Bullous Pemphigoid

Author(s): 
Chukwuemeka N. Etufugh, MD; H. Randolph Byers, MD, PhD; Tania J. Phillips, MD, FRCPC

Presentation
 

A 75-year–old, aphasic Chinese woman presented to the authors’ wound clinic with a 6-week history of widespread blisters and erosions. Initial treatment from her primary care physician consisted of oral prednisone and topical silvadene with no improvement. The prednisone had been tapered from 80 mg to 40 mg due to a history of gastrointestinal (GI) bleeding. The patient was afebrile and had no history of fever, chills, or unexplained weight loss.
The patient’s medical history was significant for cerebrovascular accident, hypertension, upper GI bleeding, dementia, and depression. Her medications included prednisone, hydrochlorothiazide, doxazosin, metoprolol, lansoprazole (Prevacid, TAP Pharmaceuticals Inc., Deerfield, Ill), lisinopril, metoclopramide, isosorbide, aspirin, senna, and albuterol.

Physical Examination

The patient presented with well demarcated hemorrhagic tense bullae measuring 1 cm to 5 cm in diameter and multiple erosions on the trunk (Figure 1), axilla (Figure 2), back, groin (Figure 3), legs, hands, and volar aspect of the wrists, arms, and feet. Also noted were erosions on the lower lips. Lymphadenopathy was not present. The differential diagnosis included bullous pemphigoid (BP), linear IgA dermatosis, bullous drug eruption, and epidermolysis bullosa acquisita. A punch biopsy was performed on a bullous lesion of the right thigh. The biopsy revealed a mild to moderately dense superficial perivascular and interstitial mixed inflammatory cell infiltrate composed of neutrophils and eosinophils (Figure 4). Direct immunofluorescence analysis of the biopsy specimen showed linear deposition of IgG (Figure 5) and the third component of complement (C3) (Figure 6) along the basement membrane zone. Taken together, the clinical, histological, and direct immunofluorescence findings rendered a diagnosis of bullous pemphigoid.
Bullous pemphigoid is an autoimmune subepidermal blistering disease that is characterized by deposits of IgG and C3 at the epidermal basement membrane zone. Bullous pemphigoid is the most common subepidermal blistering disease found in western countries.1 It accounts for 75% of autoimmune blistering cases and is commonly found among the elderly population—66% of BP cases occur in persons 80 years or older.2,3 The annual incidence of BP has been reported to be 7 cases per million in France and Germany. Bullous pemphigoid does not have any ethnic or racial predilection and occurs equally in men and women.2,4

Discussion

Classically, BP lesions are tense blisters found on normal or erythematous skin of the flexor surfaces of the arms, legs, axillae, abdomen, and groin area. Mucous membranes are generally spared; however, in a minority of patients, nonscarring BP lesions can be found in the oral mucous membranes.1,5 The bullae in BP may be filled with hemorrhagic or clear fluid. The eroded skin from ruptured bullae shows a tendency to reepithelize and does not expand beyond the periphery of the lesion. Bullous lesions can be pruritic but heal without scarring. Occasionally, erythema may be the predominant sign, and the bullous lesions may appear urticarial. This is especially seen in the early phase of the disease. The erythematous component may become extensive and appear serpiginous with peripheral blisters. Resolution of extensive bullae usually occurs from the center and may be accompanied by hyperpigmentation.5 Bullous pemphigoid generally occurs sporadically without any precipitating factors. However, several precipitating factors have been reported, such as ultraviolet light (either UVB or psoralens with UVA).6,7
In BP, the immune system reacts to components of normal cutaneous tissue. Beutner et al8 were the first to demonstrate that in patients with BP, IgG and C3 deposits are present along the epidermal basement membrane zone and IgG, which also can bind and deposit along the epidermal basement membrane of cutaneous tissue, circulates in the bloodstream. These BP autoantibodies have been found to bind to the hemidesmosome of the basement membrane, which is involved in the adherence of the epidermal basal cell to the dermis.9,10 Biopsy specimens of BP lesions demonstrate an eosinophilic-rich leukocytic infiltrate in the papillary dermis and along the basement membrane, mast cell degranulation, and dermal edema due to activation of the immune response by autoantibodies and complement. These alterations subsequently lead to subepidermal blister formation.5,11 The higher incidence of BP in the elderly has been postulated to be due to loss of tolerance and autoreactivity to additional antigens as a result of epitope spreading that can occur with age.12
Bullous pemphigoid is distinguished from other blistering skin diseases, such as linear IgA dermatosis, epidermolysis bullosa acquisita, and cicatricial pemphigoid, by the following clinical findings: lack of atrophic scars; lack of mucosal involvement; lack of head and neck involvement; and age of onset > 70 years. Cases of BP can be diagnosed clinically; however, histopathological investigations of perilesional skin using direct immunofluorescence to show linear deposition of IgG and C3 at the basement membrane is the diagnostic standard. Measurement of circulating autoantibody titer may be helpful, but it does not correlate with disease activity.8,12

Treatment

Without therapy, BP is usually a self-limited illness that can last several months to years. However, in the elderly who commonly have other comorbidities and fragile health, BP can prove to be a potentially fatal disease.5,13 Systemic steroids are the mainstay of therapy for BP. In patients with extensive disease, other immunosuppressive agents, such as cyclophosphamide, azithioprine, and mycophenolate mofetil, can be added as steroid sparing agents. Other agents with reported success in treating patients with BP include dapsone,14 combination of nicotinamide and tetracycline,15 methotrexate,16 chlorambucil,15 plasmapharesis,17 and intravenous gammaglobulin.18 Local BP lesions can be successfully treated with topical steroids. However, a recent study by Joly et al19 suggests that high potency topical steroid therapy might be more effective and safe than systemic steroid therapy.
The patient described here was continued on prednisone taper and was started on topical clobetasol ointment. The lesions showed dramatic improvement after 1 week, and most of the lesions resolved after 2 weeks (Figure 7 and 8). The patient eventually tapered off the prednisone and continued with the topical clobetasol ointment until complete resolution of the lesions. For this patient, topical class I corticosteroid therapy was highly effective. The authors recommend that this approach be used as first line treatment, particularly in the elderly, to avoid potential harmful systemic effects.

 

 

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