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Epidermolysis bullosa acquisita

Epidermolysis bullosa acquisita
Literature review current through: May 2024.
This topic last updated: Apr 29, 2024.

INTRODUCTION — Epidermolysis bullosa acquisita (EBA) is a rare, sporadic, subepithelial, mucocutaneous blistering disease that usually develops in adulthood. EBA is classically described as a mechanobullous disorder characterized by skin fragility, noninflammatory tense bullae, milia, and scarring. Alternatively, EBA can present as an inflammatory bullous eruption reminiscent of bullous pemphigoid or other subepithelial autoimmune blistering diseases.

The pathogenesis of EBA involves the production of antibodies against type VII collagen, a major component of anchoring fibrils in the basement membrane zones of skin and mucosa (figure 1). The immune-mediated disruption of the anchoring fibrils likely contributes to cleavage within the basement membrane zone and clinical blistering.

The pathogenesis, clinical manifestations, and management of EBA will be discussed here. Hereditary epidermolysis bullosa and the general approach to the diagnosis of cutaneous blisters are reviewed separately. (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features" and "Diagnosis of epidermolysis bullosa" and "Overview of the management of epidermolysis bullosa" and "Approach to the patient with cutaneous blisters".)

TERMINOLOGY — Although the name "epidermolysis bullosa acquisita" arose from the original view of EBA as a disorder reminiscent of recessive dystrophic epidermolysis bullosa (RDEB), EBA and epidermolysis bullosa are distinct diseases. RDEB is a hereditary disease that results from mutations in the COL7A1 gene that encodes type VII collagen. In contrast to EBA, RDEB usually first presents in infancy. (See "Diagnosis of epidermolysis bullosa".)

EPIDEMIOLOGY — EBA is a rare disorder of uncertain incidence. Although pediatric cases have been reported, adults are most commonly affected [1-6]. Increased risks for EBA based upon gender, ethnicity, or geographic location have not been definitively established.

PATHOGENESIS — Although the inciting factors for EBA are unknown, evidence indicates that an autoimmune process that involves the production and deposition of antibodies against type VII collagen, a major component of anchoring fibrils (adhesion structures in the dermal-epithelial junction [DEJ]) [7,8], likely contributes to the development of clinical disease (figure 1). This concept is based upon several observations:

Direct immunofluorescence (DIF) microscopy of perilesional skin from patients with EBA reveals antibody deposition at the basement membrane zone [9-11].

Antibodies against type VII collagen can be detected in serum from patients with EBA [12].

Immunoelectron microscopy demonstrates antibody deposition in the lamina densa area of the basement membrane zone, a site consistent with the location of anchoring fibrils [12].

Decreased numbers of normal anchoring fibrils are present in the DEJ in EBA [13,14], a finding consistent with skin fragility and epidermal blistering.

Animal models indicate that passive transfer of antibodies against type VII collagen can induce clinical features consistent with EBA. (See 'Pathogenic mechanism' below.)

Serum levels of type VII collagen antibodies detected by ELISA correlate with the severity of skin lesions [15].

Patients with bullous systemic lupus erythematosus, which is also associated with antibodies against type VII collagen, develop subepidermal (either sub-lamina lucida or sub-lamina densa) blistering [16].

The role of type VII collagen in the DEJ and the mechanism through which antibodies against this protein might contribute to EBA are reviewed in greater detail below.

Type VII collagen — Type VII collagen is composed of three identical alpha chains, each consisting of a 145 kDa central collagenous triple-helical segment characterized by repeating Gly-X-Y amino acid sequences. The triple-helical segment is flanked by a large 145 kDa amino-terminal, noncollagenous domain (NC1) and a 34 kDa carboxyl-terminal noncollagenous domain (NC2) [7,8,17]. The major antigenic epitopes of type VII collagen are located within the NC1 domain; thus, the type VII collagen antibodies detected in patients with EBA most frequently recognize epitopes within this site [18]. Less often, antibodies against the triple-helical domain or the NC2 domain are present [1,19-23].

The NC1 domain may play an important role in maintaining the structural integrity of the DEJ. The NC1 domain contains subdomains with partial homology to adhesive proteins (cartilage matrix protein, fibronectin type III domains, and A domains of von Willebrand factor) [24]. This feature may contribute to the ability of anchoring fibrils to stabilize the attachment of the basement membrane zone to the underlying dermis.

