|Year : 2018 | Volume
| Issue : 1 | Page : 12-15
Bullous pemphigoid: Profile and outcome in a series of 100 cases in Singapore
Siew-Kiang Tan1, Yong-Kwang Tay2
1 Department of Dermatology, Raffles Hospital, Singapore
2 Department of Dermatology, Changi General Hospital, Singapore
|Date of Web Publication||31-Jan-2018|
Dr. Yong-Kwang Tay
Department of Dermatology, Changi General Hospital, 2 Simei Street 3, Singapore 529889
Source of Support: None, Conflict of Interest: None
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
|How to cite this article:|
Tan SK, Tay YK. Bullous pemphigoid: Profile and outcome in a series of 100 cases in Singapore. J Dermatol Dermatol Surg 2018;22:12-5
| Introduction|| |
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. 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:
- Clinical findings consistent with BP – for example, tense blisters arising from erythematous or urticated lesional skin affecting the trunk and limbs [Figure 1]
- Histopathological findings of a subepidermal blister
- Direct immunofluorescence (DIF) finding of linear deposition of IgG and/or complement along the dermo-epidermal junction
- 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).
|Figure 1: Various manifestations of bullous pemphigoid including urticated plaques, intact blisters and erosions|
Click here to view
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 reviewed the case notes, investigation results, and treatment records of these patients. Demographic data, clinical features, comorbidities, investigations, treatment modalities, treatment outcomes, and mortality were analyzed. Descriptive statistics were used to report the demographic data, clinical features, and investigations.
| Results|| |
The female:male ratio was 1.3:1. The patients' age ranged from 48 to 102 years (mean, 81 years) [Table 1].
|Table 1: Demographic data, clinical features, and comorbidities of the patients|
Click here to view
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 subepidermal bulla with eosinophilic infiltrates. Eight out the nine patients who presented with nonspecific itchy rashes had biopsies done. Two showed interface dermatitis with numerous eosinophilic infiltrate and six showed eosinophilic spongiotic dermatitis. Eighty-six patients (93.5%) had typical DIF with linear C3 and/or IgG along the basement membrane. Eighty-two patients (89.1%) had typical IIF, which showed roof pattern with immune deposits on the epidermal side. As the BP180 ELISA test was only available in the recent years, seven patients had this test done, and six had positive result (85.7%).
Eighty-nine patients received topical steroids. Seventy-two patients received mid potency topical steroids such as betamethasone valerate 0.1% cream or ointment and betamethasone 0.1%/clioquinol cream whereas the other seventeen patients received potent topical steroids such as betamethasone dipropionate cream or clobetasol propionate cream.
Ninety-six patients were given oral prednisolone 0.5 mg/kg body weight. The duration of prednisolone ranged from 1 week to 60 months, with a mean of 11.6 months. The duration to remission ranged from 2 weeks to 34 months, with a mean of 7 months. Thirty-three patients on oral prednisolone had relapse within 2 days to 20 months with mean of 3.9 months. The reasons for relapse include tailing down or stopping prednisolone too fast and the patients defaulting treatment. Patients also tend to relapse when prednisolone was reduced to below 5 mg a day.
Twenty-seven patients were given doxycycline 100 mg bid and nicotinamide 500 mg bid/tds, of which four patients were on doxycycline and nicotinamide alone without systemic steroids. These four patients all had mild or localized BP.
Nine patients had dapsone 50 mg to 100 mg daily in addition to oral prednisolone. Two patients had azathioprine and one patient had cyclosporine in addition to oral prednisolone. Their BP were not well controlled with oral prednisolone alone.
For patients on systemic steroids, nine had steroid-induced hyperglycemia, six had steroid-induced hypertension, one had steroid-induced psychosis, and one developed Cushing's syndrome. For patients on azathioprine, two developed transaminitis and one had bicytopenia. Two patients had 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.
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., 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.
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%).,,,
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.
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. 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. 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. 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.
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. 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.
| 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
Conflicts of interest
There are no conflicts of interest.
| References|| |
Wong SN, Chua SH. Bullous pemphigoid seen at the national skin centre: A 2-year retrospective review. Ann Acad Med Singapore 2002;31:170-4.
Langan SM, Smeeth L, Hubbard R, Fleming KM, Smith CJ, West J, et al.
Bullous pemphigoid and pemphigus vulgaris – Incidence and mortality in the UK: Population based cohort study. BMJ 2008;337:a180.
Serwin AB, Bokiniec E, Piascik M, Masny D, Chodynicka B. Epidemiological and clinical analysis of pemphigoid patients in Northeastern Poland in 2000-2005. Med Sci Monit 2007;13:CR360-4.
Adam BA. Bullous diseases in Malaysia: Epidemiology and natural history. Int J Dermatol 1992;31:42-5.
Kyriakis KP, Paparizos VA, Panteleos DN, Tosca AD. Re-evaluation of the natural course of bullous pemphigoid. A prospective study. Int J Dermatol 1999;38:909-13.
Chang YT, Liu HN, Wong CK. Bullous pemphigoid – A report of 86 cases from Taiwan. Clin Exp Dermatol 1996;21:20-2.
Kulthanan K, Chularojanamontri L, Tuchinda P, Sirikudta W, Pinkaew S. Prevalence and clinical features of Thai patients with bullous pemphigoid. Asian Pac J Allergy Immunol 2011;29:66-72.
Nanda A, Al-Saeid K, Al-Sabah H, Dvorak R, Alsaleh QA. Clinicoepidemiological features and course of 43 cases of bullous pemphigoid in Kuwait. Clin Exp Dermatol 2006;31:339-42.
Brown A, Bernier G, Mathieu M, Rossant J, Kothary R. The mouse dystonia musculorum gene is a neural isoform of bullous pemphigoid antigen 1. Nat Genet 1995;10:301-6.
Langan SM, Groves RW, West J. The relationship between neurological disease and bullous pemphigoid: A population-based case-control study. J Invest Dermatol 2011;131:631-6.
Ogawa H, Sakuma M, Morioka S, Kitamura K, Sasai Y, Imamura S, et al.
The incidence of internal malignancies in pemphigus and bullous pemphigoid in Japan. J Dermatol Sci 1995;9:136-41.
Chan LS, Vanderlugt CJ, Hashimoto T, Nishikawa T, Zone JJ, Black MM, et al.
Epitope spreading: Lessons from autoimmune skin diseases. J Invest Dermatol 1998;110:103-9.
Cai SC, Allen JC, Lim YL, Chua SH, Tan SH, Tang MB, et al.
Mortality of bullous pemphigoid in Singapore: Risk factors and causes of death in 359 patients seen at the national skin centre. Br J Dermatol 2014;170:1319-26.
|This article has been cited by|
||Long-term oral prednisolone exposure in primary care for bullous pemphigoid: population-based study
| ||Monica SM Persson, Karen E Harman, Kim S Thomas, Joanne R Chalmers, Yana Vinogradova, Sinead M Langan, Julia Hippisley-Cox, Sonia Gran |
| ||British Journal of General Practice. 2021; 71(713): e904 |
|[Pubmed] | [DOI]|
||Characteristics of patients with bullous pemphigoid: comparison of classic bullous pemphigoid to non-bullous pemphigoid
| ||Y. Ben Mordehai,H. Faibish,N. Astman,S. Greenberger,A. Barzilai,S. Baum |
| ||Journal of the European Academy of Dermatology and Venereology. 2019; |
|[Pubmed] | [DOI]|