Clinics in Dermatology (2013) 31, 391–399

Bullous pemphigoid: Etiology, pathogenesis, and inducing

factors: Facts and controversies
Ada Lo Schiavo, MD a,⁎, Eleonora Ruocco, MD, PhD a , Gabriella Brancaccio, MD a ,
Stefano Caccavale, MD a , Vincenzo Ruocco, MD a , Ronni Wolf, MD b
a
Department of Dermatology, Second University of Naples, via S. Pansini, 5 - 80131 Naples, Italy
b
Dermatology Unit, Kaplan Medical Center, Rehovot 76100 Israel; The School of Medicine,
Hebrew University and Hadassah Medical Center, Jerusalem, Israel

Abstract The term pemphigoids includes a group of autoimmune bullous diseases characterized by
subepidermal blistering. Bullous pemphigoid (BP) is not only the most common disorder within the
pemphigoid group, but also represents the most frequent autoimmune blistering disease in general.
The onset and course of BP depend on a variable interaction between predisposing and inducing
factors. HLA genes are the most significant genetic predisposition factor to autoimmunity mechanisms.
Many studies show an association between HLA-DQβ1*0301 and distinct clinical pemphigoid variants.
Imbalance between autoreactive T helper (Th) and T regulatory cells, toll-like receptor activation, and
Th17/IL-17 pathway are the three possible autoimmunity triggers underlying BP. The pathomechanism
of BP hinges on an autoantibody response toward structural components of the hemidesmosome (BP180
and BP230). The binding of autoantibodies leads to complement activation, recruitment of inflammatory
cells, and release of proteolytic enzymes. The inflammatory cascade also may be directly triggered by
activation of Th17 cells with no intervention of autoantibodies.
The intervention of inducing factors in BP can be identified in no more than 15% of patients. Facilitating
factors in genetically predisposed individuals are various (drug intake, physical agents, and viral infections).
Drugs may act as triggers by either modifying the immune response or altering the antigenic properties of the
epidermal basement membrane. Cases of induction of BP by physical agents (eg, radiation therapy,
ultraviolet radiation, thermal or electrical burns, surgical procedures, transplants) are rare, but well-
documented events. A contributing role in inducing BP has been suggested for infections, in particular
human herpes virus (HHV) infections (cytomegalovirus, Epstein-Barr virus, and HHV-6), but also hepatitis
B and C viruses, Helicobacter pylori, and Toxoplasma gondii. Unlike pemphigus, no dietary triggers have
been suspected of being involved in the induction of BP. In all patients who have a diagnosis of BP, an
environmental agent as a potential cause should always be considered, because the prompt discontinuation
of it might result in rapid improvement or even cure of the disease.
© 2013 Published by Elsevier Inc.

Introduction

⁎ Corresponding author. Tel.: +39 081 566 68 28; fax: +39 081 546 87 59. Bullous pemphigoid (BP) is an autoimmune blistering
E-mail address: ada.loschiavo@unina2.it (A. Lo Schiavo). disease typically affecting the elderly. The name bullous

0738-081X/$ – see front matter © 2013 Published by Elsevier Inc.

http://dx.doi.org/10.1016/j.clindermatol.2013.01.006
392
pemphigoid itself is a pleonasm as pemphigoid is derived
from Greek and means form of a blister (pemphix, blister, bulla,
and eidos, form). Even so, the redundant adjective bullous
enables to distinguish it from other diseases that also belong to
the group of pemphigoids, such as pemphigoid gestationis,
mucous membrane pemphigoid, linear immunoglobulin (Ig)A
dermatosis, lichen planus pemphigoides, and anti-p200
pemphigoid. All these disorders are characterized by an
autoantibody response toward structural components of the
hemidesmosome (HD) resulting in subepidermal blistering,
but they differ from one another in clinical or histological
features. BP is not only the most common disorder within the
pemphigoid group but also represents the most frequent
autoimmune blistering disease in general. The incidence of BP
has been estimated between 4.5 and 14 new cases per 1 million
per year in central Europe.1 Hence, we deal solely with BP.
The cutaneous manifestations of BP are extremely
polymorphic. The disease usually begins with a nonbullous
phase in which the manifestations are nonspecific, with
pruritus of variable severity accompanied, or not, by
excoriated, eczematous, papular, and/or fixed urticaria-like
lesions. The features may thus mimic almost the entire
spectrum of the cutaneous inflammatory conditions. The
nonspecific presentation may persist for several months or
even remain the only sign of the disease.2 Once formed,
blisters are large and tense, with a round or oval shape.
