Epidermolysis bullosa acquisita L12.30

The first report of EBA dates back to 1895, when Elliot (1895, later ROENIGK, 1971) described two adults with acquired skin fragility. Further cases of EBA were published in the following years. Due to similar clinical manifestations, EBA was initially described in 1895 as an adult-onset form of dystrophic epidermolysis bullosa (Nieboer C et al. 1980). In 1965, Pass et al. carried out histochemical studies from which they concluded that EBA pathogenesis was related to collagen changes. The first diagnostic criteria were not established until 1971 by Roenigk et al. The autoimmune character of EBA was demonstrated by the presence of IgG deposits in the basement membrane zone (BMZ) using direct immunofluorescence evaluation. The exact location of the immune complex deposits in the lamina densa was clarified by Yaoita et al. and Nieboer et al. using immuno-electron microscopy. In 1984, Woodley et al. identified a 290 kDa protein - collagen VII - as the target antigen in EBA (Hallel-Halevy D et al. 2001).

Rare, acquired, blistering autoimmune disease with IgG (and IgA) antibodies against type VII collagen (NC1 domain), the main component of the "anchoring fibrils" in the dermoepidermal junction zone. The disease can occur after viral infections, as a paraneoplastic syndrome, also after autoimmunological reactions (e.g. after autologous stem cell transplantation).

Two main subgroups can be distinguished on the basis of their clinical appearance:

• Epidermolysis bullosa acquisita, classic/mechanobullous (non-inflammatory) EBA
• Epidermolysis bullosa acquisita, inflammatory (non-mechanobullous) EBA with the following variants:
  • Epidermolysis bullosa acquisita, bullous pemphigoid-like EBA (47%) - tight blisters on erythematous or urticarial skin, mainly trunk and extremities
  • Epidermolysis bullosa acquisita, mucous membrane pemphigoid-like EBA (7%) - lesions and scarring on the mucous membranes of the mouth, oesophagus, trachea and esophagus. oesophagus, trachea, conjunctiva
  • Epidermolysis bullosa acquisita, scarring pemphigoid-like EBA (Brunsting-Perry type) (7%) - variant under the picture of a localized scarring pemphigoid
  • Epidermolysis bullosa acquisita, linear IgAdermatosis-like EBA/IgA-EBA(3%) - variant under the picture of a linear IgA dermatosis of childhood.

Incidence in Western Europe: 0.25-1.0/1.0 million inhabitants/year. No ethnic clustering.

EBA is an autoimmune disease that belongs to the group of subepidermal bullous dermatoses. Its most important antigenic target is COLVII (collagen type 7), which is located in the sublamina densa of the BMZ. COLVII, the main component of anchoring fibrils, is a 290 kDa protein consisting of a central collagenous domain flanked by two non-collagenous domains, NC1 and NC2 (Kridin K et al. 2019). In patients with EBA, most autoantibodies target epitopes in the NC1 domain, although in a minority of cases, reactivity against the epitopes of the NC2 domains can be detected.

In general, these autoantibodies are of the IgG type. However, IgA, IgE and IgM have also been detected in some patients.

Sensitization of CD4 + T lymphocytes requires the presence of antigen-presenting cells (APCs) mediated by granulocyte-macrophage colony-stimulating factor (GM-CSF) and neutrophils. In addition to APCs, dendritic cells, macrophages and B lymphocytes are required for clonal expansion and plasma cell differentiation, with consecutive release of autoantibodies against COLVII (Koga H et al. 2018). The tissue lesions are triggered by the deposition of autoantibodies at the dermo-epidermal interface by binding to the COLVII epitope, which activates the complement system and releases pro-inflammatory cytokines. Neutrophils bind to the Fc domain of anti-COLVII22 autoantibodies and initiate a signaling cascade that includes activation of retinoid-related orphan receptor (ROR) alpha, heat shock protein HSP 90, phosphodiesterase 4 and phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) (Koga H et al. 2018). Activated neutrophils express reactive oxygen species and proteases. These lead to damage and reduction of the anchoring fibrils with subsequent formation of blisters on the skin and mucous membranes (Kim JH et al. 2013).

Occurrence is possible at any age, usually between 40 and 60 years of age. Rarely occurring in children. m:w=1:1

Integument (short description):

• In the classic, mechano-bullous form of the disease, taut, non-inflammatory blisters of varying sizes are found. The main areas affected are the hands, elbows, feet, knees and, in rare cases, the oral mucosa. Occasionally, the affected areas heal with skin atrophy or milia, hyper- and hypopigmentation.
• In the non-classical inflammatory forms, diseases are described as bullous pemphigoid, localized scarring pemphigoid (Brunsting-Perry) or linear IgA dermatosis, with blistering of the face, sometimes also as impetigo contagiosa. Important are extracutaneous manifestations with the formation of esophageal or urethral strictures. A connection between epidermolysis bullosa acquisita (EBA) and inflammatory bowel disease has been established in reviews. In 42 coincident cases, Crohn's disease (K50.9) was detected 35 times and ulcerative colitis (K51.9) 7 times. In most cases, the chronic inflammatory bowel disease preceded the skin changes (Reddy H et al. 2013). Note: The antigen of EBA (collagen type VII) is also expressed in the intestinal mucosa between the epithelium and stratum proprium.

See also under the variants of EBA.

Subepidermal blistering. Edema of the dermis. Bulky, diffusely arranged, predominantly neutrophilic infiltrates in the upper dermis, with gaping blood and lymph vessels. Diagnosis: Diffuse, superficial, predominantly neutrophilic dermatitis with subepidermal blistering.

Electron microscopy: cleft formation in the dermo-epidermal junction zone in the area of the sublamina densa zone. Reduction in the number of anchoring fibrils.

