Bullous pemphigoid (BP) is a chronic, autoimmune, subepidermal, blistering skin disorder (unlike pemphigus where the blistering is intra-epidermal). Clear diagnostic criteria can be lacking for definitive diagnosis in less than clear-cut cases.
The autoantigen is type XVII collagen (COL17), also called BP180 or BPAG2, a protein that forms the junction between the epidermis and the basement membrane of the dermis. Direct immunofluorescence (DIF) studies of the blister skin show deposition of IgG and complement (C3) at the dermal/epidermal junction.
Analysis of this skin when split, shows deposition of IgG on the epidermis half (the roof), rather than the dermal side, the floor, of the blister. This feature distinguishes BP from other autoimmune blistering skin diseases.
CD4-positive T cells are thought to play a major role in the development of BP.
- The incidence of pemphigoid in the UK is estimated at 4.3 per 100,000 persons per year.In other parts of Europe the incidence is 0.7-1.3 per 100,000.
- It is the most commonly seen autoimmune blistering disease.
- Pemphigoid can affect individuals of any age, but mean age of onset is 80 years.
- Males and females are equally affected.
It is important to ask about past medical history and medication, as this may reveal conditions associated with BP.
- Past medical history:
- BP may follow any chronic inflammatory skin disease, even those not normally associated with blisters.
- Lichen planus and psoriasis may precede the development of BP.
- Medication may be associated with onset of BP:
- Non-steroidal anti-inflammatory drugs.
- Other triggers:
- Ultraviolet irradiation.
The initial presentation of pemphigoid is very variable, as blistering skin lesions may only occur late in the course of the disease. Symptoms and signs may present with a subacute or acute onset. Symptoms and signs which may be seen in patients with all forms of BP include:
- Itch, or pruritus, which is frequently a feature. This may occur weeks or months before the appearance of any visible skin lesion.
- Rash. An urticarial or erythematous rash may precede the appearance of the blisters.
- Blisters or bullae, which are typical and often occur in skin flexures. Depending on the form of BP these may affect a single site or be more widespread.
- Mucous membranes. BP involves the mucosa in up to a quarter of patients. The blisters appear mainly on palatal mucosa. They may be clinically insignificant but can cause problems with dysphagia.
Different clinical forms
There are several distinct clinical presentations.
This is the most common form:
- Tense bullae can form anywhere but commonly around flexural areas. They can appear both on normal skin and on erythematous skin.
- Mucosal involvement is rare and not clinically significant when it does occur.
- The bullae heal without scarring.
This is a less common form:
- It presents typically with small groups of tense blisters which collect on erythematous areas of skin (rather than normal skin).
Mucous membrane pemphigoid includes a group of autoimmune bullous diseases characterised by subepithelial blisters, erosions and scarring of mucous membranes, skin or both.
Other rarer forms include vegetative, generalised erythroderma, urticarial, nodular (or pemphigoid nodularis) and acral (a childhood form associated with vaccination).
The differential diagnoses will include:
- Cicatricial pemphigoid (this is a complex condition where skin lesions are usually trivial and mucosal lesions heal with scarring. Several different autoantibodies have been implicated).
- Dermatitis herpetiformis.
- Bullous drug eruptions.
- Epidermolysis bullosa.
- Erythema multiforme.
- Linear IgA dermatosis.
Other conditions which may be considered include:
- Other blistering skin disorders such as chickenpox.
- Impetigo, which may be mistaken for the various stages of BP.
- The bullous eruption of systemic lupus erythematosus.
- Herpes gestationis or gestational pemphigoid. This presents in the late second or third trimester, and resolves on delivery. It is immunologically identical to BP.
Skin biopsy followed by DIF is the investigation most commonly used to make the diagnosis. Indirect immunofluorescence (IDIF) using fluid aspirated from the blister, may also be used.
- DIF studies. DIF demonstrates IgG in up to 90% of patients and C3 deposition in nearly 100% of patients. DIF can differentiate BP from cicatricial pemphigoid and epidermolysis bullosa acquisita by incubating the skin biopsy sample in a salt solution before DIF.
- The best skin samples for diagnosis come from apparently normal skin near a BP lesion.Fresh specimens are best, as transport media may give false negative results.
- Histological tests. These reveal a subepidermal blister with inflammatory infiltrate and usually eosinophilic predominance.
There are other experimental procedures.
- Direct and indirect immuno-electron microscopy.
- Enzyme-linked immunosorbent assay.
It had been thought that BP may be associated with the presence of malignant tumours; however, age- and sex-matched studies have concluded that no such association exists.
- One of the main aims is to reduce blister formation with the minimum dose of medication necessary.
- All therapeutic regimes should be tailored to the individual and any pre-existing conditions.
- This is particularly true for elderly patients where the use of aggressive treatment regimes may put the patient more at risk than the disease itself.
- As the disease may last some considerable time, all patients should be monitored until they are off all treatment and are in complete remission.
Recommendations have been made by the British Association of Dermatologists for the treatment of BP.These have been supplemented with information and advice from more recent papers and reviews:
- Strong topical corticosteroid treatment (clobetasol) is good as first-line in localised disease. It is safe and effective but its use in extensive disease may be limited by side-effects and practical factors. Topical corticosteroid treatment is better tolerated than oral steroids, particularly in the elderly.
- For more severe cases, systemic steroids along with immunosuppressives may be needed to control the disease. Doses varying from 0.75-1.0 mg/kg per day are used. The dose varies with the severity of the disease. Treatment to help prevent osteoporosis (calcium and vitamin D supplements, bisphosphonates) should be initiated if the systemic steroid will be given for more than one month.
- The effectiveness of adding plasma exchange or azathioprine to corticosteroids, and combination treatment with tetracycline and nicotinamide has not yet been adequately established.
Oral steroid is effective in 60-90% of patients within 1-4 weeks.Attempts to withdraw treatment should be made at 2- to 4-weekly intervals. Most patients need treatment for between six months to four years. Many have long-term remission of the disease afterwards.
Several other therapies have been studied with respect to their usefulness in the treatment of BP:
- Dapsone and sulfonamides: there is some evidence to suggest that dapsone and the sulfonamides might have an effect on BP. However, their side-effect profile is not encouraging, and these treatments should be reserved for those patients in whom other agents have been ineffective or are contra-indicated.
- Rituximab may be useful in difficult-to-treat cases.[19, 20]
- Secondary infections.
- Corticosteroid side-effects (hypertension, diabetes, osteoporosis, heart disease).
- BP is a chronic inflammatory disease which can persist with remissions and exacerbations for months or years.
- It is normally self-limiting and remits within five years.
- With optimal therapy, the mortality rate today is low and the vast majority of deaths occur in elderly patients with co-existing disease.
- Elderly patients are also particularly at risk from the immunosuppressive effects of therapy, which may place them at greater risk of life-threatening events than the disease itself.
- A recent analysis of mortality statistics from bullous skin disorders (between 1979 and 2002) in the USA showed little change in mortality rates for BP. This differs from findings in the UK.
- Patients on corticosteroids and immunosuppressants are at risk of serious side-effects - eg, peptic ulcer disease, agranulocytosis and diabetes.
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