DOI: 10.1111/jdv.

12366 JEADV

REVIEW ARTICLE

Drug-induced pemphigoid: a review of the literature

P.G. Stavropoulos, E. Soura,* C. Antoniou
1st Department of Dermatology/University Clinic, “Andreas Sygros” Hospital, Athens, Greece
*Correspondence: E. Soura. E-mail: anonaki@hotmail.com

Abstract
Bullous pemphigoid is an acquired autoimmune disease that is characterized by subepidermal blistering and affects
mainly the elderly. The pathogenesis of the condition has not yet been fully elucidated, but it is widely accepted that a
strong correlation with various medications may exist. In reality, more than 50 different drugs have been associated with
the appearance of bullous pemphigoid and as new therapies emerge, this number is very likely to increase. A number of
pathogenetic mechanisms have been proposed in the past. It is true that a delicate immunological balance is disturbed
in all patients with the disease. The variable effects that may be exhibited by the use of biological drugs could shed some
light in this complex immunological behaviour. At the same time, drug-induced bullous pemphigoid is difficult to differen-
tially diagnose from its idiopathic counterpart, as the clinical picture and histopathological findings in both conditions
may only have subtle differences. Patients who present with bullous pemphigoid and receive multiple regimens should
always be suspected of suffering from the drug-induced variant of the condition. This possibility must be considered, as
after the withdrawal of the suspect medication most patients respond rapidly to treatment and do not experience
relapses.
Received: 13 August 2013; Accepted: 11 December 2013

Conflicts of interest
None declared.

Funding sources
None declared.

Introduction antigens for drug-induced bullous pemphigoid (DIBP) have

Bullous pemphigoid is an acquired autoimmune disease that
affects mainly the elderly and is characterized by subepidermal
blistering. Although in most cases, the causative agent remains
unidentified, certain medications have been implicated in the
pathogenesis of the disease.
The drug-induced variant of bullous pemphigoid follows the
oral or (sometimes) topical administration of specific drugs. It
is difficult to differentiate clinically from classic bullous pem-
phigoid, and must always be considered as a possible diagnosis
in elderly patients who have recently changed or added a new
drug in their normal medication regimen. The main bullous
pemphigoid antigens, are bullous pemphigoid antigen 1
(BP230), which is a part of the hemidesmosomal plaque, and
bullous pemphigoid antigen 2 (BP180), a transmembrane gly-
coprotein. These are components of the hemidesmosomes
residing on the lamina lucida of the basement membrane and
are a 230 kDa and an 180 kDa antigen respectively.1 Most BP
patients have autoantibodies binding to an immunodominant
region of BP180, the non-collagenous 16A domain (NC16A).1,2
Despite the extensive research on bullous diseases, no specific
been identified and it is believed that, at least in part, they are
the same as the ones detected in the spontaneous occurring
bullous pemphigoid.3,4
Clinical and histopathological characteristics
Drug-induced bullous pemphigoid is characterized by a younger
age of onset than the spontaneous occurring bullous pemphig-
oid. Lesions usually appear as tense bullae on normally appear-
ing skin, or (more uncommonly) on an erythematous or even
urticarial base. They may be accompanied by erythema multi-
forme type of lesions such as target lesions on palms and soles5
(Fig. 1a,b). Nikolsky sign can be positive in some cases.4 Muco-
sal involvement, if present, is usually mild. The erosions left after
rupture of the bullae heal spontaneously without scarring. The
areas involved are the trunk, the limbs (most commonly the
lower legs) and the face. Patients usually complain of severe
pruritus.
Laboratory studies performed may show blood eosinophilia
and an increased amount of soluble IL-2 receptor.6 Special
markers such as macrophage migration inhibitory factor might

