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Epidermolysis Bullosa Acquisita
Introduction
Epidermolysis bullosa acquisita (EBA) is a rare, chronic autoimmune blistering disease that impacts both the skin and mucous membranes. This condition arises due to autoantibodies targeting type VII collagen—a crucial component of anchoring fibrils within the dermal-epidermal junction (DEJ).[1] These anchoring fibrils are responsible for attaching the epidermis to the underlying dermis. When autoantibodies bind to type VII collagen, they cause the detachment of the epidermis, leading to skin fragility, blisters formation, erosions, scaring, milia formation, and nail loss.[2]
Although EBA can manifest in various phenotypes clinically, the classical mechanobullous and inflammatory forms are the most common presentations.[3] Classic mechanobullous EBA resembles dystrophic epidermolysis bullosa (EB), with bullae and erosions developing at sites of trauma. However, it is noteworthy that EBA is a distinct bullous disorder primarily affecting adults, whereas EB is more commonly found in children. Both conditions share a common name due to their presumed similar clinical features.[4][5]
Conversely, the inflammatory forms of EBA present clinical manifestations similar to those found in other autoimmune blistering disorders, including bullous pemphigoid (BP), mucous membrane pemphigoid (MMP), IgA bullous dermatosis, and Brunsting-Perry pemphigoid.
Furthermore, EBA has been reported in association with various systemic diseases, including inflammatory bowel disease (IBD), thyroiditis, rheumatoid arthritis, hepatitis C infection, and diabetes mellitus.[6]
Etiology
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Etiology
EBA is characterized by the presence of tissue-bound and circulating immunoglobulin (Ig)-G (gG) autoantibodies that target type VII collagen within the lamina densa and sublamina densa of the basement membrane zone (BMZ).[7] Type IV collagen is a major component of anchoring fibrils—a crucial structural component connecting the papillary dermis to the lamina densa. This connection plays a pivotal role in upholding the integrity of the epidermal BMZ.[8]
The autoantibodies in EBA have been identified as specifically targeting the NC1 domain of type VII collagen located within the lamina densa.[9] Experimental mouse models and in vitro studies of EBA have demonstrated that autoantibodies targeting type VII collagen can induce dermal-epidermal separation.[10] These antibodies may also directly disrupt the assembly of type VII collagen into anchoring fibrils or hinder its interactions with other matrix proteins, such as laminin 332, fibronectin, or type IV collagen.[2][11] These disruptions can result in the detachment of the epidermis, leading to the skin fragility and blister formation observed in EBA.
Specific human leukocyte antigen (HLA) class II alleles are more prevalent in specific populations with EBA. For instance, a higher frequency of HLA-DRB1*13 has been reported in Korean patients [12], whereas HLA-DRB1*15:03 has been found in higher frequencies among African-American patients.[13] These data suggest that the expression of specific HLA alleles may influence the susceptibility to developing EBA. However, further research is necessary on this topic, as the available data have been derived from studies involving small groups of EBA patients.
Epidemiology
EBA is regarded as one of the rarest subepidermal bullous diseases in Western Europe, with an estimated annual incidence ranging from 0.2 to 0.5 cases per million people.[14] The prevalence appears to be higher in Korean and African-American populations.[15] Although EBA can manifest in both pediatric and adult patients, it is comparatively less common in children and predominantly afflicts adults. Gender does not appear to be a predisposing factor. Although EBA can manifest at any age, the average onset of EBA occurs between the fourth and fifth decades of life.[16]
A comprehensive meta-analysis conducted in 2018, which included 1159 EBA cases, revealed that the median age was 50 for all patients with EBA. Pediatric patients accounted for 4.6% of reported cases, whereas those aged 65 or older accounted for 11.3%. Notably, the age range in individuals of reported EBA cases has been reported to extend from 1 to 94.
