Section 1: Epidemiology and aetiology
Whenever tense bullae are present, bullous pemphigoid (BP), which is the most common autoimmune blistering condition in the developed world and one of the immunobullous disorders, must come to mind.1 However, blistering is common and there are multiple causes, some benign and others less so.
BP, which is mostly a disease of the elderly, is diagnosed from clinical, pathological and immunofluorescence (IMF) studies. The incidence has been underestimated in the past, but a recent study found it to be 4.3 (95% CI 4.0-4.6) per 100,000 person-years in the UK.2
It is likely that this figure still underestimates the true incidence, especially of those with milder forms of the condition. BP is a disease primarily affecting those over 70 years of age, so the incidence is expected to increase in future in countries with ageing populations. BP occurs very rarely in children.
The morbidity and potential for mortality caused by BP should not be underestimated. Not only are the bullous lesions themselves often painful and restrictive, they are also difficult and time-consuming to manage, especially if they are widespread.
Furthermore, the long-term systemic treatments that are often needed to control the disease carry their own risks of side-effects and even mortality. The mortality in patients with BP is twice that of the general population in the UK.2
Aetiology
BP is an acquired autoimmune disease which affects the skin, causing the development of non-scarring subepidermal bullae following the deposition of autoantibodies and complement at the basement membrane. This results in the activation of complement pathways and leukocytes, causing an inflammatory response, damage to the epithelium and blister formation.3
These autoantibodies are mainly IgG and bind to components of the hemidesmosome adhesion complex, namely the BP230 and BP180 antigens, at the basement membrane. This means the pathology is developing just underneath the epidermis, which results in a bulla that has the full thickness of the epidermis as its roof.
As such, these blisters are relatively resilient to bursting and become tense and enlarge as an inflammatory exudate builds up in them.
This is in contrast to another immunobullous disease, pemphigus vulgaris, where flaccid bullae develop which are fragile and can easily rupture. This is because in pemphigus vulgaris, the autoantibodies are directed against the intercellular cement of the epidermis, meaning that the bullae develop in the epidermis, rather than underneath it. The resultant bullae therefore only have a superficial portion of the epidermis as their roof and as a consequence, are less resilient.
Section 2: Making the diagnosis
Many patients will present insidiously with a history of a variably intense pruritus for many months or years before they develop frank blistering.
During this period, an eczematous or persistent urticaria-like eruption may have developed.4
For this reason, it is worthwhile considering BP in any elderly patient who presents with pruritus of an uncertain cause.
A patient with the tense, firm, pruritic bullae typical of BP
Alternatively, patients may present for the first time with the typical tense, firm, pruritic bullae (see image above). The bullae are classically accentuated in the flexural areas of the body and begin symmetrically on the limbs before spreading to the trunk. Localised disease may also occur. The mucous membranes are also involved in about half of all cases.
Initially, vesicles develop which rapidly enlarge to become bullae. Lesions can be found on erythematous or normal-looking skin. Over time, the tense blisters can become purulent and haemorrhagic and eventually burst, leaving behind an erosion that will crust over. Lesions can easily become secondarily infected.
Differential diagnosis
Blistering disorders can be broadly divided into immuno-bullous, traumatic, infectious and others (see table below, not an exhaustive list). Trauma such as burns, friction and oedema blisters in swollen oedematous legs should always be considered.
| DIFFERENTIAL DIAGNOSIS | |||
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| IMMUNOBULLOUS | INFECTIVE | TRAUMATIC | OTHERS |
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Differentiating clinically between the immunobullous disorders can be impossible at initial presentation and IMF studies are often needed.
Investigations
Treatment does not have to be delayed for investigations to be performed, although prolonged treatment can lead to false negative IMF results.1 Specifically, blood tests should be sent for circulating antiepidermal autoantibodies, so-called indirect IMF.
In about 70 per cent of patients with BP, indirect IMF will be positive, demonstrating autoantibodies directed against basement membrane components. In pemphigus vulgaris, indirect IMF will reveal auto- antibodies directed against the intercellular components of the epidermis and unlike in BP, titres correlate with the severity of the disease.
A preferably intact bulla should be sent for histological examination, which in BP classically shows subepidermal bulla formation with a mixed inflammatory infiltrate typically containing many eosinophils. Perilesional skin should be sent for direct IMF, which in BP will reveal linear deposits of immunoglobulin and complement along the basement membrane.
The results of IMF studies are essential in differentiating between the immunobullous disorders. However, the findings of direct and indirect IMF studies may be identical in BP, cicatricial pemphigoid and epidermolysis bullosa acquisita.
These conditions must therefore be differentiated clinically or with further IMF studies, for example on salt-split skin.
Section 3: Managing the condition
The aim of treatment is to make the disease tolerable by reducing the rate of new bullae formation.1 Treatment can be difficult because many patients are over 70 years old and have other comorbidities, so are more susceptible to side-effects from systemic agents.
The first step is to assess whether the patient has mild, moderate or severe disease. Following this, there are two equally acceptable approaches to treatment.
First, one can use a low-dose medication and titrate this upwards until clinical response is achieved. This risks leaving the patient undertreated for longer, but may be a good approach in those with mild to moderate disease and/or when there is concern about possible side-effects.
The second approach is to start patients on high-dose treatment, aiming to gain rapid control of the condition, then to reduce the doses of systemic medication as soon as possible.
This approach may be the most suitable for controlling the condition in patients who have more severe disease.
Topical steroids
Potent topical steroids such as 0.05% clobetasol propionate can be applied twice daily to BP lesions.1 Moderate potency topical steroids can be used for flexural areas. Topical treatment alone may be adequate in mild to moderate and localised disease and can be used alongside systemic agents.
