Autoimmunity Reviews 16 (2017) 445–455

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Autoimmunity Reviews

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Review

Bullous pemphigoid☆

Işın Sinem Bağcı a,b,⁎, Orsolya N. Horváth a, Thomas Ruzicka a, Miklós Sárdy a,c
a
Department of Dermatology and Allergology, Ludwig Maximilian University, Munich, Germany
b
Department of Dermatology, Ankara 29 Mayıs Government Hospital, Ankara, Turkey
c
Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary

a r t i c l e i n f o a b s t r a c t

Article history: Bullous pemphigoid (BP) is the most common autoimmune bullous disorder which is characterized by autoan-
Received 24 January 2017 tibodies against hemidesmosomal proteins of the skin and mucous membranes. Collagen XVII and dystonin-e
Accepted 31 January 2017 have been identified as target antigens. BP affects mostly the elderly. The incidence of the disease is increasing
Available online 8 March 2017
gradually and is associated with high morbidity and mortality. Clinically, BP is characterized by an intensely pru-
ritic eruption with widespread bullous lesions. The clinical diagnosis can be challenging in the setting of atypical
Keywords:
Bullous pemphigoid
presentations. Diagnosis of BP relies on the integration of clinical, histological, immunopathological, and serolog-
Autoimmune bullous diseases ical findings. The treatment is mainly based on topical and/or systemic glucocorticoids, but anti-inflammatory an-
Pemphigoid diseases tibiotics and steroid sparing adjuvants are useful alternatives. Localised and mild BP can be treated with topical
corticosteroids alone.
© 2017 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446
2. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446
3. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446
3.1. Autoimmunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446
3.2. Genetic susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
3.3. Inducing factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
3.4. Associated conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
4. Clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
4.1. Classical manifestation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
4.2. Nonbullous cutaneous pemphigoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
4.3. Other rare variants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
5. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
6. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
6.1. General remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
6.2. Monotherapeutic possibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
6.2.1. Topical or systemic treatment? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
6.2.2. Therapy with glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
6.3. Anti-inflammatory antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451
6.4. Adjuvants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451
6.5. Experimental therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451

Abbreviations: BP, bullous pemphigoid; BM, basement membrane; CCL, CC chemokine ligand; CCR, CC chemokine receptor; DIF, direct immunofluorescence; ELISA, enzyme-linked
immunoassay; IIF, indirect immunofluorescence; IL, interleukin; MHC, major histocompatibility complex; MMP, matrix metalloproteinase; MT-ATP8, mitochondrially encoded ATP
synthase 8 gene; NE, neutrophil elastase; SMR, standardized mortality ratio; TNF, tumor necrosis factor.
☆ No funding and no conflicts of interest reported.
⁎ Corresponding author at: Dept. of Dermatology and Allergology, Ludwig-Maximilian University, Frauenlobstr. 9-11, 80337 Munich, Germany.
E-mail address: Bagci.Isin_Sinem@med.uni-muenchen.de (I.S. Bağcı).

http://dx.doi.org/10.1016/j.autrev.2017.03.010
1568-9972/© 2017 Elsevier B.V. All rights reserved.
446 I.S. Bağcı et al. / Autoimmunity Reviews 16 (2017) 445–455
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Bullous pemphigoid (BP) belongs to the pemphigoid group which is
characterized by autoantibodies against structural proteins of the
hemidesmosomes and subepidermal blistering. This group also includes
pemphigoid gestationis, mucous membrane pemphigoid, linear IgA bul-
lous dermatosis, epidermolysis bullosa acquisita, and some other rare
conditions [1]. BP is the most frequently occurring representative of
the pemphigoid group, and also the most common autoimmune bullous
skin disease. It is primarily a disease of the elderly, and dramatically in-
creasing incidence rates have been reported in recent decades, especial-
ly in Western societies. Although BP rarely represents a life threatening
disease, it is associated with enhanced morbidity and mortality rates
due to significant co-morbidities and therapeutic side effects.
The hallmark of BP is the presence of tissue-bound and circulating
autoantibodies directed against structural components of the
hemidesmosomes, structures connecting basal keratinocytes with the
basement membrane (BM) [2]. Two main autoantigens, collagen XVII
(also known as BP180 or BP antigen 2) and dystonin-e (also known as
BP230 or BP antigen 1) have been identified. Clinically, the disease pre-
sents with pruritic, tense blisters which may arise on an erythematous
base or on normal skin. In daily practice, however, various non-classical
clinical forms have surpassed the classical presentation of BP, which
makes it necessary to suspect BP in itching inflammatory skin diseases
of the elderly. In this review we summarize the epidemiological data,
pathogenetic mechanisms, the broad clinical spectrum, diagnostic
methods, and treatment options for this disease.
2. Epidemiology
BP is the most frequent autoimmune bullous skin disease. The inci-
dence is increasing over time in Western Europe and North America.
The highest incidence was reported from UK, 42.8 cases per 1 million
people per year, with five-fold increase in the incidence over 11 years
[3]. Latest studies from France, Scotland, Germany, and Switzerland re-
ported annual incidences of 21.7, 14, 13.4, and 12.1 new cases per 1 mil-
lion people, respectively [4–7]. The lowest incidence among European
countries was reported from Romania with 2.5 cases per 1 million per
year [8]. Consecutive studies from Germany [9,6] and France [10,4]
showed two- and three-fold increase in the incidence of BP, respective-
ly, compared to previous results. Similar to the European studies, inci-
dence of 24 cases per 1 million person-years was reported from
United States [11].
