Bullous pemphigoid

Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease, affecting predominantly elderly people (blistering is intraepidermal in pemphigus).

It is a chronic condition, characterised by generalised pruritic urticarial plaques and tense subepithelial blisters¹ .

Pathogenesis

An abnormal T-cell immune response and synthesis of IgG and IgE autoantibodies against hemidesmosomal proteins (BP180 and BP230) lead to neutrophil chemotaxis and degradation of the basement membrane zone² .

The pathogenesis depends on the interaction between predisposing factors, such as human leukocyte antigen (HLA) genes, comorbidities, ageing, and trigger factors. Several trigger factors, such as drugs, thermal or electrical burns, surgical procedures, trauma, ultraviolet irradiation, radiotherapy, chemical preparations, transplants and infections, may induce or exacerbate bullous pemphigoid¹ .

Epidemiology³

• BP is the most common autoimmune blistering disease.

• BP occurs mainly in the elderly, with a median age at presentation in the UK of 80 years.

• In the UK, the incidence is 46 per 100,000 persons per year among those over 90 years old, but only 1.5 per 100,000 among those 50-59 years old.

Presentation⁴

Bullous pemphigoid classically presents with tense blisters over urticarial plaques on the trunk and extremities accompanied by intense pruritus² .

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 bullous pemphigoid 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 bullous pemphigoid these may affect a single site or be more widespread.

• Mucous membranes. 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.

Generalised bullous
This is the most common form:

Bullous pemphigoid leg blisters

Mohammad2018, CC BY-SA 4.0, via Wikimedia Commons

• 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.

Vesicular
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 both⁵ .

Other rarer forms include vegetative, generalised erythroderma, urticarial, nodular (or pemphigoid nodularis) and acral (a childhood form associated with vaccination)⁶ .

Differential diagnosis⁷

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.

• Urticaria.

• 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.

Investigations⁸

Diagnosis is based on clinical manifestations and confirmed with histological, immunofluorescence, and serological testing. Serological detection of the autoantibodies largely relies on indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) tests.

• Direct immunofluorescence (DIF) studies⁹ . 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 bullous pemphigoid lesion¹⁰ . Fresh specimens are best, as transport media may give false negative results.

• Histological tests. These reveal subepidermal blisters with inflammatory infiltrate and usually eosinophilic predominance.

Associated diseases

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

Bullous pemphigoid treatment^{8 11}

• The effectiveness of topical therapy with potent topical corticosteroids in localised and moderate forms of bullous pemphigoid is supported by a Cochrane review¹² .

• In localised, non-severe forms, immunomodulatory, non-immunosuppressant drugs such as doxycycline may be considered. Although its exact mechanism of action is not well understood, doxycycline proved to be as effective as oral prednisolone for short-term blister control and is safer in the long term.

• Systemic corticosteroid therapy (prednisone 0.5 mg/kg/day) is the treatment of choice for severe forms. For maintenance treatment, doses may be tapered gradually within 4-6 months of initiation of treatment.

• Adjunctive therapy includes combination with azathioprine, mycophenolate mofetil, tetracyclines plus nicotinamide, methotrexate and dapsone.

• Available data suggest that rituximab may provide clinical benefits for patients with refractory bullous pemphigoid.

• Bacterial superinfection of erosions should be treated with local antiseptics.
  Wound dressings should be considered for large wounds. Sterile puncture of large blisters is recommended.

Complications

• Secondary infections.

• Immunosuppression.

• Corticosteroid side-effects (hypertension, diabetes, osteoporosis, heart disease).

Prognosis

• Bullous pemphigoid is a chronic inflammatory disease which can persist with remissions and exacerbations for months or years.

• There is twice as high a risk of death compared with age-matched controls³ .

• 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 at risk of serious side-effects - eg, peptic ulcer disease, agranulocytosis and diabetes.