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Bullous Pemphigoid

By Daniel M. Peraza, MD, The Geisel School of Medicine at Dartmouth

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Bullous pemphigoid is a chronic autoimmune skin disorder resulting in generalized, pruritic, bullous lesions in elderly 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.

Bullous pemphigoid occurs more often in patients > 60 yr but can occur in children. IgG autoantibodies bind to certain hemidesmosomal antigens (BPAg1, BPAg2), resulting in the activation of complement to form a subepidermal blister.

Etiology

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

  • Drugs (including furosemide, spironolactone, sulfasalazine, penicillin, penicillamine, etanercept, and antipsychotics)

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

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

  • Disorders (diabetes mellitus, rheumatoid arthritis, ulcerative colitis, and multiple sclerosis)

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.

Symptoms and Signs

Pruritus is the first symptom. Skin lesions may not develop for several years, but often characteristic tense bullae develop on normal-appearing or erythematous skin of the trunk and in the flexural and intertriginous areas. 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.

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 Pemphigoid From Pemphigus Vulgaris).

Distinguishing Pemphigoid From Pemphigus Vulgaris

Disorder

Appearance of Lesion

Oral Involvement

Itching

Nikolsky Sign

Prognosis

Pemphigoid

Tense bullae on normal-appearing or erythematous skin

Rare, with small blisters

Common

Generally negative

Usually good; occasionally fatal in the elderly

Pemphigus vulgaris

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 results. The blister in bullous pemphigoid is subepidermal, often containing many neutrophils and eosinophils.

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

Without treatment, bullous pemphigoid usually remits after 3 to 6 yr but can be fatal in about one third of elderly, debilitated patients. High-dose systemic corticosteroid therapy appears to increase the risk.

Treatment

  • Corticosteroids, topical or oral

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 prednisone 60 to 80 mg po once/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 mo. If long-term therapy is necessary, a new blister every few weeks does not require increasing the prednisone dose.

Bullous pemphigoid occasionally responds to a 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, rituximab, and cyclosporine may be used.

Key Points

  • Bullous pemphigoid usually affects patients > 60 yr 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.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • NEORAL, SANDIMMUNE
  • ENBREL
  • IMURAN
  • MINOCIN
  • RAYOS
  • CUPRIMINE
  • ACZONE
  • LASIX
  • RITUXAN
  • No US brand name
  • OTREXUP
  • CLOBEX, TEMOVATE
  • ALDACTONE
  • CYTOXAN (LYOPHILIZED)
  • ACHROMYCIN V
  • ERY-TAB, ERYTHROCIN
  • AZULFIDINE

* This is the Professional Version. *