Bullous Pemphigoid and Pemphigus Vulgaris

Bullous pemphigoid and pemphigus vulgaris are two different blistering autoimmune diseases. In bullous pemphigoid, autoantibodies attack the hemidesmosomes, which connect epidermal keratinocytes to the basement membrane. This attack results in large, tense subepidermal blisters. In pemphigus vulgaris, autoantibodies attack the desmosomal proteins, which connect the keratinocytes to one another. This attack results in a more severe, potentially fatal condition with fragile, flaccid blisters, usually with significant mucosal involvement. Diagnosis is made with biopsy and IF staining to identify and localize the antibodies. Management involves immunosuppression with corticosteroids and other steroid-sparing immunomodulatory agents.

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Overview

Definition

Bullous pemphigoid: 

  • A non–life-threatening, chronic autoimmune disease
  • Characterized by subepithelial bullae
  • Caused by loss of adhesion between the epidermis and dermis

Pemphigus vulgaris: 

  • A life-threatening, chronic autoimmune disease 
  • Characterized by intraepithelial bullae
  • Caused by loss of adhesion between keratinocytes (acantholysis)

Epidemiology and etiology

Bullous pemphigoidPemphigus vulgaris
Incidence per year6‒13 per 1 million0.1‒0.5 per 100,000
Age> 60 years old40‒60 years old
Gender predominanceWomen = menWomen = men
Racial/ethnic biasNoneMore common in:
  • Ashkenazi Jewish
  • Southeast Europe
  • Middle East
  • India
EtiologyNone have been proven, but several possible associations:
  • Drugs (particularly DPP-4 inhibitors)
  • Genetics
  • Trauma
  • Radiation therapy
  • UV light
Possible associations:
  • Drugs (most commonly penicillamine, captopril)
  • Genetics (HLA-DR4 and HLA-DR14)
  • UV light
DPP-4: dipeptidyl peptidase-4
UV: ultraviolet

Pathophysiology

Both bullous pemphigoid and pemphigus vulgaris are autoimmune diseases that attack anchoring connections of the epidermal keratinocytes.

Anatomy and physiology review

  • Desmosomes:
    • Junctional complex
    • Connect epidermal keratinocytes to each other
  • Hemidesmosomes:
    • Similar to desmosomes
    • Anchor the basal epidermal keratinocyte layer to the underlying basement membrane
    • Form the dermal–epidermal junction
Epidermal keratinocyte connections

Epidermal keratinocyte connections:
Desmosomes connect keratinocytes to each other, while hemidesmosomes anchor the basal layer of keratinocytes to the basement membrane.

Image by Lecturio.

Bullous pemphigoid

  • Type II hypersensitivity reaction
  • IgG autoantibodies attack hemidesmosomal proteins:
    • Targeted proteins: Bullous pemphigoid antigens BP180 and BP230
    • Activation of complement and mast cells → neutrophils and eosinophils release inflammatory mediators
    • Proteases are produced → cause the epidermis to separate from the dermis → result in large, tense bullae
  • Desmosomes connecting keratinocytes to each other remain intact → overlying skin is strong and taut

Pemphigus vulgaris

  • Type II hypersensitivity reaction
  • IgG autoantibodies attack desmosomal proteins: 
    • Targeted proteins: desmoglein (DSG) types 1 and 3
    • Disruption of desmosomes → epidermal layers break apart → acantholysis
    • Results in fragile, flaccid bullae that easily rupture
      • Dysfunctional skin barrier
      • Susceptible to secondary infection
  • Hemidesmosomes remain intact:
    • Basal layer of keratinocytes remain anchored to the basement membrane → “row of tombstones” appearance on histology
Pathophysiology of pemphigus vulgaris and bullous pemphigoid

Pathophysiology of pemphigus vulgaris and bullous pemphigoid:
A: Location of desmosomes and hemidesmosomes in epidermis
B: In pemphigus vulgaris, antibodies to desmoglein result in disruption of desmosomes, causing acantholysis and blistering within the epidermis.
C: In bullous pemphigoid, antibodies against hemidesmosomal proteins result in separation of the epidermis from the dermis.

Image by Lecturio.

