bullous pemphigoid; parapemphigus

Introduction

Autoimmune disorder characterized by a chronic vesiculobullous dermatitis. (Also see cicatricial pemphigoid)

Etiology

• autoantibody to antigens on the surface of basal keratinocytes extending into the lamina lucida of the epidermal basement membrane
• complement activation
• attraction of neutrophils & eosinophils
• may be drug-induced
  • furosemide, antibiotics

Epidemiology

• two age groups: children & individuals 60-80 years of age
• no sex preference
• most common autoimmune bullous disease
  • up to 4.3 cases/100,000/year

Pathology

• neutrophils in single file at dermal-epidermal junction
• neutrophils, eosinophils & lymphocytes in papillary dermis
• subepidermal bullae
  • regeneration of the bullae floor
  • no acantholysis
• IgG & C3 deposits along the epidermal basement membrane
  • IgG directed against BP180 & BP230
• C3 deposits along the epidermal basement membrane may occur in the absence of IgG
• loss of dermal-epidermal adherence
• electron-microscopy:
  • junctional cleavage (split in lamina lucida of epidermal basement membrane)
  • immunoelectron microscopy: deposition of IgG at the lamina lucida & hemidesmosomes

* histopathology images

Genetics

• associated with defects in COL17A1 (BP180)

Clinical manifestations

• lesions often begin as prodromal intense pruritus or erythematous urticaria resembling erythema multiforme with evolution to tense bullae in weeks to months
  • thus patients may present with urticaria
  • lesions are not painful
  • tense bullae & prurtitus often presenting symptoms
• bullae may arise in normal or erythematous skin
• bullae do not rupture easily (tense, not flaccid)
  • some bullae may open in oval erosions with serous exudate
  • bullae do not coalesce when they do break
• lesions may be localized or generalized & scattered
• distribution: axillae, medial thighs & groin, abdomen, flexor aspect of forearms, lower legs (often 1st involved)
• in the elderly, most common on the trunk, limbs & flexural surfaces
• mucous membrane involvement
  • mouth, anus, vagina, conjunctiva
  • less common & less severe & painful than pemphigus (uncommon)
  • present in ~ 1/3 of patients
  • ~ 20%, rare in drug-induced pemphigoid
  • generally does not present with oral lesions
• other patients may present with prurigo nodularis-like lesions
• Nikolsky sign is negative

* images

Laboratory

• epidermal basement membrane IgG Ab in serum detected by indirect immunofluorescence in 70% of patients
  • ELISA using antibodies to bullous pemphigoid autoantigen-2 (COL171A, BP180), see anti-basement membrane antibody
  • check titer before discontinuing immunosuppressive therapy
  • titers do not correlate with course of disease
  • anti BP230 (gene on 6p) [homology with desmoplakin]
  • anti BP180 (gene on 10q) [transmembrane protein]
  • routine serum testing had been performed with monkey esophagus as substrate
  • sensitivity increased by use of NaCl-split human skin as substrate
    • antibodies localize to epidermal side of substrate or occasionally both epidermal & dermal side of substrate
    • in epidermolysis bullosa aquisita, antibodies localize only to dermal side of substrate
  • the major subclass of antibody is IgG4
• eosinophilia
• skin biopsy:
  • direct immunofluorescence testing of perilesional skin
  • histopathology of lesional skin
  • immunoelectron microscopy
• see ARUP consult

Complications

• not associated with increased risk of malignancy
• not associated with increased mortality
• 6-fold increase in mortality
• 5-fold increase in cardiovascular mortality

Differential diagnosis

• pemphigus - Nikolsky sign is positive
• erythema multiforme - target lesions
• dermatitis herpetiformis
  • clustered fragile vesicles break down quickly
    • leaves small erosions on the elbows, knees, or buttocks
  • intensely pruritic
  • does not involve the oral mucosa
• epidermolysis bullosa aquisita

Management

• oral glucocorticoid alone or combined with azathioprine
  • prednisone: start 50-100 mg PO QD
  • methylprednisolone 0.5 mg/kg/day with taper
• azathioprine
  • 150 mg PO QD for remission
  • 50-100 mg PO QD for maintenance
• mycophenolate 2 g/day may be used in combination with glucocorticoid
• cyclophosphamide
• rituximab 500 mg infused weekly for 4 weeks in conjunction with prednisolone 0.5 mg/kg/day tapered rapidly
• intravenous immune globulin
• dapsone 100-150 mg PO QD for milder cases
• topical steroids for very mild cases & for local recurrences
• tetracycline with or without nicotinamide may be of benefit

More general terms

• pemphigoid

Additional terms

• bullous pemphigoid antigen 1; trabeculin-beta; hemidesmosomal plaque protein; dystonia musculorum protein (DST, BPAG1, DMH, DT, KIAA0728)
• cicatricial pemphigoid (benign mucous membrane pemphigoid)
• dermatitis herpetiformis; Duhring-Brocq disease
• epidermolysis bullosa aquisita
• erythema multiforme
• pemphigus
• vesicular lichen planus

Patient information

bullous pemphigoid patient information

Database

• OMIM: https://mirror.omim.org/entry/113810
• OMIM: https://mirror.omim.org/entry/113811