Bullous Pemphigoid

Bullous pemphigoid is the most common autoimmune blistering disorder in the adult population. Recent studies suggest that the incidence of bullous pemphigoid is increasing and may be as high as 22 to 24 per 1 million per year in the United States. The disease presents as pruritic, tense blisters often on a background of urticarial plaques. It occurs most frequently in older adults. It is mediated by autoantibodies directed against hemidesmosome proteins BP180 and BP230, which trigger an inflammatory cascade that ultimately leads to blister formation.  

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Bullous pemphigoid was described as a subepidermal blistering disease with distinctive clinical and histologic features by Walter Lever in 1953. 

Overview

  • Bullous pemphigoid was described as a subepidermal blistering disease with distinctive clinical and histologic features by Walter Lever in 1953.  More than a decade later, antibodies against the dermal–epidermal junction were first described in perilesional skin and in the serum of patients by Jordon and Beutner,  confirming the separation of bullous pemphigoid from pemphigus. Over the following years, the antigenic targets were fully characterized as hemidesmosomal proteins BP180 and BP230. Diagnosis of Bullous Pemphigoid is based on clinical, histological and immunopathological findings.  

Histology (Test #003)

  • Light microscopy reveals subepidermal lesions in cases with blisters. Superficial dermal infiltrate consisting of eosinophils, neutrophils, lymphocytes, and monocytes and macrophages is observed. Early or urticarial BP demonstrates eosinophilic spongiosis without blister formation.  

Direct immunofluorescence (Test #001)

  • DIF of perilesional biopsies remains the gold standard and first step in diagnosing BP. This reveals linear deposits of IgG (predominantly IgG4 and IgG1) in the basement membrane zone area of the dermal-epidermal junction.  C3 may be the only immunoreactant in some cases. Deposits of IgA and IgM may also be seen, although the intensity of these deposits may be less compared to C3 and IgG. DIF is 91% to 98% sensitive and 98% to 100% specific. False negatives may occur in early disease, focal nature of in vivo deposits, and if the biopsy is collected from an advanced lesion. If clinical suspicion is high, repeat DIF studies on another biopsy specimen may be indicated. 

Differentiation of BP from EBA, Bullous LE, Laminin 332 pemphigoid, Laminin gamma 1 pemphigoid (Test #002)

  • DIF using salt (1.0 M NaCl) split biopsy specimens is a simple method to differentiate between BP and EBA. Deposition in BP is within the lamina lucida lucida. This site of deposition corresponds to the location of the extracellular domain of BP180 molecule that contains the dominant epitopes recognized by the pathogenic BP antibodies. In contrast, deposition of antibodies in EBA and bullous lupus is in the sublamina densa area where the target antigen, type VII collagen with in the anchoring fibrils, is present. The deposition of antibodies in laminin gamma 1 pemphigoid and laminin 332 is in the lower lamina lucida.  Accordingly, immune deposits in pemphigoid would be present on the epidermal side of the split whereas the immune deposits in EBA, bullous lupus, laminin 332 pemphigoid and laminin gamma 1 pemphigoid would be present on the dermal side. This test can be performed only on biopsy specimens that do not reveal epidermal-dermal separation or subepidermal microvesicles in the primary DIF test (#001).  For rapid and reliable differentiation, two skin biopsies can be taken: a) ~1/3 lesional skin and ~2/3 of normal skin, (b) normal skin ~3 mm. from a lesion. 

Serology (Tests #013, 014, 016, 027)

  • Indirect immunofluorescence (IIF) on monkey esophagus (Test#013) and on Salt Split human skin (SSS, Test#014) helps to detect circulating BMZ antibodies and confirm the diagnosis of BP. The sensitivity of IIF on ME ranges from 57% to 73% with specificity ranging from 97% to 100%, and IIF on SSS has a sensitivity of 73% to 93% with specificity of 99.9% to 100%. The use of normal and salt split skin substrates improves the sensitivity of the test and helps to differentiate BP from EBA, bullous lupus, Laminin 332 pemphigoid and laminin gamma 1 pemphigoid. Antibodies in BP react with the epidermal roof of the SSS. The IIF antibody titers do not usually correlate with disease extent or activity in bullous pemphigoid. 

ELISA 

  • Antibodies to BP180 (NC16a) and BP230 can be detected by ELISA. A review of the literature reveals a sensitivity of 53% to 95% and specificity of 89.8% to 100% for anti-BP180 ELISA. Anti-BP230 ELISA sensitivity and specificity range from 11% to 60% and 92% to 100%, respectively. Anti-BP180 NC16a ELISA can be used to monitor disease activity during treatment. However, ELISA should not be used as a stand-alone diagnostic tool. Approximately 7% of the normal population has anti-BP180 antibodies detectable by ELISA in the absence of clinical and histologic features of disease without age or gender predilection.  

Bullous Pemphigoid Tests:

Selected References

  • Lever  WF. Pemphigus. Medicine (Baltimore). 1953;32(1):1–123.  [PubMed: 13024494] 

  • Jordon  RE, Beutner  EH, Witebsky  E,  et al. Basement zone antibodies in bullous pemphigoid. JAMA. 1967;200(9):751–756. 

  • Culton DA, Zhi L, Diaz LA. “Bullous pemphigoid.” In: Kang S, et al. Fitzpatrick’s Dermatology. (ninth edition) McGraw Hill Education, United States of America, 2019:944-55. 

  • Gammon WR, Kowalewski C, Chorzelski TP, Kumar V, Briggaman RA, Beutner EH. Direct immunofluorescence studies of sodium chloride-separated skin in the differential diagnosis of bullous pemphigoid and epidermolysis bullosa acquisita. J Am Acad Dermatol 1990;22:664-70. 

  • Harrell J, Xiomara BR, Colton N, Sylvia H, Kiran MM.   Clinics in Dermatology. 2019;37: 692–712. 

  • Mutasim DF, Adams BB. Immunofluorescence in dermatology. J Am Acad Dermatol. 2001 Dec;45(6):803-22.