Clinical Presentation

Bullous pemphigoid

  • Prodromal phase (lasting weeks to months):
    • Pruritus (moderate to severe)
    • Skin lesions may appear:
      • Papular
      • Eczematous plaques
      • Urticaria-like
  • Subepidermal bullae develop: 
    • Tense (not easily ruptured)
    • Large (1‒3 cm)
    • Contain clear fluid
    • Numerous and widespread
    • Appear on normal or erythematous skin
    • Frequently affected locations:
      • Lower abdomen
      • Axillae
      • Extremity flexures
      • Inguinal folds
      • Mucosal involvement (10%‒30% of patients)
  • Bullae rupture:
    • Leave moist erosions and crusting
    • No scarring

Pemphigus vulgaris

Pemphigus vulgaris is characterized by bullae with the following properties:

  • Superficial acantholytic blisters
  • Flaccid
  • Rupture very easily: 
    • Leads to erosions
    • Bleed easily
  • Painful
  • Appear on normal or erythematous skin
  • Can occur anywhere on the body, most commonly:
    • Mucosa (almost always present):
      • Oral (often 1st site) → odynophagia (painful swallowing) → malnutrition
      • Esophagus
      • Nasal mucosa → epistaxis
      • Conjunctiva
      • Vulva, vagina, and cervix
      • Penis
      • Anus
    • Cutaneous:
      • Face and scalp
      • Trunk
      • Groin and axilla
  • Secondary infection is common:
    • Purulent drainage
    • Surrounding erythema and induration

Diagnosis

Diagnosis involves checking for a Nikolsky sign, biopsies for routine histopathology and IF, and ELISA testing.

Recommended workup

  • Nikolsky’s sign → helps determine the location of the defect
    • Apply scraping pressure → look for skin sloughing or blister rupture
    • Positive: skin sloughing/rupture → disease within the epidermal layer
    • Negative: no skin sloughing or rupture disease at the dermal–epidermal junction
  • Skin biopsies → to assess the tissue itself:
    • Ideal biopsy sites:
      • Bullous pemphigoid: lesional skin
      • Pemphigus vulgaris: normal-appearing perilesional skin (or mucosa)
    • Routine histopathology (H&E staining)
    • Direct IF testing
  • Serum testing → to detect circulating antibodies
    • Indirect IF
    • ELISA
Comparison of test findings
TestBullous pemphigoidPemphigus vulgaris
Nikolsky’s signNegativePositive
H&E staining
  • Subepidermal nonacantholytic blisters
  • Full-thickness epidermis
  • Dermal inflammatory infiltrate
  • Eosinophilic spongiosis (early lesions)
  • Suprabasal acantholytic blisters
  • Row-of-tombstones appearance
  • Sparse inflammatory infiltrate in the dermis
IFLinear staining along the basement membraneStaining within the epidermis in a reticular (net-like) pattern
ELISAAutoantibodies against bullous pemphigoid antigens BP180 and BP230Autoantibodies against DSG-1 and DSG-3
Bullous&Pemphigus

Histology findings in bullous pemphigoid and pemphigus vulgaris:
A: H&E staining in bullous pemphigoid reveals a subepidermal bulla and numerous eosinophils.
B: H&E staining in pemphigus vulgaris reveals a suprabasal acantholytic blister. Note the row-of-tombstone appearance (a layer of keratinocytes still attached to the basement membrane).

Image A: “Disease stabilization with pembrolizumab for metastatic acral melanoma in the setting of autoimmune bullous pemphigoid” by Beck, K. M., Dong, J., Geskin, L. J., Beltrani V. P., Phelps R. G., Carvajal, R. D., Schwartz, G., Saenger, Y. M., Gartrell, R. D. License: CC BY 4.0, edited by Lecturio.

Image B: “A rare presentation of pemphigus vulgaris as multiple pustules” by Yang, Y., Lin, M., Huang, S. J., Min, C., Liao, W. Q. License: CC BY 2.0, edited by Lecturio.
Immunofluorescence bullous pemphigoid & pemphigus vulgaris

Immunofluorescence findings in bullous pemphigoid and pemphigus vulgaris:
A: In bullous pemphigoid, staining of complement and antibodies occurs at the dermal–epidermal junction.
B: In pemphigus vulgaris, staining of antibodies occurs within the epidermis in a reticular (net-like) pattern.

Image A: “A 74-year-old woman with a 1-month history of itching and skin rash” by Ghosh, S., Ghosh, A. K., Collier, A. License: CC BY 2.0, edited by Lecturio.

Image B: “Pemphigus immunofluorescence” by Emmanuelm. License: CC BY 3.0, edited by Lecturio.

Management

The goal of therapy for both bullous pemphigoid and pemphigus vulgaris is to decrease autoantibody production while minimizing drug-induced side effects.

