Clinics in Dermatology (2013) 31, 400412

Bullous pemphigoid: Associations and management guidelines:

Facts and controversies
Eleonora Ruocco, MD, PhD a , Ronni Wolf, MD b , Stefano Caccavale, MD a ,
Gabriella Brancaccio, MD a , Vincenzo Ruocco, MD a , Ada Lo Schiavo, MD a,
a

Department of Dermatology, Second University of Naples, via S. Pansini, 5 - 80131 Naples, Italy
Dermatology Unit, Kaplan Medical Center, Rehovot 76100 Israel; The School of Medicine,
Hebrew University and Hadassah Medical Center, Jerusalem, Israel
b

Abstract Bullous pemphigoid (BP) is an organ-specific human autoimmune disease typical of the
elderly, which may be associated with many different disorders (immune, neurologic, psychiatric,
hematologic, pulmonary, and cardiovascular), as well as with different types of tumors. The crucial
question is whether these associations are casual or causal. In particular, the relationship between BP
and malignancy is still a matter of debate. Although this association often has been emphasized, it is not
clear whether the coexistent malignancy and BP are pathogenically connected or if their association is
merely linked to aging. In our survey, the BP/neoplasm association ratios have not increased with age.
Instead, significantly higher ratios have been found in younger patients; therefore, a meticulous
investigation for a malignant neoplasm should always be pursued in young or middle-aged patients with
BP, in particular regarding the severe forms of the disorder or those refractory to conventional treatment.
The management of BP strictly depends on the multifactorial pathogenesis of this disorder. In fact,
inflammation in BP seems to be more crucial for blister formation than in other autoimmune bullous
disorders, such as pemphigus. Even if first-line treatments are typically immunosuppressants, newer
therapeutic agents targeting specific pathogenic steps that are linked with inflammation have been
proposed. Treatments selectively suppressing autoantibody formation, inflammation cascade, or both
are available. Grouping therapies according to their mechanism of action may be useful to test new drug
associations or to evaluate efficacy and tolerability of drugs with the same target.
2013 Published by Elsevier Inc.

Introduction
Bullous pemphigoid (BP) is an autoimmune blistering
disease typically, but not exclusively, affecting the elderly
after the seventh decade. BP is characterized by an
Corresponding author. Tel.: +39 081 566 68 28; fax: +39 081 546 87 59.
E-mail address: ada.loschiavo@unina2.it (A. Lo Schiavo).
0738-081X/$ see front matter 2013 Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.clindermatol.2013.01.007

autoantibody response toward structural components of the

hemidesmosome. It can be considered an organ-specific
disorder because it is characterized by an autoimmune injury
that is confined to the skin and mucosa.1 The spectrum of
clinical presentations is extremely broad. The typical
presentation is an intensely pruritic eruption with widespread
blister formation. It is usually a chronic disease, with
spontaneous exacerbation and remission phases, often

Bullous pemphigoid associations and management

accompanied by significant morbidity. In fact, BP has been
reported in association with various internal diseases
(Table 1). The association of two disorders may be
representative of a common multifactorial pathogenesis,
which calls for a careful evaluation in planning the
therapeutic approach in each patient.
We shall attempt to critically review the BP associations
and investigate which may be clinically important and which
require further investigation. Additionally, this contribution
encompasses a large series of practical options for the
management of BP.
Table 1

Bullous pemphigoid associations

Neurologic diseases
Stroke
Dementia
Parkinson's disease
Alzheimer's disease
Amyotrophic lateral sclerosis
Epilepsy
Hemiplegia
Multiple sclerosis
Myasthenia gravis
Shy-Dragger syndrome
Psychatric diseases
Bipolar disorder
Unipolar disorder
Schizophrenia
Immune disorders
Dermatologic
Psoriasis
Lichen planus
Alopecia
Dermatitis herpetiformis (Duhring)
Dermatomyositis/polymyositis
Linear IgA dermatosis
Pemphigus foliaceus
Pemphigus vulgaris
Vitiligo
Hematologic
Pernicious anemia
Autoimmune neutropenia
Autoimmune thrombocytopenia
Acquired hemophilia
Acquired hypercoagulability
Others
Graves' disease
Hashimoto disease
Primary biliary cirrhosis
Rheumatoid arthritis
Immune-complex glomerulonephritis
Ulcerative colitis
AIDS
Diabetes mellitus
Pulmonary diseases
Cardiovascular diseases
Malignancies
Ig, immunoglobulin.

401

Association with neurologic diseases

Neurologic diseases have often been reported in association
with BP.27 Thirty-six percent of BP patients had at least one
neurologic disease.2 The pathologic mechanism of this
relationship is not yet understood and cannot be attributed
solely to the elderly age of the patients with BP, as some
patients in previous studies were middle-aged. Patients older
than age 80 years with neurologic disease have more than 10
times higher risk for BP compared with patients of the same age
without neurologic disease. In the age category below 80 years,
the influence of neurologic disease on BP was not proved.8
BP seems to be associated with degenerative neurologic
diseases that may involve autoimmune mechanisms, such as
Parkinson's and Alzheimer's diseases. Specific antibodies
have been found to accumulate within neurons in Alzheimer's disease and may initiate neuronal degeneration.
Conceivably, an autoimmune response initially directed
against a neuronal isoform of BPAG1 (BPAG1-n) encoded
by the dystonin gene may secondarily trigger an autoimmune
response against the epithelial isoform of BPAG1, according
to the epitope-spreading phenomenon. The two isoforms
share the same sequence in their terminal portion, which is
recognized by anti-BPAG1 antibodies from patients with BP.
The rupture of tolerance induced by neuronal degeneration or
destruction of the brain parenchyma in some neurologic
disorders may explain the delayed development of BP after
the onset of the neurologic symptoms.7
The association between BP and Parkinson's disease is
statistically significant. In 2005, a report showed that there is
a higher prevalence of BP in hospitalized patients with
Parkinson's disease.4 The rates of Parkinson's disease
among patients BP in Bastuji-Garin's casecontrol study
(14.3%)7 were consistent with those found in Cordel's
retrospective study (9%).3
Langan calculated the population attributable fraction
(PAF) for each neurologic disease and BP. The highest PAF
was for stroke, which was 6.7% of BP, assuming a causal
relationship, followed by dementia (5.1%).5 The significance
of this association is unclear. Several case reports and small
case series have suggested an association between BP and
amyotrophic lateral sclerosis, multiple sclerosis, myasthenia
gravis, hemiplegia, epilepsy, and Shy-Dragger syndrome.

