and a mixed dermal inflammatory
infiltrate containing numerous granulocytes. (c) Direct IF microscopy of perilesional skin showing continuous linear deposits of IgG at the
epidermal BMZ. (d) Indirect IF microscopy on 1 M NaCl split human skin revealing reactivity of circulating IgG against the epidermal side
of the artificial split.
areas subjected to trauma, healing of lesions with
scarring and milia formation as well as subepidermal
split formation with an only scattered dermal
inflammatory infiltrate. In contrast, the inflammatory
subtype of EBA may mimic clinical, histological, and
routine direct IF microscopy findings of BP.
Using higher magnifications of direct IF microscopy, EBA can be sometimes differentiated from BP
by distinctly shaped IgG deposits at the epidermal
BMZ, i.e. EBA revealing an u-serrated pattern and BP
a n-serrated configuration [100]. In addition, as
autoantibodies in EBA are directed against type VII
collagen, sera from these patients do not bind to the
epidermal, but to the dermal side of 1 M NaCl split
human skin. Similarly, patients with anti-p200
pemphigoid show autoantibody reactivity to a dermal
antigen. This immunopathological finding may be of
major importance since clinically, anti-p200 pemphigoid and BP may not be distinguishable. In contrast
to BP, MMP is predominantly confined to mucous
membranes.
If blisters appear on the skin of MMP patients, they
are commonly smaller, transient, and of limited
extent. Indirect IF microscopy of sera from MMP
patients may reveal epidermal, dermal, or combined
staining patterns of IgG on 1 M NaCl split human
skin. Some forms of LAD clinically resemble BP or
dermatitis herpetiformis. Continuous linear immunodeposits of IgA, most often in the absence of IgG and
C3, together with circulating IgA anti-BMZ autoantibodies, can distinguish LAD from these other
immunobullous diseases.
Treatment
BP is generally a self-limited disease that may remit
within a few months or some years. However, the
mortality rate in the first year has been shown to be as
high as 11 – 40% [95,101 – 103], and was related to old
age, poor general condition, and use of high doses of
oral corticosteroids rather than to the extent of the
disease itself [94,102]. Systemic and topical corticosteroids have been widely used in clinical practice
[104]. Initially, daily morning doses of prednisolone in
the range of 0.5 mg/kg/day usually control the disease
within a few weeks. An initial dose higher than
0.75 mg/kg/day has been shown to be not beneficial in
a controlled prospective trial [105].
A large, randomized controlled trial showed that
initial disease control and 1-year survival were
significantly better when treating severe BP with
clobetasol propionate cream 40 mg/day compared with
oral prednisolone 1 mg/kg/day, while in moderate BP,
outcomes using clobetasol cream and prednisolone
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M. Kasperkiewicz et al.
0.5 mg/kg/day were comparable [106]. Furthermore, a
mild regimen with clobetasol propionate cream 10 –
30 g/day tapering over 4 months has been shown to be
not inferior to the high-dose topical regimen with
clobetasol propionate 40 g/day [107].
Considering other randomized controlled trials in
BP, no differences in disease control were seen for
azathioprine plus prednisone compared with prednisone alone [108], for prednisolone plus azathioprine
compared with prednisolone plus plasma exchange
[108], for prednisolone plus mycophenolate mofetil or
plus azathioprine [109], and for tetracycline plus
nicotinamide compared with prednisolone [110].
Reports have also described successful treatment of
BP patients with dapsone [111,112], methotrexate
[113], high-dose intravenous immunoglobulins
(IVIG) [114], rituximab [115 – 117], omalizumab
[118], and immunoadsorption [119].
Mucous membrane pemphigoid
Pathogenesis
BP180 is the target antigen in about 70% of MMP
patients [120]. However, unlike in BP, only about
half of the patients’ sera contain antibodies to BP180
NC16A, and C-terminal epitopes of BP180 are
preferentially targeted [120 – 122]. In addition,
patients with MMP may exhibit IgG and/or IgA
autoantibodies of other specificity that recognize
BP230 [123,124], the 97/120 kDa LAD antigen,
laminin 332 (laminin 5), laminin 331 (laminin 6)
[125,126], type VII collagen [127], or the a6 and
b4 integrin subunit [128]. Considering the latter
target antigens, it has been shown that sera from
patients with generalized MMP and ocular MMP
recognize the b4 integrin subunit, while sera from
patients with oral MMP recognize the a6 integrin
subunit [129].
