Dermatology Online Journal

Familial epidermolysis bullosa acquisita
Megan H Noe¹, Mei Chen PhD², David T Woodley MD², Janet A Fairley MD³
Dermatology Online Journal 14 (12): 2

1. Department of Dermatology, University of Iowa, Iowa City, Iowa
2. Department of Dermatology, University of Southern California, Los Angeles, California
3. Department of Dermatology, University of Iowa, VA Medical Center, Iowa City, Iowa. janet-fairley@uiowa.edu

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Abstract

Epidermolysis bullosa acquisita (EBA) is an acquired blistering skin disorder caused by IgG autoantibodies directed against type VII collagen. In contrast to the genetic forms of epidermolysis bullosa, EBA is usually an acquired, sporadic disease. In this report, we describe a family with two cases of EBA in an uncle-nephew pair, and a third family member with asymptomatic circulating anti-type VII collagen antibodies. These findings provide support for the hypothesis that there is a genetic component to EBA.

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Introduction

Epidermolysis bullosa acquisita (EBA) is an acquired blistering skin disorder caused by IgG autoantibodies directed against type VII collagen [1]. Clinically, EBA presents as a non-inflammatory mechanobullous disease characterized by acral blisters that heal with scarring and milia formation [2]. However, cases mimicking bullous pemphigoid or cicatricial pemphigoid have also been documented in the literature [2, 3, 4]. The first set of diagnostic criteria, established in 1971 by Roenigk et al., was based solely on clinical findings [5]. Currently, EBA is distinguished from other bullous diseases by immunological methods such as direct immunofluorescence (IF) on salt 1M NaCl-split skin, immunoelectron microscopy or an ELISA testing for circulating antibodies directed against type VII collagen [6, 7, 8]. We identified a family with two cases of EBA in an uncle-nephew pair and a third family member with asymptomatic circulating anti-type VII collagen antibodies, suggesting there may be a genetic component to EBA.

Case report

Patient 1

Figure 1
Figure 1. Resolving lesion with scarring on the chest of patient 1

A 94-year-old white male, presented with a two-year history of pruritic blisters. There was no prior history of skin disorders among the patient's 14 siblings or three children. Based on routine histology showing a sub-epidermal blister, a diagnosis of bullous pemphigoid was made. The eruption remained localized to the trunk, thighs, and upper arms; it healed with some scarring (Fig. 1). He denied ever having scalp or mucosal involvement. The patient was placed on immunosuppressive therapy (prednisone, azathioprine) and did well until the medication was discontinued due to concerns with post-operation wound healing following valve replacement surgery. He was then referred to the Department of Dermatology. On examination, the patient had several 3-5 mm areas of erythema on the trunk and right upper arm with milia. The nails, scalp, and oral mucosa were normal. Direct IF revealed IgG and C3 at the basement membrane zone (BMZ). Indirect IF was negative. The ELISA tests for antibodies to BP180 and BP230 were negative; however an ELISA for antibodies to type VII collagen was positive, diagnostic of EBA [7].

Patient 2

Figure 2
Figure 2. Immunoelectron microscopy of a biopsy from patient 2. The arrows identify immune deposits of IgG just below the lamina densa. (x20,000)

Patient 2, the nephew of patient 1, presented with a blistering disorder at age 48. On examination he had small vesicles and erosions predominantly in the trauma-prone areas including hands, feet, and anterior shins. Oral erosions were present on the pharynx and hard palate. The cutaneous lesions healed with hypopigmented scars and milia. Histology showed a pauci-inflammatory sub-epidermal blister. Direct IF of oral mucosa showed linear deposits of IgG and C3 along the basement membrane zone (Fig. 3a). No anti-BMZ autoantibodies were detected in his serum by indirect IF. An ELISA to type VII collagen was positive. Immunoelectron microscopy showed deposition of IgG in the sub-lamina densa, consistent with EBA (Fig. 2) [6].

Additional family members

Figure 3a	Figure 3b
Figure 3. Direct immunofluorescence from the skin of the patient 2 (a) and brother without disease (b). a. Strong linear staining with FITC-conjugated anti-human IgG is seen at the basement membrane zone of a perilesional biopsy from patient 2. b. Weak linear staining with FITC-conjugated anti-human IgG is seen at the basement membrane zone of a biopsy of normal skin from the brother of patient 2. Indirect IF was negative but an ELISA for antibodies to type VII collagen was positive.

Because of the presence of EBA in two family members, a brother and sister of patient 2 were evaluated. Neither sibling had visible skin or mucosal changes. Sera from both were tested by ELISA for autoantibodies to type VII collagen. Autoantibodies were detected in the brother, but not the sister. Direct IF from the dorsal surface of the brother's hand showed focal linear deposits of IgG, IgM and C3 at the BMZ (Figure 3b). One year later his sera showed continued circulating autoantibodies, but in ten years of clinical follow-up, no skin lesions have developed.

Discussion

Epidermolysis bullosa acquisita (EBA) is a rare autoimmune bullous disease associated with autoantibodies against type VII collagen. The clinical presentation of EBA is varied and five different clinical presentations have been reported in the literature: classic, bullous pemphigoid (BP)-like, cicatricial pemphigoid (CP)-like, Brunsting-Perry Pemphigoid-like, and one similar to linear IgA bullous dermatosis [9]. In the classic presentation, patients present in adulthood with non-inflammatory acral blisters that heal with scarring and milia formation. Blisters are usually localized to trauma prone areas such as the backs of hands, knuckles, elbows, knees, and toes. The other less common presentations can clinically mimic other blistering diseases, but the presence of antibodies to type VII collagen confirms the diagnosis of EBA.

Histological examination of skin from EBA patients shows a sub-epidermal blister with a clean separation between the dermis and the epidermis. Inflammatory cells can also be present in lesions that clinically appear to be inflamed. Direct immunofluorescence (IF), performed on a perilesional site, shows IgG deposition in a linear band along the BMZ and is indistinguishable from BP. Indirect IF on salt-split skin can differentiate between these two diseases based on the fact that BP antibodies are found on the roof of the blister and EBA antibodies bind to the floor. However, when indirect IF is negative, as it is in 50 percent of EBA patients, diagnosis can be more difficult [8, 10]. Salt-split direct IF, in which a biopsy is split with 1M NaCl, may differentiate between BP and EBA, with staining observed on the roof and floor, respectively. Immunoelectron microscopy can also distinguish EBA from BP and other blistering diseases based on the location of antibodies within the BMZ [6]. Immune deposits in the lamina densa are a hallmark of EBA, whereas deposition in the lamina lucida is seen in the skin of patients with BP and several other immuno-bullous diseases such as pemphigoid gestationis, cicatricial pemphigoid, linear IgA bullous dermatosis and lichen planus pemphigoides. An ELISA that detects antibodies to type VII collagen in the serum has been shown to be highly sensitive and specific, but this ELISA is not commercially available [7].

EBA is considered to be an acquired disease, making this report of antibodies to type VII collagen in multiple family members particularly noteworthy. One other instance of familial EBA has been reported. Murakami et al. described EBA in identical twin sisters who developed generalized erythema and bullae at 18 and 19 years of age [11]. The diagnosis of EBA was confirmed by indirect immunofluorescence on salt-split skin. It is also interesting to note that both these women were HLA-DR2 positive. This is consistent with the observation by Gammon et al. that EBA patients are often HLA-DR2 positive, an immunophenotype associated with autoimmunity [12]. Taken together, these findings provide further support for the idea that EBA may develop within a genetically susceptible population; in some families there may be a genetic predisposition to autoimmunity and EBA.

References

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