Bullous pemphigoid

  • Mainstay initial therapy: 
    • Corticosteroids (topical or systemic):
      • Topical (localized disease): clobetasol propionate
      • Systemic (widespread disease): prednisone, prednisolone
    • Niacinamide
    • Tetracyclines (for anti-inflammatory effect):
      • Doxycycline
      • Tetracycline
      • Minocycline
  • Advanced and refractory disease:
    • Steroid-sparing immunomodulatory agents:
      • Mycophenolate mofetil
      • Azathioprine
      • Dapsone
      • Methotrexate
      • Cyclophosphamide
    • Biologic therapies: 
      • Monoclonal antibodies (e.g., rituximab)
      • Intravenous immunoglobulin (IVIG)
  • Prognosis: 
    • Chronic, relapsing course
    • Long-term remission is possible (after months to years).

Pemphigus vulgaris

  • Mainstay initial therapy:
    • Systemic glucocorticoids: prednisone
    • Steroid-sparing agents:
      • Rituximab
      • Azathioprine
      • Mycophenolate mofetil
      • Dapsone
      • Methotrexate
  • Refractory disease:
    • IVIG
    • Cyclophosphamide
  • Complications:
    • Secondary infection
    • Effects of long-term steroid use
  • Prognosis:
    • Often fatal without treatment
    • Sepsis is the leading cause of death.

Differential Diagnosis

  • Dermatitis herpetiformis: an uncommon autoimmune cutaneous eruption associated with celiac disease: Dermatitis herpetiformis presents with intensely pruritic, inflammatory blisters on extensor surfaces. Nikolsky’s sign is negative. Diagnosis is confirmed on biopsy and IF, which may show neutrophilic microabscesses and IgA deposits in the dermal papillary tips. Management includes dapsone and a gluten-free diet.
  • Stevens–Johnson syndrome: an immune-complex–mediated hypersensitivity reaction involving the skin and mucous membranes, commonly triggered by medications: After a flu-like prodromal phase, patients develop erythematous macules with purpuric centers, bullae, and skin sloughing. Mucosal involvement is very common. Nikolsky’s sign is positive. Diagnosis is clinical, and management is supportive. Withdrawal of the causative agent is required.
  • Staphylococcal scalded skin syndrome (SSSS): a life-threatening toxin-mediated disease, primarily of young children, caused by Staphylococcus aureus: DSG-1 is cleaved, resulting in diffuse cutaneous erythema, tenderness, formation of bullae, and superficial desquamation without mucosal involvement. Nikolsky’s sign is positive. Diagnosis is clinical and confirmed with culture data. Management is with antibiotics and supportive care.

References

  1. Yancey, K. B., Lawley, T. J. (2008). Immunologically mediated skin diseases. In Fauci, A. S., Braunwald, E., Kasper, D.L., et al. (Eds.) Harrison’s Internal Medicine. 17th Ed. pp. 336–338.
  2. Leiferman, K. M. (2019). Epidemiology and pathogenesis of bullous pemphigoid and mucous membrane pemphigoid. UpToDate. Retrieved February 17, 2021, from https://www.uptodate.com/contents/epidemiology-and-pathogenesis-of-bullous-pemphigoid-and-mucous-membrane-pemphigoid
  3. Leiferman, K. M. (2019). Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid. UpToDate. Retrieved February 17, 2021, from https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-bullous-pemphigoid-and-mucous-membrane-pemphigoid
  4. Murrell, D. F., Ramierz-Quizon, M. (2020). Management and prognosis of bullous pemphigoid. UpToDate. Retrieved February 17, 2021, from https://www.uptodate.com/contents/management-and-prognosis-of-bullous-pemphigoid
  5. Baigrie, D. (2020). Bullous pemphigoid. StatPearls. Retrieved February 17, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/18699/ 
  6. Peraza, D.M. (2020). Bullous pemphigoid. Merck Manual Professional Version. Retrieved February 18, 2021, from https://www.merckmanuals.com/professional/dermatologic-disorders/bullous-diseases/bullous-pemphigoid
  7. Hertl, M., Sitaru, C. (2020). Pathogenesis, clinical manifestations, and diagnosis of pemphigus. UpToDate. Retrieved February 17, 2021, from https://www.uptodate.com/contents/pathogenesis-clinical-manifestations-and-diagnosis-of-pemphigus 
  8. Hertl, M., Geller, S. (2020). Initial management of pemphigus vulgaris and pemphigus foliaceus. UpToDate. Retrieved February 17, 2021, from https://www.uptodate.com/contents/initial-management-of-pemphigus-vulgaris-and-pemphigus-foliaceus 
  9. Ingold, C. (2021). Pemphigus vulgaris. StatPearls. Retrieved February 17, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/26884/ 
  10. Peraza, D. M. (2020). Pemphigus vulgaris. Merck Manual Professional Version. Retrieved February 18, 2021, from https://www.merckmanuals.com/professional/dermatologic-disorders/bullous-diseases/pemphigus-vulgaris

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