Epidermolysis Bullosa Acquisita

Article Author:
Anny Xiao
Article Editor:
Arline Tsuchiya
Updated:
3/4/2020 2:42:45 PM
PubMed Link:
Epidermolysis Bullosa Acquisita

Introduction

Epidermolysis bullosa acquisita (EBA) is a rare chronic autoimmune blistering disease of the skin and mucous membranes. EBA is caused by autoantibodies to type VII collagen, a major component of anchoring fibrils in the dermal-epidermal junction (DEJ). These anchoring fibrils are responsible for attaching the epidermis to the underlying dermis, and binding of autoantibodies to type VII collagen subsequently leads to detachment of the epidermis, resulting in skin fragility, blisters, erosions, scars, milia, and nail loss.[1] Clinically, patients can present with various phenotypes. The mechanobullous and bullous pemphigoid-like forms of EBA are the two most common presentations.[2] The classic mechanobullous EBA resembles dystrophic epidermolysis bullosa (EB) with bullae and erosions occurring at sites of trauma. The inflammatory forms of EBA present with clinical manifestations similar to other autoimmune blistering disorders, including bullous pemphigoid (BP) and mucous membrane pemphigoid (MMP). EBA has been reported in association with several systemic diseases, including inflammatory bowel disease, thyroiditis, rheumatoid arthritis, hepatitis C infection, and diabetes mellitus.[3]

Etiology

Epidermolysis bullosa acquisita is characterized by tissue-bound and circulating IgG autoantibodies against type VII collagen, which is located in the lamina densa and sublamina densa of the basement membrane zone (BMZ). As the major component of anchoring fibrils, these structural components connect the papillary dermis to the lamina densa and play a significant role in maintaining the integrity of the epidermal BMZ.[4] It has been shown that autoantibodies bind to the NC-1 domain of type VII collagen within the lamina densa. Experimental mouse models and in vitro studies of EBA have demonstrated that autoantibodies to type VII collagen can induce dermal-epidermal separation.[5] These antibodies may also directly interfere with the assembly of type VII collagen into anchoring fibrils or impede the interactions of type VII collagen with other matrix proteins such as laminin 332, fibronectin, or type IV collagen.[6][1]

Certain HLA class II alleles appear to overrepresent in some populations with EBA. A higher frequency of HLA-DRB1*13 has been described in Korean patients.[7] HLA-DRB1*15:03 has been found in higher frequencies in African American patients.[8] This data suggests the expression of distinct HLA alleles may impact the susceptibility for developing EBA.

Epidemiology

Epidermolysis bullosa acquisita is one of the rarest subepidermal bullous diseases in Western Europe, with an estimated annual incidence of 0.2 to 0.5 per million people.[9] The prevalence may be higher in Korean and African-American populations.[10] EBA has been reported in both pediatric and adult patients, with no gender predisposition. The average onset of EBA occurs between the fourth and fifth decades, but the disease may occur at any age.[11] A 2018 meta-analysis of 1159 EBA cases found that the median age of all patients was 50 years, with pediatric patients accounting for 4.6% of all cases and patients aged 65 or older, accounting for 11.3%. The ages represented ranged from one-year-old to 94-years-old. 9.6% of EBA cases were associated with chronic inflammatory diseases, with inflammatory bowel disease, thyroiditis, and rheumatoid arthritis reported most frequently.[12]

History and Physical

Clinically, various phenotypes of epidermolysis bullosa acquisita have been described. The classic presentation is a non-inflammatory mechanobullous disease characterized by skin fragility, tense blisters, erosions, scarring, milia formation, and post-inflammatory dyspigmentation. These findings are localized to trauma-prone sites and extensor surfaces, such as the elbows, knees, dorsal hands, and feet.[12] Progressive acral involvement may be disfiguring, resembling dystrophic EB with pseudosyndactyly, "mitten deformity" of digits, and nail dystrophy. Scalp involvement can lead to non-healing erosions with scarring alopecia.[1] 

The inflammatory variants of EBA resemble other autoimmune bullous dermatoses and include bullous pemphigoid (BP)-like EBA, mucous membrane pemphigoid (MMP)-like EBA, linear IgA bullous dermatosis (LABD)-like EBA, and Brunsting-Perry cicatricial pemphigoid-like EBA.[12] The most common presentations are the classic non-inflammatory EBA and the BP-like EBA.[4] 

BP-like EBA features widespread pruritic tense vesicles and bullae on an erythematous base, commonly involving the trunk, intertriginous areas, and extremities. Oral mucosa may be involved in approximately 50% of cases, with erosions or intact vesicles in the mouth. The lesions heal without milia or scars.[13] 

MMP-like EBA is characterized by predominant involvement of mucous membranes, with lesions and scarring most commonly in the mouth, upper esophagus, conjunctivae, anus, and vagina.[14] Cases with ocular involvement leading to blindness have been reported.[15] 

LABD-like EBA presents with tense vesicles, blisters, and urticarial plaques in an annular or polycyclic pattern, with mucous membrane involvement.

