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Original Article

Bullous Pemphigoid: Profile and Outcome in a Series of

100 Cases in Singapore
Siew‑Kiang Tan, Yong‑Kwang Tay1
Department of Dermatology, Raffles Hospital, 1Department of Dermatology, Changi General Hospital, Singapore

Abstract
Background: Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease. Objective: We report the profile
and outcome of 100 cases of BP seen at our center. Patients and Methods: This was a retrospective study of patients with BP seen at Changi
General Hospital, Singapore from 2004 to 2012. Results: There were 57 female and 43 male patients. Other than the usual comorbidities such
as diabetes mellitus and neurological diseases, there were a high incidence of osteoporosis (29%), hypothyroidism (6%), malignancy (6%),
and hepatitis B carrier (3%). Peripheral blood eosinophilia is seen in almost half of the patients. The study results showed the higher sensitivity
of direct immunofluorescence  (93.5%) as compared to indirect immunofluorescence  (89.1%). Topical and systemic corticosteroids were
the standard treatment (96%). The duration to remission ranged from 2 weeks to 34 months, with a mean age of 7 months. Doxycycline
and nicotinamide were effective for localized BP. The mortality rate was 35%. Conclusion: In Singapore, BP is associated with significant
morbidity and mortality. High mortality of BP is related to the advanced age of the patients, associated medical conditions and complications
from the treatment.

Keywords: Bullous pemphigoid, outcome, Singapore

Introduction 1. Clinical findings consistent with BP – for example, tense

Bullous pemphigoid (BP) is the most common autoimmune
subepidermal blistering disease, predominantly affecting
the elderly and associated with significant morbidity. The
management of BP is challenging due to high age and
comorbidities of affected patients. The epidemiology of BP is
well described in the Caucasian population with limited data
in the Asian population. The minimum estimated incidence
was reported to be 7.6 per million populations per year in
Singapore.[1] The purpose of this study was to demonstrate
the demographic data, clinical features, investigations, and
therapeutic outcomes of 100  patients with BP treated at
Changi General Hospital in Singapore from 2004 to 2012, with
emphasis on the morbidity and mortality due to the disease.
Patients and Methods
Patients admitted between 2004 and 2012 with a diagnosis
of BP were identified from the hospital’s computer database.
The diagnosis of BP was made if the patient fulfils at least 3
of the 4 following criteria:
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blisters arising from erythematous or urticated lesional
skin affecting the trunk and limbs [Figure 1]
2. Histopathological findings of a subepidermal blister
3. Direct immunofluorescence  (DIF) finding of linear
deposition of IgG and/or complement along the
dermo‑epidermal junction
4. Indirect immunofluorescence  (IIF) findings of either
roof pattern or roof and floor pattern or positive
anti‑BP180 NC16A IgG antibodies measured using ELISA
(MBL Co. Ltd., Japan).
A total of 272 patients were admitted for BP from 2004 to 2012.
Those with incomplete data are excluded from the study. We
reviewed 100 of the cases by randomly selecting 100 cases
using the research randomizer program. We retrospectively
Address for correspondence: Dr. Yong‑Kwang Tay,
Department of Dermatology, Changi General Hospital, 2 Simei Street 3,
Singapore 529889, Singapore.
E‑mail: yong_kwang_tay@cgh.com.sg
This is an open access article distributed under the terms of the Creative Commons
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and build upon the work non‑commercially, as long as the author is credited and the
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For reprints contact: reprints@medknow.com

DOI: How to cite this article: Tan SK, Tay YK. Bullous pemphigoid: Profile
10.4103/jdds.jdds_1_18 and outcome in a series of 100 cases in Singapore. J Dermatol Dermatol
Surg 2018;22:12-5.

12 © 2018 Journal of Dermatology and Dermatologic Surgery | Published by Wolters Kluwer ‑ Medknow

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Tan and Tay: Bullous pemphigoid in Singapore