Lesions may be localized or generalized. BP involves the
mucosa in 10% to 25% of patients. Histologic examination
of a skin biopsy from a fresh bulla reveals a subepidermal
blister with superficial dermal inflammation consisting of
lymphocytes, histiocytes, and eosinophils. On electron
microscopy, blister formation is found to occur within the
lamina lucida of the basement membrane, with a loss of
anchoring filaments and HDs.3
Etiology and pathogenesis
BP autoantigens
The hallmark of BP is the presence of tissue-bound and
circulating autoantibodies directed against structural com-
ponents of the cutaneous basement membrane zone (BMZ).4
These anti-hemidesmosomal autoantibodies, along with
complement components, are deposited along the basement
membrane at the dermal-epidermal junction of perilesional
skin.5 Immunoblot and immunoprecipitation analyses have
shown that these autoantibodies predominantly target two
components of HDs, BP180 and BP230. BP180 (BPAG2,
collagen XVII) is a type II transmembrane protein that
consists of a globular cytoplasmic domain and a large
extracellular region containing 15 collagenous domains,
whereas BP230 (BPAG1) is a cytoplasmic protein with a
central rod flanked by globular end domains. The vast
majority of patients with BP possess IgG autoantibodies
A. Lo Schiavo et al.
directed against an immunodominant region located in the
membrane-proximal non-collagenous region 16A (NC16A)
of the BP180 ectodomain, and recent studies have identified
the presence in patients with BP of memory B cells specific
for this domain.1,4 Both patients with BP and normal
individuals have autoreactive T cells that recognize the
NC16A domain and exhibit a T helper (Th)1/Th2 mixed
cytokine profile. Because Th1 cytokines (such as interferon
[IFN]-γ) are able to induce the secretion of IgG1 and IgG2,
whereas Th2 cytokines (such as interleukin [IL]-4, IL-5, and
IL-13) have been shown to regulate the secretion of IgG4
and IgE, the detection of anti-BP180 and anti-BP230
antibodies of the IgG1, IgG4, and IgE isotypes in patients
with BP suggests that both Th1 and Th2 responses are
involved.6
Autoimmunity mechanism in BP
The production of antibodies by B cells requires the
cooperation between B cells and CD4 + Th cells. In patients
with BP, self-antigens of the BMZ (BP180 and BP230) are
caught by antigen-presenting cells, processed, bound to
major histocompatibility complex class (MHC) II and
displayed on the cell surface. The receptor-mediated
recognition of these epitopes by T cells, triggers the release
of various cytokines and, consequently, B cells are
stimulated to produce autoantibodies. HLA genes are
probably the most significant genetic predisposition factor,
due to their role in the antigen presentation process. Many
studies show an association between HLA-DQβ1*0301 and
distinct clinical pemphigoid variants.7 So far, the effort of
many scientists has been to understand how and where
autoreactive B-cell activation and, thus, production of
autoantibodies are initiated.
As it occurs in pemphigus and other autoimmune diseases,
autoimmunity activation is delivered on a loss of self-
tolerance in both T and B lymphocytes. It has been postulated
that an imbalance of the relationship between autoreactive Th
and T regulatory cells (Tregs) is critical to the outbreak of
these disorders, and the difference between patients and
healthy individuals possessing the same autoreactive T cells
consists in a deficit of the T regulating function.8 This
interplay has been deeply investigated also in BP and
represents the first big controversy on its pathogenesis. In
2006, Hertl et al studied the T-cell control in the main bullous
autoimmune disorders, pemphigus and bullous pemphigoid.
They deepened the putative T-cell network and remarked the
pivotal role of Tregs and, especially, of their subtype Tr1s,7
but a study by Rensing-Ehl et al disproved this hypothesis not
observing a reduction in number, function, or skin homing of
Tregs in patients with BP.9
Another perspective on autoimmunity mechanisms of BP
is to consider the pathway involving activation of toll-like
receptors (TLRs) as trigger, similar to what was suggested
for pemphigus.8 According to this model, autoreactive B
Bullous pemphigoid pathogenesis and inducing factors
cells are activated first, independently from T cells, due to
ligation of B-cell receptor and TLR by self-antigen that
carries an endogenous TLR ligand. This leads to breakage of
self-tolerance, activation of autoreactive T cells and,
therefore, to the set up of autoimmunity.10
Additionally, Th17 cells and the cytokines they release
(ie, IL-17) may play an added role in the pathogenesis of BP,
accounting for characteristic features of this disease, such as
neutrophil infiltration and eosinophil recruitment, which
cannot be simply explained by the presence of autoanti-
bodies. There is increasing evidence that IL-17 is implicated
as a pathogenic factor in diseases like rheumatoid arthritis,
systemic lupus erythematous, inflammatory bowel disease,
psoriasis, and atopic asthma. This interleukin is important in
initiation and maintenance of many autoimmune reactions,
and it is involved in production of pro-inflammatory
cytokines (tumor necrosis factor [TNF]-α, IL-1, IL-6, IL-
8, granulocyte-macrophage colony-stimulating factor),
matrix metalloproteinases (MMP-9, MMP-13), and recruit-
ment of neutrophils and eosinophils, all of which are
important pathogenic factors in BP. IL-17 also induces Th2
cell activation. 11 A very recent study on BP, that
quantitatively evaluated lesional IL-17 + cells for the first
time, suggests that, compared with pemphigus, BP shows
more Th17 cell-related inflammation and less Treg-related
regulation. This result could be explained with the
difference in pathogenesis between pemphigus and BP,
being inflammation more crucial for the blister formation in
BP than in pemphigus.12 Regardless, results on lesional
Tregs cells in BP are very discrepant 9,12,13 (perhaps for the
vague phenotypic and functional definitions of these cells)
and not enough data on Th17 in patients with BP are
available so far. Despite convincing progress on Th17-
related inflammation in other diseases,11 further studies are
needed for BP.
In conclusion, although more has to be investigated on the
exact etiopathogenesis of BP, especially concerning each
component participating in it (Tregs, TLRs, Th17), the
immunopathologic function of autoantibodies is certain.
Pathogenic role of BP180 autoantibodies in BP. And
what about BP230? Facts and controversies
A significant association between levels of IgG against
extracellular epitopes of BP180 (mainly IgG1 and IgG4
subclasses) and both disease severity and activity is
universally recognized. It has been recently demonstrated
that also high levels of anti-BP180 IgE are related to severe
forms of BP.1 So, IgG1, IgG4, and IgE may “co-star” in
blister formation despite different mechanisms.
Conversely, there is much controversy on the pathogenic
role of BP230 autoantibodies. As explained before, BP230 is
an intracytoplasmic antigen, and thus the attack of
extracellular BP180 domain is necessary as trigger for
autoantibody formation. According to Di Zenzo et al, after
393
this primer, autoantibodies to BP230 are actively involved in
tissue damage because they have access to their intracellular
target antigen and, thus, they are able to induce local
inflammatory response even without the coexistence of
BP180 antibodies.2 This was also postulated by Kasperkie-
wicz et al in 2007, but the same authors, in a more recent
review, question whether these antibodies alone are able to
form the blister and postulate that they are just an
epiphenomenon of keratinocyte injury.1,6 The controversy
is complex and not yet solved. Two recent studies suggest
that BP230 antibodies may be preferentially associated with
localized types of BP.1
Blister formation mechanisms in BP
The mechanism by which BP autoantibodies are thought
to be pathogenic may be summarized in four steps and
includes complement activation, recruitment of inflammatory
cells, release of proteolytic enzymes, and direct interference
with the adhesion function of the autoantigens.
