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Bullous Pemphigoid (BP)

  • #1 subepidermal autoimmune bullous disease -annual incidence 6-13 per million 
  • Often > 60 years old
  • Incidence ↑with age
  • males ˃ females
  • HLA associations: Caucasians DQB1*0301; Japanese DRB1*04, DRB1*1101, DQB1*0302

  • Target antigens belong to hemidesmosome/anchoring filaments
    • BP180/BPAG2/Type 17 collagen
    • BP230/BPAG1
  • -Involvement of cellular (Th1/Th17/Th2 CD4+ T-cells) and humoral (IgG4 > IgG1 >IgM, IgA and/or IgE antibodies) results in cascade of events leading to subepidermal blistering 
  • Other factors involved in pathogenesis:
    • Complement activation 
    • mast cells/eosinophils

  • Pre-bullous phase:
    • Prodrome lasting weeks/months 
    • Pruritus ± excoriations (BP incipiens)
    • Morphologic variants: eczematous, papular, PN-like, urticarial lesions
  • Bullous phase:
    • Tense vesicles/bullae on normal or urticarial/figurate base
    • Favors flexural, lower trunk, abdomen, intertriginous zones areas
    • Oral cavity (10-30%); rarely other mucosa
    • Resolution with hyper- or hypopigmentation ± milia
  • Labs: Eosinophilia (50%), high IgE is common
  • Associations
    • Trauma, burns, radiotherapy, PUVA
    • Dermatoses: psoriasis, lichen planus
    • Neurological disorders: Parkinson disease, dementia, psychiatric disorders, strokes, multiple sclerosis
  • Clinical variants
    • Dyshidrosiform pemphigoid 
    • Pemphigoid vegetans 
    • Vesicular pemphigoid
    • TEN-like
    • Erythrodermic pemphigoid
    • Lichen planus pemphigoides
    • Pemphigoid gestationis
    • Infantile 
    • Localized lesions: pretibial, vulvar, peristomal, umbilical, distal end of amputated limb (stump pemphigoid), paralyzed limb, sites of radiotherapy, Brunsting-Perry form
    • Drug-induced 
      • Diuretics (furosemide, spironolactone)
      • NSAIDs (ibuprofen, topical diclofenac)
      • Antibiotics (penicilline, ciprofloxacin)
      • ACE inhibitors (captopril)
      • TNF-α inhibitors 
      • Potassium iodide
      • Vaccines
      • Dipeptidyl peptidase-4 inhibitors (gliptins)
      • Checkpoint inhibitors (pembrolizumab) 
      • Gold
      • Sulfasalazine 
      • Penicillamine

Sample a complete intact small vesicle or edge of a larger bulla for H& E

Histopathology

  • pre-bullous phase: eosinophilic spongiosis 
  • bullous: subepidermal blister with superficial dermal infiltrate of eosinophils and mononuclear cells;
  • Peri-lesional bx for DIF, favor above the waist to avoid false –

Positive DIF microscopy 

  • Linear IgG and/or C3 along epidermal basement membrane – higher sensitivity than IIF and ELISA
  • False positives: bullous scabies

If DIF negative

  • Serration analysis: n-serrated (BP and LABD) vs. u-serrated (EBA)
  • IIF microscopy: salt-split normal human skin as assay: anti-basement membrane IgG autoantibodies in 60-80% of patients on epidermal or epidermal/dermal sides
  • ELISA: BP180 or BP230 antibodies in serum; fairly specific (≥90%)

Others: immunoblot, immunoprecipitation, immunelectron microscopy

Non-bullous: broad ddx of pruritic disorders in elderly

Bullous: Inflammatory EBA, LABD, MMP, bullous arthropod bites, ACD, Stevens-Johnson syndrome, bullous drug eruptions, dyshidrotic eczema, pseudoporphyria, PCT, pemphigus group, DH

Mild or localized disease

  • First line: Superpotent topical corticosteroids (clobetasol diproprionate)
  • Second line:
    • Systemic corticosteroids (SCS) – prednisone 0.5-1 mg/kg/day x 1-2 weeks (or until no new lesions or no pruritus for 2 weeks) then taper over 6-9 months (use caution in elderly)
    • Minocycline/doxycycline/tetracycline ± nicotinamide(0.5-2 g/day)
    • Dapsone – if mucosal involvement 
    • Erythromycin, penicillin, sulfonamides
    • Topical immunomodulators (tacrolimus)

Extensive disease (>10 new blisters/day or inflammatory lesions over large body surface area) or persistent disease

  • First line: 
    • Superpotent topical corticosteroids (see above) – same efficacy as SCS with few systemic side effects and lower mortality 
    • SCS – occasionally requires pulse methylprednisolone for rapid control 
    • Second line: if no response or contraindications to SCS Azathioprine (0.5-2.5 mg/kg/day), mycophenolate mofetil (1.5-3 g/day), methotrexate (7.5-15 mg/week)
    • Other: IVIG, plasma exchange, rituxumab, omalizumab, dupilumab
  • Treat for 6-12 months 

Prognosis:

  • Chronic disease with spontaneous exacerbation
  • Risk factors for relapse: extensive disease, dementia
  • 50% relapse after end of treatment
  • 10-40% mortality in elderly patients in 1st year