Additional support for the importance of the NC1 domain in the maintenance of the structural integrity of the DEJ comes from our study of a recombinant NC1 protein [25]. In the study, we found that a recombinant NC1 protein was capable of binding to components of the basement membrane zone and dermal extracellular matrix, including fibronectin, laminin 5, type I collagen, and type IV collagen.

To date, a definitive link between the epitope specificity of autoantibodies in EBA (ie, NC1 domain, NC2 domain, or the triple helical domain) and specific clinical subtypes of EBA has not been identified [26] (see 'Clinical manifestations' below). The results of a series of five patients with EBA who were evaluated with immunoelectron microscopy suggested that antibodies to the triple helical domain may be associated with inflammatory subtypes of EBA; however, additional studies are necessary to determine whether this conclusion is valid [23].

Pathogenic mechanism — Because it is conceivable that antibody formation against components of the DEJ could occur as a secondary event following skin injury, studies have been performed to determine whether the type VII collagen antibodies detected in EBA are pathogenic. Strong support for the pathogenicity of these antibodies is derived from passive transfer studies in animals [27-29]. As an example, after intradermal injection of rabbit serum containing high titers of antibodies against the NC1 domain of human type VII collagen, hairless immunocompetent mice had deposits of anti-NC1 antibodies and complement at the DEJ and developed subepithelial blistering and nail dystrophy reminiscent of human EBA [27]. Furthermore, mice injected with human EBA autoantibodies affinity-purified against an NC1 column have developed a blistering disease with clinical, immunohistologic, and ultrastructural features akin to human EBA [29].

Several theories on the mechanism through which the production and deposition of antibodies against type VII collagen could lead to mucocutaneous blistering in humans have been proposed. These include:

Autoantibody deposition on the NC1 domain of anchoring fibrils may compromise the function of type VII collagen by disturbing its interactions with other basement membrane or upper dermal components, such as type IV collagen, laminin 5, and fibronectin [25,30].

Autoantibodies may interfere with the anti-parallel dimer formation of type VII collagen, thereby inhibiting anchoring fibril assembly [21]. This could result in defective adherence of the lamina densa to the dermis.

Antibody-induced complement fixation may lead to tissue inflammation and damage at the DEJ and subsequent blister formation. This mechanism is most likely to occur in the inflammatory bullous pemphigoid-like subtype of EBA [31]. (See 'Clinical manifestations' below.)

Additional study is necessary to confirm the pathogenic mechanism of EBA.

Genetic factors — Genetics may play a role in the risk for EBA. In a study of 29 patients with EBA, the frequency of HLA-DR2 was increased when compared with healthy controls [32]. In theory, this allele could influence autoimmunity to type VII collagen in anchoring fibrils or could serve as a marker for another gene that is in linkage disequilibrium with HLA-DR2.

CLINICAL MANIFESTATIONS — EBA was initially described as a subepithelial, noninflammatory mucocutaneous bullous disease associated with skin fragility, a presentation that is now referred to as classical EBA. However, the subsequent identification of autoantibodies against type VII collagen as a diagnostic feature led to the recognition of a broader spectrum of clinical manifestations. In addition to the classical, noninflammatory presentation of EBA, EBA may manifest as an inflammatory blistering disorder characterized by features that resemble bullous pemphigoid, mucous membrane (cicatricial) pemphigoid, linear IgA bullous dermatosis, or Brunsting-Perry pemphigoid. The two most common presentations of EBA are the classical and bullous pemphigoid-like subtypes. The presence of antibodies against type VII collagen distinguishes EBA from the true forms of other autoimmune blistering diseases.

Classical (noninflammatory) epidermolysis bullosa acquisita — Patients with classical EBA present with skin fragility and the formation of noninflammatory tense vesicles and bullae that rupture, leaving erosions (picture 1A-B). The most common locations for lesion development are sites that are repeatedly subject to minor trauma, such as the hands, feet, elbows, knees, and lower back. The blisters often heal with scarring and small epidermal inclusion cysts referred to as milia (picture 2).

