Oral Lesions in Autoimmune Bullous Diseases: An Overview of Clinical Characteristics and Diagnostic Algorithm

Abstract

Autoimmune bullous diseases are a group of chronic inflammatory disorders caused by autoantibodies targeted against structural proteins of the desmosomal and hemidesmosomal plaques in the skin and mucosa, leading to intra-epithelial or subepithelial blistering. The oral mucosa is frequently affected in these diseases, in particular, in mucous membrane pemphigoid, pemphigus vulgaris, and paraneoplastic pemphigus. The clinical symptoms are heterogeneous and may present with erythema, blisters, erosions, and ulcers localized anywhere on the oral mucosa, and lead to severe complaints for the patients including pain, dysphagia, and foetor. Therefore, a quick and proper diagnosis with adequate treatment is needed. Clinical presentations of autoimmune bullous diseases often overlap and diagnosis cannot be made based on clinical features alone. Immunodiagnostic tests are of great importance in differentiating between the different diseases. Direct immunofluorescence microscopy shows depositions of autoantibodies along the epithelial basement membrane zone in mucous membrane pemphigoid subtypes, or depositions on the epithelial cell surface in pemphigus variants. Additional immunoserological tests are useful to discriminate between the different subtypes of pemphigoid, and are essential to differentiate between pemphigus and paraneoplastic pemphigus. This review gives an overview of the clinical characteristics of oral lesions and the diagnostic procedures in autoimmune blistering diseases, and provides a diagnostic algorithm for daily practice.

Fig. 1

Overlapping features in autoimmune bullous diseases, Stevens–Johnson syndrome, and oral lichen planus demonstrate that oral blistering diseases cannot be differentiated based on clinical presentation. Lesions include desquamative gingivitis (a, d, m), cheilitis (e, f, g, h, j, k), erythema and erosions and blistering of the buccal mucosa (b, i, l, n), palatum (c), and tongue (e, o)

Fig. 2

Flowchart of the diagnostic pathway in patients with oral blistering, with the focus on autoimmune bullous diseases affecting the oral mucosa

Fig. 3

Immunofluorescence results compatible with the diagnosis of pemphigoid diseases. a Direct immunofluorescence microscopy shows linear IgG along the epithelial basement membrane zone in an n-serrated pattern. b Direct immunofluorescence microscopy shows linear IgG along the epithelial basement membrane zone in a u-serrated pattern. c Indirect immunofluorescence microscopy on a substrate of salt-split skin (indirect immunofluorescence on salt-split skin), showing IgG bound to the epithelial side of the artificial split, wherein BP180 and BP230 are located. d Indirect immunofluorescence on salt-split skin showing IgG bound to the dermal side of the artificial split, wherein laminin-332, p200, and type VII collagen are located

Fig. 4

Direct immunofluorescence microscopy staining of a pemphigus patient. a IgG staining in a smooth epithelial cell surface pattern. b IgG staining in a granular epithelial cell surface pattern

Fig. 5

Diagnostic results in paraneoplastic pemphigus. a Direct immunofluorescence microscopy with an epithelial cell surface and anti-basement membrane zone pattern. b Indirect immunofluorescence microscopy on a rat bladder with IgG staining in an epithelial cell surface pattern, compatible with the diagnosis of paraneoplastic pemphigus. c Serum analyzed for IgG against paraneoplastic pemphigus antigens by immunoblotting (1) and immunoprecipitation (2). A2ML1 alpha-2-macroglobulin-like 1, EPL epiplakin, PPL periplakin