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Bullous Pemphigoid

By

Daniel M. Peraza

, MD, Geisel School of Medicine at Dartmouth University

Last full review/revision Sep 2020| Content last modified Sep 2020
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Bullous pemphigoid is a chronic autoimmune skin disorder resulting in generalized, pruritic, bullous lesions in older patients. Mucous membrane involvement is rare. Diagnosis is by skin biopsy and immunofluorescence testing of skin and serum. Topical and systemic corticosteroids are used initially. Most patients require long-term maintenance therapy, for which a variety of immunosuppressants can be used.

Bullae are elevated, fluid-filled blisters ≥ 10 mm in diameter.

Bullous pemphigoid occurs more often in patients > age 60 but can occur in children. IgG autoantibodies bind to certain hemidesmosomal antigens (BPAg1 [BP230], BPAg2 [BP180]), resulting in the activation of complement to form a subepidermal blister (see figure Skin cleavage levels in pemphigus and bullous pemphigoid).

Skin cleavage levels in pemphigus and bullous pemphigoid

Pemphigus foliaceus blisters form in the superficial layers of the epidermis. Pemphigus vulgaris blisters can form at any epidermal level but typically form in the lower aspects of the epidermis. Bullous pemphigoid blisters form subepidermally (lamina lucida of the basement membrane zone). In this figure, the basement membrane zone is disproportionately enlarged to display its layers.

Skin cleavage levels in pemphigus and bullous pemphigoid

Etiology

No cause of bullous pemphigoid has been proved; however, the following triggers have been suggested:

  • Drugs (including furosemide, spironolactone, omeprazole, PD-1 and PD-L1 monoclonal antibodies [eg, durvalumab, nivolumab, pembrolizumab], sulfasalazine, penicillin, penicillamine, etanercept, antipsychotics, and dipeptidyl peptidase-4 inhibitors)

  • Physical triggers (including trauma, radiation therapy for breast cancer, UV radiation, and anthralin)

  • Skin disorders (including psoriasis, lichen planus, and some infections)

Genetic and environmental factors may play a role.

Triggers may induce an autoimmune reaction by mimicking molecular sequences in the epidermal basement membrane (molecular mimicry, as with drugs and possibly infections), by exposing or altering normally tolerated host antigens (as with physical triggers and certain disorders), or by other mechanisms. Epitope spreading refers to the recruitment of autoreactive lymphocytes against normally tolerated host antigens, which contributes to disease chronicity and course.

Certain central nervous system (CNS) and psychiatric disorders may precede bullous pemphigoid, especially multiple sclerosis and schizophrenia, but also dementias, intracranial bleeds, stroke, delusional and personality disorders, and Parkinson disease. To a lesser degree, these disorders may be preceded by bullous pemphigoid. Hypothesized shared causes include a cross-reactive immune response between neural and cutaneous antigens (BPAg1 is expressed in the CNS), as well as triggering by certain drugs used to treat the disorders (eg, phenothiazine antipsychotics, spironolactone); however, a mechanism of triggering by drugs is not understood.

Symptoms and Signs

Pruritus is the first symptom of bullous pemphigoid. Skin lesions may not develop for several years. Bullae may develop on normal-appearing skin or may be preceded by erythematous or urticarial-appearing plaques. Often, characteristic tense bullae develop on skin of the trunk and in the flexural and intertriginous areas. Bullae may develop on normal-appearing skin or may be preceded by erythematous or urticarial-appearing plaques. Localized disease may occur at trauma sites, stomas, and anogenital and lower leg areas. Bullae usually do not rupture, but those that do often rapidly heal.

Polymorphic, annular, dusky-red, edematous lesions, with or without peripheral vesicles, can occur. Rarely, small blisters develop on the mucosa. Leukocytosis and eosinophilia are common, but fever is rare. The Nikolsky sign, where upper layers of epidermis move laterally with slight pressure or rubbing of skin adjacent to a blister, is negative.

Manifestations of Bullous Pemphigoid

Diagnosis

  • Skin biopsy and IgG titers

If blisters develop, bullous pemphigoid needs to be differentiated from pemphigus vulgaris, a blistering disorder with a worse prognosis; differentiation is usually possible using clinical criteria (see Table: Distinguishing Bullous Pemphigoid From Pemphigus Vulgaris).