JEADV 2014, 28, 1133–1140 © 2014 European Academy of Dermatology and Venereology
1134
(a)
(b)
Figure 1 (a) Tense bullae appearing on an erythematous base.
The patient reported receiving antibiotic treatment (quinolone)
2 weeks prior to the appearance of the eruption. (b) Tense bullae
on an erythematous base, accompanied by an erythema multi-
forme type eruption.
be positive. Eosinophilic cationic protein and neutrophil-derived
myeloperoxidase might be elevated in sera and blister fluids of
such patients. Finally, mast cell degranulation might be observed
towards the offending drug.7
The typical histological features of DIBP include subepider-
mal blisters, intraepidermal vesicles and necrotic keratinocytes.5
Blister cavity may contain numerous eosinophils, neutrophils
and fibrin. A dense dermal inflammatory infiltrate containing
many eosinophils, neutrophils with lymphocytes and histiocytes
may be present. Histology samples taken from normal skin are
non-diagnostic.
The findings in direct immunofluorescence and indirect
immunofluorescence are similar to those in classic bullous
pemphigoid. IgG antibodies and C3 along the linear basement
membrane zone are detected in 90% of cases with DIF,
JEADV 2014, 28, 1133–1140
Stavropoulos et al.
Table 1 Common findings in DIBP
Clinical features
Younger age of onset
Positive Nikolsky sign
Appearance of lesions on normally appearing skin
Involvement of lower leg areas
Target lesions on palms and soles
Mucosal involvement
Histological features
Marked eosinophilic infiltrate
Intraepidermal vesicles
Necrotic keratinocytes
Thrombus formation
Other
Marked eosinophilia (serum)
Improvement after administration of systemic corticosteroids
Improvement after discontinuation of specific drug
Low rates of recurrence
DIBP, drug-induced bullous pemphigoid.
whereas circulating IgG antibodies are detected in 75% of
cases with IIF.2 Common findings in DIBP are summarized
in Table 1.
Two types of DIBP have been described in the literature. The
first type is called ‘DIBP proper’ and is an acute and self-limited
condition which responds promptly when the inciting drug is
withdrawn. The second type is called ‘drug-triggered BP’ and
follows a more chronic, persistent and severe course which
resembles that of classic bullous pemphigoid.8
The eruption may appear up to 3 months after the ingestion
of the culprit medication. Several immunological and non-
immunological proposed mechanisms have been suggested for
DIBP. As in all immune mediated diseases, predisposing, precip-
itating and perpetuating factors play a major role in the patho-
genesis of the disease. In the case of DIBP, no specific Human
Leukocyte Antigen association has been made.8 It is important
to mention, though, that the immune system is represented by
the actions of many components and that genes may have vari-
able effects on many systems. Therefore, the phenotype after
exposure to a specific medication may depend on the way that
the multiple ‘activated’ genes interact in a certain individual.9
Furthermore, even if a genetic predisposition exists, the disease
may fail to appear if no appropriate environmental trigger
occurs.10
Pathogenetic mechanisms
The ‘two-step’ theory is a suggested hypothesis for DIBP which
states that two separate drugs may induce BP. It is possible that
the chemical class of a medicine could play a role in DIBP. For
instance, aromatic neuroleptics seem to induce more allergic
reactions than non-aromatics. In a susceptible person who is
© 2014 European Academy of Dermatology and Venereology
Drug-induced pemphigoid 1135

already sensitized to such an agent, cross reactivity with another
agent of the same class or of similar chemical structure may be
possible.11 As anti-BP180 and anti-BP230 autoantibodies are
more frequently detected in the elderly, one could postulate that
drug exposure is one of the reasons for the increased prevalence
of BP in this age group, as these patients are more likely to
receive multiple medications, and drugs have been suggested to
induce anti-basement membrane antibody formation by various
pathogenetic theories.12
Another theory for the pathogenesis of DIBP suggests that
drugs, in certain individuals, may cause an accidental dysregula-
tion or immune reorganization, leading to the inactivation of
endogenous regulatory processes controlling a possible disease
phenotype. 13 A change in T-regulatory (CD4+, CD25+, Foxp)
cells could cause a derepression of ‘forbidden’ B-cell clones and
the release of autoantibodies against the basement membrane
zone.7,9
Molecular mimicry is a proposed pathogenetic mechanism
for a number of autoimmune diseases. Considering the fact that
many drugs act by binding to micro RNA and other transcrip-
tional and translational regulators in a similar way to a virus, the
possibility of them being mistaken for microbial antigens is not
unlikely.14 Misidentification of drugs by the immune system, in
susceptible individuals, could lead to activation of CD4+ T cells
and initiation of the autoimmune cascade.9
Another possibility is that specific drugs may have the ability
of acting as antigenic haptens that can bind to and modify pro-
tein molecules in the basement membrane. This could lead to
the exposure of a hidden antigenic site and potentially change its
antigenic properties.8 In a recent study performed by Patsatsi
et al., an increased titre of anti-180BPNC16a autoantibody was
found in a group of patients with BP who were receiving sys-
temic medications prior to the disease, compared with a group
of patients who did not receive any medications.12 This finding
could support the drug triggering epitope spreading theory.
On the other hand, sulphur-containing drugs may have the
ability to directly disrupt the dermo-epidermal junction without
the involvement of immunological mechanisms by interacting
with the sulphydryl groups in desmosomes.7,15
Drugs associated with bullous pemphigoid
Since DIBP was first reported in 1970 in an 11-year-old boy
receiving salicylazosulphapyridine,16 multiple drugs have been
implicated in the pathogenesis of the disease (Table 2).17 Unfor-
tunately, most of the patients developing BP are treated with
multiple medications making the identification of the culprit

Table 2 List of drugs reported to induce bullous pemphigoid

Antibiotics Antiarrythmics-antihypertensives Vaccines
Actinomycin Ca+ channel blockers Influenza
Amoxicillin Amlodipine Swine flu
Ampicillin Nifedipine Tetanus toxoid
Cephalexin ACE inhibitors HZV
Ciprofloxacin Capropril Hexavalent combined
Chloroquine Enalapril vaccines
Dactinomycin Lisinopril
Levofloxacin b-blockers
Penicilline Nadolol
Rifampicin Practolol
Angiotensin II antagonists
Losartan
NSAID Salicylates Other
Azapropazone Aspirin Arsenic
Diclofenac (topical) Sulphasalazine Clonidine
Ibuprofen Salicylazosulphapyride Erlotinib
Mefenamic acid Fluoxetine
Phenacetin Flupenthixol
Diuretics Antidiabetics Gabapentine
Furosemide Sitagliptin Galantamine hydrobromide
Spironolactone Tolbutamide Gold thiosulphate
Vildagliptin Interleukin-2
Levetiracetam
Anti TNF-a Antirheumatics
Methyldopa
Adalimumab D-penicillamine
Terbinafine
Efalizumab Tiobutarit
Thiopronin
Etanercept
Omeprazole
Psoralens with UVA
Placental extracts
Potassium iodide
Risperidone
Sulphonamide

