Bullous Pemphigoid (BP)

Bullous pemphigoid (BP) is a chronic, autoimmune, subepidermal, blistering skin disorder (unlike pemphigus where the blistering is intraepidermal).¹

In this disorder, IgG antibodies are involved in an antigen-antibody interaction which results in the formation of subepidermal bullae most often in a flexural distribution. BP is characterised by the presence of IgG for specific hemidesmosomal BP antigens (BP230 and BP180). The precise role of these antigens in the pathogenesis is unclear.

The development of blisters in BP involves a sequence of events:

• IgG autoantibodies bind to skin basement membrane.
• This is followed by activation of complement and other inflammatory mediators.
• The inflammatory process leads to release of enzymes which degrade proteins in the hemidesmosomal layers.
• Blisters form when the layers split apart as a result of this protein degradation.

Other interesting associations:

• HLA type:² Immunogenetic studies point to an association with HLA dqb 1*0301.
• Age: An aging immune system or trauma may contribute to the higher incidence with age.
• Other inflammatory skin conditions: The autoimmune response may be triggered by psoriasis,³ lichen planus and skin trauma.
• Complement activation: C3 is typically deposited at the basement membrane in BP. Complement activation brings in inflammatory cells to the basement membrane zone.
• Chemokines: Eosinophilic infiltration is a hallmark of BP and migration of eosinophils is likely to be induced by chemokines.

• The incidence of pemphigoid in the UK is not known with any certainty, however the recorded incidence in France is in the order of 6-7 per million per year.⁴
• It is the most commonly seen auto-immune blistering disease in the West.
• Pemphigoid can affect individuals of any age, but is most commonly seen in the elderly with an average age of onset of 65 years.
• Males and females are equally affected.

History

It is important to ask about past medical history and medication as this may reveal conditions associated with BP.

• Past medical history:
  • Bullous pemphigoid may follow any chronic inflammatory skin disease, even those not normally associated with blisters.
  • Lichen planus and psoriasis may precede the development of bullous pemphigoid.
• Medication may be associated with onset of bullous pemphigoid:
  • Furosemide
  • NSAIDS
  • Captopril
  • Penicillamine
  • Antibiotics
• Other triggers:
  • Ultraviolet irradiation
  • Radiotherapy⁵

Common symptoms and signs

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 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 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 10 to 25% of patients. The blisters appear mainly on palatal mucosa. They may be clinically insignificant but can cause problems with dysphagia.

Different clinical forms of BP¹

There are several distinct clinical presentations:

• Generalised bullous:
  • The most common form.
  • Tenase bullae can form anywhere but commonly around flexural areas. They can appear both on normal and erythematous skin.
  • Mucosal involvement is rare and not clinically significant when it does occur.
  • The bullae heal without scarring.
  
• Vesicular:
  • A less common form.
  • It presents typically with small groups of tense blisters which collect on erythematous areas of skin (rather than normal skin).
• Vegetative:
  • An uncommon form of BP which resembles pemphigus vegitans.
  • This form is characterised by plaques in the intertriginous areas, typically axillae, neck, groin and under breasts.
• Generalised erythroderma:
  • This is a rare from of BP.
  • It is characterised by exfoliative erythroderma (and occasionally vesicles or bullae).
  • It can be difficult to distinguish from psoriasis, generalised eczema and other skin diseases presenting with erythroderma.
• Urticarial:
  • In this form BP resembles urticaria but then bullous eruptions occur.
  • Occasionally the BP continues to resemble urticaria without any bullous eruptions.
• Nodular (or pemphigoid nodularis):
  • This form resembles prurigo nodularis but with blisters.
• Acral:
  • A childhood form of BP which is associated with vaccination.⁶
  • Lesions affect palms, soles and face.

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 may be mistaken for the various stages of bullous pemphigoid.
• Urticaria.
• The bullous eruption of systemic lupus erythematosus
• Herpes gestationis or gestational pemphigoid. This presents in late second or third trimester, resolves on delivery. It is immunologically identical to bullous pemphigoid.

Skin biopsy followed by direct immunofluorescence is the investigation most commonly used to make the diagnosis. Indirect immunofluorescence using fluid aspirated from the blister, may also be used.

• Direct immunofluorescence studies (DIF). 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.
• Indirect immunofluorescence (IDIF). IDIF studies detect the patients IgG circulating autoantibodies.
• Histological tests. These reveal a subepidermal blister with inflammatory infiltrate and usually eosinophilic predominance.

There are other experimental procedures.

• Direct and indirect immunoelectron microscopy
• Immunoblotting
• Immunoprecipitation
• Enzyme-linked immunosorbent assay

It had been thought that bullous pemphigoid may be associated with the presence of malignant tumours, however age,sex matched studies have concluded that no such association exists.⁸

General points

• 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 preexisting 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.

Medication

Recommendations have been made by the British Association of Dermatologists for the treatment of bullous pemphigoid:⁹ These have been supplemented with information and advice from more recent papers and reviews.

1. Topical corticosteroids should be considered for use in all patients with bullous pemphigoid. Others consider topical steroids as the first line treatment with the major advantage of reduced complications.¹¹ For well localised areas of bullous pemphigoid,a trial of very potent topical corticosteroids should be used alone in the first instance. For more diffuse disease, topical corticosteroids may help to achieve control when used in conjunction with systemic agents. Topical steroids may be superior to oral corticosteroids in extensive disease particularly in the elderly.^11,12,13
2. In mild to moderate disease, the use of a combination of tetracycline and nicotinamide should be considered as a first line therapy but still needs further validation according to a Cochrane review.¹³ When these agents have successfully suppressed blister formation, they should be reduced slowly, one at a time over a period of several months in order to prevent a relapse.
3. Systemic corticosteroids such as prednisolone, are the best established treatment. Doses varying from 20mg per day to 70 mg per day are used , the dose varying with the severity of the disease. Treatment to help prevent osteoporosis should be initiated at the same time as the treatment with systemic steroids (calcium and vitamin D supplements, biphosphonates).
4. Immunosuppressant drugs, such as azathioprine and methotrexate, are not currently recommended as routine therapy for bullous pemphigoid, but may be used as steroid sparing agents if required. Effectiveness of plasma exchange and azathioprine has not yet been established.¹³

Potential therapies

Several other therapies have been studied with respect to their usefulness in the treatment of bullous pemphigoid:

• Dapsone and sulphonamides- There is some evidence to suggest that dapsone and the sulphonamides might have an effect on bullous pemphigoid, 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 contraindicated.
• Intravenous immunoglobulin-small studies using intravenous immunoglobulin have shown good, but very short lived, results in bullous pemphigoid.¹⁴
• Plasmapheresis-there is some evidence to suggest that the use of plasmapheresis may allow a lower dose of systemic corticosteroid to be used, and it may have a role to play in severe, uncontrolled disease or in patients with severe side effects from other therapy.¹³

• Secondary infections
• Immunosuppression
• 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 5 years . If treated BP will remit within 1.5 to 5 years.¹
• With optimal therapy, the mortality rate today is in the order of 6-41%, the vast majority of deaths occurring 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.
• Patients on corticosteroids and immunosuppressants are, for example, at risk of peptic ulcer disease, agranulocytosis and diabetes.