Diagnostic Dilemmas: Bullous Pemphigoid

Presentation A 77-year-old Chinese man with a history of Parkinson’s disease presented with a two-month history of blisters on his feet and ankles. He did not have any blisters in his mouth or on his genitalia. His medications included zinc sulfate, vitamin C, multivitamins, bromocriptine (Parlodel), oxybutynin chloride (Ditropan), carbidopa-levodopa (Sinemet), docusate sodium, and iron supplements. He had no family history of blistering disease. Physical examination revealed a slim, elderly, Asian gentleman. His head, neck, oral mucosa, chest, abdomen, back, upper extremities, and genitalia were normal. His feet showed macular hyperpigmentation in a circular pattern on the posterior right heel and right dorsal foot. There were two healing bullae on the left foot. One bullae was almost completely reepithelialized. The other was flaccid, filled with turbid fluid, and measured six centimeters in diameter (Figures 1 and 2). Initial diagnostic considerations included bullous drug eruption and bullous pemphigoid. Investigations Two biopsies were performed on the medial aspect of the left foot. Blister contents were cultured and showed no growth. Routinely stained biopsy of the lesion showed epidermal-dermal separation, eosinophil-rich vesicle fluid, and numerous superficial and deep eosinophils, consistent with bullous pemphigoid. Direct IMF of perilesional skin was negative. Diagnosis The patient was diagnosed with bullous pemphigoid (BP) on the basis of clinical and histopathologic findings. Discussion Epidemiology. BP is a blistering disorder that mainly affects patients between the ages of 60 to 80 years,1 although rare cases in children have been reported.26,31,32,58 BP is thought to affect both genders and all races and ethnic groups equally.30 However, a recent report suggested that the risk for BP is increased in men by 2:1, especially in those above 60 years of age.64 Clinical features. History. Classic BP is a chronic, self-limited, subepidermal, blistering disease.1,30 The course tends to be benign and rarely life threatening, even without treatment, unlike pemphigus vulgaris.10,30 The blistering lesions often present with pruritic, urticarial, papular lesions that progress to bullae over the period of weeks to months. The bullae then may appear as a sudden generalized eruption. Pruritus may be moderate to severe in the prodrome. Eroded bullous lesions may be tender. Usually there are no constitutional symptoms. Physical examination. The areas most commonly involved are the axillae, abdomen, thighs, groin, lower legs, and flexural surfaces of the arms. Often the lower legs are the first to be affected. Mucous membranes (mouth, anus, vagina) are not commonly affected but, when involved, can scar.30 Prodromal changes may proceed the bullae and vesicular changes by months and include erythematous papules and plaques, urticaria, eczematous, and crusted lesions. Bullae are tense, oval or round, firm topped, and large with an erythematous, normal, or urticarial base.1,30 They contain serous or hemorrhagic fluid. The lesions may be generalized or localized, as in our patient, and may be scattered or grouped in serpiginous and annular configurations.30 Ruptured bullae may present as oozing or bleeding erosions that become crusted. Nikolsky’s sign (upper layers of skin are easily slipped laterally by rubbing or slight pressure) is usually negative.30 Pathogenesis. Patients often have an autoantibody that binds to the 230 kd (50–70% of cases)13 and the 180 kd (30–50% of cases)13 antigen of the epidermal basement membrane.7,8 Circulating IgG antibody develops in 65 percent9 to 90 percent30,45–47 of patients with BP, with false positive occurring in up to three percent of controls.46,48,49 All IgG subclasses are present, although most of the complement-fixation activity is from the IgG3 lineage.30 Antibody titers do not reflect disease activity.50 Antibodies react to all stratified squamous epithelia.30 Regional variants of the distribution of BP antigen61 and of in-vivo deposition of antibody62 have been reported. The blister fluid contains elevated levels of interferon, suggesting presence of activated T lymphocytes43 and implicating a cell-mediated immune reaction in addition to the antibody reaction to components of the basement membrane zone in the pathogenesis of this disease.40 For drug-induced BP, it was proposed that development of an antigenic hapten to a cell site from a medication stimulates an immune response.15,26 Many inducing medications contain a sulfhydryl group that cleaves the epidermal