BP mainly affects elderly people. The disease frequency increases
above the age of 70 reaching maximum above 90 [7]. The risk of getting
BP increases up to 300-fold above the age of 90, compared to patients
below 60 [9]. Although BP rarely occurs in children, an incidence of
23.6 new infant cases per 1 million per year was reported from Israel
[12]. BP occurs more frequently among females than males; however,
above 80 years of age frequency is higher among males. Aging of the
general population in Western Europe and North America has been pro-
posed to be the major factor regarding the increasing incidence of BP.
Other possible explanations are the concomitant increase in the preva-
lence of neurodegenerative disorders, increasing use of some drugs
which may trigger the disease, improved diagnostics, and the recogni-
tion of atypical variants of BP which might have been overlooked in
the past [11,13].
In various studies, mortality in BP patients was found to be higher
than in the general population. Despite similar incidence rates of BP in
Europe and North America, mortality rates seem to be higher in Europe.
451
451
A standardized mortality ratio (SMR) of 6.6 was reported from France,
compared to expected age- and sex-specific overall death rates in the
general population [4]. Approximately two-fold higher mortality risk
of BP patients was reported both from the UK and the USA [1,11]. An
age-dependent SMR of 2.43 to 9.56 was reported from Korea [14]. Old
age, widespread disease, a low Karnofsky score, and high doses of oral
corticosteroids are key risk factors for death beside life threatening co-
morbidities [15,16].
3. Pathogenesis
3.1. Autoimmunity
The pathogenesis of BP has not been understood in detail yet. It is
likely that there is an interaction between predisposing and triggering
factors. An immunological pathogenesis was first shown in 1967, with
the demonstration of IgG and complement 3 (C3) bound to the BM of
skin biopsies [17], and anti-BM autoantibodies in the serum of patients
with active disease [18]. These autoantibodies target two components of
hemidesmosomes, dystonin-e (also called BP230 or BPAg1) and colla-
gen XVII (also known as BP180 or BPAg2).
Collagen XVII is a 180 kDa (hence the name BP180) transmembrane
glycoprotein with an intracellular N-terminal domain. Each molecule is
characterized by a globular intracellular domain, a short transmem-
brane stretch, and an extracellular, C-terminal, anchoring hook com-
posed of 15 collagen domains which are separated from each other by
16 non-collagenous domains [19].
Data obtained from animal models indicate that autoantibodies
against BP180 are pathogenic [20–26]. Passive transfer of rabbit anti-
murine antibodies against BP180 induced a blistering skin phenotype
in neonatal mice that resembled human BP, with the involvement of
complement cascade, mast cells and neutrophils [20–23]. With trans-
genic mice models, in which BP180 had been humanized, passively
transferred human anti-BP180 autoantibodies demonstrated the patho-
genicity of human BP180 autoantibodies through the induction of a
human disease phenotype [24–26]. Human anti-BP180 autoantibodies
also induced dermal-epidermal separation of human skin sections in
the presence of leukocytes in vitro, which confirms that BP180 plays a
key role in the pathogenesis of BP [27].
The non-collagenous 16A (NC16A) domain of BP180 represents the
immunodominant region which contains major epitopes recognized by
autoreactive T and B cells [25,28]. NC16A-specific peripheral T cell re-
sponse in BP is of a mixed Th1/Th2 type with Th2 predominance,
which is consistent with the presence of both Th2-regulated IgG4 and
Th1-regulated IgG1 autoantibodies in BP patients [29]. However, a re-
cent experimental BP model suggests that neutrophils, macrophages,
and mast cells, but not T and B lymphocytes, are required for full expres-
sion of the disease phenotype [30].
Autoantibodies binding to NC16A region play an important role in
the pathogenesis and are present in the majority of patients. However,
most patients also have IgG antibodies against epitopes outside the
NC16A domain. Furthermore, a subgroup of patients reacts with differ-
ent BP180 extracellular epitopes, but not with the NC16A domain [31,
32]. Correlation between the level of IgG (mainly IgG1 and IgG4) autoan-
tibody reactivity to BP180 and disease activity had been demonstrated
by several reports [33,34]. In active BP, autoantibodies of the IgG1 sub-
class predominantly attack the NC16A domain of BP180 [35]. A recent
report demonstrated that IgG4 autoantibodies may have an inhibitory
role in BP by blocking IgG1 and IgG3 binding to NC16A region and sub-
sequent inflammation [36]. Additionally, it has been recognized that
 I.S. Bağcı et al. / Autoimmunity Reviews 16 (2017) 445–455
anti-BP180 IgE may also be associated with BP. IgE antibodies directed
against NC16A were detected in up to 77% of BP patients [37]. The path-
ogenic role of IgE antibodies in BP was investigated using murine
models and separation at the BM was demonstrated histologically as a
response to BP180-specific IgE antibodies [38,39]. Elevated levels of cir-
culating IgE are present in 70% of untreated BP patients [40].
