Epidermolysis Bullosa Acquisita

with Extensive Mucocutaneous Involvement

First described by Elliot in 1895, epidermolysis bullosa acquisita (EBA) is a rare heterogeneous autoimmune bullous disease of cutaneous and mucosal tissue.1 Autoimmune bullous diseases can be subdivided into two main categories: pemphigus, demonstrating autoantibodies targeting desmosomal antigens, and pemphigoid, or subepidermal diseases demonstrating autoantibodies to hemidesmosomal antigens (figure 1c).2,3,4 A subepidermal bullous dermatosis, EBA results from the formation of IgG autoantibodies (figure 1b) targeting type VII collagen (C7) within the anchoring fibrils attaching the epidermis to the dermis.3 As a result, patients present with skin fragility, cutaneous and mucosal blisters, milia, nail loss, erosions and chronic scarring. 3

A rare disease, EBA is estimated to develop in only 1 per every five million individuals.2 With no reported gender predilection and primarily affecting adults, EBA’s mean age of onset is 40-50 years, although it has been reported in children and the elderly.5 Though rare, EBA has been reported in association with Crohn’s disease, systemic lupus erythematosus (SLE), and drug-exposure such as penicillamine. Not only is the diagnosis of EBA complicated by its rarity, it is further convoluted by a variable clinical presentation that closely mimics those of other subepidermal blistering diseases.5 Clinically, EBA is divided into a trauma-induced or mechanobullous variant and an inflammatory subtype. Here we present a case of EBA, initially misdiagnosed as bullous pemphigoid, with extensive mucocutaneous involvement.

A 63 year old Jamaican male presented with a 4-month history of a severe generalized cutaneous bullous eruption with intraoral lesions, accompanied by pruritus, dysphagia, odynophagia, epistaxis, loss of teeth, and changes in vocal quality. Patient reported previous hospitalization 4 months prior for similar blistering skin rash and was discharged home with a diagnosis of bullous pemphigoid, on a long-term prednisone taper, finishing three days before re-presentation. Patient denied any nausea, vomiting, abdominal pain, or penicillamine exposure.

Dermatologic examination revealed multiple tense and ruptured bullae on an erythematous base involving the head, trunk, extremities, and acralsurfaces on a background of mottled pink and light-tan hypopigmentedpatches (Figure 2). Oral examination revealed multiple tense and ruptured bullae of the tongue, gingiva, and buccal mucosa (Figure 3) with ulcerations of the inferior left labial mucosa, not extending past the vermillion border, with positive mucocutaneous nikolsky sign and no evidence of ocular involvement. Laboratory workup for SLE was negative with comprehensive metabolic panel, and complete blood count negative save for a mild normocytic, normochromic anemia.

BACKGROUND

CASE PRESENTATION

Figure 1. Graphic representation of the normal components basement membrane zone (a) and the cleavage plane location of salt-split skin, through the lamina lucida (a). Below, a depiction EBA IgG autoantibodies targeting collagen VII, a component of anchoring fibrils, resulting in a subepidermal, and specifically, sub-lamina densa cleavage in EBA (b). Above right, a depiction of the components of hemidesmosomal units in the BMZ and their interaction with the lamina densa and sublamina densa (c).

PATHOLOGY

1. Elliot FI. Two cases of epidermolysis bullosa. J Cutan Genitour Diseases 1895; 13: 10-18.2. T. Hashimoto, N. Ishii, C. Ohata, M. Furumura. Pathogenesis of epidermolysis bullosa acquisita, an autoimmune subepidermal

bullous disease. J Pathol. 2012; 228(1):1-7.3. M. Chen, G.H. Kim, L. Prakash, D.T. Woodley. Epidermolysis bullosa acquisita: autoimmunity to anchoring fibril collagen.

Autoimmunity. 2012; 45(1):91-101.4. N. Ishii, T. Hamada, T. Dainichi et al., Epidermolysis bullosa acquisita: what’s new? Journal of Dermatology, 2010; 37 (3):220-230.5. A. Barreiro-Capurro, J.M. Mascaro-Galy, P. Iranzo. Retrospective study of the clinical, histologic, and immunologic features of

epidermolysis bullosa acquisita in 9 patients. Actas Dermosifiliogr. 2013; 104(10):904-914.5. Gupta R, Woodley DT, Chen M. Epidermolysis bullosa acquisita. Clin Dermatol. 2012 2012 Jan-Feb;30(1):60-9.

Due to severity of disease and extent of involvement (>90%) a combination multi-

target immunosuppressive regimen was selected including:

• Solumedrol 1mg/kg daily

• Mycofenolate Mofetil 1,500 mg twice daily

• Rituximab 1mg/kg IV on day 1 and day 15 (Rheumatoid Arthritis protocol)

• IVIG 2gm/kg total dose, given IV over 3 days

With both cutaneous and mucocutaneous involvement, EBA patients must

continue to follow regularly with all specialties corresponding to organ systems

affected, including dermatology, ophthalmology, gastrointestinal specialists,

dentistry, otolaryngology, and pulmonology.

