Epidermolysis Bullosa Acquisita 

Updated: Mar 05, 2019
Author: Jacob Reinhart, MD; Chief Editor: Dirk M Elston, MD 

Overview

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.

 

Presentation

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 secondary scarring that often causes restriction of mobility in the extensor skin surfaces.

Patients often report rapid blister formation, within several hours of localized skin trauma. A relatively minimal amount of trauma or skin irritation can spark the formation of a bullous lesion. These blisters may remain intact for several weeks, however, before rupturing or becoming hemorrhagic.[22]

In a subset of patients with inflammatory epidermolysis bullosa acquisita, the onset of disease is somewhat rapid and more widespread. 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 mucous 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, an expert panel 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 a 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.

While many diagnoses have been linked anecdotally to epidermolysis bullosa acquisita, inflammatory bowel disease remains the only associated condition, with a reported incidence of 25% in patients with epidermolysis bullosa acquisita.[23, 24]

Epidermolysis bullosa acquisita has been reported to develop in a 73-year-old patient after a 2-week treatment of antibiotics.

Physical Examination

The skin and mucous membrane manifestations of epidermolysis bullosa acquisita (EBA) take several forms, including a noninflammatory or mildly inflammatory disease, a generalized inflammatory disease, and a predominant mucous membrane disease.

The noninflammatory or mildly inflammatory form, also known as classic or mechanobullous epidermolysis bullosa acquisita, is most common and manifests as tense vesicles, bullae, and erosions primarily on trauma-prone areas, including the extensor surfaces of hands, knuckles, elbows, knees, and ankles. The blisters may be hemorrhagic. Blisters on mucous membranes rupture easily; the most common manifestation is erosions. 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 the dominantly inherited form of epidermolysis bullosa dystrophica in children.

The generalized inflammatory form of epidermolysis bullosa acquisita 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.[25] The generalized inflammatory form usually heals with minimal scarring and milia formation.

A third variant of epidermolysis bullosa acquisita predominantly involves mucous membranes. Blisters and erosions of the buccal, conjunctival, gingival, palatal, nasopharyngeal, rectal, genital, and esophageal mucosae can occur. This variant clinically resembles mucous membrane pemphigoid and can result in significant mucosal scarring and dysfunction. A key differentiating factor, however, is that the mucous membrane lesions of epidermolysis bullosa acquisita can remain intact for extended periods, as opposed to mucous membrane pemphigoid, in which the blisters are seldom appreciated because they have already been disrupted.[22]

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.

A patient was reported to manifest with a localized form in periorbital areas.[26]

It is important to remember that individual presentations of epidermolysis bullosa acquisita may adapt over the course of disease, changing from one manifestation to another. This has been seen specifically in patients who develop mucous membrane involvement over time.[27]

 

DDx

Diagnostic Considerations

It is important that an accurate diagnosis be obtained before treatment is initiated because patients often require long-term steroids or immunosuppressants, which carry potential severe adverse effects. Monitoring for and preventing these potential adverse effects is essential.

When epidermolysis bullosa acquisita (EBA) occurs in early childhood, its resemblance to the heritable forms of blistering skin disease epidermolysis bullosa dystrophica may lead to misdiagnosis. Therefore, a direct immunofluorescence study is recommended for childhood-onset blistering diseases.

Because epidermolysis bullosa acquisita is associated with inflammatory bowel diseases, concerning GI symptoms should prompt GI diagnostic evaluation.

Epidermolysis bullosa acquisita has also been associated with internal malignancies.

Differential Diagnoses

 

Workup

Laboratory Studies

The International Bullous Diseases Group (IBDG) has created a consensus for diagnostic criteria for epidermolysis bullosa acquisita (EBA).[28] To establish a diagnosis, the following tests should be performed:

  • Histopathology of the entire new bullae or vesicle, if possible, or broad saucerization of the periphery [29]
  • Direct immunofluorescence on normal-appearing perilesional skin
  • Indirect immunofluorescence with the patient's serum on salt-split normal human skin substrate

It is important to understand that techniques of histopathology and direct immunofluorescence microscopy can only confirm a subepithelial autoimmune bullous disease, and not specifically epidermolysis bullosa acquisita. A patient with suspected epidermolysis bullosa acquisita should have a confirmation test of serration pattern analysis and fluorescent overlay antigen mapping (FOAM), although it may only be available at academic institutions.[28]

Histopathology

Histopathology documents the presence of a subepidermal blister, ie, a separation has occurred between the epidermis and the dermis. In addition, histology also reveals a mixed inflammatory cell dermal infiltrate.