Controversies
Bullous skin disease always followed the onset of the
neurologic disease at intervals varying from a few months to
a maximum of some years. The crucial question is whether
the association is casual or causal. The relationship cannot be
attributed solely to the elderly age of patients with BP. It has
been suggested that drug intake, decubital lesions, traumatic
events, and immunity aging can be triggering factors for BP
during the course of neurologic diseases. These associations
are of interest, as they may play a role in the etiology of BP

402
and may help the understanding of the basis for these
neurodegenerative disorders.4

Association with psychiatric diseases

Bipolar and unipolar disorders and schizophrenia were
found to be associated with BP in an increased frequency.
Although the association with bipolar or unipolar disorder is
statistically not significant,7 the association with schizophrenia is predominant in women with BP.3 Further studies
are needed to investigate the underlying mechanism linking
these psychiatric diseases and BP.

Association with immune disorders

BP has been reported in patients with other autoimmune
disorders, such as systemic lupus erythematosus, rheumatoid
arthritis, vitiligo, Hashimoto thyroiditis, Graves' disease,
dermatomyositis, polymyositis, autoimmune neutropenia,
autoimmune thrombocytopenia, immune-complex glomerulonephritis, and myasthenia gravis. Although a casecontrol
study did not find any increased risk for autoimmune
disorders in BP, it is likely that these associations are not
fortuitous, but reflect a genetically determined susceptibility
to develop immunity-related diseases. This may also be true
for association of BP with pernicious anemia, ulcerative
colitis, hyperthyreosis or hypothyreosis, polymyalgia rheumatica, mycosis fungoides, primary biliary cirrhosis, nephritis and glomerulonephritis, and acquired hemophilia.1

E. Ruocco et al.
disease or as an immunologic response due to formation of
complement-binding BMZ antibodies.1 It has been postulated that changes at the BMZ in psoriatic patients may be
responsible for the heterogeneous antibody response and
may trigger the bullous disease. The increased serum CCL28
levels and the possible role of T helper (Th) 17 cells in
patients with psoriasis and BP may be a further link for the
association. There is evidence that Th17 cells and interleukin
(IL)-17 may be involved in the production of proinflammatory cytokines, matrix metalloproteinases, neutrophils and eosinophils, all of which are important pathogenic
factors in BP. It is worth noting that some psoriatic patients
developed BP in absence of any previous therapy.3
The coexistence of lichen planus and BP, referred to as
lichen planus pemphigoides, shows typical clinical, histologic, and immunopathologic features of both diseases. BP
also can be associated with alopecia, dermatomyositis/
polymyositis, vitiligo, dermatitis herpetiformis (Duhring),
linear immunoglobulin (Ig)A dermatosis, pemphigus foliaceus, and pemphigus vulgaris. The coexistence of BP and
pemphigus is extremely rare. Korman et al., by reporting a
patient with pemphigus foliaceus who later developed BP,
demonstrated the coexistence of pemphigus and BP for the
first time. The patient had circulating antibodies against both
the pemphigus foliaceus and 230 kD BP antigens.8 The
presence of a bullous disease seems to facilitate the onset of a
second bullous disease in the same patient due to a possible
individual predisposition to blistering. In the case of
pemphigus, a specific genotype conferring a far greater
propensity to develop this disease has been detected.9 The
coexistence of these two autoimmune diseases should be
considered in BP patients who are nonresponsive to
conventional therapy.1

Dermatologic diseases

Hematologic diseases

BP also has been found in association with other skin

diseases, such as psoriasis and lichen planus. In these
conditions, it has been speculated that inflammation at the
dermal-epidermal junction may be responsible for the
antigen exposure to autoreactive T lymphocytes, thus leading
to a secondary immune response.1
Some authors think that the concurrence of psoriasis
vulgaris and BP is due to a combined action of diseased
psoriatic epidermis with irritant effects of antipsoriatic
therapy, which may initiate the production of basement
membrane zone (BMZ)-reactive autoantibodies in susceptible individuals. The basal membrane zone involvement may
result in an antigenic modification of proteins at the dermalepidermal junction and exposure of new antigens. Most
reported cases of BP in literature occurred after antipsoriatic
treatment, such as tar, anthralin, psoralens, sun exposure,
psoralen and UVA (PUVA) therapy, or UVA and UVB light.
UV-induced bullous lesions usually represent a phototoxic
reaction often due to an overdose of radiation. It is explained
as an abrupt outbreak of a preexisting subclinical bullous

Early cutaneous infiltration by eosinophils seems to be a

crucial event in the development of bullous lesions in BP. It is
known that eosinophils are the major intravascular source of
tissue factor (TF), an initiator of the extrinsic coagulation
pathway. The TF-mediated coagulation pathway may be
involved in BP pathogenesis. TF up-regulation in BP is
responsible for both a hypercoagulable and an inflammatory
condition. TF hypercoagulability could significantly contribute
to the inflammation, tissue damage, and blister formation in BP.
The most important clinical consequence of a hypercoagulable
state is the possible occurrence of thrombotic complications.
Acquired hemophilia has also been reported in association
with pemphigoid, which worsens the prognosis.10