Dystonin-e (also called BP230) is an intracellular protein which be-
longs to the plakin protein family. Whereas anti-BP180 autoantibodies
are known to be pathogenic in BP, the pathogenic role of BP230 antibod-
ies remains controversial. Although IgG and IgE reactivity against BP230
can be detected in serum samples of most patients, the titers of anti-
BP230 antibodies do not correlate with the disease activity [41,42].
BP230 antibodies may be associated with atypical forms of BP such as
the prurigo form, eczematous or urticarial manifestations, and the local-
ized type of BP [43–45].
Although detection of circulating BP-specific IgG autoantibodies has
been reported previously in pruritic skin conditions in elderly, the
mechanism is not yet fully understood. It was suggested that cell de-
struction caused by chronic itching and scratching might lead to the im-
munological exposure of self-antigens like BP230 and BP180 and
associated with immunosenescence may eventually lead to a loss of
self-tolerance and the induction of an IgG autoantibody-specific im-
mune response [46].
The binding of IgG 1 and IgG3 autoantibodies to their targets
triggers complement activation. Complement activation-derived
fragments C3a and C5a can induce neutrophil and eosinophil chemo-
taxis and mast cell degranulation, which are essential for the inflam-
matory cascade resulting in subepidermal blistering. Neutrophils
line up along the BM and release their proteolytic enzymes such as
matrix metallopeptidase-9 (MMP) and neutrophil elastase (NE).
Early mast cell degranulation is followed by eosinophil migration
into the lesion and the release of a variety of mediators, such as leu-
kotrienes, platelet-activating factor, and tumor necrosing factor
(TNF-α). Mast cells also play a crucial role in neutrophil recruitment
in experimental BP through release of interleukin (IL)-8 [30]. Eosin-
ophilic production of MMPs and NE further contributes to tissue
damage [47]. After being released by the neutrophils and eosino-
phils, MMP-9 and NE are thought to degrade various extracellular
matrix proteins, including the extracellular domain of BP180,
which may contribute to loss of cell-matrix adhesion within the BM
[48–50]. Interaction of autoantibodies with BP180 has also been
shown to trigger an intracellular signal transducing event and induce
an upregulation of IL-6 and IL-8 at protein and mRNA levels, which
may further contribute to the blister formation, recruitment and ac-
tivation of inflammatory cells, and release of proteases [51]. In ex-
perimental BP models, activated mast cells release mouse mast cell
protease-4, a homolog of human chymase, which activates MMP-9
and cleaves BP180 [52]. Neutrophils, lymphocytes, monocytes and
mast cells also release IL-17 and IL-23 which significantly augment
the production of MMP-9 and elastase in neutrophils [53,54].
In addition to complement-dependent mechanisms, blister forma-
tion may be induced by the direct interaction of autoantibodies and
autoantigens [55,56]. IgG4 autoantibodies have been reported to pre-
dominate in BP [57], which lack the ability to fix complement [58]. Pas-
sive transfer of IgG4 and IgG1 autoantibodies from BP patients has been
shown to induce blister formation in neonatal C3-deficient COL17-hu-
manized mice without complement activation [56]. Additionally, BP
cases with dominant IgG4 without C3 deposition at the BM have been
reported recently [59]. This suggests that IgG4 autoantibodies may con-
tribute to complement-independent blister formation in some BP cases.
BP180 depletion has been proposed as an alternative mechanism of
BP, since IgG autoantibodies have been shown to deplete BP180 in cul-
tured normal human keratinocytes and to diminish their adhesive
strength in vitro [56]. Moreover, polyclonal F(ab′)2 antibodies against
NC16A induced dermal-epidermal separation in injected neonatal
mice and reduced the amount of BP180 in cultured normal human
447
keratinocytes [60]. However, subsequent inflammatory reactions were
missing in these experimental settings.
Cutaneous inflammation in BP may be caused by increased produc-
tion of inflammatory cytokines and chemokines. Increased levels of IL-
1b, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IL-17, IL-22, IL-23, TGF-β, TNF-α,
and IFN-γ have been detected in skin lesions, serum or blister fluid of
patients with BP [61–67]. It has been shown that autoantibodies to
BP180 can directly modulate the expression of IL-6 and IL-8 in cultured
human keratinocytes [51]. CC chemokine receptor (CCR) 3 ligands such
as CC chemokine ligand (CCL)11, CCL13, CCL18, CCL26, CCL28 levels
have been shown to be increased in skin and/or sera of patients with
BP [68–71]. Additionally, increased levels of CCL1, CXCL-10 and CCL2,
which belong to other CCR subfamilies, have been demonstrated in
sera of BP patients [72,73].
3.2. Genetic susceptibility
Although genetic background of BP has not been precisely deter-
mined, current knowledge indicates the presence of a genetic predispo-
sition in the etiology. Several studies showed the presence of major
histocompatibility complex class II (MHC II) gene HLA-DQB1*0301 in
patients with BP and mucous membrane pemphigoid [74–79]. Activa-
tion of B cells requires the cooperation of CD4 + helper T cells and is
mediated through the T cell receptor-mediated recognition of MHC II-
bound peptide antigens displayed on the surface of B cells [80]. MHC
restricted T-cell responses to recombinant BP180 proteins have been
demonstrated in BP patients and healthy controls expressing the HLA-
DQB1*0301 allele. In addition, autoreactive BP180-specific CD4 + T-
cell lines produced Th1 and Th2 cytokines in BP patients [79]. IgG
reactivity to BP180 has been shown to be increased in mucous
membrane pemphigoid patients with HLA-DQB1*0301, which may be
of particular relevance to disease pathogenesis [77]. In contrast, HLA-
DRB1*04, DRB1*1101 and DQB1*0302 were detected more frequently
in Japanese BP patients than in controls, which indicates that different
HLA class II haplotypes genetically influence susceptibility to BP
among different ethnic groups [81].