Mucosal involvement is common in both classical and inflammatory EBA, and can be subclinical or may manifest as erosions or adhesions on the oral, nasal, ocular, pharyngeal, laryngeal, esophageal, or anogenital mucosa [33,34]. In one series of 12 patients with EBA, mucosal involvement was present in 11 patients (92 percent) [35]. A separate retrospective study of 12 patients with EBA found mucosal involvement in 9 patients (75 percent) [5].

Alopecia, nail loss, fibrosis of the hands and fingers (leading to a mitten-like deformity), esophageal stenosis, and esophageal webbing may occur in patients with severe disease reminiscent of hereditary dystrophic epidermolysis bullosa [20,33,36-39]. (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features", section on 'Dystrophic epidermolysis bullosa'.)

Inflammatory epidermolysis bullosa acquisita — As noted above, the inflammatory subtypes of EBA resemble other autoimmune subepithelial blistering diseases. In contrast to classical EBA, skin fragility is not a typical feature:

Bullous pemphigoid-like EBA Bullous pemphigoid-like EBA shares clinical features with bullous pemphigoid, the most common autoimmune subepithelial blistering disease (picture 3). Rather than the noninflammatory lesions of classic EBA, these patients present with tense bullae that are surrounded by inflamed or urticarial skin [31,40]. Similar to bullous pemphigoid, the lesions are widespread with a predilection for the trunk, extremities, and skin folds. Larger areas of skin that demonstrate only erythema or urticarial plaques without bullae may also be present. Pruritus is common. Scarring and milia are not prominent findings. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Clinical features of bullous pemphigoid'.)

Mucous membrane pemphigoid-like EBA EBA may present as a mucosal-predominant disorder with clinical findings that resemble mucous membrane pemphigoid (picture 4). The primary disease manifestations in these patients are erosions and scarring on the mucosal surfaces of the mouth, upper esophagus, conjunctiva, anus, or vagina [41]. Our experience with mucous membrane pemphigoid-like EBA has included a patient who developed scarring and strictures of the urethra and the larynx that led to impaired urination and vocalization. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Clinical features of mucous membrane pemphigoid'.)

IgA bullous dermatosis-like EBA – IgA bullous dermatosis-like EBA has clinical, histologic, and direct immunofluorescence (DIF) findings that resemble IgA-mediated bullous dermatoses [2,42,43]. Affected patients may present with the annular arrangement of vesicles and bullae characteristic of linear IgA bullous dermatosis or with the grouped vesicles characteristic of dermatitis herpetiformis (picture 5A-B). Concomitant mucosal involvement is common. (See "Linear IgA bullous dermatosis", section on 'Clinical manifestations'.)

Brunsting-Perry pemphigoid-like EBA – The Brunsting-Perry pemphigoid-like variant of EBA resembles Brunsting-Perry pemphigoid, a rare subepithelial blistering disorder characterized by bullae that primarily appear on the head and neck and tend to heal with scarring (picture 6) [44-46]. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Brunsting-Perry pemphigoid'.)

EBA manifesting as generalized erythroderma with inflammatory papules and urticarial plaques prior to the development of isolated vesicles and bullae has been documented in a case report [47]. Since patients with erythroderma are not routinely evaluated for antibodies against type VII collagen, it is unclear whether erythroderma is an under-recognized manifestation of EBA. One theory for the mechanism of erythrodermic EBA involves EBA occurring as a secondary event due to inflammatory skin disease. Skin injury from inflammation may generate a type VII collagen neoantigen at the basement membrane zone and lead to autoantibody formation.

Children — EBA rarely occurs in children, but also appears to manifest with various clinical presentations in this population. One retrospective study found that among 14 children with EBA, five presented with bullous pemphigoid-like disease, five with linear IgA bullous dermatosis-like disease, and four with classical EBA [2]. Mucosal involvement was common, occurring in 11 children.

ASSOCIATED DISORDERS — The concurrent existence of EBA and various systemic diseases, such as inflammatory bowel disease (IBD), systemic lupus erythematosus, amyloidosis, thyroiditis, multiple endocrinopathy syndrome, rheumatoid arthritis, pulmonary fibrosis, chronic lymphocytic leukemia, thymoma, and diabetes has been anecdotally reported [48]. Clinical experience with over 60 patients from several academic centers in the United States suggests that IBD is the systemic disease most frequently seen in association with EBA [18,49]. The presence of type VII collagen in the human colon and the detection of autoantibodies against type VII collagen in some patients with IBD support a potential link between these diseases [50-52]. Additional studies are necessary to confirm and explore the relationship of EBA to IBD and other diseases.

