The diagnosis and treatment of autoimmune blistering skin diseases

Abstract

Background: Autoimmune blistering skin diseases are a heterogeneous group of disorders associated with autoantibodies that are directed against desmosomal structural proteins (in pemphigus diseases) or hemidesmosomal ones (in pemphigoid diseases and epidermolysis bullosa acquisita), or else against epidermal/ tissue transglutaminases (in dermatitis herpetiformis). Knowledge of the clinical presentation of these disorders and of the relevant diagnostic procedures is important not just for dermatologists, but also for general practitioners, ophthalmologists, ENT specialists, dentists, gynecologists, and pediatricians.

Methods: The literature on the subject was selectively reviewed. There are no existing guidelines available in Germany.

Results: The recently developed sensitive and specific assays for circulating autoantibodies in these diseases now enable a serological diagnosis in about 90% of cases. The incidence of autoimmune blistering skin diseases in Germany has doubled in the last 10 years, to a current figure of about 25 new cases per million persons per year, because of improved diagnostic techniques as well as the aging of the population. Accurate and specific diagnosis is the prerequisite for reliable prognostication and appropriate treatment. For severe and intractable cases, more effective treatments have recently become available, including immunoadsorption, high-dose intravenous immunoglobulin, the anti-CD20 antibody rituximab, and combinations of the above.

Conclusion: The diagnostic assessment of autoimmune blistering skin diseases can be expected to improve in the near future as new serological testing systems are developed that employ recombinant forms of the target antigens. The treatments currently in use still need to be validated by prospective, controlled trials.

Figure 1

A schematic view of desmosomal and hemidesmosomal target antigens in autoimmune blistering diseases, and the interactions between them. In the histological section of normal skin at bottom left, one sees the epidermis, the dermis, and the dermo-epidermal junctional, also called the basal membrane, zone, which connects the epidermis to the dermis. Two neighboring basal keratinocytes are shown schematically. Pemphigus diseases are histologically characterized by intraepidermal cleft formation; their target antigens are desmosomal structural proteins by means of which neighboring keratinocytes adhere to each other. The desmosomal target antigens of the pemphigus diseases include desmosomal plaque proteins (envoplakin, desmoplakin, periplakin) and transmembrane proteins of the cadherin group (desmoglein 1 and 3, desmocollin 1) whose extracellular portions mediate the adhesion of neighboring keratinocytes (left side of diagram). Hemidesmosomal proteins anchor the epidermis to the dermis and are the target antigens in subepidermal autoimmune blistering skin diseases, in which cleavage occurs between the dermis and the epidermis (right side of the diagram). Hemidesmosomal plaque proteins (BP230, plectin) interact with the transmembrane proteins BP180 and α6β4-integrin, which, in turn, are connected by way of laminin 332 to type VII collagen. Type VII collagen establishes a connection to dermal collagens. Proteins that have not been found to be targets of autoantibodies are not included in this diagram.

Figure 2

The clinical features of autoimmune blistering skin diseases.

Figure 3

Indirect immunofluorescence. Indirect immunofluorescence microscopy is used as a screening test for serum autoantibodies in autoimmune blistering skin diseases. The most sensitive substrates currently used include monkey esophagus for pemphigus vulgaris and pemphigus foliaceus (a) and human skin split with 1 M NaCl solution for pemphigoid diseases (b, c). Antibodies against type XVII collagen (BP180) and BP230 bind to the epidermal side of the artificial cleft (b), while antibodies against laminin 332 (previously known as laminin 5 or epiligrin), antibodies against the laminin γ1 chain (p200 antigen), and antibodies against type VII collagen bind to its dermal side (c). The target antigens and the corresponding diseases are shown on the right side.