The results of a German study showed that polymorphism in the
mitochondrially encoded ATP synthase 8 gene (MT-ATP8) may have
an association with BP pathogenesis [82], which may suggest a contri-
bution of mitochondrial abnormalities to BP immunopathology. In addi-
tion, increased sensitivity of hemidesmosomes to reactive oxygen
species may be postulated in cells carrying an MT-ATP8 mutation [83].
CYP2D6 is one of the cytochrome P450 isoenzymes which play a role
in the drug metabolism and recently, CYP2D6 gene polymorphism
(CYP2D6*3/CYP2D6*4 genotype) was found to be more frequent in pa-
tients with BP than in controls, which may be related to predisposition
to drug-induced BP in some patients [84].
The interaction of antibodies and inflammatory cells is regulated by
the binding of the Fc-region of IgG antibodies to their corresponding re-
ceptors. FcγRIIIa, a particular Fc receptor subtype, is expressed on mac-
rophages which play a role in BP pathogenesis [30], and an increased
prevalence of low-affinity FcγRIIIa polymorphism was detected in BP
[85]. These data suggest that gene allotypes other than HLA may be in-
volved in the genetic predisposition to acquire BP.
3.3. Inducing factors
Inducing factors (e.g., drugs, physical agents, viruses, ultraviolet
(UV) or X-ray irradiation) were identified in around 15% of BP patients
[86]. The mechanisms for BP induction are not understood.
Drug-induced BP is caused by systemic or topical drugs and resolves
completely after withdrawal of the culprit [87]. A drug-triggered BP,
however, has the same clinical course as the classic, spontaneously oc-
curring disease without any response to the withdrawal of the drug.
Drugs may induce anti-BM antibody production by acting as haptens
that bind to proteins in the lamina lucida and change their antigenic
448 I.S. Bağcı et al. / Autoimmunity Reviews 16 (2017) 445–455
properties, or they may stimulate an autoimmune response by structur-
ally modifying molecules and uncovering hidden epitopes [88]. The ma-
jority of the BP-inducing medications contain or release sulfhydryl
groups (penicillamine, captopril, penicillin and its derivatives, furose-
mide, and some cephalosporins). Also drugs containing a phenol ring
(some cephalosporins and acetylsalicylic acid), angiotensin-converting
enzyme inhibitors other than captopril, most non-steroidal anti-
inflammatory drugs, immunomodulators such as vaccines, dipeptidyl
peptidase-IV inhibitors (gliptins), especially vildagliptin, and TNF-α
blockers have been reported to induce BP [88,89].
BP was reported to develop after vaccination. Although the patho-
logic mechanism remains unclear, it was suggested that vaccination
might trigger an enhanced autoimmune response in patients with a
relevant immunologic predisposition (molecular mimicry) or with a
subclinical BP [90–93]. Post-vaccination BP is reported especially in
children who mostly received influenza, tetanus, diphtheria, pertussis,
or polio vaccines alone or in combination with other vaccines [94].
There are several reports mentioning the induction of either gener-
alized or localized BP by UV light or radiation therapy [95–100]. The al-
teration of the BM antigenicity by UV or ionizing irradiation is the
proposed mechanism, which might cause stimulation of anti-BM anti-
body formation [101]. A further hypothesis suggests that UV or ionizing
irradiation might cause imbalance of reactivity of helper and suppressor
T cells, resulting in the development of autoantibodies [102]. BP lesions
can also follow thermal or electrical burns and surgical procedures
which usually disseminate after their first appearance in the trauma-
tized area [103–105]. This phenomenon may be explained by epitope
spreading, in which the first autoimmune or inflammatory reaction re-
veals hidden autoantigens and recruits autoreactive cells to the injured
site to promote or expand autoimmunity [106].
3.4. Associated conditions
BP associates significantly with neuro-psychiatric diseases. More
than one third of BP patients have been reported to have at least one
neuropsychiatric disease [107]. Stroke, dementia, and Parkinson's dis-
ease are most frequently associated with BP [108–110]. However, the
pathogenic mechanisms of these relations are not yet clearly under-
stood. BP autoantigens (mainly BP230) are not only expressed in the
skin, but also in the central nervous system. The exposure of neural iso-
forms of these antigens in elderly patients with neuropsychiatric disor-
ders and cross-reaction of autoantibodies may be an explanation for the
Fig. 1. A, Classical presentation of bullous pemphigoid with many blisters and crusted erosions on red plaques. B, Tense bullae on erythematous, edematous skin.
association between BP and neurologic diseases [111,112]. However,
plakin domain of BP230, against which autoantibodies were detected
in some neurologic disorders [113], is not an immunodominant region
of BP230 in BP [44]. Furthermore, there is no strong evidence that
anti-BP230 autoantibodies are pathogenic in BP [114]. Therefore, fur-
ther investigations are required to clarify the statistical association.