Step 1. Complement activation
It has been proven that the binding of autoantibodies to
their target causes complement activation. The role of
complement is supported by the observation that, in mice
deficient in functional complement, lesions are not pro-
duced.14 BP autoantibodies fix complement in vitro and C3
is detected by direct immunofluorescence along the BMZ of
perilesional skin in almost all cases of BP. Autoantibodies,
along with components of both the classical and alternative
pathways of complement (including C1q, C4, C5, C5-9,
factor B, B1H globulin, and properdin), have been detected
in lesional skin of patients with BP.6
Step 2. Mast cells degranulation
Subepidermal blistering induced by pathogenic autoanti-
bodies depends on mast cells, which play an essential role in
the inflammatory cascade. It is well known that mast-cell
degranulation can be induced by complement activation-
derived fragments C3a and C5a, whereas deficiency of C5
completely abolishes mast cell degranulation.6 On the other
hand, mast-cell degranulation also can be induced by IgE. It
has been speculated that IgE BP180 antibodies are bound to
eosinophils and mast cells through a high-affinity receptor
for IgE in the lesional tissue of BP and that exposure of
NC16A to these cells causes degranulation and release of
many chemical mediators.15 Data supporting this pathway
are the presence of IgE-bearing mast cells and eosinophils in
the dermis of patients with BP and the correlation of IgE
levels with disease severity.1 In our experience, almost all
patients with BP present high levels of IgE. Once
degranulated, mast cells release a variety of mediators,
such as leukotriens, platelet-activating factor, TNF-α, and
other cytokines, which provide recruitment of neutrophils
and eosinophils to the target tissue.
394 A. Lo Schiavo et al.

Step 3. Accumulation of eosinophils, neutrophils, and
their proteolytic enzymes
Neutrophils are essential for dermal-epidermal detach-
ment in the in vitro cryosection model of BP. They line up
along the BMZ, and, subsequently, through the release of
their proteolytic enzymes, such as neutrophil elastase (NE),
cathepsine G, collagenase, plasminogen activators, plasmin
and MMP-2, MMP-9, MMP-13, they lead to breakdown of
dermal-epidermal cohesion.6 Noteworthy, while in the
mouse model neutrophils predominate at the lesional site,
in the human disease an inflammatory infiltrate of eosino-
phils is the common hallmark. Early cutaneous infiltration by
eosinophils seems to be a crucial event in the development of
bullous lesions. Eosinophils are found in the upper dermal
infiltrate and in the blister cavity. Patients with BP show an
increased expression and release of various cytokines and
soluble factors involved in chemotaxis and eosinophil
activation. Eosinophil production of MMPs, elastase, and
gelatinase further contributes to tissue damage. Pathome-
chanisms other than the release of proteolytic enzymes
(tissue factor–mediated coagulation pathway) have also been
postulated.16 The elevated number of eosinophils in the
peripheral blood also supports this evidence and highlights
the pivotal role of these cells in the initiation and/or
progression of human BP.6
gus). Simple binding of the antibody variable region to the
BP180 ectodomain may trigger blister formation by
competing with its natural ligand and by blocking the key
binding sites along the BP180 antigen. In fact, autoanti-
bodies from patients with BP predominantly belong to the
noncomplement fixing IgG4 subclass. This assumption,
however, could be disproved by the recent evidence that
IgG4, like IgG1, is able to recruit leukocytes and activate
inflammatory cells skipping over the first step of comple-
ment activation. Other direct mechanisms of blister
induction by autoantibodies may involve the activation of
intracellular signaling pathways, resulting in hemidesmoso-
mal disassembly or induction of pro-inflammatory cyto-
kines. Recently, autoantibodies to BP180 have been shown
to directly modulate the expression of IL-6 and IL-8 in
cultured human keratinocytes. The pathogenic relevance of
these alternative mechanisms in BP requires further
investigation.6
In addition to the mechanism of blister formation induced
by autoantibodies, it is worth mentioning the possible
inflammatory cascade activation mediated by Th17/IL17
pathway. As explained previously, IL-17 is able to release
pro-inflammatory cytokines and proteolytic enzymes, recruit
and activate neutrophils, which by itself may result in blister
formation (Figure 1).

Step 4. Proteolytic events and blister formation

After being released by neutrophils and eosinophils,
MMP-9 and NE are thought to degrade various extracellular
matrix proteins, including the extracellular domain of
BP180.6 Mice genetically deficient in NE or MMP-9 have
been shown to be resistant to experimental BP.1
An interaction between MMP-9, NE, and the plasmino-
gen/plasmin system was demonstrated to 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). An
elevated expression and release of tPA from normal human
keratinocytes upon stimulation with antibodies to human
BP180 has been reported. In addition to plasmin, the mast
cell-specific serine protease MCP-4 (chymase) is also able to
activate MMP-9. Activated MMP-9 is believed to proteo-
lytically inactivate a1-proteinase inhibitor, the physiologic
inhibitor of NE, which allows unrestrained activity of NE.
These findings demonstrate that loss of cell-matrix adhesion
within the dermal-epidermal junction is directly mediated by
proteinases released by inflammatory cells.1

Alternative direct mechanisms

In addition to complement activation, it has been

postulated that there is a direct interference of autoantibodies
with the adhesion function of autoantigens, with no
intervention of inflammatory cells (as it occurs in pemphi- Fig. 1 Pathomechanism in bullous pemphigoid.
Bullous pemphigoid pathogenesis and inducing factors
Inducing factors
Most cases of BP occur apparently without any obvious
precipitating factor; however, in several cases, a meticulous
clinical history detects the presence of inducing agents.
Venning and Wojnarowska observed that a recognizable
factor precipitating or localizing BP was identified in no more
than 15% of patients, suggesting that an induction can only
account for a minority of BP cases.17 The mechanisms
whereby BP can be induced are unknown, but most are related
to factors that could locally disrupt the skin BMZ. Enhanced
antigenicity of BMZ components might then result from
structural modification or exposure of new epitopes. Alterna-
tively, non–antigen-specific effects (such as cytokines release)
might enhance the autoimmune response through one or more
of the mechanisms explained previously.17 Factors that
facilitate BP in genetically predisposed individuals are various
(eg, drug intake, physical agents, viral infections, and diet).