Table
icon

Distinguishing Bullous Pemphigoid From Pemphigus Vulgaris

Disorder

Appearance of Lesion

Oral Involvement

Itching

Nikolsky Sign

Prognosis

Bullous pemphigoid

Tense bullae that develop on normal-appearing or erythematous skin or urticarial-appearing plaques

Rare, with small blisters

Common

Generally negative

Usually good; occasionally fatal in older people

Flaccid bullae of various sizes

Often shearing off of skin or mucosa, leaving painful erosions

Typically starts in the mouth

Absent

Positive

Mortality 10% with treatment; higher without treatment

If bullous pemphigoid is suspected, skin biopsy is done for histology and direct immunofluorescence testing. Samples from in and around the lesion itself are often used for histology, but samples of uninvolved skin (often about 3 mm from the edge of a lesion) are used for direct immunofluorescence. The blister in bullous pemphigoid is subepidermal, often containing many neutrophils and eosinophils. Direct immunofluorescence shows linear IgG and complement deposits along the basement membrane zone (dermal–epidermal junction). Indirect immunofluorescence shows circulating IgG deposits on the epidermal side of a salt-split preparation of normal (ie, test substrate) skin.

Serum is tested for IgG antibodies to BPAg1 and BPAg2 using an enzyme-linked immunosorbent assay (ELISA). Circulating IgG autoantibodies are present in about three fourths of patients.

Prognosis

Bullous pemphigoid is a chronic, potentially fatal disease, particularly without treatment. Although topical and systemic therapies are helpful, they may cause adverse effects.

Remission is typical within months, but treatment is sometimes needed for several years.

Treatment

  • Corticosteroids, topical or oral

  • Anti-inflammatory drugs

  • Immunosuppressant drugs or biologics

High-potency topical corticosteroids (eg, clobetasol 0.05% cream) should be used for localized disease and may reduce the required dose of systemic drugs.

Patients with generalized disease often require systemic treatment with prednisone 60 to 80 mg orally once a day, which can be tapered to a maintenance level of 10 to 20 mg/day after several weeks. Most patients achieve remission after 2 to 10 months, but treatment may need to continue for several years before the disease process remits enough to allow discontinuation. If long-term therapy is necessary, a new blister every few weeks does not require increasing the prednisone dose.

Bullous pemphigoid occasionally responds to the anti-inflammatory activity of certain drugs, such as the combination of tetracycline or minocycline and nicotinamide. Other treatment options include monotherapy with dapsone, sulfapyridine, or erythromycin. IV immune globulin has been used occasionally.

For patients with generalized and recalcitrant disease, and sometimes to decrease corticosteroid dose in chronic disease, immunosuppressants such as methotrexate, azathioprine, cyclophosphamide, mycophenolate mofetil, and cyclosporine may be used. Among the biologics, rituximab and omalizumab may be used.

Key Points

  • Bullous pemphigoid usually affects patients > age 60 and is autoimmune and idiopathic.

  • Pruritus may precede development of a rash by years, and mucous membrane involvement is rare.

  • Biopsy the skin for histology and immunofluorescence testing and measure circulating autoantibodies.

  • Treat patients with high-potency topical corticosteroids when possible to avoid or minimize use of systemic corticosteroids.

  • Anti-inflammatory, immunosuppressant, and biologic therapy may be used to decrease corticosteroid dose.

  • Symptoms usually lessen within months, but treatment is sometimes needed for several years.

Drugs Mentioned In This Article

Drug Name Select Trade
CYTOXAN (LYOPHILIZED)
Gammagard S/D
ALDACTONE
KEYTRUDA
CELLCEPT
CUPRIMINE
AZULFIDINE
OTREXUP
IMURAN
ERY-TAB, ERYTHROCIN
ACHROMYCIN V
NEORAL, SANDIMMUNE
MINOCIN
ENBREL
Durvalumab
PRILOSEC
RAYOS
LASIX
XOLAIR
CLOBEX, TEMOVATE
No US brand name
OPDIVO
RITUXAN
ACZONE
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