Autoimmune blistering diseases

Autoimmune blistering diseases are skin conditions characterized by the formation of blisters, which are the result of the destruction of cellular or extracellular adhesion molecules by antibodies. The three most significant autoimmune blistering diseases are bullous pemphigoid, pemphigus vulgaris, and dermatitis herpetiformis. The most common among these is bullous pemphigoid, which leads to the formation of large, tense bullae. It is a chronic disease that mainly affects elderly individuals and responds well to treatment with steroids. Pemphigus vulgaris, which is characterized by fragile, superficial flaccid bullae that leave crusted erosions, is a rare condition that occurs mainly in middle-aged adults. In contrast to bullous pemphigoid, it is a severe condition that is more difficult to treat and can be fatal. Dermatitis herpetiformis mainly affects the extensor surfaces of the extremities and is associated with celiac disease. It has a chronic course that leads to the formation of intensely pruritic papules and vesicles. In addition to evaluating clinical appearance, the Nikolsky sign, Tzanck test, skin biopsy, and direct immunofluorescence are indicated to confirm the diagnosis. Serologic testing of autoantibodies may also be useful. Management usually consists of oral and topical steroids, as well as immunosuppressive therapy.

In bullows (bullous) pemphigoid, antibodies attack the hemidesmosomes located below the epidermis.

References:^{[1][2][3][4][5][6][7][8][9][10]}

Variant forms of bullous pemphigoid

Gestational pemphigoid ^[11]

• Definition: bullous, pemphigoid-like dermatosis during pregnancy of unknown cause (most likely immunological)
• Epidemiology: 1:50,000 pregnancies (in the US)
• Clinical features
  • Commonly starts in the periumbilical region during the 2^nd and 3^rd trimester
  • Intensely pruritic, mostly non-blistering lesions (eczema, urticarial or papular lesions) on extremities and mucous membranes
  • Grouped vesicles with herpetiform appearance (“gestational herpes”) usually occur as the disease advances.
• Diagnostics: The diagnosis is confirmed via biopsy and immunofluorescence.
• Prognosis
  • Usually self-limiting; heals spontaneously after delivery; , but associated with complications (e.g., premature labor; , increased lifetime risk of autoimmune disease)
  • Recurrence is possible, especially appearing:
    • Spontaneously in the postpartum period
    • In subsequent pregnancies
    • When taking contraceptives containing progestin or estrogen
    • During menstruation
  • Infants born to women with gestational pemphigoid can develop transient blistering that resolves spontaneously.

Variant forms of pemphigus vulgaris

Pemphigus foliaceus ^[12][13][14]

• Etiology: : autoimmune disease (only antibodies against desmoglein 1 detectable)
• Clinical features
  • Bullae in the epidermis; , which burst spontaneously because of their superficial location
  • Localized mainly on the face, head, stomach, and back
  • Almost never with mucosal involvement (unlike pemphigus vulgaris)
• Treatment
  • First-line: systemic steroids
  • Dapsone
  • Topical steroids

Epidermolysis bullosa (EB)

Epidermolysis bullosa simplex (EBS)

• Definition: a genetic condition that causes the skin to become very fragile and blister easily in response to minor injury or friction
• Epidemiology: EBS is the most common type of EB.
• Etiology
  • Autosomal dominant inheritance
  • Mutations in keratin genes (e.g., KRT5, KRT14)
• Pathophysiology: mutations in keratin proteins → defective assembly of keratin filaments → disruption of the basal layer of keratinocytes → ↑ fragility of epithelial tissue

• Diagnostics
  • First-line: skin biopsy; (e.g., showing intraepidermal cleavage in localized EBS) ^[17]
  • Genetic testing may be considered to screen for EBS in the presence of family history.
• Management: mostly supportive, including wound care and pain management (nonopioid analgesics, e.g., acetaminophen)

Epidermolysis bullosa acquisita (EBA) ^[18][19]

• Definition: acquired autoimmune disease with subepidermal blistering; associated with other autoimmune diseases
• Epidemiology: onset in adulthood (usually 40–60 years of age)
• Etiology: autoantibodies targeted against type VII collagen
• Clinical features
  • Non-inflammatory form (most common): tense vesicles and blisters on extensor surfaces that are prone to trauma (e.g., hands, knees, knuckles)
  • Inflammatory form: tense bullae and vesicles similar to bullous pemphigoid
• Diagnostics
  • Direct/indirect immunofluorescence
  • ELISA: detection of IgG antibodies against type VII collagen
• Management
  • Systemic steroids, immunosuppressants
  • Avoid physical trauma to skin

Other variants and subtypes

Mucous membrane pemphigoid (MMP) ^[20]

• Definition: : chronic autoimmune blistering disease that affects the mucous membranes and heals with scarring
• Epidemiology: : most frequently affects elderly individuals
• Etiology
  • Deposition of autoantibodies against components of the epithelial basement membrane
  • Associated with HLA-DQB1*0301 allele
• Clinical presentation
  • Blistering lesions primarily in the oral mucosa and conjunctiva, but the nasal and genital mucosa may also be affected
  • In ⅓ of patients, skin involvement with scarring is also observed.
  • If only the conjunctiva are affected: ocular cicatricial pemphigoid
• Treatment: steroids (additional/other immunosuppressants according to severity)

References:^[21][22]

In addition to evaluating clinical appearance, specific tests are performed to confirm the diagnosis of a blistering disease. For specific diagnostic findings, see differential diagnosis of autoimmune blistering diseases.

• Nikolsky sign
  • Slight mechanical pressure (by rubbing) is exerted on the skin → upper epidermal layer slips away from lower layer →separation of epidermis → blistering
  • Test is positive on previously unaffected skin
  • Nikolsky sign is present in pemphigus vulgaris , toxic epidermal necrolysis, staphylococcal scalded skin syndrome, scalding, bullous impetigo, and Stevens-Johnson syndrome
  • Not present in bullous pemphigoid
• Tzanck test
  • Microscopic examination of scrapings from the base of a lesion to look for Tzanck cells
  • Tzanck cells (multinucleated giant cells) are present in:
    • Pemphigus vulgaris
    • Herpes simplex type 1 (HSV-1) infection
    • Varicella zoster virus infection (chickenpox or shingles)
    • Cytomegalovirus
  • No detection of Tzanck cells in:
    • Bullous pemphigoid
    • Dermatitis herpetiformis
• Skin biopsy: the specimen is taken from the perilesional area and is analyzed with
  • Histology
  • Direct immunofluorescence (DIF): Autoantibodies directed against bullous pemphigoid antigen of the epithelial basement membrane
• Serology
  • Bullous pemphigoid: anti-hemidesmosome antibodies: IgG antibodies against hemidesmosomes (an epithelial cell junction that connects basal cells to underlying basement membrane)
  • Pemphigus vulgaris: anti-desmoglein antibodies: IgG antibodies against desmoglein-1 and/or desmoglein-3 (desmogleins are components of desmosomes, a cell-to-cell connection that mediates keratinocyte adherence in stratum spinosum)
• Other tests
  • Serum testing with indirect immunofluorescence (IDIF): Detection of circulating autoantibodies
  • In addition in dermatitis herpetiformis: small intestine biopsy

References:^[5][7][23]