Association with diabetes mellitus

An association of BP with diabetes mellitus has often been
suspected. Complex changes caused by glycation of proteins

Bullous pemphigoid associations and management

Table 2

Association of BP and neoplasms in literature

Year of publication

First author

Frequency of
BP/neoplasm
association (%)

1968
1974
1975
1977
1977
1977
1978
1981
1984
1990
1990
1995
1995
2001
2009

Lim21
Ebner24
Stone19
Amhed18
Moss25
Person26
Chorzelski14
Hodge27
Venencie28
Venning29
Lindelf17
Ogawa30
Chang20
Cozzani15
Marazza16

11.6
12.2
10.9
3.0
10.3
13.2
11.0
9.7
9.7
17.9
12.3
5.8
15.1
18.7
11.0

BP, bullous pemphigoid.

of the dermal-epidermal junction zone may expose hidden BP

antigens to an autoimmune response. Jedlickova found that
the diabetes mellitus frequency in BP patients in the age
group greater than 80 years was higher than in controls;
however, the link was not statistically significant11; moreover, the conventional steroid administration in BP patients
may represent a common bias regarding this association.

Association with pulmonary diseases

Langan found an approximately threefold increase in the
incidence of pneumonia and pulmonary embolism following
a diagnosis of BP compared with the general population of
similar age and sex.12 Langan's findings are coherent with a
large case series by Savin, which suggested that deaths in BP
were related to bronchopneumonia and pulmonary emboli.13
The increased risk for pneumonia may relate to the use of
high-dose oral corticosteroids for treatment of BP. Mechanisms for pulmonary emboli in BP patients include the
presence of systemic inflammatory disease, poor mobility,
and oral corticosteroid therapy.
These findings are relevant for clinical practice and may
allow reducing associated mortality by prophylaxis with
either antithromboembolic measures or antibiotic therapy.12

403
for the treatment of hypertension and heart disease can
induce BP.11

Association with neoplasia

The relationship between BP and malignancy is still a
matter of debate. In fact, BP has been reported in association
with a variety of carcinomas as well as with sarcoma,
melanoma, and lymphoproliferative disorders, so that many
authors consider BP a paraneoplastic syndrome 1430
(Table 2). A genuine association has been strengthened in
a few of these reports by a parallel clinical course between
neoplasm and blistering eruption, but there are several cases
where a correlation did not occur. The association between
malignancies and BP often has been emphasized, but it is not
clear whether the coexistent malignancy and BP patients are
pathogenically connected or if the association is merely
linked to aging. As a matter of fact, both BP and cancer are
diseases of the elderly and, therefore, the relationship
between them might only be related to age.

Bullous pemphigoid and neoplasms in literature: A

controversial relationship
In the past decades three different statements prevailed in
literature, each one proving a different relationship between
BP and cancer.
1. Some authors, such as Chorzelski,14 regarded the BPneoplasm association as a real one (causal association);
this assumption was lately supported by Cozzani15 and
Marazza.16 They found a cancer in 18.7% and in 11%
of patients, respectively, and concluded that BP can
develop concomitantly with an underlying malignancy,
particularly in middle-aged patients or in BP refractory
cases.
2. Lindelf17 and Ahmed18 regarded the association as a
merely fortuitous coexistence (casual association)
because both diseases are most common in the elderly.
3. Stone19 and Chang20 and Savin13 found only a
nonstatistically significant association in comparison
with the control groups. Chang reviewed 86 cases of
BP and compared the results with those reported in the
literature: 15% of the patients had internal malignancies but the incidence was not significantly different
from the control group.20

Association with cardiovascular diseases

Table 3

Jedlickova did not find differences for cardiovascular

diseases among patients with BP and controls. Hypertension
and ischemic heart disease play a role in the prognosis of the
BP patients, as treatment by corticosteroids may influence
blood pressure and heart disease; moreover, some drugs used

Incidence of malignancies in our BP patients

Patients with neoplasm (%)

Patients without neoplasm (%)
Total (%)
BP, bullous pemphigoid.

10 (22.2)
35 (77.8)
45 (100)

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Table 4

E. Ruocco et al.
Neoplasms recorded in our BP patients

Lung
Prostate
Uterus (including placenta)
Pancreas
Esophagus
Lymphoma

3
2
2
1
1
1

BP, bullous pemphigoid.

Our survey
We reviewed 45 patients with BP observed from 2006 to
2011. Neoplasms were detected in 10 (22.2%) of these
patients (Table 3), with a sex predilection for men. The most
frequent neoplasm associated to BP was lung cancer, found
in 3 of 45 patients (6.6%), followed by prostate and uterus
cancers (4.4% each) (Table 4, Figure 1). In nine patients
neoplasms were carcinomas (ie, tumors of epithelial origin).
The association between BP and carcinomas could be
explained by the presence of an immunologic crossreactivity between epidermis and cancer epithelial antigens.
We compared these association frequencies to the number
of expected malignancies in a population with the same age
and sex distribution (control group) and found that the rate of
a malignant disease (past, concurrent, or during follow-up) in
BP patients was higher than in controls. In our experience,
although limited and statistically not significant, a causal
relation between BP and malignancies does exist.
The association ratio of malignancy with BP was
investigated in different age groups. It is worth noting that
in our observations this ratio did not increase with age.
Instead, the association ratios were significantly higher in
the younger decades, when compared with data concerning
the risk for malignancy in general population (Table 5). In

Uterus
cancer
Lymphoma 4,4%
2,2%

most cases, the onset of BP preceded the diagnosis of tumor,

thus being the earliest marker for an underlying malignancy
(Tables 6 and 7); therefore, a meticulous investigation for a
malignant neoplasm should always be pursued in young or
middle-aged patients with BP, in particular regarding the
severe forms of the disorder or those refractory to
conventional treatment. In most of these cases, patients
had an improvement of the bullous disorder with antineoplastic therapies. Complete surgical resection was the
only curative treatment for both tumor and bullous disease,
while chemotherapy and radiation therapy yielded only
modest benefit.