DIAGNOSIS — Since EBA shares clinical, pathologic, and immunohistologic features with other subepithelial blistering disorders, the diagnosis of this disease can be challenging. Once an initial evaluation indicates the presence of an autoimmune subepithelial blistering disease and reveals findings consistent with EBA, additional tests may be used to confirm the diagnosis. (See 'Differential diagnosis' below.)

Initial evaluation — An evaluation for EBA is triggered by clinical findings that suggest an autoimmune blistering disease, such as the unexplained onset of multifocal cutaneous blistering and/or mucosal erosions. As for other subepithelial blistering diseases, the initial evaluation should include the following:

A thorough patient history and full skin examination that includes an assessment of the distribution and morphology of skin lesions – This evaluation helps to narrow the differential diagnosis. As an example, a diagnosis of classical EBA should be strongly considered in adults who present with consistent clinical features (eg, skin fragility and trauma-induced tense bullae that result in milia and scars) and lack a family history of hereditary blistering disease. Due to the various morphologies of EBA, the possibility of EBA should still be considered when clinical features suggest another subepithelial blistering disorder. (See 'Clinical manifestations' above and 'Differential diagnosis' below.)

Tissue biopsies for routine histopathology and direct immunofluorescence (DIF) microscopy A tissue biopsy of lesional skin or mucosa should be obtained for routine histologic examination to determine the site of blistering within the skin (eg, intraepithelial versus subepithelial). A biopsy of perilesional skin or mucosa for DIF microscopy should also be performed to evaluate for autoantibody deposition. A 4 mm punch biopsy is typically utilized to obtain each of the necessary tissue specimens. The specimen for DIF should not be placed in formalin. Skin biopsy procedures for the evaluation of blistering diseases are discussed in greater detail separately. (See "Approach to the patient with cutaneous blisters", section on 'Skin biopsy'.)

Immunofluorescence on basement membrane zone-split skin When clinical, histologic, and DIF findings are consistent with an autoimmune subepithelial blistering disorder, immunofluorescence on skin artificially split within the basement membrane zone is useful for ruling out bullous pemphigoid and linear IgA bullous dermatosis, thereby narrowing the differential diagnosis to EBA and a few other rare diseases. (See 'Immunofluorescence on basement membrane zone-split skin' below.)

Histopathology — The histopathologic findings in EBA vary with the stage of lesion development and the clinical subtype. Early lesions typically show vacuolar alteration along the dermal-epithelial junction (DEJ) with subjacent papillary dermal edema. In more developed lesions, there is a frank subepithelial blister (picture 7). Dermal fibrosis may be present in older lesions, a finding that correlates with the clinical development of scarring [53].

The intensity of inflammation in the dermis differs among the clinical subtypes. Classical EBA is characterized by a sparse lymphocytic infiltrate in the superficial dermis [54]. In contrast, inflammatory subtypes of EBA develop a heavy perivascular, perifollicular, and/or interstitial infiltrate in the upper dermis. The infiltrate may be rich in neutrophils or may be a mixed infiltrate that also includes variable numbers of mononuclear cells and eosinophils. (See 'Clinical manifestations' above.)

Direct immunofluorescence — DIF shows deposition of immunoreactants in nearly all cases [34,38,55,56]. The classic DIF findings in EBA are linear deposits of IgG and complement at the DEJ [54,57]. Deposition of IgA, IgM, Factor B, and properdin may also be detected.

Because linear deposition of IgG and complement at the DEJ may be seen in multiple autoimmune subepithelial blistering disorders, the DIF findings do not provide a definitive diagnosis. In addition, the key DIF finding in linear IgA bullous dermatosis-like EBA, which consists of linear deposition of IgA along the DEJ, is identical to that in linear IgA bullous dermatosis [42,58]. (See "Linear IgA bullous dermatosis", section on 'Direct immunofluorescence'.)