Drug-induced BP
Drug-induced BP (DIBP) is a term introduced to
designate cases of BP presenting clinical, histologic, and
immunopathologic features identical or closely similar to
those of the idiopathic disease, induced by systemic
ingestion or local use of certain drugs. 18 A genetic
susceptibility might be postulated because only a few people
develop the disease after the administration of certain
potentially offending drugs.
Clinical and histopathologic features
The clinical aspects of DIBP are heterogeneous and
sometimes misleading because they encompass a wide
variety of presentations, ranging from the classic features
of tense bullae arising from an erythematous, urticarial basis,
with an inconstant involvement of the oral cavity, through
mild forms exhibiting few bullous lesions, devoid of
erythematous bases, to an unusual pattern of scarring plaques
and nodules with bullae or excoriations located on scalp and
extremities (papular and nodular pemphigoid), and even to
pictures mimicking other entities such as bullous erythema
multiforme and pemphigus (overlapping variants). Other
characteristics of DIBP are the average younger age of
patients, the histopathologic findings of a perivascular
infiltration of lymphocytes with few eosinophils and
neutrophils, intraepidermal vesicles with foci of necrotic
keratinocytes, thrombi in dermal vessels, and the immuno-
logic data of possible lack of tissue-bound and circulating
anti-BMZ IgG. Special immunologic markers may be
positive tests for macrophage migration, inhibitory factor,
and/or mast cell degranulation toward the inducing drug.19
Course
The course of DIBP is not uniform. Two main types may
be distinguished: an acute, self-limited variety showing
395
definitive resolution after the withdrawal of the culprit drug,
with or without steroid therapy, which can truly be
considered a drug eruption (DIBP proper); and a chronic
type that seems merely precipitated by drug administration
and, in the long run, assumes all characteristics of the classic,
spontaneously occurring disease (drug-triggered BP).19
Pathogenesis
Drugs probably act as triggers in patients with an
underlying genetic susceptibility by either modifying the
immune response or altering the antigenic properties of the
epidermal basement membrane. Drugs may induce anti-
BMZ antibody production by acting as haptens that bind to
proteins in the lamina lucida and change their antigenic
properties, or they may stimulate an autoimmune response
by structurally modifying molecules and uncovering
hidden epitopes.19
Both systemic and topical treatments can induce BP. The
inducing medications can be grouped according to their
chemical structure. The majority of the systemic drugs
contains or releases sulfhydryl groups (thiols: penicilla-
mine, 20 captopril, 21 penicillin and its derivatives, 22,23
furosemide, and some cephalosporins), either within the
drug precursor or within a catabolized metabolite. Furose-
mide holds a position of historical importance among the
implicated sulfa drugs. The biochemistry of free sulfhydryl
groups seems to be the crucial point of DIBP.24 On the one
hand, it has been proposed that the thiol group may allow the
molecule to combine with proteins in the lamina lucida, act
as a hapten, and result in autoantibody formation to BMZ
proteins. On the other hand, certain sulfur-containing drugs
may cause a dermo-epidermal split without immune
mediation. Some sulfa drugs, such as penicillamine, are
believed to act on Treg cells, causing a decreased suppressor
cell activity with subsequent hyperproduction of different
autoantibodies against the BP antigens.20,25
Drugs containing a phenol ring (phenols: some cephalo-
sporins, and aspirin25) and non-thiol non-phenol drugs
(angiotensin-converting enzyme inhibitors other than capto-
pril,26 most nonsteroidal anti-inflammatory drugs,27,28
nifedipine,29,30 and biological modifiers of the immune
response such dermatologyas vaccines) can facilitate the
onset of BP. Several mechanisms have been postulated for
the pathogenesis of these drugs. Some authors indicate a
causal relationship between aspirin, probably the most
widely used drug in the world, and BP. They suppose that
aspirin may act as a hapten in the patient, by altering the
antigenicity of the lamina lucida or attaching to a cell site,
thus leading to the formation of autoantibodies.25
TNF-α blockers
Several cases of BP during treatment with TNF-α blocker
therapy have been reported.31-33 Although the triggering
role of these drugs remains unclear, we cannot exclude that
they could be an immunologic trigger for autoimmune
disorders, in predisposed individuals. Down-regulation of
396 A. Lo Schiavo et al.

TNF-α by TNF-α blockers (etanercept, adalimumab) might important to consider a vaccine as a potential cause of BP
lead to development of BP in these patients. The possibility because infantile idiopathic BP is very uncommon). The best
of an autoimmune cutaneous bullous disease should be evidence for rash causation is supported by rechallenge with
considered when managing patients that are under treatment subsequent rash reactivation. Because an attempt to classify
with biological agents, as triggering of BP has been drugs according to therapeutic background is very difficult, it
described in association with efalizumab therapy.34 Con- has been proposed to group medications for their rechallenge
versely, TNF-α antagonists can be an effective alternative evidence (Table 1).24,41-49 In all patients with a diagnosis of
therapy for BP, in particular when BP coexists with BP, it is essential to consider the possibility of drug
psoriasis.35,36 Further studies are needed to establish the induction. A careful investigation on drug intake is necessary
efficacy of anti-TNF in the treatment of immunobullous and useful because the prompt discontinuation of the
disorders and to solve this controversy. “culprit” drug may result in rapid improvement or even
resolutory cure.
Contact pemphigoid
External use of a number of preparations on the skin or BP and physical agents
mucous membrane has been documented to provoke cases of
BP. The irritant effect of such preparations on the skin (as There are several reports of precipitation of BP by
described for benzyl benzoate) or allergic contact hypersen- ultraviolet (UV) light, either UVB or psoralen with
sitivity (suggested for 5-fluorouracil) have been proposed as ultraviolet A (PUVA), radiation therapy (RT), thermal or
a triggering factor for the occurrence of BP.18 electrical burns, or surgical procedures.50 In these cases, BP
may become generalized or remain localized to the injured
BP and vaccinations site (immunocompromised district51).