JEADV 2014, 28, 1133–1140 © 2014 European Academy of Dermatology and Venereology
1136
drug difficult. Also, many receive various over the counter drugs
(vitamins, herbal teas, painkillers etc.) who are rarely reported to
physicians. As re-challenging the patients is out of the question
due to ethical reasons, the number of studies on the subject is
small. Bastuji-Garin et al., report a strong association of BP with
neuroleptics and antidiuretics (mainly aldosterone antago-
nists).18 In a recent case–control study by Lloyd-Lavery et al.,
that included 86 patients with BP, loop diuretics were found to
be used significantly more frequently by patients with bullous
pemphigoid compared with controls. This association was found
to be independent of age, cerebrovascular disease, dementia,
hypertension and ischaemic heart disease.19 Patsatsi et al., report
that the most commonly used drugs by the patients in their
study were angiotensin-converting enzyme inhibitors, anticoag-
ulants and diuretics. Neuroleptics, antidiabetics and antiarryth-
mics were also considered important.12 These findings are
consistent with a number of case reports published over the
years. During recent years, though, several new groups of medi-
cations have been associated with the appearance of DIBP.
TNFa inhibitors
TNFa is a cytokine that is involved in systemic inflammation
and has been associated with a number of diseases, including
rheumatoid arthritis, inflammatory bowel disease and psoriasis.
Mast cells are responsible for the secretion of TNFa and other
cytokines in patients with BP and seem to play an important role
in the pathogenesis of the disease.1 The serum levels of TNFa are
reported to be correlated with both the severity and number of
lesions.20 Also, blister fluid from BP patients contains higher lev-
els of this cytokine compared with other blistering disorders.21
In several case reports anti-TNFa agents were found to be suc-
cessful in the treatment of mucous membrane pemphigoid22–24
and bullous pemphigoid that developed in patients with psoria-
sis.25–28 At the same time, a number of case reports implicate
anti-TNFa agents such as etanercept,29 adalimumab30,31 and ef-
alizumab32,33 as inducing agents. This paradox is difficult to
explain since, although it is understood that these drugs block
TNFa, the full extent of their effects on the immune system is
still under investigation. Perhaps, the ability of an anti-TNFa
agent to induce or to cure an autoimmune disease is associated
with the immunological profile of each patient in the same way
as is the phenotype of autoimmune diseases. Liu et al. investi-
gated the effects of TNFa on eosinophils and found that these
cells have the ability to produce large amounts of both Th1 and
Th2 chemokines, depending on the microenvironment and,
more specifically, the presence of INF-c or IL-4 respectively. A
combination of TNFa and INF-c seems to induce the secretion
of CXCL9, CXCL10 and Th1 chemokines, whereas a combina-
tion of TNFa and IL-2 seems to lead to the excretion of CCL12,
CCL22 and Th2 chemokines.34 Therefore, one could suggest that
anti-TNFa drugs have both the ability to suppress Th1 response
in Th1 driven diseases (like psoriasis), and Th2 response in Th2
JEADV 2014, 28, 1133–1140
Stavropoulos et al.
driven diseases (like bullous pemphigoid) depending on the lev-
els of INF-c.
BP that was attributed to the use of anti-TNFa agents was
observed after both short-term and long-term treatment with
these drugs. In a patient who received efalizumab for the treat-
ment of psoriasis, a severe bullous reaction was observed after
6 weeks from initiation of treatment.33 On the other hand, a
patient treated with etanercept30 and a patient treated with ada-
limumab29 for rheumatoid arthritis, developed lesions consistent
with BP after 2 and 3 years of treatment respectively. All patients
improved greatly after discontinuation of the suspect drug and
administration of systemic corticosteroid treatment. Whether
the appearance of DIBP is due to the dysregulation of TNFa lev-
els on an already disrupted immune system, as a result of the
pre-existing inflammatory disease, and can be considered as a
true drug hypersensitivity reaction, or if this deregulation of
TNFa levels could cause an ‘unmasking’ of a subclinical autoim-
mune condition, and can, therefore, be considered as a trigger
factor, is something that remains to be investigated.
Vaccines
Over the years, an association of DIBP with various vaccines has
been suggested. Vaccines for influenza, swine flu, tetanus toxoid
and HZV have all been implicated. Although data from some
studies do not support the hypothesis of influenza vaccination
being an important trigger for severe bullous pemphigoid,35 a
number of case reports claim the exact opposite.36,37 More spe-
cifically, Garc
ıa-Doval et al., report the appearance of bullous
pemphigoid in a 90-year-old patient 12 hours after the adminis-
tration of an influenza vaccine.38 The type of agent used was an
inactivated subunit split vaccine that contained haemagglutinin
neuraminidase. Downs et al., report the occurrence of BP in
four patients (aged 72–90 years) 1 month after vaccination with
a similar type of vaccine. One of the patients experienced a
relapse of the disease after having received further vaccination
1 year later.39 Isolated cases of bullous pemphigoid arising after
administration of herpes zoster40 and tetanus toxoid41 vaccines
have also been reported.
Bullous pemphigoid has been reported after childhood
vaccinations as well. In all cases, a short latency period was dem-
onstrated. Hafiji et al., reported the appearance of BP in a
3-month-old boy, 8 days after receiving his first set of vaccina-
tions (diphtheria, tetanus, pertussis, polio, Haemophilus influ-
enza B and pneumococcus).42 Similarly, Baykal et al., reported
the appearance of BP in a 3.5-month-old boy, 24 hours after
receiving his first tetracoq vaccination.43 Merida et al., reported
a 2-month-old boy who was presented with bullous lesions on
palms and soles that appeared 7 days after receiving the first
dose of the hepatitis B, poliomyelitis, diphtheria, tetanus, pertus-
sis and H. influenza B vaccine. The patient was re-challenged
when he received the second dose of the vaccine (3 months
later) and experienced an exacerbation of the condition which
© 2014 European Academy of Dermatology and Venereology
Drug-induced pemphigoid 1137