Paraneoplastic or radiation-induced BP?

As it also occurs with pemphigus, the association of BP
with a cancer treated by radiotherapy raises the controversy
whether the factor inducing the bullous disorder is the tumor
itself (paraneoplastic BP) or the ionizing radiation used to
treat it (radiation-induced BP). If the lesions make their first
appearance on the skin area that has been or is being
irradiated (and even more if they remain confined within this
area in time), relationship with ionizing radiation is
convincing (or even certain) and represents a clear example
of immunocompromised district.31

Management guidelines
The management of BP strictly depends on the
multifactorial pathogenesis of this disorder. Imbalance
between autoreactive Th and T regulatory cells (tregs),
toll-like receptor activation, and Th17/IL-17 pathway are
the three possible autoimmunity triggers underlying BP. The
basic pathomechanism of BP hinges on an autoantibody
Esophagus Pancreas
cancer
cancer
2,2%
2,2%

Prostate cancer 4,4%

Lung cancer 6,6%
No
malignancy
77,8%

Fig. 1

Incidence of malignancies in our BP patients.

Bullous pemphigoid associations and management

Table 5 Association ratios of malignancy with BP in different
age groups compared with Italian Cancer Registry data
regarding general population
Age

Risk for malignancy

in our BP patients
(%)

Risk for malignancy

in general population
(%) a

All
30-39
40-49
50-59
60-69
70-79
80-89

22.2
50.0
50.0
0
50.0
14.3
20.0

Not found
0.1
0.2
0.5
1.0
1.6
3.5

y
y
y
y
y
y

BP, bullous pemphigoid.

a
Italian Cancer Registry (AIRTUM) data.

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. This inflammatory cascade also might be directly triggered by
activation of Th17 cells with no intervention of autoantibodies. In fact, inflammation seems to be more crucial for
blister formation in BP than in other autoimmune bullous
diseases, such as pemphigus.32 Therefore, even if first-line
treatments are typically immunosuppressants, newer therapeutic agents target the previously mentioned pathogenic
steps. To date, treatments selectively suppressing autoantibody formation, inflammation cascade or both are available
(Figure 2). Grouping therapies according to their mechanism of action may be useful to test new associations or to
compare drugs with the same target but having different
efficacy or tolerability.

405
this broad spectrum of action, they have a strong efficacy on
each aspect of the disease.

Dosage and therapeutic schedule

Systemic corticosteroids are still the mainstay of
management in autoimmune bullous disorders, including
BP. A starting dose of prednisone of 0.75 to 1.00 mg/kg per
day or even less may be adequate to achieve disease control.
Once the development of blisters has been arrested and
erythema has subsided, a careful tapering of the prednisone is
recommended. This objective is usually reached by the end
of second week of therapy. A weekly lowering of 5 mg to
reach 30 mg is usually scheduled. Tapering the steroids
below 30 mg should be done gradually and slowly, following
an alternate day scheme. In alternative, decreasing prednisone by 2.5 mg every week is also rewarding and prevents
relapses. Tapering of the dose must be done according to the
clinical response of the patients.33 Due to its minor side
effects, we prefer deflazacort at the dose of 60 to 75 mg per
day with a lowering of 6 mg every other day.

Controversies on the use of systemic corticosteroids

Long-term and high-dose treatment with systemic
corticosteroids carries the risk for significant adverse effects,
including severe infections, gastric ulcers, hyperglycemia,
hyperlipidemia, hypertension, steroid-induced myopathy,
cognitive disturbances, osteoporosis, and thromboembolic
complications. Therefore, steroid withdrawal is frequently
needed, especially in patients with BP, who are often elderly
and have multiple medical problems. A major goal in the
management of patients with BP is reducing the patient's
cumulative exposure to systemic corticosteroids.34

A valid alternative: Topical corticosteroids

Corticosteroids
Mechanism of action
Corticosteroids have both anti-inflammatory and immunosuppressive actions, through genomic and non-genomic
mechanisms. They cause redistribution of granulocytes,
resulting in increase of circulating granulocytes and
reduction of tissue-bound ones. They also cause lymphopenia. Moreover, corticosteroids suppress inflammatory cascade by reducing adhesion molecules, chemotactic
substances, and many cytokines. The major anti-inflammatory effects of corticosteroids are thought to be due to
repression of inflammatory and immune genes. The
inhibitory effect of corticosteroids is largely due to
proteinprotein complex interactions between activated
corticosteroid receptors and transcription factors, such as
nuclear factor-B (NF-B) and activator protein-1, which
mediate the expression of many inflammatory genes. Due to

The use of topical corticosteroids alone is a valid alternative

to systemic ones. Topical steroids are successful in treating
limited or localized BP, but more recent studies have suggested
that high-potency topical steroids can also be useful in treating
more severe disease. 33 A very well-controlled French
multicenter study, comparing topical therapy with 40 g
0.05% clobetasol propionate cream daily to systemic treatment

Table 6 Temporal relationship between BP and neoplasm in

our patients
No. of patients
Onset of BP preceded diagnosis of tumor
Onset of BP and diagnosis of tumor
were almost contemporary
Onset of BP followed diagnosis of tumor
BP, bullous pemphigoid.

