Core Dermatology Diagnoses / CategoriesInflammatory

Bullous pemphigoid

Author: Resident Reviewer:

Publish date: Posted on
Last updated: May 11, 2022

Keywords #

bullous pemphigoid
BP
blistering
bullae
autoimmune
BP180
BP230
DIF
IIF
subepidermal

Diagnosis #

Bullous pemphigoid (BP) is the most common immune-mediated subepidermal blistering disease. BP is caused by an autoimmune response against antigens BP180 and BP230, both components of the hemidesmosome, which are adhesion complexes at the dermal-epidermal junction [1]. Antibodies directed against BP180 and BP230 result in downstream complement activation and infiltration of immune cells, ultimately leading to destruction of the dermal-epidermal junction and subsequent blister formation [1, 2]. BP classically presents as an intensely pruritic eruption with blister formation, although the clinical presentation is broad [3]. It is a chronic disease with spontaneous remissions and exacerbations occurring throughout the disease course.

Key Concepts #
  • BP is a subepidermal blistering disease caused by autoimmune response against the hemidesmosome components BP180 and BP230.
  • BP classically presents in the elderly with pruritus and tense blisters on normal appearing skin. The disease can also affect the mucosal surfaces.
  • First line therapy for extensive disease is oral corticosteroids. Other common treatment modalities include systemic immunomodulatory agents.
Epidemiology #

The prevalence of BP is estimated to be about 0.012% in the United States, although prevalence is highly varied by country. The disease classically affects the elderly population, with onset typically occurring after the age of 70 [4,5]. Men are more commonly afflicted than women [5]. Although rare, BP can also occur in children. Some cases of BP are reported to be triggered by medications.  These medications include furosemide and NSAIDS among others [2].

Clinical Features #
  • Classic lesions begin as localized or widespread tense blisters on normal or erythematous skin [6]. Blisters most commonly develop on the abdomen and flexural surfaces [3].
  • After a few days, blisters will rupture and leave behind erosions and crusting which eventually heal without scaring [3].
  • The presentation is accompanied by intense pruritus [3].
  • 10-30% of people will also develop mucosal lesions, most commonly of the oral cavity [7].
  • Blistering eruption can be preceded by weeks of prodromal pruritus alone or in association with excoriated, eczematous, papular, or urticarial lesions [3, 7].
Differential Diagnoses #

    Nonbullous phase differential:

  • Drug reaction
  • Contact dermatitis
  • Prurigo
  • Urticarial dermatoses
  • Arthropod reactions

    • Bullous phase differential:

  • Pemphigus group
  • Dermatitis herpetiformis
  • Epidermolysis bullosa acquisita
  • Linear IgA bullous dermatosis
  • Mucous membrane pemphigoid
  • Pemphigoid incipiens
  • Bullous lupus erythematosus
  • Bullous arthropod bites
  • Allergic contact dermatitis
  • Bullous impetigo
  • Stevens Johnson Syndrome
  • Dyshidrotic eczema
  • Pseudoporphyia or porphyria cutanea tarda
Diagnostic Workup #

Diagnosis depends on a combination of clinical criteria, histopathology, direct immunofluorescence (DIF) microscopy, and serological studies. Tissue samples for DIF should always be obtained from uninvolved perilesional skin. In the bullous phase, H&E will show a subepidermal blister with a net of fibrin and inflammatory cells and a dermal infiltrate consisting of eosinophils and neutrophils. In the non-bullous phase, findings are non-specific. DIF is the most reliable and sensitive diagnostic test for BP [7]. The diagnostic hallmark consists of a linear deposition of IgG and/or C3 along the epidermal basement membrane [6]. Antibody deposition in salt-split skin reveals deposition on the epidermal side (roof) of the skin [7].

Serological studies include indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA), and are used to detect presence of circulating antibodies. The substrate of choice for IIF studies is salt-split human skin, but other substrate choices include monkey esophagus or normal skin [6]. Around 60-80% of patients will have circulating anti-basement membrane zone antibodies that will bind to the epidermal side of salt-split skin [8] or monkey esophagus. BP180 and BP230 antibodies can also be detected in the serum using ELISA [6].

Treatment #

Treatment is guided by disease severity. Treatment options include topical and oral corticosteroids or other oral immunosuppressive therapies. First line treatment for moderate-to-severe disease include oral corticosteroids or high-dose topical corticosteroids [6]. For refractory or unresponsive disease, most frequently used therapies include azathioprine, chlorambucil, dapsone, mycophenolate mofetil, methotrexate, or the combination of tetracycline antibiotics plus nicotinamide [6, 9].

Localized or mild disease is most frequently treated with high-dose topical steroids. Systemic corticosteroids or anti-inflammatory antibiotics can also be used. IVIG, rituximab, omalizumab, and plasmapheresis are reserved for treatment-resistant cases [6]. Dupilumab has also recently shown some promise in small case series [10].

References #
  1. Yang, M., et al., The pathogenesis of bullous skin diseases. J Transl Autoimmun, 2019. 2: p. 100014.
  2. Genovese, G., et al., New Insights Into the Pathogenesis of Bullous Pemphigoid: 2019 Update. Front Immunol, 2019. 10: p. 1506.
  3. Schmidt, E. and D. Zillikens, Pemphigoid diseases. Lancet, 2013. 381(9863): p. 320-32.
  4. Wertenteil, S., et al., Prevalence estimates for pemphigoid in the United States: A sex-adjusted and age-adjusted population analysis. J Am Acad Dermatol, 2019. 80(3): p. 655-659.
  5. Kridin, K. and R.J. Ludwig, The Growing Incidence of Bullous Pemphigoid: Overview and Potential Explanations. Front Med (Lausanne), 2018. 5: p. 220.
  6. Venning, V.A., et al., British Association of Dermatologists’ guidelines for the management of bullous pemphigoid 2012. Br J Dermatol, 2012. 167(6): p. 1200-14.
  7. Di Lernia, V., et al., Pemphigus Vulgaris and Bullous Pemphigoid: Update on Diagnosis and Treatment. Dermatol Pract Concept, 2020. 10(3): p. e2020050.
  8. Kelly, S.E. and F. Wojnarowska, The use of chemically split tissue in the detection of circulating anti-basement membrane zone antibodies in bullous pemphigoid and cicatricial pemphigoid. Br J Dermatol, 1988. 118(1): p. 31-40.
  9. Salman, S., et al., Treatment options for autoimmune bullous dermatoses other than systemic steroids: A systematic review and network meta-analysis. Dermatol Ther, 2020: p. e13861.
  10. Abdat, R., et al., Dupilumab as a novel therapy for bullous pemphigoid: A multicenter case series. J Am Acad Dermatol, 2020. 83(1): p. 46-52.
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