Direct immunofluorescence

See the image below. Direct immunofluorescence documents the immune-mediated disease process. Usually, it detects a thick band of IgG, and to a lesser extent C3, deposited linearly at the basement membrane zone. Other immunoreactants such as IgM or IgA may be seen. A U-serrated pattern is typical of epidermolysis bullosa acquisita, whereas an n-serrated pattern is typical of pemphigoid. If the specific serration pattern cannot be discerned, a repeat perilesional skin biopsy should be pursued in order to make an accurate diagnosis.

FOAM is a technique that can be used if the serration pattern cannot be identified from the standard approach. This process uses a visual comparison of the level of antibody deposition to a known topographic marker. The two images are overlaid and then visually compared to identify a match.[30]

Direct immunofluorescence performed on perilesiona 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.

Indirect immunofluorescence

See the image below. Indirect immunofluorescence demonstrates the presence of IgG circulating autoantibodies in the patient's serum that target the skin basement membrane component, type VII collagen. Usually, it detects IgG circulating autoantibodies in patient's serum that bind to the dermal floor (lower part) on salt-split normal human skin substrate. This test differentiates epidermolysis bullosa acquisita from bullous pemphigoid because IgG autoantibodies from patients with bullous pemphigoid bind to the epidermal roof (upper part) of salt-split skin. The dermal floor pattern of indirect immunofluorescence on salt-split skin substrate is also found in sera of patients with bullous systemic lupus erythematosus (SLE), antiepiligrin cicatricial pemphigoid (with autoantibodies to laminin-5 and laminin-6), and anti-p105 pemphigoid (with autoantibodies to a 105-kd lower lamina lucida protein).[31]

Indirect immunofluorescence performed on salt-spli 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.

Other Tests

Other investigative studies available that further document the diagnosis of epidermolysis bullosa acquisita (EBA) include direct and indirect immunoelectron microscopy, immunoblotting, enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, and type IV collagen immunomapping.

Direct and indirect immunoelectron microscopy

Direct and indirect immunoelectron microscopy document the ultrastructural localization of in vivo‒bound IgG autoantibodies (by direct method) or the binding site of circulating IgG autoantibodies (by indirect method) at the basement membrane. This technique detects IgG autoantibodies at the lamina densa and sublamina densa areas of the skin basement membrane. In contrast, bullous pemphigoid IgG autoantibodies are localized to the hemidesmosome and upper lamina lucida.[32]

Immunoblotting

Immunoblotting documents the specific skin basement membrane antigen recognized by the patient's IgG autoantibodies. This test detects a denatured 290-kd skin basement membrane protein or globular chain of the alpha chain (145 kd) of type VII collagen.

Enzyme-linked immunosorbent assay

ELISA[33] documents the specific basement membrane antigen recognized by the patient's IgG circulating autoantibodies. ELISA is preferred over immunoblotting because the ELISA method uses nondenatured type VII collagen, usually in a recombinant form. It is a more sensitive and specific method than immunoblotting.

Immunoprecipitation

Immunoprecipitation demonstrates the specific basement membrane antigen in its native form recognized by the patient's IgG circulating autoantibodies. This method detects a 290-kd protein either from cultured keratinocytes or from fibroblasts. It is a more difficult method to use than immunoblotting.

Type IV collagen immunomapping

Collagen IV immunomapping can help distinguish epidermolysis bullosa acquisita from bullous pemphigoid and anti-epiligrin cicatricial pemphigoid (AECP). Type IV collagen is a major component of the lamina densa, and staining delineates this region of the basement membrane zone. Positive type IV collagen staining in the roof of the blister suggests autoantibodies against epitopes below the lamina densa, such as in epidermolysis bullosa acquisita. In comparison, the type IV collagen staining in bullous pemphigoid and AECP would be in the floor of the blister. Type IV collagen immunomapping has been found to be more sensitive than indirect immunofluorescence.[34]

 

Treatment

Medical Care

Patients with epidermolysis bullosa acquisita (EBA) may require therapy with oral corticosteroids, anti-inflammatory agents, and immunosuppressants.[35, 36, 37, 38, 39]

For patients who are on long-term systemic corticosteroid treatment, daily calcium, vitamin D, and potentially bisphosphonate therapy are important for reducing steroid-induced osteoporosis.

All forms of epidermolysis bullosa acquisita may generate significant quality-of-life considerations. The “autoimmune bullous disease quality of life” (ABQOL) and “treatment-based autoimmune bullous disease quality of life” (TABQOL) are two surveys that assess disease impact and track patient progress to treatment.[40, 41]

Consultations

Coordination of care with the patient's primary care provider is important for monitoring adverse effects of therapy and the overall health of the patient.

