section name header

Info


A. Definition

  1. A blistering disorder predominantly affecting the elderly
  2. Skin lesions are very pruritic and may initially be mistaken for urticaria
  3. Oral lesions are rare
  4. Family of Autoimmune Blistering Diseases [4]
    1. Bullous Pemphigoid (BP, 74% of cases)
    2. Cicatricial Pemphigoid (12%)
    3. Herpes Gestationis (4%)
    4. Linear IgA Dermatitis (5%)
    5. Chronic Bullous Disease of Childhood
    6. Epidermolysis Bullosa Acquisita (3%)
    7. Bullous Systemic Lupus Erythematosus (SLE; 2%)
  5. Pemphigoid: subepidermal blister (contrast pemphigus vulgaris)

B. Symptoms and Signs of BP

  1. Occurs mainly in late adulthood (>60 years of age)
  2. Intact blisters usually filled with clear fluid but may become hemorrhagic
  3. Round to oval, tense blisters
  4. Urticarial plaques, erosions
  5. Pruritis often prominant
  6. Lesions usually on abdomen, flexor forearms, lower legs
  7. Cannot extend the blisters with fingers (negative Nikolsky sign)
  8. Disease was fatal in many patients prior to glucocorticoid therapy

C. Pathology of BP [4]

  1. Subepidermal Blister
    1. Many infiltrating neutrophils and eosinophils
    2. Early lesions may be restricted to eosinophils
    3. Blister formation occurs within lamina lucida of basement membrane
    4. Loss of anchoring filaments and hemidesmosomes
  2. Antibody (Ab) mediated Inflammatory Disease
    1. Type II Hypersensitivity
    2. Prelesional skin shows linear IgG and C3 deposition along basement membrane
    3. Symptomatic skin shows Immunoglobulin (IgM/IgG) and complement (C') deposition
    4. Ig and C' are found on epithelial basement membrane
    5. Complement mediated destruction of normal basement membrane occurs
    6. Eosinophils are activated by C5a, Mast cells by C3a
  3. Autoantiboides are specific for various hemidesmosomal proteins (see below)
  4. Fibrin clot may form between dermis and epidermis
  5. Cell detachment occurs due to inflammatory response causing blisters

D. Bullous Pemphigoid Antigens (BPAG) [4]

  1. BP auto-Abs found within the lamina lucida of BMZ (basement membrane zone)
  2. Immunoprecipitation identifies primary 220-240K (230K) and another 180K protein
    1. Primary 230K protein called BPAG1
    2. Secondary 180K protein found in ~50% of BP patients called BPAG2
    3. Both antigens are key components of the hemidesmosome
    4. Hemidesmosomes mediate linkage of intermediate filaments to basement membrane
  3. BPAG1 (230K)
    1. Intracellular protein that is one of the plakins
    2. Occurs in the hemidesmosome within the cell
    3. Links BPAG2 (transmembrane protein) to cytoskeletal keratins
  4. BPAG2 (180K)
    1. Unique transmembrane protein with two extracellular domains
    2. Short-non-collagenous ectododomain adjacent to the plasma membrane
    3. Long collagenous external domain interacts with anchoring proteins of basement membrane including Type VII collagen
    4. Also called Type XVII collagen due to the collagenous repeats
    5. BPAG2 involved in other blistering diseases (see below)
  5. BPAGs are also expressed in injured epithelia; may play a role in wound healing

E. Treatment of BP [3]

  1. Glucocorticoid [5]
    1. Topical high potency glucocorticoid more effective and safer than systemic for severe disease
    2. Clobetasol propionate cream (40mg/d) is recommended topical for severe disease
    3. Clobetasol associated with 76% 1-year survival versus 58% with 1mg/kg/d prednisone
    4. Oral prednisone 0.5mg/kg or high potency topical agent for moderate disease
  2. Immunosuppressive Agents
    1. Usually used as glucocorticoid-sparing drugs
    2. Usually given with glucocorticoids at onset of severe disease
    3. Mycophenolate mofetil (CellCept®) 1-2gm qd is probably least toxic and is effective [6]
    4. Combination of mycophenolate and glucocorticoids has cleared refractory BP [6]
    5. Azathioprine (Imuran®) is typically used at 2-3mg/kg/day orally
    6. Methotrexate (Rhematrex®) may be used in patients unable to tolerate glucocorticoids
    7. Cyclophosphamide (Cytoxan®) - 1-4mg/kg/day orally (only for resistant cases)
  3. Plasmapheresis may be used in severe cases
  4. Doxycycline 100mg po bid may be of some benefit as glucocorticoid sparing agent [3]