The pattern of the antibody deposition at the DEJ may offer additional clues for diagnosis [59-61]. A study of skin biopsies from 157 patients with subepithelial blistering diseases found that a u-serrated pattern is most often seen in EBA and bullous systemic lupus erythematosus, whereas an n-serrated pattern is more typical of bullous pemphigoid, mucous membrane pemphigoid, and linear IgA bullous dermatosis [59].

Immunofluorescence on basement membrane zone-split skin — The basement membrane zone-split skin technique involves the artificial induction of cleavage within the lamina lucida of the basement membrane zone by incubation in 1 M sodium chloride (salt-split skin) or 20 mM ethylenediaminetetraacetic acid (EDTA). Subsequent visualization of the location of autoantibody binding in reference to the site of cleavage is utilized to narrow the differential diagnosis. This technique may be performed utilizing perilesional tissue (DIF on basement membrane zone-split skin) or serum from the patient and a human skin substrate (indirect immunofluorescence [IIF] on basement membrane zone-split skin).

Antibody binding to only the dermal side of basement membrane zone-split skin (floor of blister) is consistent with EBA, which contrasts with bullous pemphigoid, which presents with linear deposits of IgG on the epidermal side of salt-split skin (roof of blister) or to both the epidermal and dermal side of the split. Immunofluorescence on basement membrane zone-split skin is also useful for distinguishing linear IgA bullous dermatosis-like EBA from the more common form of linear IgA bullous dermatosis, which is characterized by epidermal binding on basement membrane zone-split skin. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Diagnosis' and "Linear IgA bullous dermatosis", section on 'Diagnosis'.)

A downfall of IIF on basement membrane zone-split skin is that the test may be negative in patients with low levels of circulating type VII collagen antibodies [36,62]. Although IIF on salt-split skin was positive and showed dermal staining in all 10 patients with EBA in one series [63], IIF on basement membrane zone-split skin was negative in around one-third of patients in two other small series [5,62]. In these patients with low levels of circulating type VII collagen antibodies, the enzyme-linked immunosorbent assay (ELISA) will also likely be negative. It is also important to note that although immunofluorescence on salt-split skin that shows antibody binding to only the dermal side of split skin supports a diagnosis of EBA, it does not rule out the possibility of several rare subepithelial blistering disorders. (See 'Additional studies' below.)

Additional studies — Additional studies may be useful to support a diagnosis of EBA in the setting of a negative IIF and may aid in the differentiation of EBA from other subepithelial blistering disorders. Examples of test options include [18]:

Transmission electron microscopy This test is readily available in many hospitals and can be used to identify a reduction in anchoring fibrils in the DEJ. It also can demonstrate amorphous material beneath the lamina densa that may represent immunoglobulin deposits on anchoring fibrils.

Enzyme-linked immunosorbent assay (ELISA) ELISA systems based upon the NC1 and NC2 domains of type VII collagen are commercially available tests that can be used to identify, with high sensitivity and specificity, antibodies that bind to type VII collagen [64-67]. However, when the level of circulating antibodies against type VII collagen is low (eg, patients in whom IIF on basement membrane zone-split skin is negative), the ELISA often is negative [68].

Direct or indirect immunoelectron microscopy (IEM) – These ultrastructural tests are generally used in the research setting. IEM can identify the location of antibody deposits in perilesional tissue (direct IEM) or the location where antibodies in patient serum bind within a human skin substrate (indirect IEM). Antibody deposition in the sublamina densa zone (the site of anchoring fibrils) is consistent with EBA. IEM is considered the gold standard for diagnosis.

Examples of other studies that have been used in research settings to aid in the diagnosis of EBA include immunoblotting (demonstrates a 290 kDa band that represents the alpha chain of type VII collagen ± a 145 kDa band that represents the NC1 domain) [18]; indirect immunofluorescence utilizing recombinant NC1 domain on the surface of HEK293 cells [66]; and fluorescent overlay antigen mapping (FOAM) [69,70]. FOAM uses computer analysis to compare the location of immunoglobulin deposits in perilesional skin to the sites where monoclonal antibodies to various components of the basement membrane zone bind. In EBA, antibody deposits are localized below the lamina densa.