Linear deposits of IgG and C3 at the BMZ are present in the perilesional skin in 93% of patients. These findings are not unique to EBA and can also be found in other subepidermal autoimmune bullous dermatoses (ABD). Fluorescence with anti-C3 is observed in 89% of cases, followed by anti-IgG in 79% of cases;45 IgA (47%) and IgM (21%) are observed less frequently. Exclusive IgA deposits are found in 2.4 % of cases, which correspond to IgA EBA (Iwata H et al. 2018). Analysis of the deposition pattern of the immune complex can increase the sensitivity of DIF . A u-jagged fluorescence pattern indicates the presence of autoantibodies bound to COLVII of the anchoring fibrils, while the n-jagged fluorescence pattern indicates the identification of antigens located over the lamina densa, such as BP180, p200, laminin 332 and laminin γ. The salt cleavage skin technique can be performed on the fragment obtained from the skin lesion and shows fluorescence on the skin side of the cleavage.

Immunoelectron microscopy: Detection of IgG, C3 and IgA deposits in the anchoring fibrils beneath the lamina densa by direct immunoelectron microscopy remains the gold standard method for the diagnosis of EBA. As this method is not available in most institutions, additional tests are recommended to confirm the diagnosis of EBA.

Immunohistochemistry: Formalin-fixed and paraffin-embedded fragments from the lesional skin of patients with EBA are stained with anti-collagen IV located in the lamina densa. Since the cleavage in EBA occurs below the lamina densa, collagen IV is positive on the upper surface of the blister.

In approximately 50-60% of patients, IgG and/or IgA autoantibodies against type VII collagen can be detected serologically. Detection is initially by indirect IF using salt-split skin as substrate. In EBA, the autoantibodies bind to the bottom of the artificial bladder. However, this is not conclusive for EBA, as p200 antigen and laminin-332 are also expressed at the bottom of the bladder.

ELISA (NC1/NC2) or immunochip (with cells expressing COL7) can be used to detect collagen 7-specific antibodies. Also possible is detection by Western blot on dermal extract with detection of a band at 290 kD.

Clinic and detection of a u-serrated pattern in direct IF confirm the diagnosis.

If the pattern does not present in the direct IF, the diagnosis can be made in the case of linear Ig/C3 deposits in the direct IF as follows:

1. Serological detection of type VII collagen specific autoantibodies.
2. Immunoelectron microscopy

Epidermolysis bullosa dystrophica (difficult to compare as larger disease group; detection of mutations in a collagen VII gene)

Bullous medicinal exanthema: medical history; blistering on the trunk, possibly mucous membranes, not on mechanically altered areas such as hands, elbows, feet, knees

Dermatitis herpetiformis: small burning blisters. IF: granular IgA deposits in the tips of the papillae.

Pemphigus vulgaris: detection of specific antibodies

Pemphigoid, bullous: detection of specific antibodies

EBA-associated diseases: Several systemic diseases associated with EBA have been identified, including amyloidosis, thyroiditis, multiple endocrinopathy, rheumatoid arthritis, pulmonary fibrosis, chronic lymphocytic leukemia, thymoma and diabetes mellitus. However, most of these have only been described in isolated cases. The only indisputable link is between MSD and inflammatory bowel disease (IBD), in particular Crohn's disease (K50.9). This association is observed in about 25% of MSD patients in the US and is less common in other countries, probably due to the presence of type VII collagen in the BMZ of the colon wall. In most patients, IBD occurs before the onset of MSD (Reddy H et al. 2013).

Systemic therapy is indicated in cases of generalization or mucosal involvement. Only some patients (especially with a strong inflammatory component) respond well to monotherapy with systemic glucocorticoids, medium dosage (60-80 mg/day prednisone equivalent). Therefore, the combination of glucocorticoids with the following immunosuppressants is recommended:

• Azathioprine (e.g. Imurek) 1-2 mg/kg bw/day
• Cyclophosphamide (e.g. Endoxan) 50 mg/day
• DADPS (e.g. Dapsone Fatol) 100-150 mg/day
• Ciclosporin A (e.g. Sandimmun) 5-7 mg/kg bw/day
• Colchicine (e.g. Colchicine Dispert Drg.) 0.5-2 mg/day.

A therapy trial is also possible with high doses of vitamin E (e.g. Evit Kps.) 600-1200 mg/day. Complete healing has been described in individual cases with this therapy, but improvement only occurs over a long period of time.

Newer therapeutic approaches:

• IVIG: Immunoglobulins (e.g. pentaglobin) 5 ml/kg bw/day i.v. for 3-7 consecutive days should lead to better results in combination with e.g. prednisolone or ciclosporin A treatment. According to the literature, intravenous immunoglobulins only appear to have an initial therapeutic effect. Long-term improvements have not been described.
• Dupilumab is considered a safe therapeutic trial if immunosuppressive therapy is not tolerated or possible (Diehl R et al. (2024).
• Plasmapheresis can reduce the maintenance dose of glucocorticoids and immunosuppressants as an accompanying measure.

Preventing new lesions includes educating patients about protecting the skin from additional trauma with soft clothing and non-sticky dressings, cleaning lesions appropriately with soap and water, avoiding foods that can cause additional damage to the oral mucosa when chewed and swallowed, such as hot drinks and acidic, rough/crunchy products.

In individual cases, the simultaneous occurrence of malignancies has been described (cervical carcinoma, multiple myeloma, pancreatic carcinoma, liver carcinoma).

Associations with other autoimmune diseases have frequently been described: autoimmune thyroiditis, systemic lupus erythematosus, Crohn's disease.

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