Approximately 9.6% of EBA cases were identified to be associated with chronic inflammatory diseases. The most frequently reported associations included IBD, thyroiditis, and rheumatoid arthritis.[17] Although the evidence supporting the connection between EBA and IBD is increasing, additional research is needed to establish the relationship between these 2 conditions.[18][19]
Pathophysiology
The exact cause of EBA remains uncertain, but current evidence suggests a link to the production of antibodies against type VII collagen. This collagen type is a critical component of anchoring fibrils, essential for preserving the integrity of the DEJ.[20] Type VII collagen is a homotrimer composed of repeat Gly-X-Y chains, surrounded by globular NC1 and NC2 domains at its amino and carboxy termini. In EBA, the NC1 domain is believed to be the primary antigen targeted by the autoimmune response.[21]
The evidence for the involvement of type VII collagen in EBA is supported by various observations, including the presence of type VII collagen antibodies in histopathological examinations and the serum of affected patients. In addition, this presence correlates with the severity of the disease.[22][23][24] Moreover, similarities between EBA and other bullous diseases, such as bullous lupus erythematosus (LE), which share a similar pathogenesis involving type VII collagen, provide additional support for its role in EBA pathophysiology.[25]
Animal studies have also provided evidence regarding the pathogenicity of type VII collagen in EBA.[24][26][27] However, the exact mechanisms underlying the formation of these autoantibodies and their specific role in blister formation remain incompletely understood.
Current theories suggest that exposure to the neoantigen in the NC1 domain of type VII collagen, often related to trauma, can lead to antibody production, potentially compromising the adherence between the dermis and epidermis.[28][29][30] However, further research is required to establish a more comprehensive understanding of the complete pathogenesis of this disease.
Histopathology
Diagnosing EBA through histopathology can pose challenges due to its similarity and overlap with other bullous diseases. During hematoxylin and eosin (H&E) staining analysis, EBA typically displays distinctive features such as subepidermal vesiculation, milia formation, and, in later lesions, dermal fibrosis due to scarring. In addition, fibrin deposition may be observed, potentially accompanied by neutrophils along the base of the vesiculation.[31][32][33] However, these features can remain somewhat indistinct in the context of blistering diseases, offering fewer distinctive characteristics when compared to conditions such as BP and linear IgA bullous dermatosis (LABD).[25] Therefore, to establish a definitive diagnosis of EBA, additional testing with techniques such as direct immunofluorescence (DIF), indirect immunofluorescence (IIF), or immunoelectron microscopy (IEM), which is considered the gold standard, may be required.[34]
In DIF, a distinctive feature in EBA is the linear deposition of IgG and C3 at the DEJ. DIF is preferred over indirect immunofluorescence (IIF) because the latter may not contain sufficient antibodies in the patient's serum for accurate diagnosis.[35][36] Another useful diagnostic tool is the salt-split skin examination, which can be conducted using either 1 M sodium chloride or 20 mM EDTA. This test reveals that the deposition of immune complexes is on the floor (dermal side) rather than the roof (epidermal side), as observed in BP or bullous LE. As a result, EBA exhibits a classic u-serrated pattern, in contrast to the n-serrated pattern observed in other bullous diseases.[20][37]
In addition to these established methods, newer testing options may involve immunoelectron or transmission electron microscopy and enzyme-linked immunosorbent assay (ELISA), which can reveal the presence of neutrophils surrounding the affected area.[2]
History and Physical
EBA can manifest with various clinical phenotypes, and the classic presentation involves a noninflammatory mechanobullous disease characterized by skin fragility, tense blisters, erosions, scarring, milia formation, and postinflammatory dyspigmentation. These findings are localized to trauma-prone sites and extensor surfaces, including the elbows, knees, dorsal hands, and feet.[17] Progressive acral involvement may be disfiguring, resembling dystrophic EB with pseudosyndactyly, mitten deformity of digits, and nail dystrophy. In some cases, scalp involvement can lead to nonhealing erosions with scarring alopecia.[2]
The inflammatory variants of EBA resemble other autoimmune bullous dermatoses and include BP-like EBA, MMP-like EBA, LABD-like EBA, and Brunsting-Perry cicatricial pemphigoid–like EBA.[17] Classic noninflammatory EBA and BP-like EBA are the most frequently observed presentations among these variants.[8] BP-like EBA is characterized by widespread pruritic tense vesicles and bullae on an erythematous base, typically affecting the trunk, intertriginous areas, and extremities. Around 50% of cases may include the oral mucosa, leading to erosions or intact vesicles inside the mouth. Unlike classic noninflammatory EBA, lesions in BP-like EBA tend to heal without forming milia or scars.[38]
MMP-like EBA is distinguished by its primary involvement of mucous membranes, with lesions and scarring most commonly observed in the mouth, upper esophagus, conjunctivae, anus, and vagina.[39] In some cases, severe ocular involvement has also been reported, which can lead to blindness.[40]
Tense vesicles, blisters, and urticarial plaques arranged in an annular or polycyclic pattern characterize LABD-like EBA. This variant of EBA can also affect mucous membranes and skin lesions.