7/10
1/10
2/10

406

E. Ruocco et al.

Table 7 Interval between onset of BP and diagnosis of cancer

in our patients
Patient
Patient
Patient
Patient
Patient
Patient
Patient
Patient
Patient
Patient

1: pancreas cancer
2: lung cancer
3: lung cancer
4: prostate cancer
5: prostate cancer
6: lung cancer
7: lymphoma
8: esophagus cancer
9: uterus cancer
10: uterus cancer

2 mo a
2 mo
+ 2 mo b
16 mo
3 mo
13 mo
+ 2 mo
0
7 mo
2 mo

a
Minus sign indicates that onset of BP preceded diagnosis of
cancer.
b
Plus sign indicates that onset of BP followed diagnosis of cancer.

with 1 mg/kg prednisolone equivalent daily, demonstrated

superiority of topical glucocorticosteroid therapy with regard
to disease control and survival rate in highly active BP (N 10
new blisters daily).35 Moreover, the addition of steroid-sparing
agents, such as those listed in the next sections, may facilitate
tapering of systemic corticosteroids and help minimize
corticosteroid-associated adverse events.

Azathioprine
Mechanism of action
Azathioprine (AZA) is an imidazolyl derivative of
mercaptopurine that antagonizes purine metabolism and
inhibits synthesis of DNA, RNA, and proteins; it also may

Fig. 2

interfere with cellular metabolism and inhibit mitosis. In

addition to its effects on nucleic acid synthesis, AZA also
affects the immune system in a number of ways. It reversibly
reduces the number of monocytes and Langerhans cells,
impairs -globulin synthesis and T-cell lymphocyte function, and impedes the responses of B cells that depend on Th
cells as well as the function of suppressor B cells.36

Dosage and therapeutic schedule

AZA is the best-characterized first-line immunosuppressive and steroid-sparing agent for the treatment of autoimmune blistering diseases, including BP. The recommended
dosage of AZA is 1 to 3 mg/kg daily. A daily dosage at the
lower range is recommended for elderly patients. There
might be a latent period of 3 to 6 weeks before AZA becomes
effective. Alone, AZA may control disease in a few patients
with mild BP. The combination of AZA with oral
corticosteroids at low or medium-high doses is the standard
protocol for patients with moderate to severe relapsing BP
that does not respond to corticosteroids.34

Controversies on the use of azathioprine

Despite its steroid-sparing effect, there are no statistically
significant differences in disease control and mortality when
AZA is added to prednisone treatment.33 Severe AZA side
effects include leukopenia, thrombocytopenia, anemia,
pancytopenia, and hepatotoxicity. Moreover, long-term
immunosuppression increases the risk for infections and
neoplasia. AZA has also a mutagenic potential in both men

Management of bullous pemphigoid according to its pathomechanism steps.

Bullous pemphigoid associations and management

and women as well as possible hematologic toxicities.
Individuals with an inherited deficiency of the enzyme
thiopurine S-methyltransferase (TPMT), which deactivates
6-mercaptopurine, may be unusually sensitive to the
myelosuppressive effects of thioguanine and prone to rapid
bone marrow suppression after the initiation of AZA
treatment. Serum levels of TPMT should be tested to prevent
this complication. Because TPMT testing may not identify
all patients at risk for severe toxicity, close monitoring of
clinical and hematologic parameters is required. For practical
purposes, an abrupt increase in serum transaminase levels
observed soon after administration of AZA is a clue for a
deficient TPMT activity. Apart from genetic polymorphisms
of TPMT, concurrent therapy with TPMT-inhibiting drugs,
such as olsalazine, mesalazine, or sulfasalazine, can also
increase the risk for myelotoxicity.

407
antimetabolite adjuvant of choice in the treatment of many
autoimmune and inflammatory disorders, including BP.
Concerns about the tolerability of mycophenolate mofetil,
particularly regarding gastrointestinal (GI) side effects, led to
the development of enteric-coated mycophenolate sodium
(EC-MPS), which has bioequivalence with mycophenolate
mofetil. The EC-MPS formulation leads to a decreased need
for dose reductions due to GI side effects and, therefore,
provides potentially improved efficacy. Side effects are usually
mild, but GI symptoms, myalgia, neutropenia, lymphopenia,
and various infections may occur. Mycophenolate mofetil, in
particular EC-MPS, seems to be a promising immunosuppressive and steroid-sparing drug. Moreover, it is also less
myelosuppressive and hepatotoxic than AZA.34

Leflunomide
Mycophenolate mofetil

Mechanism of action

Mechanism of action

Leflunomide is an isoxazole derivative. It is largely

converted into A77 1726, its active metabolite, which
inhibits dihydroorotate dehydrogenase (DHODH), a key
enzyme in the de novo synthesis of uridine monophosphate.
The de novo pathway for pyrimidine synthesis is required for
clonal expansion and terminal differentiation of lymphocytes. Additionally, leflunomide exhibits anti-inflammatory
effects such as the inhibition of cyclooxygenase-2 and
histamine release in basophils. The active metabolite of
leflunomide inhibits eotaxin release by IL-4 and tumor
necrosis factor (TNF)-stimulated fibroblasts. This mechanism is not mediated by the inhibition of pyrimidine de
novo synthesis. It has been shown that leflunomide can also
inhibit TNF- action by preventing IB-degradation and
release of NF-B.37 Leflunomide seems to have more an
anti-inflammatory than an immunosuppressive action; in
fact, it is used in BP more frequently than in other pure
autoantibody-mediated diseases such as pemphigus.38

Mycophenolate mofetil, a drug originally produced for the

treatment of psoriasis and tumors, has potent immunosuppressive effects. Mycophenolate is rapidly absorbed after oral
administration and is then hydrolyzed to its active metabolite
mycophenolic acid (MPA), which selectively inhibits inosine
monophosphate dehydrogenase and therefore inhibits the de
novo pathway of purine synthesis in T and B cells. Unlike
most other cells, lymphocytes rely on the de novo pathway
more than the salvage pathway for purine biosynthesis.
Because MPA specifically inhibits the de novo pathway,
lymphocytes are the primary target of MPA action in vivo,
which minimizes unwanted effects on other cell types.34

Dosage and therapeutic schedule

The use of mycophenolate mofetil in BP has been limited
to case reports and small case series with proven efficacy.
Some of these reports have even shown successful control of
disease using mycophenolate mofetil as monotherapy in
selected patients, although it is usually added to systemic
corticosteroids for potential steroid-sparing effect.33 In adult
patients, we use a daily dosage of 1 to 1.5 g in monotherapy.
For more severe cases of BP we combine mycophenolate
mofetil with 30 mg daily of deflazacort. After the remission
has been achieved, deflazacort is gradually reduced and then
discontinued, whereas mycophenolate mofetil intake is
prolonged for a variable time.