An independent association of BP with psoriasis has been reported
recently [115]. Paraneoplastic BP has been reported several times
[116–119]; however, the relationship between cancer and BP might
only be related to age [120], and does not justify extensive screening ex-
aminations if no tumor can be suspected in the patient's history.
4. Clinical presentation
4.1. Classical manifestation
The cutaneous manifestations of BP are polymorphic. The disease
usually begins with a non-bullous, pruritic phase which may persist
for some days to several months and sometimes remains the only sign
of BP [121]. During this phase, urticarial or excoriated, eczematous
plaques, or prurigo-like lesions appear which are difficult to diagnose
correctly [122].
Classical BP is clinically characterized by tense, serous or
haemorrhagic bullae of 1–3 cm diameter which appear on erythema-
tous or apparently normal skin [123] (Fig. 1A and B). In almost all
patients, severe pruritus is present. The disease has a symmetric
distribution, and the predilection sites include the lower abdomen, flex-
or surfaces of the limbs, groins and axillae [124]. Blisters evolve into
eroded and crusted areas, and then heal without scars. Sometimes
post-inflammatory changes (milia, hyper- or hypopigmentation)
might be visible. BP involves the mucosa in 10–25% of the patients.
Oral mucosa is more frequently affected than the conjunctiva, nose,
pharynx, esophagus, and anogenital area [125]. The course is usually
chronic with spontaneous exacerbations and remissions but self-limited
with healing within a few years. Skin or mucosal lesions are usually not
life-threatening, but mortality of BP patients is around 6× higher than
that of healthy, age-matched population [4].
4.2. Nonbullous cutaneous pemphigoid
In some patients, characteristic bullae do not develop and the initial
nonspecific lesions, which are mentioned above, remain as the only
 I.S. Bağcı et al. / Autoimmunity Reviews 16 (2017) 445–455
manifestation. This non-classical presentation has been named differ-
ently in the literature; we prefer the term ‘nonbullous cutaneous pem-
phigoid’ [126]. This subtype has been reported to occur in up to 20% of
BP patients [13,127].
Eczematous variant presents with erythematous, excoriated pap-
ules, nodules or eczematous plaques with severe pruritus. Pruritic urti-
carial papules and plaques are the main features of urticarial variant
[128]. Pemphigoid nodularis presents with pruritic, prurigo-like nod-
ules on the distal extremities of elderly patients. Blisters are usually ab-
sent; if present, they may precede or follow the development of nodular
lesions and arise at sites of nodular lesions or on uninvolved skin [13].
4.3. Other rare variants
Vesicular BP presents with multiple grouped, small, tense vesicles
with a symmetric distribution that mimic dermatitis herpetiformis
[129]. Dyshidrosiform pemphigoid is characterized by vesicles resem-
bling pompholyx confined to the palmoplantar area and later may
spread to other parts of the body [130]. Pemphigoid vegetans is clinical-
ly similar to pemphigus vegetans with vegetating and purulent lesions
localized in intertriginous areas [131]. Erythrodermic BP is a rare pre-
sentation of BP which is characterized by erythroderma with or without
accompanying blistering [132]. Lichen planus pemphigoides represents
the clinical and histopathological features of an overlap of lichen planus
and BP [133]. It affects mainly younger age groups and shows a relative-
ly benign course. Rare cases of erythema multiforme-like and toxic epi-
dermal necrolysis-like BP have also been described. Although there is no
clear association of BP with malignancies, figurate erythematous lesions
can be a warning sign of an underlying malignancy [134].
BP occurs less frequently in children. Childhood BP has similar fea-
tures to those in adults; however, acral involvement may predominate
the clinical picture. Childhood BP has usually a good prognosis and re-
solves rapidly after initiation of treatment [94].
Brunsting-Perry pemphigoid is characterized by recurrent blisters
limited to the head and neck region. It typically affects elderly men
and the lesions heal with atrophic scarring [135]. It is considered to be
a variant of bullous pemphigoid, mucous membrane pemphigoid or
epidermolysis bullosa acquisita as various target autoantigens have
been reported such as BP180, BP230, type VII collagen, laminin-332,
and desmoplakins [136–138].
Although vulvar involvement was described in 9% of adult and 40%
of pediatric BP patients, it can rarely occur as a localized variant of the
disease [139]. It is characterized by non-scarring, recurrent vesicles
and erosions confined to the vulva which show a good response to top-
ical steroids [140].
BP lesions may sometimes be confined to other body parts, such as
umbilicus [141] and pretibial area [142–143]. Unilateral BP in hemiple-
gic patients has been described previously with typical BP lesions local-
ized only on the hemiplegic side [144].
As described above, BP may clinically mimic or accompany other cu-
taneous diseases, thus the diagnosis should always be based on the re-
sults of the immunopathologic findings.
5. Diagnosis
Diagnosis of BP relies on the combination of clinical features, histo-
pathological and immunofluorescence findings. Typically, BP should
be suspected in elderly patients with generalized itch with or without
frank blistering or inflammatory skin signs. Non-scarring lesions sparing
mucous membranes and the head and neck region are characteristic
clinical features pointing out BP. A detailed medical history should be
obtained including the presence of pruritus, date of onset and evolution
of the lesions, associated neurological, and psychiatric diseases, malig-
nancies and recent drug intake (over a 1–6-month period). Associated
cardiovascular diseases and immune deficiencies are important for the
potential treatment of choice [145,146].