was finally diagnosed as bullous pemphigoid. No other relapses
were observed in a 5-year follow-up period.44 Bullous pemphig-
oid with similar clinical manifestations is described by Valdiv-
ielso-Ramos et al., in a 3-month-old girl, appearing 3 weeks
after the first vaccination with a hepatitis B, diphtheria, tetanus,
pertussis, polio, haemophilus influenza B, meningococcal C and
pneumococcus vaccine. Fifteen months later, the child remains
disease free.45
The processes through which vaccines can cause bullous pem-
phigoid remain unidentified. As there are no similarities between
the structure of basement membrane proteins and the impli-
cated vaccines, it is highly improbable that a direct antibody
response to the vaccines could be the cause of the condition.
Many studies claim that patients may exhibit a subclinical form
of the disease by expressing high levels of bullous pemphigoid
antigens without any clinical symptoms.46 Furthermore, experi-
mental studies in mice have shown that constantly high levels of
circulating BP180 can induce a loss of tolerance to type XVII
collagen and finally lead to bullous pemphigoid.47 Therefore, it
could be possible that the inflammation caused by vaccination
may lead to disruption of the basement membrane, followed by
subsequent production of anti-basement membrane specific
Table 3 Topical agents associated with bullous pemphigoid
according to reported cases
Anthraline
Benzyl benzoate (30%)
Coal tar
Diclofenac
5-FU
Iodophor adhesive band
antibodies in predisposed individuals.48 The pathogenesis of
DIBP in children may be similar to that of the adults. Some
authors, though, claim that bullous pemphigoid antibodies may
be transferred from the mothers. So far, studies have not been
able to detect such antibodies in maternal sera.49
Dipeptidyl peptidase 4 inhibitors
Another new category of drugs that has been increasingly linked
to cases of bullous pemphigoid are the dipeptidyl peptidase 4
inhibitors. Pasmatzi et al., reported two patients (a 59 -year-old
man and a 67-year-old woman) who presented with bullous pem-
phigoid 2 months after initiation of therapy with combination of
metformin and vidagliptin. Complete remission was observed in
both patients after discontinuation of therapy and concomitant
administration of oral corticosteroids.50 Similarly, Skandalis
et al., reported five patients who presented with bullous pem-
phigoid after receiving combination drugs containing metformin
and vildagliptin (three patients) or sitagliptin (two patients).
Interestingly, the only patient experiencing a relapse was the one
who discontinued the medication after he was discharged from
the hospital. All patients improved rapidly upon discontinuation
of the suspect drug and no relapses were noted.51 Finally, a recent
case report implicates vildagliptin, used as monotherapy, as an
inciting agent in a 61-year-old man presented with BP.52
Dipeptidyl peptidase 4 inhibitors are incretin-based drugs
used to treat type 2 diabetes mellitus and possess a pluripotent
biological role. In the past there have been reports of patients
developing photosensitivity,53 or more generalized skin erup-
tions after their administration.54 In preclinical studies per-
formed in monkeys, necrotic skin lesions were observed after
administration of vildagliptin and saxagliptin.55 Perhaps gliptins

Table 4 Suggested differences between DIBP and classic bullous pemphigoid

Drug-induced bullous pemphigoid Classic bullous pemphigoid
History Receives multiple therapeutic regimens May or may not receive multiple therapeutic regimens
Patient was treated with a new drug recently Patient did not receive any new drug recently
Clinical picture Younger age of onset Older age of onset
Possible positive Nikolsky sign Nikolsky sign is negative
Appearance of lesions on normally appearing skin Frequent appearance of lesions on an erythematous
or urticarial base
Mucosal involvement may be present Mucosal involvement is very rare
Histology findings Marked eosinophilic infiltrate Eosinophilic infiltrate present
Intraepidermal vesicles may be present Intraepidermal vesicles are not present
Necrotic keratinocytes may be present Necrotic keratinocytes are rarely seen
Thrombus formation may be seen Thrombus formation is very rarely seen
Laboratory findings Marked eosinophilia in serum Eosinophilia present
Clinical course Responds rapidly to treatment with oral corticosteroids May exhibit prolonged course despite oral
corticosteroid treatment
Improves after discontinuation of inciting drug No inciting drug is identified
Rarely relapses Relapses often

DIBP, drug-induced bullous pemphigoid.