Brunsting-Perry cicatricial pemphigoid–like EBA presents as a vesiculobullous eruption primarily localized to the head and neck region, with little to no involvement of mucous membranes. Involvement of the scalp results in scarring alopecia.[41]
Patients with EBA may present with a single described subtype or exhibit a combination of 2 subtypes simultaneously. Reports of clinical features shifting from one particular variant to another exist during the course of the disease.[11]
Evaluation
Diagnosing EBA can be challenging due to various inflammatory variants that closely resemble other blistering diseases, both in terms of clinical presentation and histological features.
In histological examination, a skin biopsy obtained from lesional EBA skin typically reveals features such as papillary edema and vacuolar degeneration along the DEJ in early lesions. In later lesions, a subepidermal blister becomes apparent, and the degree of inflammatory infiltrate varies based on the clinical variant of EBA.[11]
The classic EBA presentation is pauci-inflammatory, displaying a limited neutrophilic inflammatory infiltrate in the papillary dermis. In contrast, BP-like EBA features a dermal inflammatory infiltrate composed of neutrophils, lymphocytes, monocytes, and eosinophils, resulting in a histological appearance closely resembling BP.
In suspected cases of EBA, performing a perilesional biopsy for DIF microscopy is advisable. DIF typically reveals linear deposits of IgG along the epidermal BMZ. Less commonly, linear deposits of C3, IgA, or IgM may also be detected.[11] A "u-serrated" immunodeposition pattern at the BMZ aids in distinguishing EBA from other subepidermal blistering disorders, which typically exhibit an "n-serrated" pattern.[42]
Furthermore, salt-split skin immunofluorescence preparations can reveal immune deposits on the dermal side of the cleavage. This is in contrast to the pattern observed in BP, where deposits are located on the epidermal side of the separation.[11]
IIF may detect circulating autoantibodies to the BMZ in patients with EBA. Approximately 50% of EBA patients have detectable anti-BMZ IgG antibodies in their serum, resulting in a linear fluorescent band along the DEJ.
Furthermore, performing IIF on salt-split skin can provide additional insights. The patient's serum is applied to artificially split skin in this test. If EBA-specific autoantibodies are present, they will bind to the dermal side of the artificial blister, indicating a positive result for EBA.
Transmission electron microscopy of the DEJ reveals cleavage in the sublamina densa zone, a decreased number of anchoring fibrils emerging from the lamina densa, and the presence of an amorphous, electron-dense material beneath the lamina densa in EBA skin. This material corresponds to the IgG deposits bound to the anchoring fibrils.[43]
IEM is the traditional "gold standard" for diagnosing EBA. This technique can reveal immune deposits specifically localized to anchoring fibrils within the sublamina densa, setting it apart from other subepidermal blistering disorders where immune deposits in the hemidesmosome area (as in BP) or lamina lucida (as in MMP).[44]
Western blot analysis of serum from patients with EBA reveals the binding of circulating autoantibodies to a 290-kDa protein and, occasionally, a 145-kDa protein. These proteins correspond to the alpha chain of type VII collagen and its NC1 domain.[22]
ELISA is a rapid and effective test with a high specificity of more than 96%. This test utilizes recombinant NC1 and NC2 domains of type VII collagen purified from human cells to detect EBA autoantibodies targeting all potential antigenic epitopes within NC1 and NC2. This method can also quantify levels of autoantibodies that correlate with disease severity.