Specialized testing is also necessary to distinguish EBA from rare subepithelial blistering diseases with similar findings on basement membrane zone-split skin immunofluorescence, including bullous systemic lupus erythematosus, anti-laminin 332 (laminin 5/epiligrin) mucous membrane pemphigoid [71], anti-p105 pemphigoid [72], and anti-laminin 311 (p200/laminin gamma 1) pemphigoid [73]. Bullous systemic lupus erythematosus occurs in patients with systemic lupus erythematosus, and therefore can be ruled out when evidence for underlying systemic lupus erythematosus is absent. ELISA testing for type VII collagen antibodies or IEM can be used to distinguish EBA from the other rare subepithelial blistering disorders. As noted above, the availability of IEM is primarily limited to research environments.

DIFFERENTIAL DIAGNOSIS — Multiple disorders share clinical features with EBA. Some of the disorders most commonly mistaken for EBA are reviewed below:

Bullous pemphigoid – The inflammatory, urticarial plaques and tense blisters of BP may also occur in inflammatory EBA (picture 3). Immunofluorescence on basement membrane zone-split skin is useful for differentiating these diagnoses. (See 'Immunofluorescence on basement membrane zone-split skin' above and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)

Linear IgA bullous dermatosis – Linear IgA bullous dermatosis is a subepithelial blistering disorder that occurs in children and adults. An annular configuration of blisters is common (picture 5A). Immunofluorescence on basement membrane zone-split skin is useful for distinguishing linear IgA bullous dermatosis from the linear IgA bullous dermatosis-like form of EBA. (See 'Immunofluorescence on basement membrane zone-split skin' above and "Linear IgA bullous dermatosis".)

Porphyria cutanea tarda – Porphyria cutanea tarda is an inherited or acquired metabolic disorder that presents with photodistributed, noninflammatory vesicles, bullae, crusts, and milia (picture 8A-B). The dorsal hands and forearms are common sites for involvement. Associated clinical findings include hyperpigmentation, facial hypertrichosis, and localized sclerodermoid plaques. Porphyria cutanea tarda is diagnosed through the detection of elevated levels of porphyrins in plasma or urine. In addition, direct immunofluorescence (DIF) microscopy typically reveals deposition of IgG around dermal blood vessels [74]. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".)

Bullous systemic lupus erythematosus – Bullous systemic lupus erythematosus is a rare subepithelial blistering disorder that occurs in the setting of systemic lupus erythematosus (picture 9). As with EBA, antibodies to type VII collagen have been implicated in the pathogenesis of bullous systemic lupus erythematosus. The presence of an underlying diagnosis of systemic lupus erythematosus in a patient with immunofluorescence findings similar to those in EBA suggests the possibility of this diagnosis.

Recessive dystrophic epidermolysis bullosa – Recessive dystrophic epidermolysis bullosa is a rare, inherited blistering disorder characterized by the congenital absence of type VII collagen. Patients first present in infancy. Severe skin fragility and generalized blisters that resolve with scarring and milia formation are characteristic (picture 10). Fusion of the digits of the hands and feet (mitten deformity) is common. (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features" and "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features", section on 'Dystrophic epidermolysis bullosa'.)

TREATMENT — EBA is notoriously difficult to treat; disease refractory to multiple interventions is common. Randomized therapeutic trials of this rare disorder are lacking and the optimal approach to treatment remains unclear [75].

General measures — In addition to pharmacologic therapy, efforts to minimize disease severity are often beneficial in patients with EBA. These include:

Avoidance of incidental and iatrogenic trauma to the skin

Gentle cleansing of skin during bathing and avoidance of vigorous scrubbing and harsh soaps

Education of patients regarding signs of cutaneous infection to promote early recognition and treatment

For wound care, we typically use hydrogel or semiocclusive hydrocolloid dressings on new, clean wounds. For lower extremity wounds, we often apply a silver impregnated dressing that is changed every 48 hours to minimize the risk for infection. (See "Basic principles of wound management".)

Patients with mucosal involvement usually require multidisciplinary management to minimize consequences of the disease. Ocular disease may result in conjunctival scarring and blindness. Thus, patients with ocular involvement should be managed jointly with an ophthalmologist to assist with following the response to treatment and the use of adjunctive topical therapies. Symptoms of dysphagia or diarrhea are an indication for a referral to gastroenterology to evaluate for the presence of esophageal strictures or inflammatory bowel disease, respectively. Last, patients with oral involvement may benefit from joint management with a dentist who is familiar with the care of patients with autoimmune blistering diseases [76].