Dosage and therapeutic schedule

The usual dose of leflunomide in BP is 20 mg daily,
combined with 20 mg daily of prednisone for 5 weeks.
Subsequently, the corticosteroid is gradually tapered and
leflunomide is reduced to 10mg per day.38 A recent review
reports that in two patients with BP, responsive only to high
doses of prednisone, leflunomide was used successfully. The
patients remained in clinical remission after a reduction of
leflunomide dose to 10 mg daily and 10 mg every other day,
respectively.37

Controversies on the use of mycophenolate mofetil

Controversies in the use of leflunomide
There are no big controversies on the use of mycophenolate
mofetil. In fact, because of its effectiveness and safety profile,
mycophenolate mofetil is gradually replacing AZA as the

Nausea, vomiting, diarrhea, alopecia, and hypertension

are common side effects of leflunomide. Elevation of hepatic

408
enzymes may occur. This elevation occurs within the first
6 months of therapy and often resolves during follow-up.
Vasculitis, pancytopenia, peripheral neuropathy, acute
interstitial pneumonia, toxic epidermal necrolysis, erythema
multiforme, and subacute cutaneous lupus erythematosus
also have been reported.37

Cyclophosphamide
Mechanism of action
Cyclophosphamide is a synthetic alkylating agent chemically related to the nitrogen mustards with antineoplastic
and immunosuppressive activities. In the liver, cyclophosphamide is converted to the active metabolites aldophosphamide and phosphoramide mustards, which bind to DNA
and thereby inhibit DNA replication and initiate cell death.

Dosage and therapeutic schedule

Cyclophosphamide is used as alternative drug to treat
patients with several autoimmune diseases, including
pemphigus vulgaris and BP. Adjuvant immunosuppressive
treatment with cyclophosphamide is considered if patients
with autoimmune bullous diseases (1) failed to achieve
remission with combinations of corticosteroid and azathioprine or mycophenolate mofetil, (2) had clinically significant
side effects with previous therapies, or (3) have rapidly
progressive disease with extensive skin and mucosal
lesions.34 Several reports have suggested that cyclophosphamide also may be useful in cases of severe or refractory
BP when given in either oral daily (15 mg/kg daily) or pulse
intravenous dosing. No large or randomized trials have been
performed with this medication.33

E. Ruocco et al.

Methotrexate
Mechanism of action
Methotrexate (MTX) inhibits the reduction of folic acid
by the enzyme dehydrofolate reductase, leading to depletion
of nucleotide precursors, which in turn impairs the synthesis
of DNA, RNA, and proteins. As an antimetabolite,
immunosuppressive agent, and anti-inflammatory drug,
MTX is used in the treatment of cancer and autoimmune
diseases.33 Initial observations indicated that the antiinflammatory effects might be of greater magnitude than
the immunosuppressive ones. This valuable aspect of MTX
may account for the lower incidence of infections in patients
treated with MTX compared with those on cyclophosphamide, mycophenolate mofetil, or AZA.39

Dosage and therapeutic schedule

Although no randomized controlled trials have been
performed, there are several reports of low-dose weekly
MTX being effective in combination with oral or topical
corticosteroids.33 A review of the available literature on
pemphigus and BP, showed that MTX is likely to be more
beneficial in patients with BP than in patients with
pemphigus, presumably due to the major role of inflammatory cascade in BP. The use of MTX in twice-weekly oral
doses (525 mg weekly) has been reported to control disease
and allow a significant reduction in prednisone dosages.
Low-dose MTX as a systemic monotherapy appears to be a
safe and effective treatment of BP. The use of MTX in BP is
recommended for patients who have an absolute or relative
contraindication for systemic corticosteroids, for elderly
patients with multiple medical problems, multiple drug
therapies and fragile constitution, and for patients with mild
or limited disease.39

Controversies on the use of cyclophosphamide

Controversies on the use of methotrexate
Whatever the additional benefit of cyclophosphamide
therapy, it must be balanced against its great toxic effects.
Adverse effects include chemotherapy-induced nausea and
vomiting, stomach pain, diarrhea, hemorrhagic cystitis,
darkening of the skin/nails, alopecia, changes in color and
texture of hair, and lethargy. Cyclophosphamide suppresses
production of blood cells from the bone marrow, causing
leukopenia, anemia, and thrombocytopenia, and accounting
for hemorrhagic cystitis, which can be prevented by adequate
fluid intake and administration of sodium 2-mercaptoethane
sulfonate. Cyclophosphamide is itself carcinogenic, potentially causing transitional cell carcinoma of the bladder as a
long-term complication. It can lower immunocompetence
and can cause temporary or, rarely, permanent gonadal
problems. Gonadal toxic side effects are represented by
amenorrhea, azoospermia, and infertility.36

