eMedicine Specialties > Dermatology > Bullous Diseases

Epidermolysis Bullosa Acquisita

Author: Lawrence Chan, MD, Department Head and Director of Skin Immunology Research, Professor, Departments of Dermatology and Microbiology/Immunology, University of Illinois College of Medicine
Coauthor(s): David Woodley, MD, Co-Chair, Professor, Department of Medicine, Division of Dermatology, University of Southern California
Contributor Information and Disclosures

Updated: Oct 22, 2008

Introduction

Background

Epidermolysis bullosa acquisita (EBA) is a chronic autoimmune subepidermal blistering disease of the skin and mucus membranes. Epidermolysis bullosa acquisita is characterized clinically by blisters, scars, and milia primarily at the trauma-prone areas. However, a subset of patients has a generalized inflammatory skin blister phenotype. Immunologically, epidermolysis bullosa acquisita is characterized by the presence of immunoglobulin G (IgG) autoantibodies (in most patients) targeting the noncollagenous (NC1) domain of type VII collagen, the major component of anchoring fibrils that connect the basement membrane to dermal structures. A small group of patients demonstrated IgG autoantibodies to the central triple-helical (collagenous) domain of type VII collagen. However, a small subset of patients exhibited immunoglobulin A (IgA), rather than IgG, class autoantibodies that target the type VII collagen.

Epidermolysis bullosa acquisita is rare in humans. In animals, epidermolysis bullosa acquisita has been reported in dogs only. In canine epidermolysis bullosa acquisita, the IgG autoantibodies also target the type VII collagen noncollagenous (NC1) domain, which shares greater than 80% homology in amino acid sequence with the human NC1 domain.1,2

Pathophysiology

Epidermolysis bullosa acquisita primarily involves the skin, but it also can affect mucus membranes. The trauma-prone areas of the skin, such as the extensor surfaces of elbows, knees, ankles, and buttocks, most commonly are affected.

IgG autoantibodies specific for anchoring fibrils (type VII collagen) of the skin basement membrane have a heterogeneous subclass and light chain composition, and their complement-activating capacities do not correlate with the inflammatory phenotype. It is hypothesized that autoantibodies and trauma are contributing factors to the disease process.3,4

Passive transfer of antibodies raised in rabbits against mouse type VII collagen induced blister formation in mice, thus confirming the potential role of antitype VII collagen antibody in the pathogenesis of the disease. The failure to induce blisters in C5-deficient mice by these rabbit antimouse type VII collagen antibodies supports a role for complement activation in the disease pathogenesis.

Induction of an active model of autoimmunity against type VII collagen in a hairless mouse strain (SKH1) revealed that regulatory T cells, which have been identified for their ability to inhibit the development of autoimmune diseases, do not inhibit the development of autoantibodies against the self-protein mouse-type VII collagen.

Frequency

United States

Epidermolysis bullosa acquisita is a rare disease; its frequency of occurrence is not known.

International

Epidermolysis bullosa acquisita has been reported in Europe and Asia. Since it is a rare disease, the frequency of occurrence in other countries is not known.

Mortality/Morbidity

Epidermolysis bullosa acquisita is a chronic inflammatory disease with periods of partial remissions and exacerbations. Mortality as a direct consequence of the disease is rare; however, epidermolysis bullosa acquisita is relatively unresponsive to treatment and can cause significant morbidity. Adverse effects associated with the medications used to treat epidermolysis bullosa acquisita also are associated with significant morbidity.

  • The chronic inflammation and scar formation on patients' extensor surfaces can severely hinder the daily activities of patients.
  • Oropharyngeal mucus membrane involvement can lead to periodontal disease, oral mucosal erosions, and esophageal strictures, which limit oral intake, and supraglottic stenosis with airway compromise. Ocular involvement can lead to obstruction of nasolacrimal ducts, conjunctival scarring, and blindness.
  • The scarring nature of epidermolysis bullosa acquisita can lead to nail destruction and hair loss.