Vaccinations have been reported to induce BP in less than
20 cases in recent years. Anti-influenza vaccine,37-39 tetanus Radiation therapy
toxoid booster, and tetracoq vaccine40 were the possible BP induced by RT was observed predominantly in female
inducers. The majority involved flu vaccination, but a patients with breast cancer (78%). RT might itself change
controversy exists on the matter.38 antigenic properties and induce autoantibody formation
Although the pathologic relationship remains obscure, it through the direct alteration of the basal membrane with
is possible that vaccination, by causing inflammation into unmasking of antigens. Binding antibodies to BP antigens
the skin, leads to disruption of the basement membrane leads to complement activation and, by means of chemotac-
architecture with subsequent generation of anti-basement tic factors, it results in leukocyte attraction. This causes
membrane-specific antibodies. It is unlikely that the proteolytic cleavage of the lamina lucida and hence the
vaccines themselves would activate anti-BMZ antibody formation of bullae. Additionally, patients who develop BP
production as there are no similarities between the structure may already have circulating low-titre anti-BMZ antibodies,
of the implicated vaccines and the relevant basement and the tissue damage by RT may enhance the deposition of
membrane proteins; however, an important question is these antibodies through an alteration of permeability of
why the reports of vaccine-triggered bullous pemphigoid are
so rare when vaccination practice is so widespread.
Vaccination might trigger an enhanced autoimmune re- Table 1 Medications associated with onset of BP.24,41-49
sponse in patients with a relevant immunologic predisposi-
tion or with a subclinical BP.37 Likely Probable Questionable
association a association b association c
DIBP: Controversies Furosemide Penicillamine Chloroquine
There are some controversies concerning the incidence Phenacetin Ampicillin Topical fluorouracil
and even the actual existence of DIBP. First, before the Enalapril Penicillin UVA with psoralen
introduction of immunopathologic criteria for the diagnosis Ibuprofen Sulfapyridine Captopril
Influenza vaccine Cephalexin Amiodarone
of autoimmune subepidermal bullous diseases, several cases
Bumetanide Sulfonamide
of DIBP may have not been diagnosed. Another source of Spironolactone Tetanus toxoid
skepticism is that idiopathic BP is primarily a disease of Fluoxetine Interleukin-2
elderly people who often are treated for several reasons, and Omeprazole
with more than one medication. Many of the implicated Risperidone
pharmacologic agents or treatments only have been tempo- BP, bullous pemphigoid; UVA, ultraviolet A.
rarily associated with the onset of BP in a middle-aged to a
Rechallenge evidence supports association.
b
elderly age group that is otherwise normally susceptible to Young age group with BP and temporarily associated medication,
developing BP. Temporary occurrence, however, in a or spontaneous resolution of BP after drug withdrawal alone (without
younger age group, where BP is extremely rare, may be topical or systemic corticosteroid therapy).
c
Elderly age group and temporarily associated medication.
more supportive of a causative association (in children it is
Bullous pemphigoid pathogenesis and inducing factors
blood vessels. RT influences the amount of MMP-9 and
growth factors (as vascular endothelial growth factor) and
can induce local modifications of the immune system. As
explained previously, immune imbalance could lead to
inhibition of Treg activity, which in turn results in
overproduction of antibodies. BP can appear during early
or late after RT and, after the first onset within the irradiated
area, it may become generalized. This fact may be explained
by the epitope spreading, whereby a relatively restricted
immune response spreads to involve different sites on the
same autoantigen and different autoantigens.52-54
UV radiation
UV radiation is another important physical factor capable
of inducing BP. UV exposure may induce the production of
BP autoantibodies. Muramatsu et al suggested that BP
antigen is susceptible to UVB exposure, which probably
leads to configurational changes in antigen.55 The occur-
rence of BP often can be linked with UVA therapy.56 After
UVA exposure, serum levels of IL-1 rise, which can
contribute to polyclonal activation of B cells.57 Many
cases of BP occurred after physical antipsoriatic treatments,
such as sun exposure, PUVA therapy,58,59 or UVA60 and
UVB therapy.55 Recently, we observed also a 35-year-old
white man with psoriasis who developed blisters on his
extremities after receiving whole-body UVB phototherapy.
Similar to ionizing rays, UV radiation might alter BMZ
antigenicity and expose or release altered antigens that, in
turn, might result in the stimulation of antibody formation
against the BMZ.56
After ruling out other possible causes, in particular drug
intake, we regard UV therapy (in particular UVA-1) as the
most likely trigger of the disease.
Thermal or electrical burns
BP lesions following thermal or electrical burns usually
appear in the burned areas and later extend to other skin
regions.61 Attention should be paid to distinguish BP lesions
from physical injuries, such as sauna bathing burns, because
the latter could be initially misdiagnosed as BP. In literature,
the following features occurring in BP triggered by a boiling
water burn suggest that the burn and the subsequent BP
might not be coincidental: (1) the patients often suffered
from a burn some weeks prior to the occurrence of BP; (2)
blistering lesions initially occurred in the previously burned
areas and later spread to distant parts of the body; (3) no
relapse occurred once the triggering factor, thermal or
electrical burn, was eliminated.62-64
Surgical procedures
Surgical procedures also have been reported as exogenous
factors capable of inducing BP. Surgical or accidental
traumas are often the starting point of immune skin disorders.
BP confined to an accidentally traumatized limb or on an
amputation stump are clear examples of a trauma-related
regional imbalance of the immune response.51 BP lesions
397
often appear following different types of surgical procedures
(percutaneous endoscopic gastrostomy [PEG],65 urost-
omy, 66,67 around venous access site in hemodialysis
patient,68 and so on69). These cases might be directly related
to the damage to dermal-epidermal junction with subsequent
antigen exposure and activation of the immune response.