Side effects of MTX are well known and include

pancytopenia and hepatotoxicity. Patients with renal
disease, those on nonsteroidal anti-inflammatories, and
those with no folic acid supplementation are at increased
risk for pancytopenia. Folinic acid (leucovorin) can be
given as a rescue for myelosuppression if needed. Hepatic
fibrosis and cirrhosis can occur after chronic administration. Patients with liver issues (hepatitis B or C, alcohol
use, diabetes, and obesity) are at increased risk for liver
complications. Photosensitivity and radiation recall are
known complications of MTX therapy. The most common
side effects include fatigue, nausea, and vomiting, which
can often be overcome with folinic acid supplementation.
Monitoring liver function and complete blood counts are
needed.33

Bullous pemphigoid associations and management

Dapsone

409
Dermatologists often have used the tetracycline nonantimicrobial benefits in immunity-related disorders.41

Mechanism of action
Dosage and therapeutic schedule
Dapsone is a drug used primarily in the treatment of
leprosy, pneumonia by Pneumocystis jiroveci and malaria,
but also has been used in autoimmune bullous diseases for its
steroid-sparing and anti-inflammatory effects. Dapsone
blocks myeloperoxidase, which converts hydrogen peroxide
(H2O2) into hypochlorous acid (HOCl) as part of the
neutrophil respiratory burst. HOCl is the most toxic and
potent oxidant generated by neutrophils, which may cause
significant tissue damage in many inflammatory diseases.
Dapsone reversibly inhibits myeloperoxidase activity by
promoting the formation of an inactive intermediate of the
enzyme, thus preventing the conversion of H2O2 to HOCl.
Moreover, dapsone acts on lysosomal membranes reducing
the release of proteolytic enzymes.

Tetracyclines appear to be a useful alternative to systemic

steroids in the treatment of BP. The usual dosage is 1.5 to 2 g
per day of tetracycline. Doxycycline may substitute
tetracycline in patients who do not tolerate tetracycline GI
or neurologic side effects. Also erythromycin (2g per day for
48 weeks in monotherapy) gave good results in BP.38

Controversies on the use of antimicrobials

Antimicrobials are well tolerated and may be useful for
elderly patients with multiple medical problems. Despite
that, there are not enough data on the efficacy of these drugs
in BP management.33

Dosage and therapeutic schedule

In BP, it is reported an efficacy rate close to 84%, either
alone or combined with systemic corticosteroids or other
immunosuppressants.40 Standard protocol therapy consists
of 100 mg per day combined with 60 mg per day of
prednisone. If there are no improvements, it can be increased
from 50 mg weekly to 200 mg per day maximum.

Controversies in the use of dapsone

Dapsone is useful in treating patients with bullous
diseases, including BP. Adverse events are dose dependent
and usually reversible, even if they also may be severe.
Hemolysis and secondary anemia are the most common, but
metahemoglobinemia, nausea, vomiting, peripheral neuropathy and liver diseases are also reported. 40 Absolute
contraindication to the use of dapsone is glucose-6phosphate dehydrogenase deficiency.38

Antimicrobials
Mechanism of action
Many non-antimicrobial actions of tetracyclines have
been proposed. Pathways affected by these medications often
are overexpressed in various dermatologic disorders. Matrix
metalloproteinases (MMPs) are enzymes best known for
breaking down connective tissue proteins and are upregulated in conditions involving dermal destruction.
Inhibition of MMPs by tetracyclines has been emphasized
as one of the major non-antimicrobial effects of these drugs.
Others include inflammatory cytokine regulation, inhibition
of leukocyte chemotaxis and activation, and anti-oxidation.

Intravenous Immunoglobulin
Mechanism of action
The exact mechanism of action of IVIg treatment in
autoimmune bullous diseases is not completely known. IVIg
treatment is thought to produce its clinically beneficial
effects by one or more of the following pathways: (1)
interactions with Fc receptors, (2) reduction in titers of
pathogenic antibodies, (3) induction or suppression of
cytokine production, (4) apoptotic effects, (5) neutralization
of toxins, and (6) alteration in sensitivity to corticosteroids.
In autoimmune bullous diseases, IVIg may work as an antiinflammatory or as an immunomodulatory agent.36

Dosage and therapeutic schedule

Treatment with IVIg is an important addition to the
therapeutic options available to a physician treating BP. The
diagnostic criteria for the use of IVIg treatment include
failure of conventional therapy, significant adverse effects of
conventional therapy, contraindications to the use of highdose long-term systemic corticosteroid, progressive disease
that is uncontrolled, rapid, and debilitating, and pregnancy.
The cumulative published experience suggests that a dose of
2 g/kg per cycle is most likely to produce desired or expected
results. Some patients, especially those whose disease is not
very active clinically but who show catastrophic adverse
effects to conventional therapies, may respond to 1 to 1.5 g/kg
per cycle. A cycle consists of the total dose divided into three
equal doses, each given on 3 consecutive days. Some
investigators prefer to use 400 mg/kg daily, given over a
course of 5 days, to constitute one cycle. The infusion is given

410
slowly over 4 to 4.5 hours. During the infusion, vital signs
should be monitored. The initial frequency is generally one
cycle every 3 to 4 weeks.36

Controversies on the use of IVIg

Adverse reactions associated with the use of IVIg are
usually mild and self-limiting. The incidence of adverse
effects of IVIg in patients treated for autoimmune diseases is
usually lower than 1%. Reactions such as headache, back
pain, chills, flushing, fever, hypertension, myalgia, nausea,
and vomiting appear to be related to the infusion rate rather
than the dose. Erythema, pain, phlebitis, and eczematous
dermatitis may occur at the infusion site.36 Potential severe
side effects, such as anaphylaxis, infection, thrombosis, and
renal failure, are rarely reported.33 Additionally, this therapy
is quite expensive, which often limits its use.