cementing substance, resulting in an autoantibody. Many believe that the sulfhydryl groups are a necessary criterion for drug-induced BP.21,25 Penicillamine,15–17 furosemide,18-20 captopril,21 enalapril,9 penicillin and its derivatives,22–24 sulfasalazine,25 salicylazosulfapyridine,26 phenacetin,27 nalidixic acid,28 and topical fluorouracil29 have all been reported to induce bullous pemphigoid. Penicillamine and furosemide are the most frequent culprits.9 Ultraviolet light56 has also been implicated in causing BP. Laboratory features. BP is associated with peripheral blood eosinophilia.5 An elevated IgE level is found in 37 to 70 percent of bullous pemphigoid patients.6,11,12 Sixty-five to ninety percent of cases of BP patients exhibit serum anti-basement membrane zone antibodies directed against 230 kd or 180 kd antigen in the lamina lucida.13,14,30,45–47 Serum levels of complement components remain normal.53 In the blister fluid, there is marked reduction of components of C1 through C7 and mild reduction of C8 and C9.53 Light microscopy. Subepidermal bullae are present. Dermal changes include neutrophilic, eosinophilic, and lymphocytic infiltrates. Neutrophils may be present in “Indian-file” at the epidermal-dermal junction. Electron microscopy. Electron microscopy usually shows a split in the lamina lucida of the basement membrane. There may be basal cellular changes of inter- and intracellular edema and subjacent endothelial cells.30 Eosinophil and histiocyte infiltration may be present.30 The basal lamina tends to remain on the floor of the early bullae, then disintegrates eventually.30 Histopathology and immunofluorescence (IF). There is usually a subepidermal bullae with eosinophilia.30 The upper dermis often has helper/inducer T lymphocytic, neutrophilic, and histiocytic infiltrate of varying severity.30,40 Epidermal necrosis is not observed.30 Direct IF of involved and uninvolved (less characteristically) skin demonstrates a linear deposition of immunoglobulins, typically IgG, and complement components from the classic and alternative pathways in the same pattern.51 Linear deposition of IgG or complement components (or both) are highly specific and reasonably sensitive for detecting BP.30 Direct immunofluorescence is generally agreed to be the principal diagnostic test for BP. However, Wiegand, et al.,59 found that direct IF was a less useful diagnostic test in localized BP than in generalized BP.59 In their study, localized disease had a tendency for weak or even negative direct IF, and the amount of immunoreactant roughly correlated with the extent of the disease. Light microscopy may be a more reliable diagnostic test than IF in localized lesions.59 Treatment. Although usually having a benign course, untreated BP can cause significant morbidity and can even be fatal.40 Mortality rate for patients older than 65 years of age is reported to be 27 percent.41 There are many treatment options depending on the extent of involvement. Topical steroids alone (clobetasol propionate followed by maintenance therapy with less potent topical corticosteroids) are successful in treatment of localized BP.63 Localized BP35 and generalized BP35 have been treated successfully by tetracycline alone, combinations of tetracycline with nicotinamide, niacinamide, erythromycin, and/or topical steroids.31,33,35-37,60 Dapsone has also been reported to treat BP effectively.30,38 Doxycycline has been reported as unsuccessful in treating BP, which was attributed to differences in anti-inflammatory, immunosuppressive, or pharmacokinetic properties between doxycycline and tetracycline.39 Systemic corticosteroids (prednisone, prednisolone) in moderate to high doses (40 to 240mg per day) have been traditionally used to treat generalized BP.10,30,31,41,42 Other immunosuppressants, such as azathioprine, methotrexate, cyclophosphamide, and chlorambucil, can be used alone or as steroid-sparing agents.31,40 Side effects of systemic corticosteroids and immunosuppressives in some cases may actually be worse than the disease itself, especially in elderly patients with complicated preexisting medical conditions.33,34 Management For patient comfort, bullae were drained under sterile conditions. Lesions were treated with topical clobetasol propionate cream 0.05 percent. The patient improved dramatically with no recurrence of bullae. There were residual hyperpigmented patches in the areas of skin previously involved by bullous lesions on his lower extremities (Figures 3 and 4). We advised the patient to stop the topical steroids but to resume them immediately if the lesions recurred.