Epidermolysis bullosa acquisita L12.30

Authors: Prof. Dr. med. Peter Altmeyer, Prof. Dr. Ralf Ludwig

All authors of this article

Last updated on: 14.06.2022

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Synonym(s)

Acquired epidermolyis acquisita; dermolytic pemphigus; Dermolytic pemphigus

History
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Elliot, 1895; Kablitz, 1904

Definition
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Rare, acquired, blistering autoimmune disease with antibodies to type VII collagen, the major component of 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).

Classification
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A distinction is made between 3 clinical variants:

  • Classical, acrally accentuated mechano-bullous form (blistering only at mechnaically stressed sites).
  • Generalized, inflammatory form, clinically corresponding to bullous pemphigoid (blistering ubiquitous).
  • Localized form with the appearance of scarring pemphigoid.

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

Etiopathogenesis
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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.

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

Clinical features
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Integument:

  • In the classic form of the disease, tight, non-inflammatory blisters of various sizes are found, mainly 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) proceeds under the image of a bullous pemphigoid as a generalized, itchy, inflammatory disease under the image of a bullous pemphigoid.
  • Another variant is localized scarring pemphigoid Brunsting-Perry.

Extracutaneous manifestations: In rare cases 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, regional enterocolitis (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 epithelium and stratum proprium.

Histology
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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.

Direct Immunofluorescence
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Linear IgG andC3 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 deposition can be detected, which is typical of EBA: the so-called u-serrated pattern (Br J Dermatol. 2004 Jul;151(1):112-8). 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 used by very few centers and is reserved for special cases.

Indirect immunofluorescence
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IgG and/or IgA autoantibodies against type VII collagen can be detected serologically in about 50-60% of patients. The detection is initially performed by indirect IF with salt-split skin as substrate. In MSDs, the autoantibodies bind to the bottom of the artificial bladder. However, this does not prove the presence of MSDs, as the p200 antigen and laminin-332 are also expressed at the bottom of the bladder.

By means of ELISA (NC1/NC2) or immunochip (with COL7 expressing cells) the detection of collagen 7 specific antibodies can be performed. Also possible is the detection by Western blot on dermal extract with the detection of one band at 290 kD.

Diagnosis
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Clinical and evidence of an u-serrated pattern in direct IF assure the diagnosis.

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

  1. Serological detection of type VII collagen specific autoantibodies
  2. Immunoelectron Microscopy
  3. FOAM

Differential diagnosis
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Therapy
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Overall, the aggressiveness of the treatment should be adapted to the acute nature of the disease.

External therapy
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In case of localized epidermolysis, external glucocorticoids may be sufficient (e.g. Ecural solution). Avoidance or therapy of secondary infections and pressure relief.

Internal therapy
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  • Systemic therapy is indicated for generalisation or mucosal involvement. Only some patients (especially those with highly inflammatory components) respond well to monotherapy with systemic glucocorticoids, medium dosage (60-80 mg/day prednisone equivalent). Therefore, the combination of glucocorticoids with the following immunosuppressive drugs should be aimed at:
  • Therapy can also be tried with high doses of vitamin E (e.g. Evit Kps.) 600-1200 mg/day. In individual cases, complete healing is described under this therapy, but the improvement only occurs over a long period of time.
  • Newer therapy approaches:
    • IVIG: Immunoglobulins (e.g. pentaglobin) 5 ml/kg bw/day i.v. on 3-7 consecutive days in combination with e.g. prednisolone or Ciclosporin A treatment should lead to better results. According to literature references, intravenous immunoglobulins seem to have a therapeutic effect only initially. Long-term improvements are not described below.
    • Plasmapheresis can reduce the maintenance dose of glucocorticoids and immunosuppressants as an accompanying measure.

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

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

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

Literature
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  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 neuroendocrine pancreatic 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. Elliot GT (1895) Two cases of epidermolysis bullosa. J Cutan Genitourinary Dis (Chicago) 13: 10-18
  6. Goebeler M, Zillikens D (2003) Blistering autoimmune diseases of childhood]. dermatologist 54: 14-24
  7. Hertl M, Schuler G (2002) Bullous autoimmune dermatoses. 1: Classification. dermatologist 53: 207-219
  8. Jappe U et al. (2000) Epidermolysis bullosa acquisita with ultraviolet radiation sensitivity. Br J Dermatol 142: 517-520
  9. Kasperkiewicz M et al(2016) Epidermolysis Bullosa Acquisita: From Pathophysiology to Novel Therapeutic Options. J Invest Dermatol 136:24-33.

  10. Ludwig RJ et al (2017) Mechanisms of Autoantibody-Induced Pathology.Front Immunol 8:603.

  11. Mohr C et al (1995) Successful treatment of epidermolysis bullosa acquisita using intravenous immunoglobulins. Br J Dermatol 132: 824-826

  12. Niederau D (1995) Epidermolysis bullosa acquisita - Successful treatment with dapsone in combination with glucocorticosteroids. Z Hautkr 70: 454-455
  13. Reddy H et al (2013) Epidermolysis bullosa acquisita and inflammatory bowel disease: a review of theliterature
    . Clin Exp Dermatol 38:225-229; quiz 229-30.
  14. Roenigk HH et al (1971) Epidermolysis bullosa acquisita: Reports of three cases and review of all published cases. Arch Dermatol 103: 1-10
  15. 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
  16. Schmidt E et al (2013) Pemphigoid diseases. Lancet 381:320-332.
  17. Trigo-Guzman FX et al (2003) Epidermolysis bullosa acquisita in childhood. J Dermatol 30: 226-229
  18. 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
  19. Vodegel RM et al (2002) IgA-mediated epidermolysis bullosa acquisita: two cases and review of the literature. J Am Acad Dermatol 47: 919-925
  20. Woodley DT et al (1984) Identification of the skin basement-membrane autoantigen in epidermolysis bullosa acquisita. N Engl J Med 310: 1007-1013

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Last updated on: 14.06.2022