Approach to treatment — The preferred first-line treatments for EBA are agents that both have appeared to be effective based upon the limited available data and are generally well tolerated.

Although systemic glucocorticoids are often utilized in EBA, clinical experience suggests that classical EBA may be less likely to respond to systemic glucocorticoids than inflammatory subtypes of EBA, and that overall, systemic glucocorticoids are less effective for EBA than for other subepithelial blistering diseases [18,77]. The long-term side effects of systemic glucocorticoid therapy are an additional concern. Thus, we prefer a different approach to initial therapy.

In our practice, the initial treatment for most patients consists of colchicine or dapsone, both of which have been reported to be effective when administered in combination with systemic glucocorticoids; monotherapy with colchicine has also been reported as effective in several patients [5,77]. If satisfactory improvement is not attained with colchicine or dapsone monotherapy, we combine these agents. If this is not effective, we consider treatments for refractory disease, most often utilizing rituximab (particularly for patients with classical EBA) or a trial of the addition of a short course of prednisone to colchicine and dapsone therapy. (See 'Refractory disease' below.)

In severe cases in which acute improvement is needed, treatment with prednisone may be initiated at the start of treatment with colchicine or dapsone to attempt to accelerate improvement of disease.  

Colchicine — Typical doses of colchicine for EBA in adults range from 0.5 to 3 mg per day, with the maximum dose typically limited by the development of dose-related gastrointestinal adverse effects. In our experience, tolerance to the drug is improved when the dose is increased gradually.

In adults, we typically begin colchicine at 0.5 or 0.6 mg per day and increase by 0.5 or 0.6 mg per week until diarrhea occurs. We then reduce the dose to a level that was tolerated without diarrhea. In our experience, most adults are able to tolerate up to a daily dose of 2 to 3 mg per day, and higher doses of colchicine generally are not necessary. Due to the high likelihood of gastrointestinal adverse effects, we usually avoid the use of colchicine in EBA patients who also have inflammatory bowel disease [78,79]. (See 'Associated disorders' above.)

Dapsone — Treatment with dapsone and systemic glucocorticoids has been associated with clinical improvement in adults and children with EBA [5,80,81]. Dapsone is typically given as 1 to 2 mg/kg per day [77], beginning with a low dose (eg, 25 mg in adults) and increasing as tolerated.

Hemolytic anemia is a common side effect of dapsone therapy that occurs to some degree in all patients, resulting in a mild, typically asymptomatic drop in hemoglobin. Individuals with glucose-6-phosphate deficiency have an increased risk for severe hemolytic anemia. Thus, we test for G6PD deficiency prior to initiating therapy with this agent.

Refractory disease — Patients who fail to respond well to colchicine or dapsone require more aggressive therapy. Treatments that may be of benefit in this population include immunosuppressants, intravenous immunoglobulin (IVIG), and rituximab. The high costs and requirements for infusion of IVIG and rituximab limit the use of these agents for some patients:

Immunosuppressants – Although the efficacy of systemic glucocorticoids for EBA is inconsistent, a trial of the addition of a short course of prednisone to colchicine and dapsone may be performed in an attempt to augment improvement. Prednisone is administered in doses of 0.5 to 1.5 mg/kg per day, with the doses on the lower end of this range used for less severe disease. Prednisone is subsequently tapered as tolerated, with an ideal goal of limiting the course of systemic glucocorticoid therapy to six weeks [77].

Case reports and a case series have documented clinical improvement with immunosuppressive therapy such as cyclosporine, azathioprine, cyclophosphamide, methotrexate, and mycophenolic acid [77,82]. However, clinical experience suggests the benefit of these agents is particularly limited in patients with the classical presentation of EBA. Patients with the inflammatory, bullous pemphigoid-like presentation may be more likely to respond to these therapies.