The pathogenicity of anti-laminin 332 antibodies
has been documented in vivo. Passive transfer of antilaminin 332 IgG to neonatal or adult mice induced
subepidermal blisters of skin and mucous membranes
that mimicked clinical, histological, and immunopathologic features seen in MMP patients [130]. The
same findings were seen in mice injected with Fab
fragments directed against laminin 332 as well as in
mice lacking complement, mast cells or T cells,
suggesting that such antibodies may elicit epidermal
detachment in vivo in a non-inflammatory and direct
manner [130,131].
The pathogenicity of patients’ autoantibodies was
further confirmed in an experimental human skin
graft model, in which human anti-laminin 332
autoantibodies induced subepidermal blisters [132].
Additionally, accumulating evidence indicates that
fibrogenic cytokines, matrix metalloproteinases, and
collagen type I secreted in high amounts by
pemphigoid fibroblasts may actively be involved in
ocular MMP-associated scarring processes [133,134].
Diagnosis
MMP is a chronic autoimmune blistering disease
of mucous membranes and skin. An international
consensus conference defined the predominant involvement of mucous membranes as the major clinical
diagnosis criterion of MMP [135]. The oral mucosa
is the most common site affected by MMP followed
by ocular disease (Figure 3). It may also involve nasal,
pharyngeal, laryngeal, esophageal, and anogenital
mucous membranes. Progressive scarring potentially
may lead to serious complications, such as blindness
or asphyxiation. Histologically, MMP is characterized
by subepidermal blisters with a chronic inflammatory
infiltrate in the lamina propria that is composed of
lymphocytes, histiocytes, scattered neutrophils, and
eosinophils. Anti-BP180 and anti-laminin 332
MMP cannot be differentiated from each other by
histology [136].
Direct IF microscopy shows linear IgG and C3
deposits at the BMZ. Indirect IF microscopy using
1 M NaCl split human skin distinguishes between
antigens on the epithelial side of the split (BP180,
BP230, and a6b4 integrin) and those of the dermal
side (laminin 332). However, as only about one-half of
sera are reactive in indirect IF microscopy, ELISA and
Western blotting using relevant target antigens are
important additional diagnostic methods in MMP.
Although only half of the MMP patients develop
antibodies to the NC16A domain of BP180, the other
patients with BP180 reactivity react with LAD-1 or
the C-terminal portion of BP180 by Western blotting
[130]. Importantly, testing for IgA anti-BP180
antibodies in addition to the IgG isotype will further
increase the detection rate [130,137].
Assaying for anti-laminin 332 reactivity is of
particular importance as 25% of patients with laminin
332-specific antibodies develop a malignancy. In these
Figure 3. Clinical presentation of MMP. Ocular involvement with
symblepharon formation.
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Update on pemphigoid
patients, a tumor search is indicated [138,139].
Immunoprecipitation with human keratinocytes has
been reported to be the most sensitive technique for
the detection of serum autoantibodies against laminin
332, whereas immunoblotting with extracellular
matrix of cultured HaCaT cells was found to be the
most practical alternative [140]. The term cicatricial
pemphigoid, previously applied for patients with MMP,
is currently only used for the rare clinical variant in
which mucous membranes are not predominantly
affected and skin lesions heal with scarring [135].
Brunsting –Perry pemphigoid is a rare variant of
cicatricial pemphigoid first described in 1957 [141].
It is characterized clinically by blisters, hemorrhagic
crusts and atrophic scars confined to the head and
neck without mucosal involvement. It probably
represents a heterogeneous disorder with several
target antigens. Most patients with this type of
pemphigoid disease have been reported to have
autoantibodies against type VII collagen, therefore,
representing a localized form of EBA [142]. Although
the clinical features of Brunsting – Perry pemphigoid
are completely different from those of MMP, it has
recently been reported that they may share the same
target antigens, e.g. the C-terminal domain of BP180
and laminin 332 [143,144].
Treatment
Treatment of MMP is largely tempered by its severity
and sites of involvement. A consensus conference on
this disease differentiated high-risk and low-risk
patients. Although in low-risk patients, lesions are
limited to the oral cavity and the skin and are more
amenable to treatment, patients with conjunctival
involvement usually require aggressive management to
avoid blindness. Mild lesions of the oral mucosa and
skin can sometimes be effectively treated with topical
glucocorticoids or topical calcineurin inhibitors
combined with good oral hygiene. For more severe
lesions in low-risk patients, initial treatment may
include dapsone (1.0 – 1.5 mg/kg/day) and prednisolone (0.5 – 1.0 mg/kg/day).
An alternative for these patients may also be
tetracyclines combined with nicotinamide. Prednisolone (1.0 –1.5 mg/kg/day) in combination with oral
cyclophosphamide (1.0 –2.0 mg/kg/day) may be tried
in patients at high risk (ocular, nasopharyngeal,
genital, and esophageal involvement) [145,146].