Skin damage selectively occurred in PEG and in other
ostomy sites, but most patients had widespread lesions,
possibly due to the presence of newly formed anti-BMZ
antibodies in the bloodstream. On the other hand, indwelling
tracheal tube was not associated with BP despite skin
damage occurring at the tracheotomy, suggesting that PEG
may have some special meaning on the pathogenesis. The
skin around the PEG tube is frequently inflamed by gastric
juice and chronically irritating skin may induce activation of
the immune system, which can make the difference between
PEG and tracheal tube.65
Localized forms of BP due to physical agents: An
example of immunocompromised district
BP induced by physical agents (RT, UV radiation,
thermal and electrical burns, surgical procedures) may be
generalized or may remain localized to the traumatized site.
For instance, post-radiotherapy BP can occur outside of the
irradiated area, but it is often confined to the radiation field.
As explained previously, most probably these factors cause
structural modifications of the BMZ or exposure of new
epitopes, thus leading to an enhanced antigenicity of BMZ
components. Anyway, a localized form of BP (as it occurs
with other disimmune diseases) could be explained consid-
ering the injury that physical agents exert on lymphatic
vessels and nerve fibers, because any alteration of these
structures can lead to an imbalance of the local immune
response, thus creating an immunocompromised district.51
BP and transplant
The occurrence of BP in transplant patients is rare, with
only few cases reported in the literature (above all, BP is
associated with renal transplant). It is noteworthy that all of
the patients described in the literature responded only
partially to systemic corticosteroids. The skin lesions in
two cases cleared after removal of the graft.70 These
observations might indicate that renal allograft is involved
in the pathogenesis of BP in these patients. Autoantibody
formation in renal allografts may result from chronic
allogeneic stimuli. An immune cross-reactivity between the
skin and the kidney also may have a role. Persistent self-
antigenemia due to chronic rejection may contribute to the
pathogenesis. BP in renal transplant patients also could be
associated with medications, in particular immunosuppres-
sants, given to avoid rejection response. Autoimmunity and
graft tolerance via direct suppression of Th and B cells
strictly depend on Tregs. Decreased numbers of Tregs in the
peripheral blood were found in solid organ transplant
recipients who received tacrolimus treatment. These cells
398
need low-dose IL-2 signals to survive and retain their
function. Tacrolimus and other immunosuppressive drugs
selectively block the expression of the IL-2 gene, and thus
suppress the number of Tregs. A deficiency of Tregs
indirectly contributes to autoantibody induction.70
BP also has been described after liver transplantation for
liver failure in a child with Coomb’s positive autoimmune
hemolytic anemia and giant cell hepatitis.71
BP and infections
Experimental investigations have hinted at a possible role
of infections, in particular herpes virus infections, in the
pathogenesis of BP. There are reports of human herpesvi-
ruses (HHVs) (cytomegalovirus, Epstein-Barr virus, HHV-6)
in the vesicular fluid and of antibodies to HHV-8 in the
serum of patients with BP. The well-known latency of HHVs
in a specific set of cells questions the etiopathogenic role of
these viruses.72 A contributing role in inducing BP has been
suggested also for hepatitis B and C viruses, Helicobacter
pylori, and Toxoplasma gondii.73
Viruses can induce autoimmune diseases in several, not
mutually exclusive, ways. First, because of damage to
infected cells, a virus may insert, expose, modify, or release
antigens usually hidden and may stimulate the latter to
recognize them as foreign. Second, new antigens may
derive from the incorporation of fragments of the cell
membrane into the envelope of the virus. Third, the virus
may share epitopes with its host, thus leading to the
development of cross-reactive autoantibodies (molecular
mimicry). Additional mechanisms also are possible.
Viruses, for example, may activate polyclonal B cells to
produce autoantibodies and influence T cells or their
lymphokine release. Antiviral antibodies also may harm
the host by eliciting anti-idiotypic antibodies or immune
complexes with viral antigens.72
BP and food
Unlike pemphigus, no dietary triggers are suspected of
being involved in the induction of BP. One case of
dyshidrosiform pemphigoid induced by nickel in the diet
resolved completely on a nickel-free diet.74 The presence of
antigliadin antibodies in the sera of BP patients may indicate
that some BP patients have gluten sensitivity. There have
been no reports, however, of BP improving with a gluten-
free diet.74
References
1. Kasperkiewicz M, Zillikens D, Schmidt E. Pemphigoid diseases:
pathogenesis, diagnosis, and treatment. Autoimmunity 2012;45:55-70.
2. Di Zenzo G, Marazza G, Borradori L. Bullous pemphigoid:
physiopathology, clinical features and management. Adv Dermatol
2007;23:257-88.
A. Lo Schiavo et al.
3. Patrıcio P, Ferreira C, Gomes MM, Filipe P. Autoimmune bullous
dermatoses: a review. Ann N Y Acad Sci 2009;1173:203-10.
4. Di Zenzo G, Thoma-Uszynski S, Fontao L, et al. Multicenter
prospective study of the humoral autoimmune response in bullous
pemphigoid. Clin Immunol 2008;12:415-26.
5. Heimbach L, Li Z, Berkowitz P, et al. The C5a receptor on mast cells is
critical for the autoimmune skin-blistering disease bullous pemphigoid.
J Biol Chem 2011;286:15003-9.
6. Kasperkiewicz M, Zillikens D. The pathophysiology of bullous
pemphigoid. Clin Rev Allergy Immunol 2007;33:67-77.
7. Hertl M, Eming R, Veldman C. T cell control in autoimmune bullous
skin disorders. J Clin Invest 2006;116:1159-66.
8. Grando SA. Pemphigus autoimmunity: hypothesis and realities.
Autoimmunity 2012;45:7-35.
9. Rensing-Ehl A, Gaus B, Bruckner-Tuderman L, Martin SF. Frequency,
function and CLA expression of CD4+CD25+FOXP3 + regulatory T
cells in bullous pemphigoid. Exp Dermatol 2007;16:13-21.
10. Shlomchik MJ. Activating systemic autoimmunity: B’s, T’s, and tolls.
Curr Opin Immunol 2009;21:626-33.
