Bullous Pemphigoid 1_0712 Derm Dx
Bullous Pemphigoid 2_0712 Derm Dx
Bullous Pemphigoid 3_0712 Derm Dx
Bullous Pemphigoid 4_0712 Derm Dx
Bullous Pemphigoid 5_0712 Derm Dx
Bullous Pemphigoid 6_0712 Derm Dx
Bullous Pemphigoid 7_0712 Derm Dx
Bullous Pemphigoid 8_0712 Derm Dx
Bullous Pemphigoid 9_0712 Derm Dx
A 75-year-old woman presents with extremely itchy red plaques on her trunk and extremities, which she reports were present for months. Initially the eruption started on her shins, but subsequently generalized. Her face and genitals are spared, and she denies any blisters or erosions in her mouth. Symptom review is otherwise negative.
The patient has a history of hypothyroidism for which she takes levothyroxine. She presented to several other physicians, who treated her with both oral and topical antifungals for presumed tinea corporis. Despite these therapies, the eruption has worsened with blistering in some areas.
A skin biopsy demonstrates a subepidermal blister with eosinophils. Special fluorescent stains for complement and immunoglobulin G (IgG) show a linear staining pattern along the dermal-epidermal junction. What’s your diagnosis?
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Bullous pemphigoid (BP) is an autoimmune blistering disease. Patients with BP have auto-antibodies against a specific protein called BP180, a component of the hemidesmosomes responsible for attaching the basal keratinocytes of the epidermis to the dermis.
Patients with BP may also have auto-antibodies against a second protein called BP230, but BP180 is considered to be the pathogenic antibody in this disease. When the auto-antibodies bind to their targets in the skin, an inflammatory reaction ensues resulting in the clinical manifestations of the disease.
BP rarely occurs in children. It is generally a disease of the elderly, presenting most commonly in patients aged 60 years and older. Risk for developing the disease increases with age — for example a 90-year-old has a 300-fold greater risk for developing BP than those younger than 60 years. BP incidence is higher in men than women.
BP has a broad spectrum of clinical presentations. The classic presentation is a pruritic eruption with the development of tense blisters. Prior to blister onset, patients may experience a prodromal non-bullous phase for weeks to months. Manifestations of the non-bullous phase include pruritis without rash, eczematous plaques or excoriated urticarial lesions. A certain percentage of patients never progress to the bullous phase of BP.
Patients in the bullous phase of the disease develop vesicles and bullae on normal-appearing skin or in associated with urticarial or eczematous plaques. The vesicles and bullae may rupture leaving crusted erosions. The characteristic distribution includes the trunk, thighs, groin, axilla and volar forearms, with the shins frequently implicated as the initial site of the eruption. About 20% of patients experience oral mucosa involvement. Other mucus membranes are rarely involved. Approximately 50% of patients develop peripheral blood eosinophilia.
There are several clinical variants of BP, including vesicular pemphigoid, pemphigoid nodularis and erythrodermic pemphigoid. Vesicular pemphigoid presents as small, tense grouped vesicles. Pemphigoid nodularis is a variant that can resemble prurigo nodularis, and consists of pruritic papules and nodules distributed on the scalp and extremities. In erythrodermic pemphigoid, patients present with erythroderma.
Rarely, BP may occur in association with lichen planus in a variant termed lichen planus pemphigoides. When localized to the palms and soles, BP may resemble dyshidrotic eczema and is termed dyshidrosiform pemphigoid.
Other variations included vulvar childhood pemphigoid, in which young girls present with lesions limited to the vulva, and gestational pemphigoid, in which women present in the second or third trimester of pregnancy with urticarial plaques that subsequently develop vesicles and bullae. The lesions in gestational pemphigoid most commonly involve the abdominal region, including the umbilicus. This contrasts with another pregnancy dermatosis called pruritic urticarial papules and plaques of pregnancy, which characteristically spares the umbilicus.
All variants of BP share common histological features and are due to autoantibodies to BP180.
BP is generally not believed to be a paraneoplastic syndrome; however, there are rare instances in which BP is clearly associated with the onset of a malignancy. Other autoimmune diseases, such as autoimmune thyroid diseases and collagen vascular diseases, are not clearly associated with BP. Occasionally systemic medications such as furosemide, D-penicillamine and captopril are implicated in BP.
Because of the polymorphic presentation of BP, establishing the diagnosis requires a high degree of clinical suspicion and typically involves two skin punch biopsies.
One biopsy is taken from an obviously diseased skin area, such as a blister or urticarial plaque. This specimen will be sent for routine hemotoxylin and eosin staining. If a frank blister is present, the blister will be in a subepidermal location, and the blister cavity will have eosinophils and occasionally neutrophils. If the biopsy is taken from an urticarial or non-bullous area, then the findings are less specific and may include sub-epidermal clefting and eosinophilic spongiosis.
The second biopsy is taken from perilesional skin — that is normal appearing skin immediately adjacent to clinically involved skin. This specimen will be sent for direct immunofluorescent (DIF) microscopy. In DIF microscopy, the specimen is processed with a fluorescent stain for complement (C3) and various immunoglobulins (IgG, IgM and IgA). In BP, the DIF microscopy demonstrates linear deposits of C3 and IgG along the epidermal basement membrane.
When the diagnosis is in doubt, the specimen can be split at the dermal-epidermal junction. In BP, the fluorescent staining will appear on the epidermal side of the split. This contrasts with certain other subepidermal autoimmune blistering diseases such as epidermolysis bullosa acquisita, in which the stain appears on the dermal side of the split.
Another way to establish the diagnosis is through testing the patient’s serum for circulating autoantibodies against BP180 or BP230. There is now a commercially available enzyme-linked immunosorbent assay (ELISA) to assess for these autoantibodies.
BP can be distinguished from the other answer choices by the characteristic findings on immunofluorescence and histopathology. Additionally, patients with pemphigus vulgaris and Stevens-Johnson syndrome almost always have oral mucosal involvement. Porphyria cutanea tarda presents with blisters and skin fragility on sun exposed skin.
There are few controlled clinical studies pertaining to BP treatment. Treatment guidelines are based on clinical experience and consensus opinion.
Oral prednisone at a dose of 0.5-1mg/kg/day will typically control the disease within weeks. The prednisone is subsequently tapered over a period of months. It is important to monitor and provide prophylaxis when applicable for adverse events associated with long-term oral corticosteroid therapy, including osteoporosis, hypertension, infection and cataracts.
Potent topical corticosteroids may be as effective as oral corticosteroids with fewer side effects. Other treatments include other oral immunosuppressive medications such as azathioprine, methotrexate, cyclosporine, mycophenolate mofetil, cyclophosphamide or chlorambucil. Novel therapies include the combination of niacinamide and tetracycline.
In this case, the patient was treated with oral prednisone at an initial dose of 60 mg daily. Within four weeks, the patient’s skin was clear. The steroids were tapered over the subsequent four weeks. Fortunately, her skin has remained clear for six months.
Adam Rees, MD, is a graduate of the University of California Los Angeles School of Medicine and a resident in the Department of Dermatology at Baylor College of Medicine in Houston.
- Bolognia J, Jorizzo JL and Rapini RP. “Chapter 31: Pemphigoid Group.” Dermatology. St. Louis, Mo.: Mosby/Elsevier, 2008.
- James WD, Berger TG, Elston DM et al. “Chapter 21: Chronic Blistering Dermatoses.” Andrews’ Diseases of the Skin: Clinical Dermatology. Philadelphia: Saunders Elsevier, 2006.