JEADV 2014, 28, 1133–1140 © 2014 European Academy of Dermatology and Venereology
1138 Stavropoulos et al.

have the ability of altering or modifying the immune response in in a case report BP resembled clinically contact dermatitis, and
genetically predisposed individuals. Eosinophil recruitment into the patient exhibited positive patch tests for formaldehyde and
the dermis may be enhanced by dipeptidyl peptidase 4 inhibitors methylchloroisothiazolinone/methylisothiazolinone. The authors
via the CCL11/eotaxin chemokine.56 Also, dipeptidyl peptidase could not offer an explanation of this occurrence.63
expression has been closely correlated with T-cell function and
population distribution in murine models.57 On the other hand, Treatment of drug-induced bullous pemphigoid
gliptins may be capable of altering the antigenic properties of the Treatment of bullous pemphigoid aims mainly to control symp-
basement membrane. Although they do not possess a gelatinase toms with minimum adverse effects if possible. The choice of
activity,55 they do exhibit an antifibrotic potential and have an treatment in classic bullous pemphigoid is done according to
antiproliferative effect on keratinocytes.58 Therefore, they may guidelines which are mainly based in uncontrolled studies and
play a role in collagen metabolism, but their effect on BP180 includes the use of oral and topical corticosteroids together with
remains a mystery. various adjuvant drugs.64 In the case of DIBP no specific guide-
lines exist. Most data on choice of treatment and efficacy come
The association of BP with neuroleptics and neurological from isolated case reports and short case series and are, there-
disease fore, based on the personal experience of each author. One of
There is a great possibility that patients who develop bullous the most important aspects in the treatment of DIBP is the
pemphigoid are, actually, genetically predisposed to do so. Due
to this fact, the implication of specific drugs, like neuroleptics, (a)
remains controversial. Various studies have shown a statistically
important correlation between bullous pemphigoid and neuro-
logical disease. Langan et al. report a threefold increase in the
odds of BP, in patients with dementia and Parkinson’s disease
and a twofold increase in patients with stroke history or epi-
lepsy.59 In a study by Jedlickova et al., it is reported that 48% of
BP patients suffered from some kind of neurological disorder,
compared to 18% of patients in a control group with other types
of skin diseases.60 Both skin and nervous system are derived
from neural crest. In a recent study by Li et al., it is demon-
strated that antibodies extracted from patients with neurological
disease and BP can recognize BPAG1 in both brain and epider-
mis. As a temporal relationship between BP and neurological
(b)
disease exists, it would not be illogical to speculate that nervous
system damage, in the course of neurological disease, could
expose the neuronal isoform of BPAG1 and lead to an immune
reaction that could result to the development of BP.61 On the
other hand, various studies link neuroleptic drugs but not neuro-
logical disease with bullous pemphigoid.12,18 Whether neurologi-
cal disease can be considered as a causative agent for BP, or if
neuroleptics are responsible for causing a true DIBP is something
that remains to be elucidated. Perhaps both assumptions are
true, but more studies are needed to support either hypothesis.

Topical drugs
The issue of topical agents being able to induce bullous pem-
phigoid remains controversial. A number of agents have been
reported, but no direct association has been made in most cases
(Table 3).17 Epidermal damage could lead to increased exposure
of BP antigen to immune cells and cause subsequent antibody
formation. Various agents such as irritants, UV radiation etc.,
combined with genetic predisposition can lead to the expression
of the disease phenotype via activation of T lymphocytes, anti-
gen presenting cells and a number of cytokines.62 Interestingly,
Figure 2 (a) Marked improvement of bullous pemphigoid lesions
after discontinuation of the possible inciting drug and 3 weeks of
treatment with oral prednisolone. (b) Cessation of the appearance
of new lesions and marked improvement of inflammation was
observed within 3 weeks from initiation of oral corticosteroid treat-
ment and after discontinuation of the inciting drug. Two years later
the patient is still in remission and is not receiving any treatment.