Alternatively, i.v. dexamethasone pulses (100 mg on
3 consecutive days) combined with i.v. cyclophosphamide pulses (500 –1000 mg) in 2- to 4-week
intervals can be given. In patients who do not tolerate
cyclophosphamide, other immunosuppressants such
as azathiorpine, mycophenolate mofetil, and methotrexate can be applied [145,146].
Good therapeutic efficacy of IVIG has been
reported in patients with MMP. IVIG therapy, usually
61
given at 2 g/kg/cycle initially every 4 weeks, avoided
progression of the disease and was more effective than
conventional immunosuppressive treatment [104].
In one study, IVIG given as monotherapy halted
progression of scarring and visual deterioration during
the study period, and serological and clinical remission was sustained for several months after cessation of
IVIG infusions [147]. Recent case reports also
described the beneficial use of rituximab and TNF-a
inhibitors for severe and treatment-resistant cases of
MMP [105,107,148].
Pemphigoid gestationis
Pathogenesis
PG, formerly referred to as herpes gestationis, is
another disease in which BP180 has been identified as
the major target [149]. Occasionally, PG is associated
with a trophoblastic tumor, hydatidiform mole or
choriocarcinoma. The disease may appear for the first
time during any pregnancy, but then rarely skips
subsequent gestations [149]. The immunopathologic
hallmark of PG is linear deposits of C3 and, to a lesser
extent, of IgG along the DEJ in perilesional skin
biopsies. Circulating-complement fixing autoantibodies “HG factor” can be detected by indirect IF
on intact or NaCl split skin.
The autoantibodies react with BP180 and, less
frequently, with BP230 [16,150]. IgG autoantibodies
in most PG sera target the NC16A domain of BP180
[16,32,151 – 153]. However, antigenic sites outside
NC16A have also been identified both extra- and
intracellularly [153]. Epitope mapping studies identified two well-defined antigenic sites within a 22 amino
acid segment of BP180 (NC16A2 and NC16A2.5) as
major antigenic targets for PG sera [152]. In addition,
using overlapping synthetic peptides, PG autoantibodies were shown to bind to two defined epitopes
within the NC16A domain (aa 500 – 514 and aa 511 –
523). Importantly, preadsorption using an affinity
matrix containing these epitopes completely abolished
dermal– epidermal separation ex vivo induced by PG
autoantibodies [154].
In contrast to findings in BP [155], reactivity to
NC16A is dominated by IgG1 and IgG3 antibodies in
PG patients [152]. As IgG1 and IgG3 are the IgG
subclasses with the strongest complement fixing
properties, these observations may well explain
complement deposition at the DEJ, which is the
most consistent immunopathological feature in PG. In
PG patients tested for T-cell autoreactivity, BP180specific T cells exclusively reacted with the NC16A2
domain. Proliferative responses of these cells were
restricted to HLA-DR and cells expressed a CD4 þ
Th1-type memory phenotype [156]. These results
underline other findings that PG is strongly associated
with HLA-DR3 and -DR4 haplotypes [149].
62
M. Kasperkiewicz et al.
Diagnosis
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PG usually presents during the second or third
trimester of pregnancy or in the immediate postpartum
period with a pruritic urticarial, papulovesicular
eruption. Skin lesions often start around the umbilicus
and then spread over abdomen and thighs [149]. PG
frequently presents as a nonbullous disease with
eczematous lesions, erythema multiforme-like
changes or erythematous papules and plaques.
Diagnosis is based on detection of C3 deposits in
perilesional skin biopsies as well as circulating
autoantibodies by the complement binding test and
ELISA using recombinant BP180 NC16A [19,157].
Treatment
Treatment is aimed at suppression of new blister
formation and relief of the intense pruritus. In milder
cases, this can be achieved by the use of topical
corticosteroids in combination with oral antihistamines. In more severe cases, the administration of
prednisolone at an initial dose of 0.3 – 0.5 mg/kg/day
is generally sufficient. This dose can usually be
decreased during the course of the disease. Flares
postpartum may require a temporary increase in the
corticosteroid dose [149].
in older patients, predominantly IgG anti-BMZ
antibodies were found [173].
LAD may be either idiopathic or drug-induced (e.g.
vancomycin). The mechanism for blister formation
is not fully understood, but is likely to involve IgAand complement-mediated neutrophil chemotaxis.
The pathogenic relevance of LAD-associated autoantibodies has been shown by the passive transfer of
IgA murine monoclonal antibodies against LAD
autoantigen to SCID mice bearing human skin grafts.
