Background
Epidermolysis bullosa acquisita (EBA) is a chronic autoimmune subepidermal blistering disease of the skin and mucus membranes. Epidermolysis bullosa acquisita is caused by antibodies targeting type VII collagen, the major component of anchoring fibrils that connect the basement membrane to dermal structures. The classic presentation is characterized by blisters, mild mucosal involvement, and healing with dense scars primarily at trauma-prone areas. A second clinical presentation, the inflammatory form of epidermolysis bullosa acquisita, involves a generalized vesiculobullous eruption primarily on the trunk and flexural areas.
Epidermolysis bullosa acquisita is rare in humans. In animals, epidermolysis bullosa acquisita has been reported in dogs only. In canine epidermolysis bullosa acquisita, the immunoglobulin G (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 (EBA) is characterized by the presence of IgG autoantibodies targeting the noncollagenous (NC1) domain of type VII collagen, the major component of anchoring fibrils that connect the basement membrane to dermal structures. A subset of patients have variations in which either IgG autoantibodies bind the central triple-helical collagenous (NC2) domain of type VII collagen, or immunoglobulin A (IgA), rather than IgG, targets type VII collagen. The NC2 domain mediates antiparallel dimer formation in experimental conditions. Therefore, the targeting of the NC2 domain by autoantibodies may destabilize anchoring fibrils by interfering with antiparallel dimer formation, leading to dermoepidermal disadherence. [3] 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. [4] These antibodies compromise the strength of the basement membrane zone, leading to skin fragility and trauma-induced blister formation.
Various murine models have contributed to the understanding of the pathogenic role of antitype VII collagen antibodies and pathophysiology of epidermolysis bullosa acquisita. Initial studies demonstrated that rabbit antimouse type VII collagen antibodies, as well as rabbit antibodies raised against human recombinant protein type VII collagen, were able to induce blisters in mice. [5, 6] More recently, affinity-purified antitype VII collagen autoantibodies from epidermolysis bullosa acquisita patients have induced blisters in an adult hairless mouse strain (SKH1), further supporting a pathogenic role of antitype collagen VII autoantibodies. [7] The failure of rabbit antimouse type VII collagen antibodies to induce blisters in C5-deficient mice supports a role for complement activation in the disease pathogenesis. [8, 9]
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.
Immunization of type VII collagen in athymic nude SJL mice did not induce an autoimmune response, whereas the repletion of T cells from type VII collagen–immunized wild-type mice to the thymic mice showed autoantibody production and resulted in a blistering disease phenotype, supporting the role of T cells in the induction of epidermolysis bullosa acquisita. [10]
The fact that epidermolysis bullosa acquisita is responsive to rituximab antibody to CD20 supports the role of B cells. [11, 12]
Etiology
Epidermolysis bullosa acquisita (EBA) is an autoimmune disease, manifested by autoantibodies that target type VII collagen, the major protein of anchoring fibrils and the one that connects the epithelial basement membrane to the dermis. Autoantibodies specific for type VII collagen alter the dermoepidermal junctional adhesion and lead to dermoepidermal separation. The initiating event that leads to autoantibody production is unknown.
Some evidence suggests a genetic predisposition to the disease. Epidermolysis bullosa acquisita affecting several family members has been reported. Additionally, black patients of African descent who develop epidermolysis bullosa acquisita have been found to have a genetic predisposition, owing to a link to HLA-DRB1*15:03. Most patients involved with this study had very atypical clinical presentations. In addition, immunogenetic studies revealed that most black patients from the southeastern part of the United States had an association with HLA-DR2. Subsequent studies on a larger population of white patients failed to reveal any statistically significant HLA allele associations with epidermolysis bullosa acquisita. [13]
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. [14]
Epidermolysis bullosa acquisita is also 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 gastrointestinal tract.
In some patients with epidermolysis bullosa acquisita and bullous SLE, 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. [15, 16, 17]
Epidemiology
Frequency
Epidermolysis bullosa acquisita (EBA) is a rare disease, with an incidence of 0.26 case per million population, which is 5% of all blistering diseases. [18]
Race
The race distribution of epidermolysis bullosa acquisita (EBA) is not known.
Sex
The sex distribution of epidermolysis bullosa acquisita (EBA) is not known.
Age
Epidermolysis bullosa acquisita (EBA) can occur at any age. It more frequently affects elderly persons, with a peak in age of onset in the seventh decade of life; however a second peak has been observed in the second decade. [19] Children have also been reported, including one child with the onset of epidermolysis bullosa acquisita in utero. [20]
Prognosis
Patients with epidermolysis bullosa acquisita (EBA), if treated and cared for properly, should expect to live a normal life span.
Epidermolysis bullosa acquisita is a chronic inflammatory disease with periods of partial remissions and exacerbations. Prognosis from one retrospective analysis showed a median time to remission of 9 months. Tracking of complete remission at 1 year, 3 years, and 6 years was reached in 33%, 33%, and 45% of patients, respectively. [21] Although complete remission may be achieved, long-term maintenance therapy is likely required for disease control.
Mortality as a direct consequence of epidermolysis bullosa acquisita 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 are also associated with significant morbidity.
Patient Education
Since both trauma and autoantibodies contribute to blister formation in epidermolysis bullosa acquisita (EBA), patients require education about the disease. They also require significant education about the medications and the associated adverse effects and drug interactions of these medicines.
The first aspect of patient education is trauma avoidance. Patients with epidermolysis bullosa acquisita should be instructed to avoid contact sports whenever possible and to use protective padding on their extensor skin surfaces on a regular basis. Those with oral involvement need instruction on oral hygiene and diet. They should avoid foods that induce significant mucosal injury such as pretzels, nuts, chips, and other hard foods.
The second aspect of education is their medication. Patients with epidermolysis bullosa acquisita should be educated about the potential adverse effects of their medication, such as infection, malignancies, osteoporosis, aseptic necrosis, peptic ulcer disease, and adrenal insufficiency. Patients should be familiar with the symptoms and signs of these adverse effects and should report any changes in their health status to their physicians.
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Direct immunofluorescence performed on perilesional skin biopsy specimen from a patient with epidermolysis bullosa acquisita detects a linear band of immunoglobulin G deposit along the dermoepidermal junction.
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Indirect immunofluorescence performed on salt-split normal human skin substrate using serum from a patient affected with epidermolysis bullosa acquisita detects immunoglobulin G class circulating autoantibodies that bind to the dermal (base) side of the basement membrane.