Previous authors have established the diagnostic criteria for EBA. These criteria include the presence of a bullous disorder within the defined clinical spectrum of EBA, the absence of a family history of bullous disease, histological evidence of a subepidermal blister, DIF examination of perilesional skin revealing IgG deposits within the DEJ, and IEM of perilesional skin confirming the localization of IgG deposits within the lower lamina densa or sublamina densa of the DEJ. Alternative tests, such as IIF, salt-split skin, ELISA, and Western blotting technique, may be conducted instead of IEM.[11]
Treatment / Management
Managing EBA can be difficult because some patients may not respond positively to treatment. Supportive therapy should be a fundamental component of EBA treatment for all affected individuals. This involves ensuring proper wound care and maintaining optimal nutrition, which are paramount in minimizing the risk of complications.
Patients should receive counseling on strategies to prevent skin trauma, such as limiting exposure to harsh soaps and hot water, refraining from vigorous skin rubbing, and avoiding prolonged sun exposure.[11] Furthermore, educating patients on recognizing signs of secondary skin infections and when to seek medical care to prevent further complications is crucial.(B3)
Regular monitoring of patients is essential to detect the development of mucosal lesions. Periodic comprehensive reviews of their systems and physical exams are necessary for identifying changes or disease progression. Due to its rarity, pharmacological treatment data for EBA primarily relies on anecdotal reports.[40] However, some therapeutic approaches have shown promising results in managing the various variants of EBA.(B2)
High doses of colchicine have demonstrated effectiveness in patients with classic mechanobullous EBA and its inflammatory variants.[45] Although the mechanism of action remains unclear, colchicine is believed to reduce the production of antibodies and inhibit antigen presentation to T cells.[46] (B3)
For BP-like EBA and other inflammatory variants, systemic corticosteroids and immunosuppressive medications, including azathioprine, cyclophosphamide, cyclosporine, methotrexate, and mycophenolate mofetil, may prove effective.[47] Dapsone has been reported to offer some benefits, especially in EBA patients with neutrophilic dermal infiltrates. In cases of childhood EBA, studies have recommended a combination of dapsone and prednisolone.[40] In severe cases of EBA refractory to conventional immunosuppressive therapy, case reports have indicated successful use of rituximab and intravenous immunoglobulins (IVIG).[48](B2)
Differential Diagnosis
The differential diagnosis for EBA includes other subepidermal blistering disorders, such as dystrophic EB, BP, MMP, porphyria cutanea tarda (PCT), pseudoporphyria, IgA bullous dermatosis, Brunsting-Perry pemphigoid, and bullous LE.
Dominant dystrophic EB may bear a clinical resemblance to the mechanobullous type of EBA. However, it can be differentiated by a positive family history of a bullous disorder, onset at birth, and negative DIF findings.
BP and MMP can exhibit clinical similarities to the inflammatory variants of EBA. However, they can be differentiated by the presence of an n-serrated DIF immunodeposition pattern, as seen in IgA bullous dermatosis. Other diagnostic tests, including IIF with salt-split skin substrate, ELISA, Western immunoblotting, or IEM, can assist in ruling out other autoimmune bullous diseases.