E. Ruocco et al.

Rituximab
Mechanism of action
Rituximab is a monoclonal humanized antibody directed
against the B-cellspecific cell surface antigen CD20.
Rituximab binds to CD20-expressing B lymphocytes,
including immature B cells in the bone marrow, autoantigen-activated follicular B cells, autoantigen-activated marginal zone B cells, and memory B cells. B stem cells and
plasma cells are not targeted. After the binding of rituximab
to its cell surface receptor, CD20-bearing B cells are killed
by a combination of antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and apoptosis, and
remain absent from the circulation for 6 to 12 months. The
removal of mature CD20 + B lymphocytes that are
committed to differentiation into autoantibody-producing
plasma cells is presumably the major effect of rituximab and
makes its use particularly attractive in those autoimmune
diseases in which pathogenically relevant autoantibodies
are present.

Plasmapheresis
Mechanism of action

Dosage and therapeutic schedule

As BP is also mediated by autoantibodies, several

therapies are aimed at their elimination. Plasmapheresis
involves removal of large amounts of plasma over the course
of several days and is performed during a hospitalization,
given the risk for fluid overload during the fluid/protein
replacement phase.

According to a recent review,42 adjuvant rituximab is

effective and well tolerated not only in patients with
pemphigus, where autoantibody action is predominant, but
also in patients with BP. Efficacy and safety of rituximab are
maintained when it is readministered during relapses42;
however ,in this study only two patients with BP were treated
with rituximab. This treatment has been reported previously
only in 10 patients with BP. Patients are currently treated
with four cycles of IV rituximab at doses of 375 mg/m2 at
weekly intervals, a regimen similar to that used in lymphoma
patients.36

Dosage and therapeutic schedule

The addition of plasma exchange to steroid treatment
allows reducing the steroid dosage (both daily and
cumulative dose) necessary to achieve disease control
(defined as lack of new blister formation and resolution of
old lesions) at 1-month follow-up.33 The number and
frequency of plasma exchanges as well as the steroid dosage
are tailored to each patient's requirements.

Controversies on the use of plasmapheresis

Due to its high cost and potential morbidity, plasmapheresis should not be recommended as routine therapy for BP,
but it is a useful adjunct in steroid-resistant cases.
Nevertheless, in some cases plasmapheresis failed to add
any benefit to prednisolone.33 This evidence corroborates the
crucial role of inflammation compared with that of
autoantibodies in BP. Because it is an invasive practice in
contrast with age and comorbility of BP patients, some
authors do not use it even in resistant cases.

Controversies on the use of rituximab

Due the low number of patients studied so far, the
effectiveness of rituximab in BP needs further evaluation.
Mild to moderate infusion reactions consisting of fever and
chills/rigors may occur in most patients during the first
rituximab infusion. Other frequent symptoms following the
infusion include nausea, pruritus, angioedema, asthenia,
hypotension, headache, bronchospasm, throat irritation,
rhinitis, urticaria, dermatitis, vomiting, myalgia, dizziness,
and hypertension. These reactions generally occur 30 to 120
minutes after the beginning of the first infusion and resolve
with slowing or interrupting the rituximab infusion and with
supportive care. Serious adverse reactions, some with fatal
outcome, have also been reported, including severe mucocutaneous reactions; hepatitis B reactivation with fulminant
course; progressive, multifocal leukoencephalopathy; other
viral infections; cardiac arrhythmias; renal toxicity; bowel

Bullous pemphigoid associations and management

obstruction and perforation; hematologic troubles, including
lymphopenia, neutropenia, leukopenia, and anemia. Although rare, some of these serious adverse reactions,
including fatal outcome, have been described in patients
with BP. Most patients generally respond within the first 3
months after initiation of rituximab; however, late responses,
after almost 1 year, also have been reported. The
combination of rituximab and IVIg or extracorporeal
immunoadsorption appears to be advantageous in severe
cases. Randomized controlled trials are necessary to better
determine the efficacy and adverse effects of rituximab in the
treatment of autoimmune blistering diseases, including BP.
Moreover, rituximab, like other biologic agents, is not
readily available in all dermatology units or departments due
to its high cost.36

Other monoclonal antibodies: facts

and controversies
So far the best-characterized monoclonal antibody (mAb)
active in BP is omalizumab. It is a recombinant humanized
mAb that binds to the Ce3 domain of IgE and prevents free IgE
from binding to the basophils and the mast cell high-affinity
IgE receptor. 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. 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. In our experience, almost all BP patients
present high levels of IgE. Therefore, omalizumab may be a
valid therapeutic option.33 The omalizumab dose is usually
calculated according to the asthma dosing nanogram.43
Although TNF- blockers such as etanercept or adalimumab are considered as inducing factors of BP, in some cases
they can be an effective alternative therapy for this disease,
especially when BP coexists with psoriasis, using the same
therapeutic protocol. 32 Further studies are needed to
establish the efficacy of anti-TNF in the treatment of
immunobullous disorders and, thus, solve this controversy.
Besides the mechanism of blister formation induced by
autoantibodies, the inflammatory cascade in BP may also be
activated by TH17/IL-17 pathway, because IL-17 is able to
release pro-inflammatory cytokines and proteolytic enzymes,
recruit and activate neutrophils, which by itself may result in
blister formation.32 As the expansion of TH17 cells is
promoted by IL-23, a new approach to BP treatment may be
the use of ustekinumab, a mAb that prevents the interaction
of IL-23 and IL-12 with their receptors, consequently
blocking both TH17 and TH1 differentiation. Currently,
we have been treating with ustekinumab a patient who
developed first BP and, subsequently, psoriasis, using the
psoriasis therapeutic protocol. After the second administra-

411
tion (first follow-up), a visible lesion reduction of both
diseases was achieved.
As our understanding of BP pathogenesis has progressed
in recent years,32 these new targeted therapies have
considerably improved (and probably will still be improving)
quality of life and prognosis of these patients.

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