449
Histopathologic examination of a skin biopsy from the edge of a
fresh blister reveals subepidermal bulla with superficial upper dermal
inflammation consisting of neutrophils, eosinophils, and lymphocytes.
Eosinophilic spongiosis or an infiltrate of eosinophils lining the BMZ
are typically observed. All histopathological findings are, however,
non-specific [147].
Direct immunofluorescence microscopy (DIF) of perilesional skin is
the diagnostic gold standard for autoimmune bullous diseases. DIF
was shown to be the most sensitive diagnostic technique for BP [148],
although it is not specific. It reveals linear deposits of tissue-bound IgG
and/or complement C3 along the BM. Less frequently, IgA and IgE can
also show a similar pattern. Salt-split DIF allows further distinction of
BP from other subepidermal bullous diseases, such as epidermolysis
bullosa acquisita, mucous membrane pemphigoid, and anti-p200 pem-
phigoid. With this technique, the patients' skin is examined for tissue-
bound autoantibodies after the incubation of the tissue in 1 mol/L
NaCl solution which causes an artificial blister at the level of BM. Im-
mune deposits located in the BM of the roof of the blister are compatible
with BP. The n-serrated pattern of BP in DIF microscopy may be helpful
to differentiate it from epidermolysis bullosa acquisita which may show
a u-serrated pattern [149]. Beside the linear immunofluorescence of
epidermal basement membrane, adnexa appear to have a diagnostic
value in BP. In our recent study, we were able to show the positive fluo-
rescence of adnexa and high specificity of sweat gland ducts with strong
fluorescence in BP patients [150]. However, DIF alone is not specific
enough to differentiate BP from other autoimmune subepidermal
blisteringdiseases.
Indirect immunofluorescence microscopy (IIF) shows the presence
of circulating IgG antibodies binding to the BM. The most specific IIF
substrate for BP is salt-split skin (healthy human skin in which subepi-
dermal splitting was induced by 1 mol/L NaCl solution). Similar to DIF,
immune deposits are detected on the epidermal side of the blister in
BP. Use of non-split, normal human skin, rabbit or monkey esophagus
has similar sensitivity [148,151]. IIF on salt-split skin was shown to
have a specificity of 100% for BP [148]. Thus, it is recommended to per-
form indirect IF microscopy on human salt-split skin in every patient
with clinically suspected BP [146].
Enzyme-linked immunoassay (ELISA) shows presence of circulating
autoantibodies targeted against BP180 NC16A and BP230 proteins. Au-
toantibody titres have been shown to correlate with disease activity
[33] and the high serum concentrations of anti-BP180 NC16A antibodies
are associated with risk of relapse [152]. Thus, ELISA may be used for
further therapeutic decisions [153], but in our hands the clinical condi-
tion is of greater importance. Low serum concentrations of anti-BP180
or anti-BP230 antibodies can also be seen in about 4% of dermatological
patients who do not have BP, especially in those with pruritic dermato-
ses [154,155]. In these patients, direct immunofluorescence microscopy
is required to exclude BP [151].
The majority of BP patients also have elevated serum total IgE levels
and/or peripheral eosinophilia. Linear deposition of IgE autoantibodies
along the BM was detected in up to 41% of BP patients [156].
6. Treatment
6.1. General remarks
The first important step of therapeutic management is to stop or
change the provoking drug, if any identified, and treat underlying ma-
lignancy, if a tumor was found. Most immunosuppressive drugs are
strictly contraindicated in case of malignancy in the history.
There are only a few published studies concerning the therapy of BP,
the main information sources are up-to-date guidelines [157–159]. De-
spite of existence of guidelines, there is no worldwide-accepted ap-
proach to treat BP. Even if there is consensus that the treatment of BP
should be adjusted to the manifestation and severity of disease, there
is no universally accepted tool to assess the severity of BP. In the
450 I.S. Bağcı et al. / Autoimmunity Reviews 16 (2017) 445–455
German guideline, mild BP was defined under 10% skin involvement,
moderate disease between 10% and 30%, and severe BP above 30%
[157]. Joly et al. defined severity by the number of new blisters develop-
ing daily; N 10 new blisters defined severe disease [15]. However, this
latter grading system cannot be used in the non-blistering forms of BP.
In Europe, only 3 guidelines are currently available, the European,
the German and the British guidelines [157–159]. All these agree that
the therapy of BP should be generally based on glucocorticosteroids
which may be supplemented by an adjuvant.
Mycophenolate mofetil and its active metabolite mycophenolic acid
do not differ significantly from each other (500 mg mycophenolate mo-
fetil corresponds to 360 mg mycophenolic acid), thus, although we will
write only about mycophenolate mofetil, the two drugs should be
regarded equivalent. Analogously, we will present data only about pred-
nisolone, but other glucocorticoids might also be efficient if their phar-
macokinetic features are suitable.
6.2. Monotherapeutic possibilities
6.2.1. Topical or systemic treatment?
Topical treatment is always recommended in BP [157–159]. Accord-
ing to the German guideline, it should be used as monotherapy if the
disease is mild (b 10% affected skin surface); otherwise, it may be used
either in monotherapy or in addition to systemic therapy [157]. We
fully agree with this recommendation (Table 1) [160].