11. Toosi S, Bystryn JC. Potential role of interleukin-17 in the pathogenesis
of bullous pemphigoid. Med Hypothesis 2010;74:727-8.
12. Arakawa M, Dainichi T, Ishii N, et al. Lesional Th17 cells and
regulatory T cells in bullous pemphigoid. Exp Dermatol 2011;20:
1011-37.
13. Torchia D, Caproni M, Volpi W, Fabbri P. Naturally occurring
regulatory T cells in mucous membrane pemphigoid lesions. Acta
Dermatovenerol Alp Panonica Adriat 2009;18:3-6.
14. Liu Z, Giudice GJ, Swartz SJ, et al. The role of complement in
experimental bullous pemphigoid. J Clin Invest 1995;95:1539-44.
15. Iwata Y, Komura K, Kodera M, et al. Correlation of IgE autoantibody to
BP180 with a severe form of bullous pemphigoid. Arch Dermatol
2008;144:41-8.
16. Marzano AV, Tedeschi A, Fanoni D, et al. Activation of blood
coagulation in bullous pemphigoid: role of eosinophils, and local and
systemic implications. Br J Dermatol 2009;160:266-72.
17. Venning VA, Wojnarowska F. Induced bullous pemphigoid. Br J
Dermatol 1995;132:831-2.
18. Vassileva S. Drug-induced pemphigoid: bullous and cicatricial. Clin
Dermatol 1998;16:379-87.
19. Ruocco V, Sacerdoti G. Pemphigus and bullous pemphigoid due to
drugs. Int J Dermatol 1991;30:307-12.
20. Popadic S, Skiljevic D, Medenica L. Bullous pemphigoid induced by
penicillamine in a patient with Wilson disease. Am J Clin Dermatol
2009;10:36-8.
21. Mallet L, Cooper JW, Thomas J. Bullous pemphigoid associated with
captopril. DICP 1989;23:63.
22. Wozniak K, Kowalewski C, Hashimoto T, Ishii N, Glinska-
Wielochowska M, Schwartz RA. Penicillin-induced anti-p200
pemphigoid: an unusual morphology. Acta Derm Venereol 2006;
86:443-6.
23. Hodak E, Ben-Shetrit A, Ingber A, Sandbank M. Bullous pemphigoid
—an adverse effect of ampicillin. Clin Exp Dermatol 1990;15:50-2.
24. Walsh SR, Hogg D, Mydlarski PR. Bullous pemphigoid: from bench to
bedside. Drugs 2005;65:905-26.
25. Durdu M, Baba M, Seçkin D. A case of bullous pemphigoid induced by
aspirin. J Am Acad Dermatol 2011;65:443-4.
26. Smith EP, Taylor TB, Meyer LJ, Zone JJ. Antigen identification in drug-
induced bullous pemphigoid. J Am Acad Dermatol 1993;29:879-82.
27. Laing VB, Sheretz EF, Flowers FP. Pemphigoid-like bullous eruption
related to ibuprofen. J Am Acad Dermatol 1998;19:91-4.
28. Pompeová L. Bullous pemphigoid induced by taking Brufen. Cesk
Dermatol 1981;56:256-8.
29. Ameen M, Harman KE, Black MM. Pemphigoid nodularis associated
with nifedipine. Br J Dermatol 2000;142:575-7.
30. Brenner S, Ruocco V, Bialy-Golan A, et al. Pemphigus and
pemphigoid-like effects of nifedipine on in vitro cultured normal
human skin explants. Int J Dermatol 1999;38:36-40.
Bullous pemphigoid pathogenesis and inducing factors
31. Kluk J, Goulding JM, Bhat J, Finch TM. Drug-induced bullous
pemphigoid: cases triggered by intravenous iodine and etanercept. Clin
Exp Dermatol 2011;36:871-3.
32. Bordignon M, Belloni-Fortina A, Pigozzi B, Tarantello M, Alaibac M.
Bullous pemphigoid during long-term TNF-alpha blocker therapy.
Dermatology 2009;219:357-8.
33. Toosi S, Bystryn JC. Does adalimumab cause bullous pemphigoid?
Clin Exp Dermatol 2010;35:795.
34. Duong TA, Buffard V, André C, et al. Efalizumab-induced bullous
pemphigoid. J Am Acad Dermatol 2010;62:161-2.
35. Cusano F, Iannazzone SS, Riccio G, Piccirillo F. Coexisting bullous
pemphigoid and psoriasis successfully treated with etanercept. Eur J
Dermatol 2010;20:520.
36. Yamauchi PS, Lowe NJ, Gindi V. Treatment of coexisting bullous
pemphigoid and psoriasis with the tumor necrosis factor antagonist
etanercept. J Am Acad Dermatol 2006;54:121-2.
37. Walmsley N, Hampton P. Bullous pemphigoid triggered by swine flu
vaccination: case report and review of vaccine triggered pemphigoid.
J Dermatol Case Rep 2011;5:74-6.
38. García-Doval I, Mayo E, Nogueira Fariña J, Cruces MJ. Bullous
pemphigoid triggered by influenza vaccination? Ecological study in
Galicia, Spain. Br J Dermatol 2006;155:820-3.
39. Mérida C, Martínez-Escribano JA, Frías JF, Sánchez-Pedreño P,
Corbalán R. Bullous pemphigoid in an infant after vaccination. Actas
Dermosifiliogr 2005;96:255-7.
40. Baykal C, Okan G, Sarica R. Childhood bullous pemphigoid developed
after the first vaccination. J Am Acad Dermatol 2001;44:348-50.
41. Lee JJ, Downham 2nd TF. Furosemide-induced bullous pemphigoid:
case report and review of literature. J Drugs Dermatol 2006;5:562-4.
42. Baz K, Ikizoglu G, Kaya TI, Koca A. Furosemide-induced bullous
pemphigoid. J Eur Acad Dermatol Venereol 2002;16:81-2.
43. Kashihara M, Danno K, Miyachi Y, Horiguchi Y, Imamura S. Bullous
pemphigoid-like lesions induced by phenacetin. Report of a case and an
immunopathologic study. Arch Dermatol 1984;120:1196-9.