In some of these challenged mice, the transferred
autoantibodies produced neutrophil-rich infiltrates
and subepidermal vesicles [174].
Diagnosis
LAD mainly shows vesicobullous lesions affecting the
skin and mucosal surfaces, sometimes forming
characteristic collarettes of vesicles or blisters as new
lesions arise in the periphery of old lesions (Figure 4).
On histopathology, the bullae are subepidermal, with
collections of neutrophils along the epidermal BMZ
and occasionally in the dermal papillary tips. Direct IF
microscopy of perilesional skin shows linear deposition of IgA at the epidermal BMZ, sometimes in
combination with linear IgG deposits. Patients have
Linear IgA dermatosis
Pathogenesis
LAD is an autoimmune subepidermal blistering
disease characterized by circulating IgA anti-BMZ
autoantibodies. Autoantibodies in LAD were shown
to target antigens with various molecular weights,
including 97-, 120-, 180-, 200-, 230-, 280-, 285- and
290-kDa proteins [158 –160]. The two most characteristic target antigens are the protein of 97 kDa and
the 120 kDa protein, termed the LABD antigen 1
(LABD97) and LAD-1, respectively [159,161]. These
proteins present a cleaved portion of the extracellular
domain of BP180 [160,162 – 165]. Recently, the
sheddases ADAM 9 and 10 have been reported to be
involved in generation of LAD-1 from BP180, while
formation of LABD97 has been shown to be
dependent on plasmin [166,167].
In contrast to BP, only 20% of sera of patients with
LAD react with the NC16A domain [168]. In
addition, IgA antibodies to BP230, type VII collagen
and laminin 332 have been reported [169– 171]. Since
the majority of LAD sera also contain IgG antibodies
against BP180 and in most BP sera, IgA anti-BP180
antibodies can be detected, LAD and BP may be
regarded as different ends of a continuous spectrum
[172]. In fact, the isotype of anti-BMZ reactivity was
associated with the age of the patients: in younger
patients, IgA autoantibodies predominated, whereas
Figure 4. Clinical presentation of LAD. Erythema multiforme-like
lesions with partly clustered annular tense blisters on proximal lower
extremity.
Update on pemphigoid
63
circulating IgA autoantibodies that mostly bind the
epidermal side of 1 M NaCl split human skin on
indirect IF microscopy (lamina lucida type), but
combined epidermal and dermal staining as well as
dermal labeling alone (sublamina densa type) has also
been observed. Autoantibodies to LAD-1 in the
lamina lucida type of LAD are detected by immunoblotting with conditioned concentrated medium of
cultured human keratinocytes [159].
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Treatment
Skin lesions in LAD commonly respond when treated
with dapsone. As dapsone may cause hemolytic
anemia, decreased hemoglobin values or even methemoglobinemia, glucose-6-phosphate dehydrogenase
deficiency should be excluded before the drug is
initiated. An alternative treatment is Sulfapyridine,
usually given at a dose of 15 – 60 mg/kg/day [175].
Some patients may require low-dose prednisone
initially to suppress blister formation. In unresponsive
patients, erythromycin, colchicine, flucloxacillin,
IVIG, and immunoadsorption have been administered
successfully [176].
Lichen planus pemphigoides
Pathogenesis
Regarding the pathogenesis of LPP, it is most likely
that the lymphocytic inflammatory process directed
against basal keratinocytes in lichen planus leads to a
release of hidden antigenic determinants within the
DEJ, resulting in an autoimmune response against
hemidesmosomal structures [177 – 180]. Immunoblotting studies have identified BP180 and BP230 as
target molecules but also a new antigen of 200 kDa of
keratinocyte derivation. The latter finding reinforces
the hypothesis that LPP might have a unique antigen
and thus represent a distinct entity from BP
[178,179]. In line with this assumption, it has been
shown that the epitope within the C-terminal NC16A
domain of BP180 antigen, targeted in LPP, differs
from BP, localizing to NC16A4 as opposed to
NC17A1 through NC16A3 [180].
Diagnosis
Most patients with LPP have typical lichenified
plaques or papules of lichen planus initially, followed
after weeks to months by tense vesicles and blisters
which arise, in contrast to bullous lichen planus,
independent of the lichenoid lesions (Figure 5).
Histologically, blisters resemble those in BP [177].
Direct IF microscopy of a papule shows Civatte
bodies, but when a blister is evaluated, IgG and C3 are
present as in BP. Indirect IF microsocopy on salt split
skin shows binding of IgG to the epidermal side.