6.2.2. Therapy with glucocorticoids
6.2.2.1. Topical treatment. The most practical approach can be found in
the German guideline [157] which recommends a stage-adjusted treat-
ment depending on the affected skin surface area. Under 10% involve-
ment, only topical glucocorticoid monotherapy is recommended;
above 30%, a combination of topical and systemic glucocorticoids is in-
dicated. Between 10% and 30%, the addition of systemic therapy is op-
tional [157]. The most effective topical agent is clobetasole cream
applied twice daily. In mild BP, it should be applied only to the affected
area; however, in moderate or severe BP, the whole body surface (spar-
ing the head) should be treated including non-lesional skin. Very potent
topical steroids are effective and safe treatments for BP, although their
efficiency in extensive disease may be limited [161–163], even if Joly
et al. found topical clobetasol propionate superior to oral prednisone
(1 mg/kg body weight daily) in extensive disease and suggested topical
Table 1
Therapeutic recommendations based on the authors' opinion and personal experience [160].
Drug
First line treatment in monotherapy Topical glucocorticosteroids
or combination
Systemic glucocorticosteroids
Doxycycline
Drugs suitable for mono- or adjuvant Methotrexate
therapy
Dapsone
Adjuvant therapy only Azathioprine
Mycophenolate mofetil
therapy as standard treatment for BP [15]. These results are promising,
but prolonged use of clobetasol is contraindicated, and the compliance
is usually limited due to time consuming and inconvenient application
of the cream all over the body, the patients' age, comorbidities and men-
tal status (Table 1).
The application of a glucocorticoid cream usually leads to relevant
systemic resorption [164,165] and therefore may exert systemic effects
including side effects. Long-term topical therapy with clobetasole is as-
sociated with severe skin atrophy which is a serious limitation; there-
fore, switch to a less atrophogenic substance (such as mometasone
furoate) or reduction of the application frequency and the amounts
used must be considered after achieving disease control.
6.2.2.2. Systemic treatment. Systemic glucocorticoids should be used in
severe BP and considered also in moderate BP [157]. We recommend
an initial dose of 0.2–0.5 mg/kg body weight prednisolone equivalent
daily (Table 1) with an administration mode that ensures a relevant
serum glucocorticoid level for 24 h, i.e. oral tablets. Administration of
the initial daily dose in three divided doses may help to reduce the
total amount of glucocorticoid which is important, because the use of
systemic corticosteroids leads to an increased, dose-dependent mortal-
ity in BP [16]. In practice, we prefer to give 0.16–0.4 mg/kg body weight
methylprednisolone tablets either in a single dose every morning or in a
tapered, divided dose (e.g., 50%, 30%, 20% of daily dose). For instance, a
patient of 80 kg body weight with a severe BP would receive either
32 mg in the morning as a single dose of oral methylprednisolone or
16 mg in the morning, 10 mg at noon time, and 6 mg in the evening.
In therapy resistant cases or diabetes mellitus, equal distribution is rec-
ommended (e.g., 10 mg methylprednisolone tablets three times a day).
This recommendation is based on the experience of the authors, litera-
ture data including the three European guidelines and pharmacokinetic
considerations. The goal of initial glucocorticoid therapy is not the
suppression of autoantibody production which occurs with a delay of
several days, but the suppression of inflammation and blistering.
According to our hypothesis, the suppression of blistering requires ade-
quate continuous glucocorticoid levels in order to permanently inhibit
the effects of the pathological intracellular signaling cascades in basal
keratinocytes induced by the autoantibodies. As a consequence, much
higher dose may be needed if a glucocorticoid is given intravenously
or has a short half-life.
When new lesions cease to develop, systemic glucocorticoid dose
should be tapered with a shift to single-dose oral administration in
Remarks
- Possible skin atrophy
- Psychosocial issues, lack of long-term compliance common
- Maximal initial dose: 0.5 mg/kg/day
- Logarithmic dose reduction
- Most common side effects and relative contraindications: diabetes mellitus, arterial hypertension,
gastric ulcer
- Dose: 200 mg/day p.o.
- Side effects: phototoxicity, gastritis
- 10–20 mg weekly p.o./s.c.
- Folic acid on the day after treatment (5–10 mg)
- First monthly, later 2–3 monthly, laboratory controls
- Relative contraindications and possible side effects: anemia, malignancies, liver and kidney
insufficiency, leukopenia
- 1–1.5 mg/kg/day p.o.
- Not recommended by the authors due to potentially severe side effects in the elderly
- Activity of glucose-6-phosphate dehydrogenase to be determined before initiation of therapy
- Side effects and contraindications: anemia, liver and kidney insufficiency, neutropenia, dizziness,
fatigue
- 1.5–3 mg/kg/day p.o. if the activity of thiopurinmethyltransferase is normal
- Biweekly laboratory controls in the first 2 months of treatment due to possible liver toxicity
- Racial differences in metabolism: 1 g daily for East-Asians, 2 g/day for Caucasians 3 g/day for Africans
- Measurement of serum mycophenolic acid levels recommended in case of side-effects or in
patients with mixed genetic background
 I.S. Bağcı et al. / Autoimmunity Reviews 16 (2017) 445–455
the morning. Usually, a logarithmic reduction is recommended (dose
reduction of 25–35% until 20 mg prednisolone equivalent daily every
7–14 days followed by reduction by 5 mg every 2–4 weeks until
10 mg daily, and further reduction by 2.5 mg every 1–3 months). In
case of therapy resistance or relapse, the dose may be increased up to
1 mg/kg body weight prednisolone equivalent daily.
