Epidermolysis bullosa acquisita L12.30

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).

A distinction is made between 3 clinical variants:

• Classic, acral, mechano-bullous form (blistering only in mechanically stressed areas).
• Generalized, inflammatory form, clinically corresponding to bullous pemphigoid (blistering ubiquitous).
• Localized form under the picture of scarring pemphigoid.

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

Blister-forming autoimmune disease; autoantigen is collagen type VII, which is the main component of the anchoring fibrils of the papillary dermis. The antibodies bind to the NC1 domain of collagen type VII.

Occurrence is possible at any age, usually between the 40th and 60th year of life. Rarely also occurring in children. m:w=1:1;

Integument:

• In the classic form of the disease, tight, non-inflammatory blisters of various sizes are found, predominantly on mechanically traumatized skin regions (especially hands, elbows, feet, knees) and, in rare cases, on the oral mucosa. Occasionally, the affected areas heal with skin atrophy or milia, hyper- and hypopigmentation.
• A second clinical variant (30% of cases) presents as a generalized, pruritic, inflammatory disease with the appearance of bullous pemphigoid.
• A third variant presents as localized Brunsting-Perry scarring pemphigoid.
• A fourth variant has been described under the picture of a linear IgA dermatosis, with blistering of the face, partly under the picture of impetigo contagiosa.

Extracutaneous manifestations: In rare cases, formation of esophageal or urethral strictures.

Reviews have identified an association between epidermolysis bullosa acquisita (EBA) and inflammatory bowel disease (IBD). In 42 coincident cases, Crohn's disease (K50.9) was detected 35x and ulcerative colitis (K51.9) 7x. In most cases, inflammatory bowel disease preceded the skin lesions (Reddy H et al 2013). Note: The antigen of EBA (collagen type VII) is also expressed in the intestinal mucosa between epithelium and stratum proprium.

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

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

Linear IgG and_{C3 deposition} in the basement membrane zone. Pattern corresponding to the localization of collagen VII in the sublamina densa zone of the skin.

At high magnification, a typical pattern of IgG deposits can be detected, which is typical for EBA: the so-called "U-serrated pattern" (Br J Dermatol 2004). This is an important diagnostic criterion, since circulating autoantibodies can be detected in only about 50-60% of EBA patients. With the detection of the "U-serrated pattern" in direct IF, the diagnosis of EBA is unequivocal.

In immunoelectron microscopy IgG deposits below the lamina densa, partly also at the anchoring fibrils. However, this method is only used by very few centers and is reserved for special cases.

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, evidence 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

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.

Preventive; if possible, no exceptional mechanical stress on the skin.

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.

1. Bari B et al. (1996) Colchicine for epidermolysis bullosa acquisita. J Am Acad Dermatol 34: 781-784
2. Bauer JW (1999) Ocular involvement in IgA-epidermolysis bullosa acquisita. Br J Dermatol 141: 887-892
3. Busch JE et al (2007) Epidermolysis bullosa acquisita and pancreatic neuroendocrine carcinoma-coincidence or pathogenetic association. JDDG 10: 916-918
4. Caldwell JB et al (1994) Epidermolysis bullosa acquisita - Efficacy of high dose intravenous immunoglobulins. J Am Acad Derm 31: 827-828
5. Diehl R et al. (2024) Dupilumab for the treatment of epidermolysis bullosa acquisita. JDDG 22: 1417-1419
6. Elliot GT (1895) Two cases of epidermolysis bullosa. J Cutan Genitourinary Dis (Chicago) 13: 10-18
7. Goebeler M, Zillikens D (2003) Blistering autoimmune diseases of childhood] Dermatologist 54: 14-24
8. Hertl M, Schuler G (2002) Bullous autoimmune dermatoses. 1: Classification. Dermatologist 53: 207-219
9. Jappe U et al. (2000) Epidermolysis bullosa acquisita with ultraviolet radiationsensitivity. Br J Dermatol 142: 517-520
10. Kasperkiewicz M et al.(2016) Epidermolysis Bullosa Acquisita: From Pathophysiology to Novel Therapeutic Options. J Invest Dermatol 136:24-33.
11. Ludwig RJ et al. (2017) Mechanisms of Autoantibody-Induced Pathology.Front Immunol 8:603.
12. Mohr C et al. (1995) Successful treatment of epidermolysis bullosa acquisita using intravenous immunoglobulins. Br J Dermatol 132: 824-826
13. Niederau D (1995) Epidermolysis bullosa acquisita - Successful treatment with dapsone in combination with glucocorticosteroids. Z Hautkr 70: 454-455
14. Reddy H et al. (2013) Epidermolysis bullosa acquisita and inflammatory bowel disease: a review of the
15. literature. Clin Exp Dermatol 38:225-229; quiz 229-30.
16. Roenigk HH et al. (1971) Epidermolysis bullosa acquisita: Reports of three cases and review of all published cases. Arch Dermatol 103: 1-10
17. Schmidt E (2002) Childhood epidermolysis bullosa acquisita: a novel variant with reactivity to all three structural domains of type VII collagen. Br J Dermatol 147: 592-597
18. Schmidt E et al (2013) Pemphigoid diseases. Lancet 381:320-332.
19. Trigo-Guzman FX et al (2003) Epidermolysis bullosa acquisita in childhood. J Dermatol 30: 226-229
20. Vodegel RM (2003) Anti-epiligrin cicatricial pemphigoid and epidermolysis bullosa acquisita: differentiation by use of indirect immunofluorescence microscopy. J Am Acad Dermatol 48: 542-547
21. Vodegel RM et al. (2002) IgA-mediated epidermolysis bullosa acquisita: two cases and review of the literature. J Am Acad Dermatol 47: 919-925
22. Woodley DT et al. (1984) Identification of the skin basement-membrane autoantigen in epidermolysis bullosa acquisita. N Engl J Med 310: 1007-1013