Figure 5. Clinical presentation of LPP. Lichenified plaques and
tense blisters on the foot.
By immunoblotting, reactivity is primarily directed
against BP180 with NC16A being the immunodominant domain [180]. Less often, antibodies against
BP230 or other yet uncharacterized antigens are
found [177– 179]. The following observations suggest
that LPP is not a coincidental association of BP and
lichen planus: (i) the average age of BP patients is 77
years, whereas in LPP it is 44 years; (ii) lichenoid
papules are not seen in BP; (iii) autoantibodies in LPP
react with C-terminal epitopes of NC16A, which is
very uncommon in BP; and (iv) LPP is usually a
milder disease and more therapy-responsive than BP.
Therapy
It is important to treat existing lichen planus to avoid
further immunostimulation. In this context, acitretin
has proven valuable. Otherwise, treatment is the same
as in BP.
Anti-p200 pemphigoid
Anti-p200 pemphigoid is a subepidermal blistering
skin disease characterized by circulating autoantibodies against a 200-kDa molecule (p200 protein) of
the lower lamina lucida of the BMZ [181]. Recently, it
has been shown that 90% of the anti-p200 pemphigoid sera react with the C-terminus of laminin g1
[182]. Subsequently, the term anti-laminin g1
64
M. Kasperkiewicz et al.
artificial blister by indirect IF microscopy on 1 M
NaCl split human skin [181]. Classically, autoantibodies in anti-p200 pemphigoid react with a 200-kDa
protein in extracts of human dermis by Western blotting. Recently, laminin g1-specific antibodies could
be detected by Western blotting or ELISA using the
recombinant C-terminus of laminin g1 [182,183].
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Treatment
Figure 6. Clinical presentation of anti-p200 pemphigoid. Tense
blisters and erosions on the palms.
pemphigoid was proposed for this disease. Because
not all anti-p200 pemphigoid sera react with laminin
g1 [182,183], we suggest not applying the two terms
synonymously and only diagnosing an anti-laminin g1
pemphigoid when reactivity with laminin g1 has
actually been identified.
Pathogenesis
Anti-p200 pemphigoid shows organ-specific pathogenicity, although laminin g1 is expressed not only at
the DEJ but also in the BMZ of dermal blood vessels
[184]. This has been explained by the assumption that
laminin g1 in the epidermal BMZ has different
posttranslational modifications, such as glycosylation,
compared with laminin g1 expressed in blood vessels
[185]. However, the pathogenicity of anti-p200/laminin g1 antibodies has hardly been studied yet, with the
exception of a single patient whose IgG, in contrast to
BP IgG, did not induce IL-8 secretion following
incubation with human cultured keratinocytes [186].
Anti-p200 pemphigoid can be treated in a similar
way as BP and typically shows a prompt response
to topical class IV corticosteroids and dapsone (1.0 –
1.5 mg/kg/day). In more severe cases, prednisolone
(0.5 mg/kg/day) may be added [187]. Recently, adjuvant immunoadsorption has been successfully applied
in a severe case of anti-p200 pemphigoid with
concomitant active gastric ulceration [189].
Conclusion
Considerable progress has been made in the last years
regarding our understanding of pemphigoid diseases.
Experimental animal models of these diseases and
advances in translational research provided essential
insight into the pathophysiology of these disorders.
Intense scientific research on the autoantibody
response has led to new diagnostic techniques,
allowing the serological diagnosis in the great majority
of patients. Novel, more specific therapeutic avenues
are, however, needed to further reduce the long-term
adverse effects of the currently available immunosuppressants.
Declaration of interest: This work was supported by
grant EXC 306/1 Inflammation at Interfaces (Research
Areas E and H) from the Deutsche Forschunggemeinschaft to E.S. and D.Z. The authors report no
conflicts of interest. The authors alone are responsible
for the content and writing of the paper.
Diagnosis
Patients with anti-p200 pemphigoid typically
develop tense blisters and urticarial eruptions, sometimes with itching, closely resembling those of BP
(Figure 6). Usually, patients with anti-p200 pemphigoid can only be clinically differentiated from BP by
their considerably younger age with an average of 61
years at diagnosis [187]. Histopathologically, skin
biopsy specimens demonstrate subepidermal blistering and a linear infiltrate of neutrophils, and sometimes eosinophils, along the epidermal BMZ.
With this method, anti-p200 pemphigoid cannot be
differentiated from other pemphigoid disorders [188].
Direct IF microscopy of perilesional skin biopsies from
patients with p200 pemphigoid demonstrate linear
deposits of IgG and C3 along the epidermal BMZ.
Typically, autoantibodies bind to the floor of the
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