Pathogenesis:The pathogenesis of EBA is due to circulating and tissue-bound IgG

reactive to collagen VII (C7) (Figure 1b), a common target antigen with bullous systemic lupus erythematosus (BSLE). The target antigen, C7, is a comprised of three 145-kDa alpha-chains with central collagenous triple helixes, a 145-kDa amino terminal non-collagenous domain (NC1), and a 34-kDa carboxy-terminal non-collagenous domain (NC2).3 IgG autoantibody destruction of C7 results in disruption of anchoring fibrils and consequent separation at the dermal epidermal junction (figure 1b).4 When injecting C7 reactive IgG antibodies into laboratory mice the mice develop an EBA-like blistering disease, thus confirming the IgG antibodies targeting C7 as primary pathogenic agent in the development of EBA.5

Diagnosis:Distinguishing EBA from its more common counterparts remains a

clinical and histologic challenge, reinforcing the importance of both routine H&E staining, as well as DIF. Ensuring diagnostic accuracy when addressing autoimmune bullous diseases requires clinicians utilize both clinical and histopathologic information (table 1). Clinically EBA, can look identical to BP, especially the inflammatory subtype in earlier stages, with the exception of scarring, milia formation, and occasionally extensive mucocutaneousinvolvement. Histopathologically, it can be differentiated by fibrosis (figure 6a), and specific patterns of DIF and salt-split skin (figure 6b, 6c).

DISCUSSION

TREATMENT & MANAGEMENT

REFERENCES

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Brittany P. Smirnov, DO (PGY-3)1, Alexis Stephens, DO (PGY-4)

1, Elyse Julian, DO (PGY-1)

2, Carlos H. Nousari, MD

3

1) Dermatology Resident, Department of Dermatology, Broward Health Medical Center 2) Traditional Rotating Intern, Broward Health Medical Center 3) Program Director, Department of Dermatology, Broward Health Medical Center, Graduate Medical Education

Department, Fort Lauderdale, FL 33316

Figure 4 (above). Tense, and denuded bullae on the background of mottled pink

hypopigmented patches, with milia, of extremities, trunk, hands, lateral face, tense bullae

involving lingual and buccal mucosa, associated with dental loss.

Figure 5 (left). Upper endoscopy demonstrated intra-esophageal bullae and ulcerations of

mucosa (a), and bullae (white arrow) and erosions (black arrow) of epiglottis (b). subsequent

laryngoscopy confirmed bullae involving aeryepiglottic folds as well (not pictured).

CLINICAL IMAGES

Figure 7. Clinical response 3 months after multi-target immunosuppressive therapy including Solumedrol,

IVIG, Rituximab, Mycofenolate mofetil. Residual tan hypopigmented patches and milia (black arrow), no

active bullae or erythematous patches or plaques.

A

B C

Figure 6. Hematoxylin and eosin (H&E) staining of lesional skin at 10x magnification (a) demonstrated a

subepidermal blister with light admixed infiltrate of eosinophils and neutrophils (figure a, insert, 20x

magnification), festooning of dermal papillae, and dermal and peri-vascular fibrosis. Direct

Immunofluorescence (DIF) of peri-lesional skin (b) revealed thick, linear deposition of IgG, with scant linear C3

deposition. Salt-split demonstrated staining adhering the dermal side of salt split skin (c).

Table 1. (below) Clinical and histopathologic differentiation of subepidermal autoimmune blistering diseases,

inflammatory variant of EBA notated by (I) and mechanobullous variant with (M).A

B C

Disease Clinical differentiation Histopathologic differentiation

EBA +scarring +milia +cutaneous and mucocutaneous involvement +erythematous blister base (I) +pruritus (I)

+ fibrosis +subepidermal blister +pauci-cellular (M) +PMNs and Eos (I) DIF: linear IgG, scant C3 salt-split: dermal staining

Bullous Pemphigoid (BP) -Scarring -milia +pruritus +cutaneous involvement -mucocutaneous involvement (MC involvement rare) +erythematous blister base

- Fibrosis, +subepidermal blister, +Eos sometimes PMNs, DIF: thick linear IgG and C3, salt-split: epidermal staining

BSLE +ANA, +history of lupus -mucocutaneous involvement Histologically almost identical

Linear IgA Bullous Dermatosis(LABD)

-scarring (rare) -mucocutaneous involvement +erythematous blister base +typical targetoid appearance (esp drug-induced)

-fibrosis +subepidermal blister +PMNs and Eos DIF: linear IgA

Mucous Membrane Pemphigoid (MMP)

+scarring -cutaneous involvement (usually very limited) +mucocutnaeous involvement (extensive)

+ perivascular and dermal fibrosis +subepidermal blister*biopsy specimen c/w mucocutaneous sites

Porphyria Cutanea Tarda(PCT)

+milia -scarring +photodistributed +dorsal hands -erythematous blister base (non-inflammatory) -mucocutaneous involvement

+pauci-cellular +subepidermal blister +caterpillar bodies DIF: linear and peri-vascular staining

A B