Systemic steroids
Systemic steroids in the form of oral prednisolone are the most established treatment used to bring about rapid and reliable clinical remission in moderate to severe cases of BP.
Doses vary from 20mg to 80mg daily. There is evidence that doses over 0.75mg/kg per day (over 60mg daily in an 80kg patient) confer no additional benefit compared with lower doses, and are associated with more adverse outcomes.1 It is reasonable to start each patient on a dose ranging from 20 to 60mg daily, depending on clinical severity and risk of using higher doses.
Measures to prevent osteo-porosis must be implemented from the start of treatment.1
Tetracyclines
There is emerging evidence that tetracycline antibiotics, with or without nicotinamide, are effective in controlling localised and mild to moderate BP.
Optimal doses are yet to be established but doxycycline 200mg daily, tetracycline 500-2,000mg daily and minocycline 100-200mg daily have been used.1 Treatment should always be combined with topical steroids. Tetracycline should be avoided in renal and hepatic disorders and in children.
Children can be treated with erythromycin if needed because there is emerging evidence of its efficacy. If used, nicotinamide should be started at 500mg daily and slowly increased to 1,500-2,000mg per day.
Azathioprine
Mostly used as an adjunct and steroid-sparing agent alongside systemic steroids, azathioprine is the second most commonly used systemic agent in BP.
Doses up to 2.5mg/kg per day are used (100mg twice daily for an 80kg patient). However, there are conflicting reports on its efficacy and it is not established as a sole or initial therapeutic agent in BP.1
Other systemic agents
There is little further evidence for use of the following but they may have a role in certain cases: cyclophosphamide, IV steroids, plasmapheresis, mycophenolate mofetil, IV immunoglobulin, ciclosporin, chlorambucil, dapsone and sulfonamide have all been used with varying degrees of success.
Methotrexate can be considered in patients with BP and psoriasis.
Section 4: Prognosis
Haemorrhagic blisters will eventually burst, leaving behind an erosion that crusts over
Patients with BP should be followed up regularly until they are in complete remission. The disease itself usually remits within five years. Once a treatment regimen is established which is adequately controlling the disease, patients should be seen at least monthly for a medication review. If the lesions have remained quiescent, doses of systemic steroids should be slowly reduced over a number of months.
Stopping one or more treatments suddenly can lead to a severe relapse of disease and should be avoided. Patients should be weaned off treatments slowly and separately. The appearance of a few new blisters each month while the patient is receiving therapy must not be regarded as treatment failure, especially if they are well tolerated by the patient. If numerous new lesions are developing, treatment should be returned to the last regimen that adequately controlled the patient's condition.
Section 5: Case study
A 75-year-old man presented with the sudden appearance of blisters on his legs, arms and groin. He reported having been itchy 'all over' for a few months before this and had developed some red spots. A relative thought that these spots looked like urticaria.
The patient was systemically well and had no previous skin problems. Past medical history revealed type-2 diet-controlled diabetes mellitus only. He was taking no regular medications.
Blisters and erosions
On examination, there were six tense, firm blisters involving the proximal limbs and groin. There were a few erosions with crusting present around the groin and lower abdomen, but no features of active infection.
Blood tests were taken for inflammatory markers and indirect IMF. Bacterial swabs were performed.
A 6mm punch biopsy was taken to remove a recently developed intact bulla for histological examination.
A 4mm punch biopsy was taken of perilesional skin, which was sent for direct IMF.
Treatment was started with topical 0.05% clobetasol propionate cream to be applied twice daily to red or blistered lesions.
Oral doxycycline was started at a dose of 100mg twice daily.
An antimicrobial-containing emollient was prescribed, to be used regularly as a soap substitute, and a greasy emollient to be used regularly. The patient was not sleeping well because of the pruritus, so a sedating antihistamine was prescribed in the form of hydroxyzine 10-20mg at night. Paracetamol as required was advised for analgesia.
Histological and IMF investigations revealed findings typical of BP, which correlated with the clinical presentation.
On review four weeks later, the patient remained well but had continued to develop new blisters each week.He remained comfortable, so treatment was continued and at review the following month, only two or three new lesions had developed over the past four weeks, with all other lesions continuing to heal well.
The doxycycline was continued at 100mg twice daily with a view to reducing the dose in four weeks if the patient's condition remained stable.
Section 6: Evidence base
Guidelines
- Wojnarowska F, Kirtschig G, Highet AS, et al; British Association of Dermatologists. Guidelines for the management of bullous pemphigoid. Br J Dermatol 2002; 147: 214-21.
- Bone and Tooth Society of Great Britain, National Osteoporosis Society and Royal College of Physicians. Glucocorticoid-induced osteoporosis: Guidelines for prevention and treatment. London, December 2002.
Key texts
Three comprehensive texts on all aspects of dermatology:
- Bolognia JL, Jorizzo JL, Rapini RP. Dermatology (second edition). London, Mosby, 2007.
Online
Comprehensive resource of dermatological images and information.
Another comprehensive resource of images of dermatological conditions.
A helpful article on BP.
Reflect on this article and add notes to your CPD Organiser on MIMS Learning
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References
1. Wojnarowska F, Kirtschig G, Highet AS et al; British Association of Dermatologists. Guidelines for the management of bullous pemphigoid. Br J Dermatol 2002; 147: 214-21.
2. Langan SM, Smeeth L, Hubbard R et al. Bullous pemphigoid and pemphigus vulgaris - incidence and mortality in the UK: population based cohort study. BMJ 2008; 337: a180.
3. Sitaru C. Bullous pemphigoid: a prototypical antibody-mediated organ-specific autoimmune disease. J Invest Dermatol 2009; 129: 822-4.
4. Nakatani T, Inaoki M, Takehara K. Bullous pemphigoid with a prolonged prodrome. J Dermatol 2008; 35: 433-6.
