An 80-year-old woman with celiac sprue presented with an acute bullous eruption on the bilateral flexural forearms. She had coincident onset of diarrhea and vomiting which led to dehydration, renal failure, and hospitalization. She denied a history of similar eruptions. Prehospitalization medications were unchanged over the past year and included clonidine, olmesartan, simvastatin, diphenoxylate/atropine, omeprazole, and furosemide.

Cutaneous examination revealed erythematous targetoid plaques with dusky centers symmetrically distributed on the chin, neck, flexural forearms, central chest, breasts, flanks, inner thighs, and anterior legs (Figure 1 and Figure 2). In addition, there were numerous tense vesicles and bullae in the same distribution (Figure 1). Palms, soles, and mucous membranes were spared. Laboratory studies revealed a mild leukocytosis and findings consistent with acute renal failure.

Figure 1: Left flank with erythematous targetoid plaques with dusky centers; forming areas of confluent erythema and coalesced tense vesicles.

Figure 2: Central chest with erythematous targetoid plaques with dusky centers; forming areas of confluent erythema.

Histologic examination demonstrated intraepidermal and subepidermal bullae, spongiosis with microvesicular formation, and focal subepidermal vesiculation (Figure 3). Within the bullae, proteinaceous material and an eosinophil-predominant infiltrate were present. In the upper dermis, an intense perivascular infiltrate was composed of neutrophils and numerous eosinophils. Direct immunofluorsecence (DIF) demonstrated linear deposits of IgG and C3 at the basement membrane zone. Treatment with the following resulted in clinical improvement: oral prednisone taper starting at 60mg/dL daily, mycophenolate mofetil 1000mg BID, and cessation of furosemide. At 21-month follow-up the patient remained asymptomatic.

Figure 3: Biopsy of vesicle from flexoral surface of right arm showing intraepidermal and subepidermal bullae, spongiosis with microvesicular formation (hematoxylin and eosin stain; original magnification 100X).

The clinical diagnosis of bullous pemphigoid (BP) can be challenging in the setting of erythema multiforme (EM)-like lesions. To our knowledge, only four case reports describe EM-like BP [1,2]. In one report, multiple medications-citalopram, thioridazine, and flupenthixol-were suspected, none of which had previously been associated with BP [2]. Three additional cases of EM-like BP describe patients who developed severe bullous eruptions after receiving various penicillins-amoxicillin, penicillin G, and phenoxymethyl penicillin [1]. Of interest, bullous disease with clinical and histological features of both EM and BP has been reported [3].

The diagnosis of BP is based on clinical suspicion but is sometimes difficult as the disease is polymorphic. Therefore, the diagnosis should be confirmed by histology and DIF [4]. In the present case, the clinical diagnosis of bullous EM was initially suspected. However, review of the biopsy specimens suggested BP.

BP is usually idiopathic but may be associated with malignancy, medications, and rarely autoimmune disorders [4]. It is unclear if the presentation of BP in our patient was causally related to her underlying celiac sprue. The onset of diarrhea, presumed to be a flare of celiac sprue, was in fact temporally correlated with the onset of her bullous disease. One documented case exists of BP developing in a child with untreated celiac sprue, however the case lacked sufficient evidence to support a causal relationship between the two conditions [5]. Of note, antigliadin antibody, an autoantibody associated with celiac sprue, can also be found in 40-80% of BP and pemphigus vulgaris patients. However, the presence of antigliadin antibody may be age-related [6].

Unlike the weak association of BP with autoimmune disorders, furosemide-associated BP has been supported in the literature [4,7,8]. The first report of furosemide-associated BP by Ebringer et al in 1969 described remission upon discontinuation of the medication [7]. Another similar case documented recurrence of BP upon rechallenge with furosemide [8]. Additionally, at least another 8 cases have been reported linking furosemide use with onset of BP [4,9-13]. These cases all involve elderly patients with cardiac disease, renal disease, or both. It does not appear that development of BP while on furosemide is dose or duration dependent [4,7,13]. The authenticity of furosemide induced BP has been debated; a prospective multi-centered trial failed to demonstrate an association between BP and furosemide [14].

The exact mechanism for furosemide-induced and medicationinduced BP is not known, however several immunological mechanisms have been proposed. One theory suggests that the offending medication possibly behaves as an antigenic hapten inducing antibodies to the basement membrane zone via binding to a protein in the lamina lucida and somehow uncovering a hidden antigenic site and altering its antigenic properties [15-17]. Alternatively, another mechanism proposed that medication-induced antibody production alters T suppressor cell function which then no longer represses certain B cell clones [15]. A third possibility is that sulfur-containing medications, including furosemide, may cause a biochemical dermal-epidermal splitting which occurs independent of immunologic mechanisms [15,18]. There has also been a "two-step" theory for medicationinduced BP in which 2 separate medication work together to initiate and exacerbate the disease, suggesting a multi-factorial etiology of medication-induced BP [19].

Our experience emphasizes the need to consider BP in the differential diagnosis of bullous lesions even when morphology is atypical. Moreover, while the pathogenesis of BP remains unclear, the discontinuation of any medication known to be associated with BP induction is prudent when clinically feasible. Furosemide associated BP is rare, yet clinically relevant especially given the widespread use of this medication in the elderly population. Timely discontinuation of furosemide generally leads to resolution of BP.