6.2.2.3. How to choose the right initial dose for systemic glucocorticoids?
The dose should be adjusted mainly to the severity of the disease, the
comorbidities, the compliance and the age of the patient. Severe disease
requires higher dose; however, old age, lack of compliance, and signifi-
cant comorbidities such as diabetes mellitus, severe osteoporosis, psy-
chotic conditions, hypertension, etc., require a lower dose. If systemic
glucocorticoids are contraindicated, topical corticosteroids on a large
skin surface area may also be contraindicated due to the significant
resorption.
There are many relative contraindications such as old age, neurolog-
ic and other systemic diseases (low Karnofsky score) [166,167]. There-
fore, the initial dose of prednisolone should not be N0.75 mg/kg/day
[168], and lower doses are preferred due to their better side effect pro-
file. Instead of increasing the dose of glucocorticoids over the recom-
mended maximum, administration in three divided doses or addition
of a steroid sparing adjuvant such as methotrexate is recommended.
In clinical practice, doses as low as 5–10 mg prednisolone can be effec-
tive in combination with topical therapy and an optional adjuvant drug
without any side effects even in patients with poor medical condition.
6.3. Anti-inflammatory antibiotics
Surveys showed that anti-inflammatory antibiotics (tetracyclines)
are prescribed by 79% of dermatologists treating BP in the UK [169],
while in Germany, dermatologists rarely consider it as an option
and prefer glucocorticoids [170]. There are case reports about the
effectiveness of doxycycline alone or in combination with other
immunosuppressants [171], but there is no evidence to give clear
recommendation about the use of corticosteroids vs. tetracyclines.
This issue is addressed by the ongoing Bullous Pemphigoid Steroids
and Tetracyclines (BLISTER) trial [172,173] in which the safety and
effectiveness of doxycycline (200 mg/day, Table 1) and oral predniso-
lone (0.5 mg/kg/day) will be compared.
6.4. Adjuvants
There are only a few studies about the effect of adjuvant therapy in
BP. The efficiency of immunoadsorption, azathioprine, mycophenolate
mofetil, dapsone, methotrexate, tetracycline and nicotinamide
(Table 1) need confirmation in future investigations [162]. Adjuvant
therapy with azathioprine or mycophenolate mofetil in combination
with methylprednisolone has shown comparable results with a differ-
ence only in the side effect profile [174]. Despite the lack of reliable
data, all guidelines recommend the use of adjuvants as glucocorticoid-
sparing agents. According to the German guideline, azathioprine is the
adjuvant of first choice followed by mycophenolate mofetil [157].
Methotrexate in BP has not been investigated in randomized, con-
trolled trials, only in open studies [175–177]; however, a recently con-
ducted, randomized, controlled study should be published in the near
future [178]. According to the authors' experience, methotrexate is the
best adjuvant therapy in elderly patients without severe renal or liver
insufficiency. It is safe and effective even in monotherapy. A Danish
study reported methotrexate as the second most frequently used adju-
vant drug after azathioprine [179].
Dapsone has been investigated by a few studies [180,181], but no
randomized, controlled studies are available. It has been suggested
being efficient, but in elderly patients, side effects are common, long-
term tolerability limited, and the therapy needs to be closely monitored
because of risk for sudden and severe complications.
451
6.5. Experimental therapies
According to our experience, resistance to treatment is usually a con-
sequence of inadequate pharmacokinetics of the used glucocorticoid.
Experimental therapies are required only in rare cases.
Omalizumab is a novel therapeutic option for treating BP. Only a few
cases have been reported which showed good therapeutic response
[182–187].
Immunoabsorption can be used in different dermatological disor-
ders, including BP [188]. Kasperkiewicz et al. published a case-series of
effective adjuvant immunoabsorption in BP, but further studies are
needed [189]. In addition, a new, specific immunoabsorber has been re-
cently reported for use in BP [190].
Several reports have shown efficacy of rituximab [191–206], but its
use is associated with increased mortality in high age [207], and thus
the drug should be used in elderly patients with BP only if other options
are ineffective or contraindicated.
In the guidelines, the following additional agents are recom-
mended or may be considered: cyclosporine, cyclophosphamide,
plasmapheresis/immunoapheresis, sulfonamides, topical tacroli-
mus, TNFα inhibitors and other biologic agents [157–159]. The use
of high-dose intravenous immunoglobulins may also be considered
as adjuvant therapy [191,204].
7. Conclusions
BP is the most common autoimmune bullous skin disease showing
increasing incidence in the last decades. It presents usually with many
blisters on itching, inflamed skin in elderly patients. However, the clin-
ical manifestation is very variable, non-bullous forms are common, and
therefore, BP should be considered in each elderly patient with a prurit-
ic, inflammatory skin disease. The current diagnostic methods are suffi-
ciently sensitive and highly specific. The treatment is mainly based on
topical and/or systemic glucocorticoids, but anti-inflammatory antibi-
otics and steroid sparing adjuvants are useful alternatives. Prospective,
randomized, controlled studies are needed to provide more evidence
for safe and efficient therapy options.
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