44. Czechowicz RT, Reid CM, Warren LJ, Weightman W, Whitehead FJ.
Bullous pemphigoid induced by cephalexin. Australas J Dermatol
2001;42:132-5.
45. Boulinguez S, Bernard P, Bedane C, le Brun V, Bonnetblanc JM. Bullous
pemphigoid induced by bumetanide. Br J Dermatol 1998;138:548-9.
46. Modeste AB, Cordel N, Courville P, Gilbert D, Lauret P, Joly P.
Bullous pemphigoid induced by spironolactone. Ann Dermatol
Venereol 2002;129:56-8.
47. Rault S, Grosieux-Dauger C, Verraes S, Bernardeau K, Durlach A,
Bernard P. Bullous pemphigoid induced by fluoxetine. Br J Dermatol
1999;141:755-6.
48. Millard TP, Smith HR, Black MM, Barker JN. Bullous pemphigoid
developing during systemic therapy with chloroquine. Clin Exp
Dermatol 1999;24:263-5.
49. Wijeratne C, Webster P. Risperidone and bullous pemphigoid. Am J
Psychiatry 1996;153:735.
50. Khandpur S, Verma P. Bullous pemphigoid. Indian J Dermatol
Venereol Leprol 2011;77:450-5.
51. Ruocco V, Brunetti G, Puca RV, Ruocco E. The immunocompromised
district: a unifying concept for lymphoedematous, herpes-infected and
otherwise damaged sites. J Eur Acad Dermatol Venereol 2009;23:1364-73.
52. Isohashi F, Konishi K, Umegaki N, Tanei T, Koizumi M, Yoshioka Y.
A case of bullous pemphigoid exacerbated by irradiation after breast
conservative radiotherapy. Jpn J Clin Oncol 2011;41:811-3.
399
53. Srifi N, Benomar S, Zaghba N, et al. Generalized bullous pemphigoid
induced by radiotherapy. Ann Dermatol Venereol 2011;138:311-4.
54. Mul VE, Verschueren TA, van Geest AJ, Baumert BG. Bullous
pemphigoid (BP) induced by radiotherapy. Radiother Oncol 2007;82:
105.
55. Muramatsu T, Yamashina Y, Shirai T, Onishi T. UVB irradiation
reduces the expression of pemphigoid antigens in organ-cultured
normal human skin. Arch Dermatol Res 1994;286:142-4.
56. Washio H, Hara H, Suzuki H, Yoshida M, Hashimoto T. Bullous
pemphigoid in psoriasis lesions after UVA radiation. Acta Derm
Venereol 2005;85:561-3.
57. Fabbri P. Pemfigoide Bolloso. Immunodermatologia 2nd ed. ISED:4:
291-304.
58. Kao CL, Krathen RA, Wolf Jr JE, Fuerst JF, Hsu S. Psoralen plus
ultraviolet A-induced bullous pemphigoid. J Drugs Dermatol 2008;7:
695-6.
59. Barnadas MA, Gilaberte M, Pujol R, Agustí M, Gelpí C, Alomar A.
Bullous pemphigoid in a patient with psoriasis during the course of
PUVA therapy: study by ELISA test. Int J Dermatol 2006;45:
1089-92.
60. Sacher C, König C, Scharffetter-Kochanek K, Krieg T, Hunzelmann N.
Bullous pemphigoid in a patient treated with UVA-1 phototherapy for
disseminated morphea. Dermatology 2001;202:54-7.
61. Balato N, Ayala F, Patruno C, Turco P, Ruocco V. Bullous pemphigoid
induced by a thermal burn. Int J Dermatol 1994;33:55-6.
62. Bachmeyer C, Cabanne-Hamy A, Moguelet P, Doizi S, Callard P.
Bullous pemphigoid after boiling water burn. South Med J 2010;103:
1175-7.
63. Xu HH, Xiao T, He CD, et al. Bullous pemphigoid triggered by a
boiling water burn. Eur J Dermatol 2008;18:466-7.
64. Kluger N, Laipio J, Virolainen S, Ranki A, Koljonen V. A fatal case of
hot air sauna burn in an elderly patient initially misdiagnosed as bullous
pemphigoid. Acta Derm Venereol 2011;91:732-3.
65. Nozu T, Mita H. Bullous pemphigoid and percutaneous endoscopic
gastrostomy. Intern Med 2010;49:971-5.
66. Batalla A, Peón G, De la Torre C. Localized bullous pemphigoid at
urostomy site. Indian J Dermatol Venereol Leprol 2011;77:625.
67. Torchia D, Caproni M, Ketabchi S, Antiga E, Fabbri P. Bullous
pemphigoid initially localized around urostomy. Int J Dermatol
2006;45:1387-9.
68. Yesudian PD, Dobson CM, Ahmad R, Azurdia RM. Trauma-induced
bullous pemphigoid around venous access site in a haemodialysis
patient. Clin Exp Dermatol 2002;27:70-2.
69. Neville JA, Yosipovitch G. Flare of bullous pemphigoid in surgically
treated skin. Cutis 2005;75:169-70.
70. Chen TJ, Lai PC, Yang LC, Kuo TT, Hong HS. Bullous pemphigoid in
a renal transplant recipient: a case report and review of the literature.
Am J Clin Dermatol 2009;10:197-200.
71. Kerkar N, Cohen S, Dugan C, et al. Bullous pemphigoid after liver
transplantation for liver failure. Liver Transpl 2006;12:1705-10.
72. Drago F, Nozza P, Casazza S, Brusati C, Bandelloni R, Rebora A.
Human herpesviruses in bullous pemphigoid lesions. Br J Dermatol
2005;152:375-6.
73. Sagi L, Baum S, Agmon-Levin N, et al. Autoimmune bullous diseases
the spectrum of infectious agent antibodies and review of the literature.
Autoimmun Rev 2011;10:527-35.
74. Fedeles F, Murphy M, Rothe MJ, Grant-Kels JM. Nutrition and bullous
skin diseases. Clin Dermatol 2010;28:627-43.