JEADV 2014, 28, 1133–1140 © 2014 European Academy of Dermatology and Venereology
Drug-induced pemphigoid
immediate cessation of the suspect inciting drug. Patients with
DIBP respond well to treatment with low-dose oral corticoster-
oids (prednisone 0.5 mg/kg/day), used together with potent top-
ical corticosteroids. The dose of oral corticosteroids is tapered
after suppression of inflammation and blistering are achieved
and according to the clinical course of each patient. In these
patients adjuvant drugs are usually not needed as most achieve
complete remission within 6 weeks from initiation of ther-
apy.33,48,50,51,65–67
Conclusion
Over the years, more than 50 medications have been associated
with bullous pemphigoid.17 In everyday clinical practice, the dif-
ferential diagnosis between classic BP and DIBP can prove to be
quite difficult. As no clear cut histological or clinical criteria can
be set, one must follow indications from the presenting symp-
toms of the patients, the recent history of received medications
and the histopathological picture of the disease to set a possible
diagnosis (Table 4). Unfortunately, even if a suspect drug is
identified, rechallenging a patient is impossible and no definite
proof can be established. Considering the fact that after with-
drawal of a suspect medication most patients respond rapidly to
treatment and do not experience relapses of the condition
(Fig. 2a,b), the possibility of DIBP must always be considered by
the treating physicians. In the future, as new therapies emerge,
the number of drugs thought to cause BP will probably increase.
Therefore, more studies are needed to identify those regimens
that are more commonly associated with DIBP and those
patients that are more prone to develop the condition.
References
1 Kasperkiewicz M, Zillikens D. The pathophysiology of bullous pemphig-
oid. Clin Rev Allergy Immunol 2007; 33: 67–77.
2 Kalaaji NE, Nicolas MEO. Linear basement membrane zone staining pat-
tern. In Kalaaji NE, Nicolas MEO eds. Mayo Clinic Atlas of Immunofluo-
rescence in Dermatology. Mayo Clinic Scientific Press, Taylor & Francis
Group, Boca Raton, FL, 2006: 1–3.
3 Smith EP, Taylor TB, Meyer LJ, Zone JJ. Antigen identification in drug-
induced bullous pemphigoid. J Am Acad Dermatol 1993; 29(5 Pt 2): 879–
882.
4 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: 1196–1199.
5 Alcalay J, David M, Ingber A, Hazaz B, Sandbank M. Bullous pemphigoid
mimicking bullous erythema multiforme: an untoward side effect of pen-
icillins. J Am Acad Dermatol 1988; 18(2 Pt 1): 345–349.
6 Hofmann M, Audring H, Sterry W, Trefzer U. Interleukin-2-associated
bullous drug dermatosis. Dermatology 2005; 210: 74–75.
7 Ruocco V, Sacerdoti G. Pemphigus and bullous pemphigoid due to
drugs. Int J Dermatol 1991; 30: 307–312.
8 Lee JJ, Downham T. Furosemide induced bullous pemphigoid: case
report and review of literature. J Drugs Dermatol 2006; 5: 562–564.
9 Bowman C, Delrieu O. Immunogenetics of drug-induced skin blistering
disorders. Part I: perspective. Pharmacogenomics 2009; 10: 601–621.
10 Ahmed AR, Mohimen A, Yunis EJ et al. Linkage of pemphigus vulgaris
antibody to the major histocompatibility complex in healthy relatives of
patients. J Exp Med 1993; 177: 419–424.
JEADV 2014, 28, 1133–1140
1139
11 Park B, Sanderson J, Naisbitt D. Drugs as haptens, antigens, and immuno-
gens. In Pichler WJ, ed. Drug Hypersensitivity. Karger, Basel, 2007: 55–65.
12 Patsatsi A, Vyzantiadis TA, Chrysomallis F, Devliotou-Panagiotidou D,
Sotiriadis D. Medication history of a series of patients with bullous pem-
phigoid from northern Greece – observations and discussion. Int J Der-
matol 2009; 48: 132–135.
13 Newport MJ, Goetghebuer T, Marchant A. Hunting for immune response
regulatory genes: vaccination studies in infant twins. Expert Rev Vaccines
2005; 4: 739–746.
14 Baum H, Butler P, Davies H, Sternberg MJ, Burroughs AK. Autoimmune
disease and molecular mimicry: a hypothesis. Trends Biochem Sci 1993;
18: 140–144.
15 Ruocco V, de Luca M, Pisani M, de Angelis E, Vitale O, Astarita C. Pem-
phigus provoked by D(-)penicillamine. An experimental approach using
in vitro tissue cultures. Dermatologica 1982; 164: 236–248.
16 Bean SF, Good RA, Windhorst DB. Bullous pemphigoid in an 11-year-
old boy. Arch Dermatol 1970; 102: 205–208.
17 Vassileva S. Drug-induced pemphigoid: bullous and cicatricial. Clin Der-
matol 1998; 16: 379–387.