Because epidermolysis bullosa acquisita (EBA) can involve esophageal mucosa and is strongly associated with inflammatory bowel disease, patients with epidermolysis bullosa acquisita should be asked about symptoms related to their GI tract. If there are any symptoms suggestive of esophageal lesions or inflammatory bowel disease, patients with epidermolysis bullosa acquisita should be referred to a gastroenterologist.

In patients with oral involvement, coordination of care with the patient's dentist is recommended.

In patients with ocular involvement, consultation with an ophthalmologist is recommended.

Diet

In patients with oral involvement, hard or brittle foods and foods with high acid content (eg, tomatoes, orange juice) should be avoided. Ingestion of these foods may traumatize mucosa and precipitate new lesions.

Activity

Because epidermolysis bullosa acquisita (EBA) primarily affects trauma-prone skin surfaces, patients are instructed to avoid direct physical trauma to their skin surfaces. When physical activities are planned, patients are instructed to use protective pads to cover their extensor skin surfaces. Additionally, gentle but thorough daily oral hygiene should be encouraged.

Complications

Infection is a possible consequence of open erosions and wounds in the setting of immunosuppression.

Malignancies may occur, secondary to chronic inflammation and immunosuppressive treatments.

Bone marrow suppression is possible, secondary to medication.

Growth retardation may occur, secondary to medications used during childhood.

Complications secondary to prednisone treatment for epidermolysis bullosa acquisita (EBA) include adrenal insufficiency, osteoporosis, and cataracts.

The chronic inflammation and scar formation on patients' extensor surfaces can severely hinder the daily activities of patients.[42] The scarring nature of epidermolysis bullosa acquisita can lead to nail destruction and hair loss.

Oropharyngeal mucous 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.

Prevention

It is important to monitor and prevent complications of prolonged systemic corticosteroid therapy. The American College of Rheumatology 2010 guidelines for prevention and treatment of glucocorticoid-induced osteoporosis recommend calcium and vitamin D supplementation, lifestyle modification counseling, and consideration of bisphosphonate therapy.[43] The indication for bisphosphonate therapy is based on risk stratification considering age, steroid dose, duration of treatment, and Fracture Risk Assessment Tool (FRAX) score. Prolonged corticosteroid treatment is also a risk factor for cataracts, and patients should be screened by an ophthalmologist.

Long-Term Monitoring

Patients with epidermolysis bullosa acquisita (EBA) should be monitored regularly by physicians with experience in treating autoimmune skin disease. During the active disease stage, patients should be monitored by their physicians on a monthly basis. When in remission, patients should be monitored by their physicians annually.

 

Medication

Medication Summary

In epidermolysis bullosa acquisita (EBA), as in other autoimmune blistering diseases, treatment is directed at decreasing the development of new blisters, promoting healing, and preventing scarring and the sequelae of scarring.

The main goal of treatment is to modify or reduce the autoimmune response and decrease the production of autoantibodies. To date, only non–target-specific immunosuppressive and anti-inflammatory agents are available. There have been no randomized controlled trials to assess epidermolysis bullosa acquisita treatments. Most treatments are based on case reports and retrospective case series. Corticosteroids remain a mainstay of treatment, although many patients do not respond well and require various other immunosuppressants.

Prednisone doses commonly range from 0.5-1.5 mg/kg/day.[44] A retrospective analysis of 30 epidermolysis bullosa acquisita patients demonstrated that high-dose methylprednisolone (>8 mg/day) for at least 1 month achieved remission in 3 months as compared with remission in 12 months in those treated with a low dose (< 8 mg/day) methylprednisolone.[21]

Dapsone is an antibiotic as well as an anti-inflammatory agent used to treat non‒pathogen-related inflammatory diseases. It can be used as an adjunctive therapy to systemic corticosteroids, or as monotherapy. A review in 2011 summarized the treatment of 18 patients who received dapsone at doses of 25-100 mg/day or 1-2 mg/kg/day in conjunction with prednisone. Clinical improvement was noted in all 18 patients, of which half were able to discontinue steroid use.[45] A retrospective review in 2014 documented seven patients treated with dapsone (50-150 mg/day) in conjunction with corticosteroids. Two patients achieved complete remission and two patients achieved partial remission. Of note, adverse effects occurred in two patients, both at doses greater than 100 mg.[18]

Colchicine administration at a dose of 0.5-2.0 mg/day has been reported in 15 patients, both as a sole agent and in combination with other treatments. Some form of remission occurred in 13 of 15 patients, with a majority requiring maintenance therapy.[18, 45] Diarrhea is a common adverse effect. Colchicine may have an improved overall adverse effect profile compared with other agents, particularly if they have limited efficacy. As such, it can be considered a first-line agent for mild cases.[46]