F. Cicatricial Pemphigoid [3,4]

  1. Rare blistering disease of mucous membranes and skin
    1. Severe erosive mucous membrane lesions predominate and heal with scarring
    2. Skin involvement in ~33% of patients (scalp, face, upper trunk)
    3. Ocular involvement can occur with conjunctivitis
  2. Female : Male is 2:1
  3. Typical age of onset 40-60 years
  4. Blisters are subepidermal, surrounded by mixed inflammatory infiltrate
    1. Mucous membrane lesions usually involve mononuclear cells, plasma cells, histiocytes
    2. Skin lesions usually involve eosinophils and neutrophils
  5. Direct immunofluorescence: linear deposition of C3 and IgG on basement membrane
  6. Autoantigens: BPAG2, integrin ß4, laminin-5 or -6, type VII collagen
  7. Treatment
    1. Mild lesions and oral mucosa: topical glucocorticoids (gel or occlusive base)
    2. Swish and spit dexamethasone (Roxane®) mouthwash for oral lesions
    3. Dapsone may be of benefit
    4. Systemic glucocorticoids ± dapsone for severe cases
    5. Severe ocular involvement: prednisone with azathioprine or cyclophosphamide
  8. Aggressive early treatment is essential or lesions can be devastating

G. Other Bullous Diseases [3,4]

  1. Linear IgA Dermatitis
    1. Rare autoimmune bullous disorder, occurs in age >30 years
    2. Heterogeneous, pruritic, involves extensor surface, mucous membranes (70%)
    3. Autoantigens: BPAG2, Type VII Collagen, LAD-1
    4. LAD-1 is a 97K protein in lamina lucida that may be a processed form of BPAG2
    5. Subepidermal blister with linear IgA deposition along basement membrane
    6. Collections of neutrophils along basement membrane, occasionally on papillary tips
    7. Lesions respond rapidly to dapsone or sulfapyridine (see above)
    8. Low dose prednisone may be used initially to suppress new blister formation
    9. Disease may be chronic with waxing and waning course
  2. Chronic Bullous Disease of Childhood
    1. Unknown frequency, occurs in children <5 years old
    2. Similar pathology to linear IgA Dermatitis
    3. Tense blisters, perineal and perioral, mucous membranes (70%)
    4. Autoantigens: BPAG2, Type VII Collagen, LAD-1
    5. Treatment similar to linear IgA dermatitis
    6. Self limited within 2 years
  3. Herpes Gestationes
    1. Mainly occurs during 2nd or 3rd trimester of gestation, some post-partum
    2. Papulovesicular, pruritic, involvement of abdomen, self-limited
    3. Autoantigen: BPAG2
  4. Epidermolysis Bullosa Acquisita (EBA)
    1. Adults, associated with inflammatory bowel disease
    2. Tense blisters, noninflammatory, fragile skin, scarring, milia, acral distribution
    3. Autoantigen: Type VII Collagen
  5. Bullous SLE
    1. Occurs in patients with SLE or history of SLE
    2. Resembles EBA and SLE skin lesions
    3. Autoantigen: Type VII Collagen

References

  1. Leung DYM, Diaz LA, DeLeo V, Soter NA. 1997. JAMA. 278(22):1914 abstract
  2. Nousari HC and Anhalt GJ. 1999. Lancet. 354(9179):667 abstract
  3. Bickle KM, Roark TR, Hsu S. 2002. Am Fam Phys. 65(9):1861 abstract
  4. Stern RS. 2002. NEJM. 346(5):364 abstract
  5. Joly P, Roujeau JC, Benichou J, et al. 2002. NEJM. 346(5):321 abstract
  6. Grundmann-Kollmann M, Korting HC, Behrens S, et al. 1999. J Am Acad Dermatol. 40:957 abstract