Table  1: Demographic data, clinical features, and

comorbidities of the patients
Number of patients
Sex
Female 57
Male 48
Ethnic
Chinese 72
Malay 14
Indian 6
Eurasian 8
Clinical features
Blisters and erosions 80
Urticated plaques 11
Nonspecific itchy rash 9
Figure 1: Various manifestations of bullous pemphigoid including urticated Oral mucosa involvement 2
plaques, intact blisters and erosions Localized blistering 44
Generalized blistering 54
reviewed the case notes, investigation results, and treatment Comorbidities
records of these patients. Demographic data, clinical features, Hypertension 55
comorbidities, investigations, treatment modalities, treatment Diabetes mellitus 32
outcomes, and mortality were analyzed. Descriptive statistics Hyperlipidemia 32
were used to report the demographic data, clinical features, Ischemic heart disease 33
and investigations. Dementia 35
Stroke 33
Results Parkinson’s disease 17
Hypothyroidism 6
Demographic data Anemia of chronic disease 15
The female:male ratio was 1.3:1. The patients’ age ranged from Depression 7
48 to 102 years (mean, 81 years) [Table 1]. Malignancy 6
Hepatitis B carrier 3
Investigations
Osteoporosis 29
Forty‑nine patients had peripheral blood eosinophilia, which
ranged from 6% to 34.6%. Ninety‑two patients had a skin
biopsy, DIF and IIF done. Eighty‑four biopsies showed remission ranged from 2 weeks to 34 months, with a mean
subepidermal bulla with eosinophilic infiltrates. Eight out of 7 months. Thirty‑three patients on oral prednisolone had
the nine patients who presented with nonspecific itchy rashes relapse within 2 days to 20 months with mean of 3.9 months.
had biopsies done. Two showed interface dermatitis with The reasons for relapse include tailing down or stopping
numerous eosinophilic infiltrate and six showed eosinophilic prednisolone too fast and the patients defaulting treatment.
spongiotic dermatitis. Eighty‑six patients (93.5%) had typical Patients also tend to relapse when prednisolone was reduced
DIF with linear C3 and/or IgG along the basement membrane. to below 5 mg a day.
Eighty‑two patients (89.1%) had typical IIF, which showed
roof pattern with immune deposits on the epidermal side. As the Twenty‑seven patients were given doxycycline 100 mg bid and
BP180 ELISA test was only available in the recent years, seven nicotinamide 500 mg bid/tds, of which four patients were on
patients had this test done, and six had positive result (85.7%). doxycycline and nicotinamide alone without systemic steroids.
These four patients all had mild or localized BP.
Treatment
Eighty‑nine patients received topical steroids. Seventy‑two Nine patients had dapsone 50 mg to 100 mg daily in addition
patients received mid potency topical steroids such as to oral prednisolone. Two patients had azathioprine and one
betamethasone valerate 0.1% cream or ointment and patient had cyclosporine in addition to oral prednisolone. Their
betamethasone 0.1%/clioquinol cream whereas the other BP were not well controlled with oral prednisolone alone.
seventeen patients received potent topical steroids such as Treatment‑induced morbidity
betamethasone dipropionate cream or clobetasol propionate For patients on systemic steroids, nine had steroid‑induced
cream. hyperglycemia, six had steroid‑induced hypertension, one
Ninety‑six patients were given oral prednisolone 0.5 mg/kg had steroid‑induced psychosis, and one developed Cushing’s
body weight. The duration of prednisolone ranged from 1 week syndrome. For patients on azathioprine, two developed
to 60 months, with a mean of 11.6 months. The duration to transaminitis and one had bicytopenia. Two patients had