Race

The race distribution of epidermolysis bullosa acquisita is not known. In one of the largest patient groups (24 patients) followed by the authors, 19 were white and 5 were black. This distribution is roughly proportional to the general population of whites and blacks in the United States; thus, there appears to be no significant racial predilection.

Sex

The sex distribution of epidermolysis bullosa acquisita is not known. In the 24 patients followed by the authors, the male-to-female ratio is 1:1.4.

Age

Epidermolysis bullosa acquisita can occur at any age. Epidermolysis bullosa acquisita more frequently affects elderly persons; however, children with epidermolysis bullosa acquisita have been reported including one child with the onset of epidermolysis bullosa acquisita at age 3 months. Internationally, about 25 cases of childhood onset epidermolysis bullosa acquisita have been reported in the literature. In the 24 patients followed by the authors, the average age of onset was 53 years.

Clinical

History

Most patients with epidermolysis bullosa acquisita (EBA) experience a slow onset and chronic disease that affects the trauma-prone extensor skin surfaces. The nature of the disease usually leads to skin fragility, and the secondary scarring often causes restriction of mobility in the extensor skin surfaces.

  • In a subset of patients with generalized disease, the onset of disease is somewhat rapid, more wide spread, and inflammatory. In this group of patients, blisters occur in both trauma-prone and non–trauma-prone areas. Clinically, this phenotype resembles bullous pemphigoid or linear IgA bullous dermatosis.
  • In a subset of patients with predominant mucus membrane involvement, the disease manifests with blisters and scar formation in the oral, ocular, vaginal, and other mucous membranes, leading to significant dysfunction, such as visual function loss, dysphagia, malnutrition, or even mortality.
    • The clinical phenotype of this subset of patients is indistinguishable from that of mucous membrane pemphigoid.
    • In a published international consensus statement on mucous membrane pemphigoid, 26 international experts of mucous membrane pemphigoid had decided to include this group of patients (previously designated as epidermolysis bullosa acquisita based in part on their autoantibodies to type VII collagen) in the category of mucous membrane pemphigoid.
    • The rationale for such inclusion is that this subset of patients has the clinical phenotype of mucous membrane pemphigoid and that the autoantibodies of patients with mucous membrane pemphigoid (as a group) target not single, but multiple skin basement membrane components, such as bullous pemphigoid antigen 2 (BP180), integrin beta-4 subunit, laminin-5, and laminin-6. Because this subset of patients cannot be distinguished from mucous membrane pemphigoid by clinical phenotype and autoantigen identity alone cannot be used to include or exclude a diagnosis of mucous membrane pemphigoid, it seems reasonable to include this subset of patients under the general category of mucous membrane pemphigoid.
  • Epidermolysis bullosa acquisita has been reported to develop in a 73-year-old patient after a 2-week treatment of antibiotics.

Physical

The skin and mucus membrane manifestations of epidermolysis bullosa acquisita (EBA) take several forms, as follows: a noninflammatory or mildly inflammatory disease affecting trauma-prone extensor skin surfaces, a generalized inflammatory disease, and a predominant mucus membrane disease.

