Knowledge on rare diseases and orphan drugs

Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. It has an estimated prevalence of 1/4,000 in Europe. The incidence is reported to be increasing but currently ranges between 2-22/1,000,000 worldwide.

BP predominantly affects the elderly with an average age of 80 years and is significantly associated with neurological disorders. Some cases have also been described in children and young adults. The disease is characterized clinically by tight, often large, bullae with a clear content, developing primarily on the edge of erythematous plaques. Intense itching is common. Some patients may have mucosal involvement (10-20% of cases). The rare infantile forms differ from the adult form by its palmo-plantar involvement, especially in children under 1 year of age, and its greater frequency of mucosal involvement.

BP is immunologically characterized by the production of autoantibodies directed against two structural proteins found in the dermal-epidermal junction and ensuring dermal-epidermal cohesion: BP antigen 1 (BPAG1 or AgBP230), and BP antigen 2 (BPAG2, AgBP180 or collagen XVII). The binding between the autoantibodies and these proteins leads to the separation between the dermis and the epidermis and the formation of blisters. Some drugs are associated with the onset of BP (diuretics, antiarrhythmics, neuroleptics, gliptins, immunotherapies).

The diagnosis is based on clinical features and skin biopsy showing typical light microscopy findings (subepidermal bullae containing eosinophils and/or neutrophils, associated with a dermal infiltrate of eosinophils and /or neutrophils, or a marginalization of eosinophils along the dermal-epidermal junction) and positive direct immunofluorescence microscopy findings (linear deposits of IgG and/or C3 along the dermal-epidermal junction). Blood samples are also needed in order to search for circulating IgG anti-basement membrane autoantibodies by indirect immunofluorescence microscopy studies and anti-BP180 IgG antibodies and anti-BP230 IgG antibodies by ELISA.

The main differential diagnoses are some forms of acquired bullous epidermolysis and anti-P200 pemphigoid. BP with mucosal involvement may look like mucous membrane pemphigoid even if mucosal involvement is rarely predominant in BP.

Systemic corticosteroids (CS) (prednisone: 0.5-1 mg/kg/day) is referred as the standard treatment in most countries. The European consensus for first line treatment is with super-potent topical corticosteroids to the whole-body surface sparing the face, or applied to lesions only where the disease is localized/limited, and is followed by a maintenance or tapering schedule as required. In patients with recalcitrant BP and in those with multiple relapses, immunosuppressive drugs (methotrexate, mycophenolate mofetil) are usually used. Doxycycline can be used, especially in patients with contraindications to immunosuppressive drugs or in poor general condition. Recently, new therapeutics have been tested in particular rituximab and omalizumab whose indications remain as yet unclear.

BP is a serious disease. In some cases, the prognosis for BP patients is poor.

Last update: April 2020 - Expert reviewer(s): Pr Pascal JOLY | ERN-Skin*

* European Reference Network