18 Bastuji-Garin S, Joly P, Picard-Dahan C et al. Drugs associated with bul-
lous pemphigoid. A case–control study. Arch Dermatol 1996; 132: 272–
276.
19 Lloyd-Lavery A, Chi Chi C, Wojnarowska F, Taghipour K. The associa-
tions between bullous pemphigoid and drug use. A UK case–control
study. JAMA Dermatol 2013; 149: 58–62.
20 Ameglio F, D’Auria L, Cordiali-Fei P et al. Bullous pemphigoid and pem-
phigus vulgaris: correlated behaviour of serum VEGF, sE-selectin and
TNF-alpha levels. J Biol Regul Homeost Agents 1997; 11: 148–153.
21 Rhodes LE, Hashim IA, McLaughlin PJ, Friedmann PS. Blister fluid cyto-
kines in cutaneous inflammatory bullous disorders. Acta Derm Venereol
1999; 79: 288–290.
22 Kennedy JS, Devillez RL, Henning JS. Recalcitrant cicatricial pemphigoid
treated with the anti-TNF-alpha agent etanercept. J Drugs Dermatol 2010;
9: 68–70.
23 Canizares MJ, Smith DI, Conners MS, Maverick KJ, Heffernan MP. Suc-
cessful treatment of mucous membrane pemphigoid with etanercept in 3
patients. Arch Dermatol 2006; 142: 1457–1461.
24 Heffernan MP, Bentley DD. Successful treatment of mucous membrane
pemphigoid with infliximab. Arch Dermatol 2006; 142: 1268–1270.
25 Nin M, Tokunaga D, Ishii N, Komai A, Hashimoto T, Katoh N. Case of
coexisting psoriatic arthritis and bullous pemphigoid improved by etaner-
cept. J Dermatol 2013; 40: 55–56.
26 Yamauchi PS, Lowe NJ, Gindi V. Treatment of coexisting bullous pem-
phigoid and psoriasis with the tumor necrosis factor antagonist etaner-
cept. J Am Acad Dermatol 2006; 54(3 Suppl. 2): S121–S122.
27 Saraceno R, Citarella L, Spallone G, Chimenti S. A biological approach in
a patient with psoriasis and bullous pemphigoid associated with losartan
therapy. Clin Exp Dermatol 2008; 33: 154–155.
28 Cusano F, Iannazzone SS, Riccio G, Piccirillo F. Coexisting bullous pem-
phigoid and psoriasis successfully treated with etanercept. Eur J Dermatol
2010; 20: 520.
29 Bordignon M, Belloni-Fortina A, Pigozzi B, Tarantello M, Alaibac M. Bul-
lous pemphigoid during long-term TNF-alpha blocker therapy. Dermatol-
ogy 2009; 219: 357–358.
30 Boussemart L, Jacobelli S, Batteux F et al. Autoimmune bullous skin dis-
eases occurring under anti-tumor necrosis factor therapy: two case
reports. Dermatology 2010; 221: 201–205.
31 Stausbøl-Grøn B, Deleuran M, Sommer Hansen E, Kragballe K. Develop-
ment of bullous pemphigoid during treatment of psoriasis with ada-
limumab. Clin Exp Dermatol 2009; 34: 285–286.
32 Duong TA, Buffard V, Andr
e C et al. Efalizumab-induced bullous pem-
phigoid. J Am Acad Dermatol 2010; 62: 161–162.
33 Monnier-Murina K, Du Thanh A, Merlet-Albran S, Guillot B, Dereure O.
Bullous pemphigoid occurring during efalizumab treatment for psoriasis:
a paradoxical auto-immune reaction? Dermatology 2009; 219: 89–90.
© 2014 European Academy of Dermatology and Venereology
1140
34 Liu LY, Bates ME, Jarjour NN, Busse WW, Bertics PJ, Kelly EA. Genera-
tion of Th1 and Th2 chemokines by human eosinophils: evidence for a
critical role of TNF-alpha. J Immunol 2007; 179: 4840–4848.
35 Garc
ıa-Doval I, Mayo E, Nogueira Fari~ na J, Cruces MJ. Bullous pemphig-
oid triggered by influenza vaccination? Ecological study in Galicia, Spain.
Br J Dermatol 2006; 155: 820–823.
36 Lear JT, Tan BB, English JS. Bullous pemphigoid following influenza vac-
cination. Clin Exp Dermatol 1996; 21: 392.
37 Fournier B, Descamps V, Bouscarat F, Crickx B, Belaich S. Bullous pem-
phigoid induced by vaccination. Br J Dermatol 1996; 135: 153–154.
38 Garc
ıa-Doval I, Ros
on E, Feal C, De la Torre C, Rodr
ıguez T, Cruces MJ.
Generalized bullous fixed drug eruption after influenza vaccination, simu-
lating bullous pemphigoid. Acta Derm Venereol 2001; 81: 450–451.
39 Downs AM, Lear JT, Bower CP, Kennedy CT. Does influenza vaccination
induce bullous pemphigoid? A report of four cases. Br J Dermatol 1998;
138: 363.
40 Chac
on GR, Sinha AA. Bullous pemphigoid after herpes zoster vaccine
administration: association or coincidence? J Drugs Dermatol 2011; 10:
1328–1330.
41 Lohrisch I, Haustein UF, Baumert A, Szeskus H. Immune response to tet-
anus toxoid in bullous pemphigoid. Dermatol Monatsschr 1985; 171: 153–
157.
42 Hafiji J, Bhogal B, Rytina E, Burrows NP. Bullous pemphigoid in infancy
developing after the first vaccination. Clin Exp Dermatol 2010; 35: 940–941.
43 Baykal C, Okan G, Sarica R. Childhood bullous pemphigoid developed
after the first vaccination. J Am Acad Dermatol 2001; 44(2 Suppl.): 348–
350.
44 M