  • A noninflammatory or mildly inflammatory form is the most common form of epidermolysis bullosa acquisita, manifested as tense vesicles and bullae, and erosions primarily on the extensor surfaces of hands, knuckles, elbows, knees, and ankles. The blisters may be hemorrhagic. Blisters on mucus membranes rupture easily; the most common manifestation is erosion.
    • This form of epidermolysis bullosa acquisita usually heals with significant scar and milia formation. Nail dystrophy and scarring alopecia also have been observed in some patients.
    • This form clinically resembles porphyria cutanea tarda in elderly patients, and it resembles the dominantly inherited form of epidermolysis bullosa dystrophica in children.
  • The generalized inflammatory form presents with widespread, tense vesicles and bullae (some hemorrhagic), and is not localized to trauma-prone sites. Generalized erythema, urticarial plaques, and generalized pruritus may occur in some patients.
    • This form of epidermolysis bullosa acquisita clinically resembles bullous pemphigoid or linear IgA bullous dermatosis.5
    • The generalized inflammatory form usually heals with minimal scarring and milia formation.
  • A third variant of epidermolysis bullosa acquisita predominantly involves mucus membranes.
    • This form of epidermolysis bullosa acquisita can affect mucous membranes of buccal, conjunctival, gingival, palatal, nasopharyngeal, rectal, genital, and esophageal mucosae.
    • This variant clinically resembles mucous membrane pemphigoid and can result in significant mucosal scarring and dysfunction. A recent international consensus statement published in Archives of Dermatology (March 2002) has reassigned this group of patients to the category of mucous membrane pemphigoid.6
  • Some patients with epidermolysis bullosa acquisita present with marked head and neck involvement, scarring, and minimal mucosal disease, which resembles the Brunsting-Perry variant of cicatricial pemphigoid.
  • An inflammatory variant with autoantibodies to central collagenous domain
    • Three young patients with Japanese ethnic background were reported to have a generalized inflammatory blistering disease.
    • These patients were readily responsive to systemic corticosteroids treatment, and the disease healed without scarring.
    • The IgG autoantibodies from these 3 patients did not recognize the NC1 domain, but it did recognize the central triple-helical collagenous domain of type VII collagen.

Causes

Epidermolysis bullosa acquisita (EBA) is an autoimmune disease, manifested by IgG autoantibodies that target a major skin basement membrane component, collagen VII. Collagen VII is the major protein of anchoring fibrils and connects the epithelial basement membrane to the dermis. Autoantibodies specific for collagen VII alter the dermal-epidermal junctional adhesion and lead to dermal-epidermal separation. The initiating event that leads to autoantibody production is unknown. Recently, a subset of epidermolysis bullosa acquisita, which is milder clinically, has been identified to be mediated by IgA, rather than IgG autoantibodies. A small group of patients had autoantibodies to the collagenous domain, rather than the NC1 domain of collagen VII.7