PCT classically involves the hands but can be distinguished from EBA by performing specific porphyrin studies. PCT is associated with elevated levels of porphyrins in urine and stool, which are not seen in EBA. Likewise, pseudoporphyria may resemble EBA, but patients with pseudoporphyria would also have a history of chronic kidney disease, renal dialysis, or the use of specific drugs, such as nonsteroidal anti-inflammatory drugs, furosemide, antibiotics, and retinoids.[49]
Bullous LE can seldom manifest as a mechanobullous eruption, displaying features such as tense blisters, milia, and scarring. Nevertheless, histological examination of bullous LE reveals subepidermal bullae with a predominantly neutrophilic infiltrate and dermal papillary microabscesses that resemble dermatitis herpetiformis.[2] Bullous LE would also typically show significant improvement with initiating systemic LE treatment, whereas EBA typically has a poor response to treatment.[50]
Prognosis
EBA is a chronic blistering disease characterized by recurring periods of exacerbations and remissions. The prognosis of the condition depends on the severity at the time of diagnosis and the response to treatment. In a retrospective analysis conducted by Kim et al, the median time to remission after treatment with immunosuppressive agents was approximately 9 months. After 1 year, approximately 33% of patients achieved complete remission, and this percentage increased to 45% by 6 years.[40] Long-term maintenance therapy is often necessary to sustain disease control.[51]
Mortality directly related to EBA is rare, and patients who receive adequate treatment and proper management can expect an average life span. The prognosis and response to treatment may be more favorable in children than adults.[52]
Complications
EBA is a challenging condition to treat and can lead to significant morbidity[23]. Severe exacerbations of EBA may heal with rapid scarring, causing joint contractures, syndactyly, and nail loss.[53] EBA can affect the ocular, gastrointestinal, and respiratory mucosa, potentially causing significant functional impairment.[54] Complications of mucosal involvement include ankyloglossia, periodontal disease, symblepharon formation, nasal synechiae, esophageal strictures, and supraglottic stenosis.[55] Mucosal disease in EBA can often remain subclinical, resulting in delayed diagnosis and an increased risk of serious complications.[55]
Immunosuppressive medications to treat EBA, such as systemic corticosteroids, dapsone, cyclosporine, or colchicine, can result in significant morbidity, especially when prolonged treatment is required for disease control.
Deterrence and Patient Education
EBA causes the skin to be fragile and forms blisters easily, especially at trauma sites. Patients should be educated on the preventative measures for skin trauma.[32] To prevent skin trauma, it is recommended that patients with EBA be instructed to follow the below-mentioned steps.
- Patients should avoid vigorous rubbing or excessive skin washing because these actions can lead to blister formation.
- Patients must refrain from using adhesive bandages or tape on the skin, which can cause additional trauma.
- Patients can minimize friction and pressure on the skin by wearing loose-fitting clothing and comfortable shoes.
- Patients can reduce blister formation by keeping their skin cool and avoiding prolonged exposure to heat and humidity.
- Patients should avoid using shower water warmer than body temperature because hot water can harm fragile skin.
Patients with EBA should receive guidance on properly caring for eroded blisters.[56] To minimize the risk of developing a secondary bacterial infection, it is recommended to apply antibacterial ointment over skin erosions. When dressing wounds, individuals should opt for nonadhesive dressings and consider using gauze wraps for loose and gentle coverage while avoiding adhesives that may cause further trauma to delicate skin. Healthcare providers should instruct patients on recognizing signs of secondary skin infection and when to seek medical care for nonhealing or worsening wounds. Physicians may also need to provide nutritional support for optimal wound healing and monitor patients for dietary deficiencies.[57]
Enhancing Healthcare Team Outcomes
Managing the complex and varied clinical presentations of EBA, as well as its potential complications, requires a multidisciplinary team of healthcare providers consisting of dermatologists, wound care specialists, nutritionists, occupational therapists, and physical therapists to treat EBA in patients.
Regular monitoring for the development or progression of mucosal involvement is essential for patients. If mucosal lesions are present or suspected, patients should seek specialized evaluation and treatment from ophthalmologists, otolaryngologists, dentists, and gastroenterologists.
A collaborative healthcare team approach ensures comprehensive care for the patient's condition, thereby improving outcomes and a more favorable prognosis. Timely diagnosis and treatment are essential for effectively managing the disease and preventing further complications. Educating patients and their families about the condition, symptom management, and adherence to the prescribed treatment plan is also essential to address the treatment effectively.
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