erida C, Mart
ınez-Escribano JA, Fr
ıas JF, S
anchez-Pedre~no P, Corbal
an
R. Bullous pemphigoid in an infant after vaccination. Actas Dermosifiliogr
2005; 96: 255–257.
45 Valdivielso-Ramos M, Vel
azquez D, Tortoledo A, Hernanz JM. Infantile
bullous pemphigoid developing after hexavalent, meningococcal and
pneumococcal vaccinations. An Pediatr (Barc) 2011; 75: 199–202.
46 Jedlickova H, Racovska J, Niedermeier A, Feit J, Hertl M. Anti-basement
membrane zone antibodies in elderly patients with pruritic disorders and
diabetes mellitus. Eur J Dermatol 2008; 18: 534–538.
47 Hirose M, Recke A, Beckmann T et al. Repetitive immunization breaks
tolerance to type XVII collagen and leads to bullous pemphigoid in mice.
J Immunol 2011; 187: 1176–1183.
48 Walmsley N, Hampton P. Bullous pemphigoid triggered by swine flu vac-
cination: case report and review of vaccine triggered pemphigoid. J Der-
matol Case Rep 2011; 5: 74–76.
49 Chiav
erini C, Hamel-Teillac D, Gilbert D, De Prost Y. Absence of anti-
BP180 antibodies in mothers of infants with bullous pemphigoid. Br J
Dermatol 2006; 54: 839–843.
50 Pasmatzi E, Monastirli A, Habeos J, Georgiou S, Tsambaos D. Dipeptidyl
peptidase-4 inhibitors cause bullous pemphigoid in diabetic patients:
report of two cases. Diabetes Care 2011; 34: 133.
JEADV 2014, 28, 1133–1140
Stavropoulos et al.
51 Skandalis K, Spirova M, Gaitanis G, Tsartsarakis A, Bassukas ID. Drug-
induced bullous pemphigoid in diabetes mellitus patients receiving dip-
eptidyl peptidase-IV inhibitors plus metformin. J Eur Acad Dermatol
Venereol 2012; 26: 249–253.
52 Aouidad I, Fite C, Marinho E, Deschamps L, Crickx B, Descamps V. A
case report of bullous pemphigoid induced by dipeptidyl peptidase-4
inhibitors. JAMA Dermatol 2013; 149: 243–245.
53 Stricklin SM, Stoecker WV, Rader RK, Hood AF, Litt JZ, Schuman TP.
Persistent edematous-plaque photosensitivity observed with sitagliptin
phosphate. Dermatol Online J 2012; 18: 9.
54 Nakatani K, Kurose T, Hyo T et al. Drug-induced generalized skin erup-
tion in a diabetes mellitus patient receiving a dipeptidyl peptidase-4
inhibitor plus metformin. Diabetes Ther 2012; 3: 14.
55 Andukuri R, Drincic A, Rendell M. Alogliptin: a new addition to the class
of DPP-4 inhibitors. Diabetes Metab Syndr Obes 2009; 2: 117–126.
56 Schmiedl A, Pabst R, Wagner L et al. Inhibition of CD26/dipeptidyl pep-
tidase IV enhances CCL11/eotaxin-mediated recruitment of eosinophils
in vivo. J Immunol 2008; 181: 1120–1127.
57 Kruschinski C, Skripuletz T, Bedoui S et al. CD26 (dipeptidyl-peptidase
IV)-dependent recruitment of T cells in a rat asthma model. Clin Exp
Immunol 2005; 139: 17–24.
58 Thielitz A, Vetter RW, Schultze B et al. Inhibitors of dipeptidyl peptidase
IV-like activity mediate antifibrotic effects in normal and keloid-derived
skin fibroblasts. J Invest Dermatol 2008; 128: 855–866.
59 Langan SM, Groves RW, West J. The relationship between neurological
disease and bullous pemphigoid: a population-based case–control study.
J Invest Dermatol 2011; 131: 631–636.
60 Jedlickova H, Hlubinka M, Pavlik T, Semradova V, Budinska E, Vlasin Z.
Bullous pemphigoid and internal diseases – a case–control study. Eur
J Acad Dermatol Venereol 2010; 20: 96–101.
61 Li L, Chen J, Wang B, Yao Y, Zuo Y. Sera from patients with bullous pem-
phigoid (BP) associated with neurological diseases recognized BP antigen
1 in the skin and brain. Br J Dermatol 2009; 160: 1343–1345.
62 Chorzelski T, Jablonska S, Beutner EH. Bullous pemphigoid: relationship
of immunopathology to clinical findings. In Beutner EH, Chorzelski T,
Bean SF, eds. Immunopathology of the Skin, 3rd edn. John Willey, New
York, 1987: 337–352.
63 Soni BP, McAlvany JP, Fleischer AB, Sherertz EF. Bullous pemphigoid
mimicking contact dermatitis. Contact Dermatitis 1996; 35: 314.
64 Venning VA, Taghipour K, Mohd Mustapa MF, Highet AS, Kirtschig G.
British Association of Dermatologists’ guidelines for the management of
bullous pemphigoid 2012. Br J Dermatol 2012; 167: 1200–1214.
65 Diab M, Coloe J, Bechtel MA. Bullous pemphigoid precipitated by galan-
tamine hydrobromide. Cutis 2009; 83: 139–140.
66 Aksakal BA, Ozsoy E, Arnavut O, Ali G€ urer M. Oral terbinafine-induced
bullous pemphigoid. Ann Pharmacother 2003; 37: 1625–1627.
67 Kali

nska-Bienias A, Rogozi
nski TT, Wo
zniak K, Kowalewski C. Can pem-
phigoid be provoked by lisinopril? Br J Dermatol 2006; 155: 854–855.
© 2014 European Academy of Dermatology and Venereology