Oral Manifestations of Autoimmune Blistering Diseases Workup

Updated: Feb 11, 2019
  • Author: Nita Chainani-Wu, DMD, MS, MPH, PhD; Chief Editor: William D James, MD  more...
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Workup

Laboratory Studies

Direct immunofluorescence microscopy

Direct immunofluorescence microscopy (DIF) determines the types and locations of immune deposits within patients' epithelial tissues. DIF detects deposits at the epithelial cell surfaces and at the epithelial basement membrane zone of the perilesional skin biopsy specimens obtained from patients with the diseases of the pemphigus and pemphigoid groups, respectively. Note the images below.

Direct immunofluorescence microscopy performed on Direct immunofluorescence microscopy performed on epithelial biopsy specimen obtained from a patient with pemphigus vulgaris detects immunoglobulin G deposits at the epithelial cell surfaces.
Direct immunofluorescence microscopy performed on Direct immunofluorescence microscopy performed on biopsy specimen obtained from a patient with mucous membrane pemphigoid detects linear immunoglobulin G deposits at the epithelial basement membrane zone.

In paraneoplastic pemphigus, DIF usually reveals deposits at both the epithelial cell surfaces and the epithelial basement membrane zone.

In a study of the sensitivity of DIF on oral mucosal tissues for oral diseases, it was found that positive DIF findings were detected in 100% of pemphigus vulgaris cases, 67% of cicatricial pemphigoid cases, and 56% of bullous pemphigoid cases. Interestingly, biopsy specimens taken from oral tissue location distant to the actual lesion provide essentially the same positive rate as those taken perilesionally. In addition, punch biopsies yielded significantly better positive rates than shave biopsies. [20]

Indirect immunofluorescence microscopy

Indirect immunofluorescence microscopy (IIF) determines the patterns of patients' circulating autoantibodies that bind the epithelial components.

IIF detects epithelial cell surface-binding and epithelial basement membrane zone-binding autoantibodies in patients with diseases of the pemphigus and pemphigoid groups, respectively. The titer of the circulating autoantibodies corresponds to the severity of disease in pemphigus.

In addition to binding to squamous epithelial cell surfaces (eg, skin, esophagus substrates), circulating autoantibodies from patients with paraneoplastic pemphigus also label transitional epithelium (eg, lumen of rat bladder).

Indirect immunofluorescence on salt-split substrate

Indirect immunofluorescence on salt-split substrate (ssIIF) uses epithelial substrates in which the lamina lucida of the basement membrane zone has been split at the middle, leaving the target antigens for the autoantibodies of bullous pemphigoid and epidermolysis bullosa acquisita to the roof and the base of the split substrate, respectively.

Using salt-split epithelial substrates, ssIIF detects the circulating autoantibodies from patients with bullous pemphigoid and epidermolysis bullosa acquisita binding respectively to the roof and the base of the substrates, thus distinguishing these two diseases.

In patients with mucous membrane pemphigoid, their circulating autoantibodies can bind to the roof, the base, or both, corresponding to the heterogeneity of the target antigens recognized by these autoantibodies.

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Imaging Studies

No imaging studies generally are needed for establishing diagnoses for patients with oral manifestations of autoimmune blistering diseases; however, in patients with paraneoplastic pemphigus, a vigorous search for internal malignancies should be performed. Whenever patients' symptoms are suggestive, perform imaging studies (eg, CT scan, radiograph, bone scan, MRI, ultrasound).

Order dental periapical x-rays in patients with autoimmune blistering disease affecting the gingival mucosa to rule out periodontal disease.

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Other Tests

Immunoelectron microscopy

Two methods of immunoelectron microscopy (IEM) can be used to delineate the ultrastructural location of the target antigens, direct method of IEM (DIEM) and indirect method of IEM (IIEM). [21] Whereas DIEM uses patients' epithelial tissues, IIEM uses patients' circulating autoantibodies (serum study). IEM tests are used primarily to study the various autoantigens in the epithelial basement membrane zone.

IEM detects the target antigens (BP180) for bullous pemphigoid, linear IgA bullous dermatosis, and a certain subset of mucous membrane pemphigoid at the upper lamina lucida/hemidesmosome areas [22] ; detects the target antigens laminin-5 and laminin-6 for a certain subset of mucous membrane pemphigoid at the lower lamina lucida; and detects the target antigen, type VII collagen, for epidermolysis bullosa acquisita at the lamina densa and sublaminar densa areas.

Immunoblotting

Immunoblotting (IB) test delineates the molecular sizes of the target antigens that are immunolabeled by patients' autoantibodies. [23, 24]

IB test is able to detect that the autoantibodies from patients with bullous pemphigoid and certain subsets of mucous membrane pemphigoid recognize a 230-kd (BPAg1) and/or a 180-kd (BPAg2) epithelial proteins; that the autoantibodies from patients with certain subset of mucous membrane pemphigoid recognize one or all of the 3 protein subunits, 200-kd/165-kd (alpha chain), 140-kd (beta chain), and 155-kd/105-kd (gamma chain) of laminin-5; and that the autoantibodies from patients with epidermolysis bullosa acquisita recognize the 290-kd type VII collagen.

Enzyme-linked immunosorbent assay

Enzyme-linked immunosorbent assay (ELISA) test detects the target antigens of circulating autoantibodies from patients using the known recombinant proteins. [25] ELISA test detects autoantibodies that recognize their autoantigens in nondenatured form; therefore, it is a more sensitive detection method than IB test. ELISA test also can be a quantitative method.

Immunoprecipitation

Immunoprecipitation (IP) test detects the target antigens of circulating autoantibodies from patients. IP test detects autoantibodies that recognize their autoantigens in native form; therefore, it is a more sensitive detection method than IB test but is more difficult to perform.

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Procedures

No diagnostic procedures for cancer detection above those age-related tests generally are needed for oral manifestations of autoimmune blistering diseases; however, when encountering patients with paraneoplastic pemphigus, a vigorous search for internal malignancies should be performed. Besides a thorough history and physical examination, when patients' symptoms are suggestive, proper use of diagnostic procedures (eg, colonoscopy, upper GI endoscopy) may be needed. [26]

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Histologic Findings

Histology determines the levels in which the blisters occur and the types of inflammatory infiltrates, both of which help determine the final diagnosis. Histopathology delineates the blisters occurring within the epithelium and below the epithelium for the diseases of the pemphigus and pemphigoid groups, respectively. In addition to blisters occurring at the epithelium level, histology of paraneoplastic pemphigus reveals a lichenoid pattern of inflammatory cell infiltration and necrotic epithelial cells.

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