Brunsting–Perry cicatricial pemphigoid-like EBA features a vesiculobullous eruption localized to the head and neck with minimal to no involvement of mucous membranes. Involvement of the scalp results in scarring alopecia.[16] 

Patients may present with one of these subtypes alone or a combination of two subtypes simultaneously. Conversion of clinical features from one variant to another during the disease has been reported.[6]

Evaluation

The diagnosis of epidermolysis bullosa acquisita may be challenging due to the various inflammatory variants that mimic other blistering diseases, both clinically and histologically. 

On histology, a skin biopsy taken from lesional EBA skin shows features of papillary edema and vacuolar degeneration along the DEJ in early lesions. Later lesions demonstrate a subepidermal blister with varying degrees of inflammatory infiltrate depending on the clinical variant.[6] The classic EBA presentation is pauci-inflammatory with sparse neutrophilic inflammatory infiltrate in the papillary dermis. At the same time, BP-like EBA features a dermal inflammatory infiltrate of neutrophils, lymphocytes, monocytes, and eosinophils, and appears histologically similar to BP. 

A perilesional biopsy should be taken for direct immunofluorescence (DIF) microscopy, which would show linear deposits of IgG along the epidermal BMZ. Less commonly, linear deposits of C3, IgA, or IgM may also be detected.[6] A "u-serrated" immunodeposition pattern at the BMZ helps to differentiate EBA from other subepidermal blistering disorders, which have an "n-serrated" pattern.[17] Salt-split skin immunofluorescence preparations show immune deposits located on the dermal side of the cleavage, in contrast to BP, which has deposits located on the epidermal side of the separation.[6]

Indirect immunofluorescence (IIF) may be able to detect circulating autoantibodies to the BMZ in patients with EBA. Approximately 50% of patients with EBA have detectable anti-BMZ IgG antibodies in their serum, which would result in a linear fluorescent band along the DEJ. IIF on salt-split skin would demonstrate EBA autoantibodies in the serum binding to the dermal side of the artificial blister.

Transmission electron microscopy of the DEJ would show cleavage in the sublamina densa zone, a decreased number of anchoring fibrils emerging from the lamina densa, as well as an amorphous, electron-dense material beneath the lamina densa in EBA skin. This material is thought to correspond to the IgG deposits bound to the anchoring fibrils.[18]

Immunoelectron microscopy (IEM) is the traditional "gold standard" for diagnosis of EBA and would reveal immune deposits localized to anchoring fibrils within the sublamina densa, in contrast to other subepidermal blistering disorders with immune deposits in the hemidesmosome area (BP) or lamina lucida (MMP).[19]

Western blot analysis of serum from EBA patients demonstrates binding of circulating autoantibodies to a 290 kDa protein and less frequently a 145 kDa protein, which corresponds to the alpha chain of type VII collagen and its NC1 domain, respectively.[20]

Enzyme-linked immunosorbent assay (ELISA) is a quick and efficient test with high specificity (>96%). It uses recombinant NC1 and NC2 domains of type VII collagen purified from human cells to detect EBA autoantibodies that target all possible antigenic epitopes within NC1 and NC2. It can detect levels of autoantibodies, which correlate with disease severity.

The diagnostic criteria for EBA have been established by previous authors and are comprised of a bullous disorder within the defined clinical spectrum, lack of family history of bullous disease, a subepidermal blister on histology, DIF of perilesional skin showing IgG deposits within the DEJ, and IEM of perilesional skin indicating 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 blot may be done instead of IEM.[6]

Treatment / Management

The treatment of epidermolysis bullosa acquisita is challenging, and many patients are recalcitrant to therapy. Supportive therapy, including proper wound care and good nutrition, is paramount for all EBA patients to minimize the risk of complications. Patients should be counseled on strategies for avoiding trauma, including limiting exposure to harsh soaps and hot water and abstaining from vigorous skin rubbing and prolonged sun exposure.[6] Patients should be educated on how to recognize secondary skin infections and when to seek medical care. Patients should be routinely monitored for the development of mucosal lesions with a thorough review of systems and physical exam periodically.