Immunosuppressives are used in patients with severe disease. Azathioprine, cyclophosphamide, methotrexate, mycophenolate mofetil, and cyclosporine have all been described as treatments in small case reports and case series. Immunosuppressive agents can be used in combination with steroids or other anti-inflammatory treatments.[44, 45]

Azathioprine is the most commonly used adjunctive agent. However, its documented efficacy is limited, and, owing to multiple adverse effects such as hepatitis, leukopenia, and pancreatitis, it may be a suboptimal choice.[47]

Methotrexate has not been studied directly in patients with epidermolysis bullosa acquisita, but its efficacy for bullous pemphigoid suggests that it could be incorporated into a treatment regimen. A dose of 20-25 mg weekly would be suggested when used in conjunction with other immunosuppressives. The adverse effect profile of anemia, nausea, and potential infection is documented.[48]

Mycophenolate mofetil may be an effective adjunct, or as a steroid-sparing monotherapy. Randomized clinical trials for adjuvant therapy used in patients with bullous pemphigoid suggest a moderate adverse effect profile, but not of significant difference from that of azathioprine when used in conjunction with systemic corticosteroids.[47] However, in one case-series study, some patients were effectively treated with mycophenolate mofetil as a steroid-sparing approach.[49]

Extracorporeal photochemotherapy (photophoresis) has been shown to be effective in three of four patients after three to six cycles of treatment.[45]

Rituximab is an anti-CD20 monoclonal antibody that has resulted in complete resolution in a 2018 retrospective analysis.[47] Most commonly, it was used as 375 mg/m2 weekly for a total of 4 weeks. This is a promising agent that has also shown efficacy in reduced development of antigen-specific CD4+ T cells in animal models.[50] In one study of seven patients with refractory disease, rituximab resulted in clinical improvement in five of seven patients.[18]  

Intravenous immunoglobulin (IVIg) may be an option in severe disease. A 2011 review documented 15 cases of IVIg use in patients mostly with severe widespread refractory disease. Clinical improvement was noted in 14 of 15 patients. Thirteen of 15 patients remained on IVIg for maintenance treatment.[45] A 2012 retrospective case series demonstrated similar clinical response rates, but suggested IVIg may induce a more sustained remission.[51] Ten patients, all nonresponsive to conventional treatments, were started on 2 g/kg/cycle of IVIg for a mean of 23 cycles over 39 months. All 10 demonstrated clinical response and were able to completely withdraw their previous therapy; no recurrence was observed during a mean follow-up period of 54 months after cessation of treatment.

Anti-inflammatory agents

Class Summary

In the inflammatory form of epidermolysis bullosa acquisita (EBA), there may be an inflammatory cell infiltration near the basement membrane zone. Theoretically, anti-inflammatory agents would block the inflammatory process and improve the disease. Prednisone, dapsone, and colchicine all have been reported to induce clinical improvement.

Prednisone (Deltasone)

Prednisone is used as a sole agent or in conjunction with other medications (eg, immunosuppressives) to treat epidermolysis bullosa acquisita (EBA). It may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Dapsone (Avlosulfon)

Dapsone is bactericidal and bacteriostatic against mycobacteria; its mechanism of action is similar to that of sulfonamides where competitive antagonists of PABA prevent the formation of folic acid, inhibiting bacterial growth. It is used in conjunction with other anti-inflammatory medications and immunosuppressives. In children, physicians should consult the patient's pediatrician before prescribing this medication.

Colchicine (Colcrys, Mitigare)

Colchicine is an anti-inflammatory agent that disrupts cytoskeletal functions by inhibiting B-tubulin polymerization, preventing neutrophil activation, degranulation, and migration.

Photophoresis agents

Class Summary

Extracorporeal photochemotherapy (photophoresis) a therapeutic method that uses ultraviolet-sensitizing medication (psoralen) and extracorporeal ultraviolet A irradiation of the sensitized WBCs. The photoinactivated cells are reinfused into the patient.

Methoxsalen (8-MOP, Oxsoralen)

Methoxsalen inhibits mitosis by binding covalently to pyrimidine bases in DNA when photoactivated by ultraviolet A.

Biological response modulators

Rituximab (Rituxan)

Rituximab is a monoclonal antibody that specifically targets the immune cell surface marker CD20, which is primarily expressed by B lymphocytes.

Immune Globulins

Immune globulin IV (IGIV) (Bivigam, Carimune, Carimune NF)

IVIg is a purified preparation of gamma globulin. It is derived from large pools of human plasma with four subclasses of antibodies, approximating the distribution of human serum. They may decrease autoantibody production and increase solubilization and removal of immune complexes.