  • Immunogenetic studies revealed that most black patients from the southeastern part of the United States had an association with human leukocyte antigen DR2 (HLA-DR2). Subsequent studies on a larger population of white patients failed to reveal any statistically significant HLA allele associations with epidermolysis bullosa acquisita.
  • Rarely, patients with systemic lupus erythematosus (SLE), a systemic autoimmune disease, develop a generalized blistering skin disease with clinical and immunopathologic features of epidermolysis bullosa acquisita.
    • These patients have a subepidermal blistering skin disease characterized by IgG, IgA, and C3 deposition at the skin basement membrane zone. Sera from these patients recognize the NC1 domain of type VII collagen, the same target antigen recognized by patients with epidermolysis bullosa acquisita.
    • The fact that epidermolysis bullosa acquisita, an organ-specific autoimmune disease, can develop in patients who already have a systemic autoimmune disease suggests that systemic autoimmunity can provoke an organ-specific autoimmune disease. Alternatively, the nonspecific inflammatory process present in systemic lupus may induce the release and exposure of basement membrane antigens to autoreactive lymphocytes by a process termed epitope spreading, subsequently leading to autoimmunity against the epidermolysis bullosa acquisita antigen.8
  • Epidermolysis bullosa acquisita also is associated with Crohn disease, an inflammatory bowel disease characterized by T-cell infiltration in the small intestine. Type VII collagen is expressed in intestinal epithelial basement membranes. The association of epidermolysis bullosa acquisita and inflammatory bowel disease may have an immunologic basis. It has been observed that a significant number of patients with Crohn disease have circulating IgG autoantibodies that recognize the NC1 domain as demonstrated by enzyme-linked immunosorbent assay (ELISA), although they do not have epidermolysis bullosa acquisita clinically. The presence of these autoantibodies may represent a preclinical epidermolysis bullosa acquisita phenomenon, induced by the release and exposure of intestinal type VII collagen to autoreactive lymphocytes because of epitope spreading caused by the inflammatory reaction in their gut.
  • An initial experiment of passively transferring IgG autoantibodies from human patients with epidermolysis bullosa acquisita to mice does not induce clinical disease in mouse skin. The failure of passive transfer experiments to induce disease may be due to several possible reasons. Subsequently, however, rabbit antibodies raised against human recombinant protein type VII collagen were able to induce blisters in mice, as did rabbit antibodies raised against mouse type VII collagen.9,10 Lately, affinity-purified antitype VII collagen autoantibodies from epidermolysis bullosa acquisita patients have been shown to induce blisters in an adult hairless mouse strain (SKH1), further supporting a pathogenic role of these autoantibodies.11
    • The binding of pathogenic IgG to type VII collagen may be a necessary but insufficient step for blister formation. Additional steps required for blister formation, such as recruitment and release of inflammatory mediators, may not occur in this model.
    • The binding of human anti–type VII collagen autoantibodies may not recognize critical sites on mouse type VII collagen, thus rendering these autoantibodies incapable of inducing blister formation.
    • The turnover of existing anchoring fibrils may be very slow such that epidermolysis bullosa acquisita develops only after autoantibodies inhibit new anchoring fibril formation over a prolonged period of time. This would not be similar to short-term neonatal mouse studies.
  • In some patients with epidermolysis bullosa acquisita and bullous systemic lupus erythematosus, circulating autoantibodies against other skin basement membrane components, such as bullous pemphigoid antigens, laminin-5, and laminin-6, in addition to type VII collagen, have been reported. These observations further support the role of epitope spreading.6,12,13
  • An active experimental animal model of epidermolysis bullosa acquisita would facilitate the understanding of the disease pathogenesis; however, it is currently unavailable.
  • New findings were recently reported that autoantibodies from patients affected with epidermolysis bullosa acquisita recognized not only the NC1 domain but also the NC2 domain of type VII collagen. Furthermore, the NC2 domain mediates antiparallel dimer formation in experimental conditions. Therefore, the targeting of the NC2 domain by epidermolysis bullosa acquisita autoantibodies may destabilize anchoring fibrils by interfering with antiparallel dimer formation, leading to dermal-epidermal disadherence.
  • Rabbit antimouse type VII collagen antibodies induced subepidermal blisters in mice, identically as occurs in human patients with epidermolysis bullosa acquisita, supporting the role of antitype VII collagen autoantibodies in the pathogenesis of epidermolysis bullosa acquisita. Rabbit antimouse type VII collagen antibodies were not able to induce blisters in C5-deficient mice, pointing to a role for complement activation in the pathogenesis of epidermolysis bullosa acquisita.

More on Epidermolysis Bullosa Acquisita

Overview: Epidermolysis Bullosa Acquisita
Differential Diagnoses & Workup: Epidermolysis Bullosa Acquisita
Treatment & Medication: Epidermolysis Bullosa Acquisita
Follow-up: Epidermolysis Bullosa Acquisita
Multimedia: Epidermolysis Bullosa Acquisita
References
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References

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Further Reading

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Keywords

epidermolysis bullosa acquisita, acquired epidermolysis bullosa, EBA

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Contributor Information and Disclosures

Author

Lawrence Chan, MD, Department Head and Director of Skin Immunology Research, Professor, Departments of Dermatology and Microbiology/Immunology, University of Illinois College of Medicine
Lawrence Chan, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Association of Professors of Dermatology, Chicago Dermatological Society, Dermatology Foundation, Illinois State Medical Society, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Coauthor(s)

David Woodley, MD, Co-Chair, Professor, Department of Medicine, Division of Dermatology, University of Southern California
David Woodley, MD, Co-Chair is a member of the following medical societies: American Academy of Dermatology, American Association for the Advancement of Science, American College of Emergency Physicians, American College of Physicians, American Federation for Medical Research, American Society for Clinical Investigation, New York Academy of Medicine, Society for Investigative Dermatology, and Southern Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Ponciano D Cruz Jr, MD, Vice-Chair, JB Shelmire Professor, Department of Dermatology, University of Texas Southwestern Medical Center
Ponciano D Cruz Jr, MD is a member of the following medical societies: Texas Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: 3M Pharmaceutical Grant/research funds Other; Graceway Pharmaceuticals Grant/research funds Other

Managing Editor

Edward F Chan, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine
Edward F Chan, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

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