As with all rare conditions, pharmacologic treatment data for EBA is largely based on anecdotal reports.[15] High doses of colchicine have been reportedly effective in patients with classic mechanobullous EBA as well as inflammatory variants of EBA.[21] The mechanism is unknown, but it is thought to reduce the production of antibodies and inhibit antigen presentation to T cells.[22] Systemic corticosteroids and immunosuppressive medications, including azathioprine, cyclophosphamide, cyclosporine, methotrexate, and mycophenolate mofetil, may be effective in BP-like EBA and other inflammatory variants.[23] Dapsone has been reported to have some benefit and may be especially beneficial in EBA patients with neutrophilic dermal infiltrates. Studies have recommended a combination of dapsone and prednisolone for childhood EBA.[15] In severe cases of EBA refractory to conventional immunosuppressive therapy, rituximab and intravenous immunoglobulins (IVIG) have been used successfully in case reports.[24]

Differential Diagnosis

The differential diagnosis for epidermolysis bullosa acquisita includes other subepidermal blistering disorders, such as dystrophic EB, BP, MMP, porphyria cutanea tarda (PCT), pseudoporphyria, and bullous lupus erythematosus (LE). Dominant dystrophic EB clinically resembles the mechanobullous type of EBA but would have a positive family history of a bullous disorder, onset at birth, and negative DIF findings. BP and MMP can appear clinically identical to the inflammatory variants of EBA but can be distinguished by an n-serrated DIF immunodeposition pattern. Other diagnostic tests, including IIF with salt-split skin substrate, ELISA, Western immunoblotting, or immunoelectron microscopy, can help exclude other autoimmune bullous diseases.

PCT classically involves the hands but would be distinguished by positive porphyrin studies. Similarly, pseudoporphyria may mimic EBA, but patients would have an additional history of chronic kidney disease, renal dialysis, or ingestion of specific drugs, such as non-steroidal anti-inflammatory drugs, furosemide, antibiotics, and retinoids.[25] 

Bullous LE can infrequently present as a mechanobullous eruption with milia and scarring, however, on histology, it demonstrates subepidermal bullae with a primarily neutrophilic infiltrate with dermal papillary microabscesses resembling dermatitis herpetiformis.[1] Bullous LE would also improve significantly with the initiation of systemic LE treatment, while EBA typically has a poor response to treatment.[26]

  • Bullous pemphigoid
  • Bullous systemic lupus erythematosus
  • Mucous membrane pemphigoid
  • Dystrophic epidermolysis bullosa
  • Epidermolysis bullosa dystrophica
  • Linear IgA dermatosis
  • Porphyria cutanea tarda

Prognosis

Epidermolysis bullosa acquisita is a chronic blistering disease with a disease course characterized by periods of exacerbations and remissions. Prognosis depends on the severity at the time of diagnosis and response to treatment. A retrospective analysis by Kim et al. showed a median time to remission of 9 months after treatment with immunosuppressive agents. Complete remission at 1 year was achieved in 33% of patients and 45% of patients by 6 years.[15] Long-term maintenance therapy is generally required to maintain disease control.[27] Mortality as a direct consequence of EBA is rare, and patients who are treated effectively and properly managed should live a normal life span. Prognosis and response to treatment may be better in children compared to adults.[28]

Complications

Epidermolysis bullosa acquisita is often unresponsive to treatment and can lead to significant morbidity. Severe exacerbations may heal with rapid scarring and can result in joint contractures, syndactyly, and loss of nails. EBA can affect ocular, gastrointestinal, and respiratory mucosa, which may lead to significant functional impairment. Many complications from mucosal involvement have been reported, including ankyloglossia, periodontal disease, symblepharon formation, nasal synechiae, esophageal strictures, and supraglottic stenosis. Mucosal disease is often subclinical, resulting in delayed diagnosis and subsequent increased risk of serious complications.[29]

Adverse effects of immunosuppressive medications used to treat EBA, such as systemic corticosteroids and cyclosporine, can also cause significant morbidity, especially when prolonged use is required for disease control.

Deterrence and Patient Education

Epidermolysis bullosa acquisita is characterized by skin fragility and the development of blisters at sites of trauma; therefore patients should be educated on methods for preventing skin trauma. Patients should be counseled to reduce friction on their skin by avoiding vigorous rubbing or washing. Avoid adhesive bandages or tape on the skin. Loose-fitting clothing and shoes should be worn. Patients should attempt to keep the skin cool and avoid prolonged exposure to heat and humidity. Shower water should not be warmer than body temperature.  

Patients should receive guidance on proper wound care for any eroded blisters. Application of antibacterial ointment over skin erosions is recommended to decrease the risk of developing a secondary bacterial infection. Wounds should be covered with a non-adhesive dressing and loosely wrapped with gauze rather than adhesives. Patients should be instructed on how to recognize a secondary skin infection and when to seek medical care for non-healing or worsening wounds. Nutritional support may be needed for optimal wound healing, and patients should be monitored for nutritional deficiencies.

Enhancing Healthcare Team Outcomes

Given the diverse range of clinical presentations and potential complications of epidermolysis bullosa acquisita, patients are best managed by a multidisciplinary team consisting of dermatology, wound care, nutrition, occupational therapy, and physical therapy. Patients should be monitored regularly for the development or progression of mucosal involvement. If mucosal lesions are present or suspected, patients should be evaluated and treated by ophthalmology, otolaryngology, and gastroenterology. Interprofessional team care, along with prompt diagnosis and treatment, patient education, and close monitoring, can improve outcomes and optimize prognosis for patients with EBA.


References

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