Intravenous immunoglobulin – Intravenous immunoglobulin (IVIG) has been utilized for the treatment of pemphigus vulgaris and other autoimmune diseases. Multiple case reports suggest that the periodic administration of IVIG alone or in combination with other agents is also effective for improving the clinical manifestations of EBA [5,83-86]. In a 2011 review of published reports, 14 of 15 patients given IVIG as monotherapy or in conjunction with other therapies achieved clinical improvement [77]. Multiple cycles of IVIG were typically given; each cycle usually consisted of a total of 1.5 to 2 g/kg of IVIG given over the course of three to five days.

Side effects of IVIG are usually mild and transient; however, serious adverse effects occasionally occur. The adverse effects of IVIG are reviewed separately. (See "Intravenous immune globulin: Adverse effects".)

RituximabRituximab, a monoclonal antibody against CD20 that depletes B lymphocytes, has been given in combination with immunosuppressants, IVIG, or immunoadsorption for refractory EBA in small numbers of patients with favorable results, including patients with the classical variant of EBA [5,87-92].

Caution must be used with rituximab as potential side effects include life threatening infections, pancytopenia, severe mucocutaneous reactions, and bowel obstruction, among others. One EBA patient treated with rituximab developed a fatal Pseudomonas pneumonia [93]. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)

Other therapies — Other treatments that have been reported to be effective in individual patients with refractory EBA include daclizumab [94], plasmapheresis [95], and extracorporeal photophoresis [96-98].

PROGNOSIS — Although the course of EBA varies, the disease most commonly has a prolonged course, persisting for years. Mucosal involvement can lead to long-term consequences, such as blindness and esophageal strictures. Uncontrolled cutaneous involvement may lead to joint contractures [99].

A cure for EBA does not exist. Thus, the goal of treatment is suppression of disease. In a retrospective study of 30 patients with EBA, all of whom were initially treated with a combination of methylprednisolone, dapsone, and colchicine (six who did not respond were subsequently treated with other immunosuppressants), 8 of 24 patients (33 percent) achieved complete remission and 5 of 24 (21 percent) achieved partial remission within one year [100]. The overall prognosis and response to treatment may be less favorable in adults than in children [2,101].

SUMMARY AND RECOMMENDATIONS

Epidermolysis bullosa acquisita (EBA) is a rare subepithelial blistering disorder that primarily affects adults. EBA is a disease distinct from hereditary epidermolysis bullosa. (See 'Epidemiology' above and 'Terminology' above.)

EBA is an autoimmune disease characterized by the production of antibodies against type VII collagen, a major component of anchoring fibrils in the dermal-epithelial junction (figure 1). Immune-mediated disruption of the anchoring fibrils likely contributes to the clinical development of blistering. (See 'Pathogenesis' above.)

EBA is characterized by several clinical presentations. The most common presentations are classical EBA and bullous pemphigoid-like EBA. Classical EBA presents as a mechanobullous disorder associated with skin fragility and noninflammatory tense bullae, with a predilection for acral areas (picture 1A-B). Bullae often heal with milia and scarring (picture 2). Bullous pemphigoid-like EBA is an inflammatory form of EBA that is characterized by urticarial plaques and widespread inflammatory bullae. (See 'Clinical manifestations' above.)

Anecdotal reports document the occurrence of EBA in association with multiple other systemic diseases. The most common disorder seen in association with EBA is inflammatory bowel disease. (See 'Associated disorders' above.)

The approach to the diagnosis of EBA resembles that for other autoimmune subepithelial blistering disorders. The initial evaluation includes a patient history, full skin examination, and skin biopsies for hematoxylin and eosin staining and direct immunofluorescence. Immunofluorescence on basement membrane zone-split skin provides valuable clues for further narrowing of the differential diagnosis. (See 'Diagnosis' above.)

Although the clinical evaluation, biopsies, and immunofluorescence studies provide evidence to support a diagnosis of EBA, they do not rule out the possibility of several other rare subepithelial blistering diseases. (See 'Additional studies' above.)

Data are limited on the treatment options for EBA. Thus, the optimal approach to treatment has not been established. For patients with EBA we suggest colchicine or dapsone as initial treatment (Grade 2C). If treatment is not effective, these agents may be used simultaneously.

EBA that is refractory to colchicine and dapsone requires more aggressive therapy. Agents that may have efficacy for refractory EBA include immunosuppressants, intravenous immunoglobulin, and rituximab. (See 'Refractory disease' above.)

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Topic 15299 Version 14.0

References

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