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Tan and Tay: Bullous pemphigoid in Singapore
dapsone‑induced hemolytic anemia and one patient had
cyclosporine‑induced hypertension. There was an increased
risk of infection when these elderly patients were given
systemic steroids. Five patients had urinary tract infection,
three had pneumonia, three had methicillin‑resistant
Staphylococcus aureus wound infection, four had scabies and
one had herpes zoster infection during treatment.
Mortality
The duration of follow‑up ranged from 1  week to 6  years,
with a mean follow‑up duration of 13.2 months. Thirty‑five
patients died during the follow‑up. The most common cause
of death was sepsis (n = 14). Six died from pneumonia, four
from urinary tract infection, three from cellulitis and one from
gangrene of the left leg. There were four patients who died
from ischemic heart disease, one died from carcinoma of the
cervix, and one died from the end‑stage renal failure. For the
remainder 15 patients who passed away, the causes of death
were unknown.
Discussion
The mean age of onset in our patients was in the eighth
decade of life. Females were affected more than males with
a female:male ratio of 1.3:1. These findings are similar to
studies from the United  Kingdom and Poland. [2,3] There
was a predilection for the Chinese ethnic in our study as the
Chinese formed the majority at 74% of the Singapore resident
population, followed by the Malays with 13%, the Indians with
9.1% and the others with 3.3% in 2013. In a Malaysia study,
the incidence of BP was highest in the Indians.[4]
Nine percent of our patients presented with nonspecific itchy
rashes without blisters and were treated as for eczema and
scabies before they presented to us. Itchy rashes in elderly
patients that do not improve with emollients or topical
steroid should be investigated for the nonbullous phase of
BP. Blood investigations can be sent for serum IIF or BP180
ELISA test. There were only two patients with oral mucosal
involvement  (2%). On the contrary, mucous membrane
involvement was higher in reports from Greece  (24.3%),
Taiwan (12.8%), Thailand (15.5%), and Kuwait (37%).[5‑8]
The frequencies of metabolic syndromes for our patients
were 55% hypertension, 32% diabetes mellitus, and 32%
hyperlipidemia. There was a high incidence of osteoporosis
in our patients  (29%). As the mainstay treatment for BP
is systemic corticosteroids, it is important to screen the
patients by performing bone density study and start the
patients on calcium/vitamin D supplements. Patients who have
osteoporosis should be started on bisphosphonate.
In our study, six patients had hypothyroidism. Four had
hypothyroidism after radio‑iodine therapy. Three out of the
four patients had Grave’s disease. The other two patients had
hypothyroidism secondary to Hashimoto’s thyroiditis. The
association of BP with thyroid diseases is probably related to
autoimmunity.
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There are multiple case–control studies and case reports
reporting strong associations between previous neurological
diseases and the later development of BP. Specific associations
have been suggested between BP and Parkinson’s disease,
dementia, stroke, multiple sclerosis and epilepsy. BP antigen has
been identified in the brain and neuronal tissue.[9] Degenerative
neurological diseases could lead to autoimmune triggers against
neuronal BPAg1, leading to later BP. This is supported by the
association between the dystonin gene, encoding for the neuronal
isoform of BPAg1 and degenerative neurological disease in
mice. In this study, 35 patients had dementia, 33 had stroke and
17 had Parkinson’s disease. Langan et al.[10] reported the first
population‑based case–control study examining the association
between BP and neurological diseases. A 3‑fold increase in the
odds of BP was seen with dementia and Parkinson’s disease and
a 2‑fold increase for stroke and epilepsy.
Reports in Asia suggested an increased incidence of
malignancies in BP patients compared to age‑matched controls.
In Japan, 5.8% of 1000 BP patients had malignancies.[11] The
incidence of internal malignancy in our study was 6%. Two
patients had carcinoma of the cervix, two had colorectal
carcinoma, one had bladder carcinoma and one had breast
carcinoma. It is postulated that the carcinoma may produce
BP 180 antigen or may expose these normally sequestered
antigens. The latter is described as the phenomenon of epitope
spreading, where the injured mucosa or the carcinoma might
expose the BP 180 antigen inducing the onset of BP.[12]
Asia is known for high endemicity for hepatitis B virus (HBV)
infection. Three patients were hepatitis B carriers. Care should
be exercised when using high doses of corticosteroids to treat
BP in HBV carriers, because these drugs may aggravate HBV
infections and cause liver failure. These patients should be
referred to a gastroenterologist for co‑management. Some
patients may need preemptive treatment with an antiviral agent
such as lamivudine, and lately with the more potent tenofovir
or entecavir, to prevent HBV reactivation.
Seven out of the nine patients who presented with nonspecific
itchy rashes without blisters had peripheral eosinophilia. BP
should be included in the differential diagnosis of itchy or
bullous skin conditions in the elderly with eosinophilia.
There was a significantly increased risk of infection in these
elderly patients on systemic corticosteroids  (16%). During
follow‑ups, the blood sugar and blood pressure should be
monitored. They should be counseled on the risk of infections
while on long‑term corticosteroids.
The mortality rate in our study was 35%. The most common
cause of death was sepsis and infections  (14%), followed
by ischemic heart disease  (4%), cancer  (1%), and renal
failure  (1%). Cai et al.[13] reported 1‑, 2‑, 3‑year mortality
rates were 26.7%, 38.4%, and 45.7%, respectively. The
3‑year standardized mortality risk for BP patients was 2.74
(95% confidence interval: 2.34–3.19) times compared to the
age‑ and sex‑matched general population.
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Tan and Tay: Bullous pemphigoid in Singapore
Conclusion
Topical and systemic corticosteroids are the mainstay of
treatment. The mean duration to remission was about 7 months.
There was a high relapse rate of about 33% due to tailing
of systemic steroids. The high mortality of BP is related to
advanced age, associated medical conditions and complications
from treatment. Patients should be monitored for all these
treatment complications during follow‑ups.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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