ReviewModern diagnosis of autoimmune blistering skin diseases
Introduction
Autoimmune blistering dermatoses comprise a heterogeneous group of diseases that are characterized by autoantibodies to structural components of the skin and adjacent mucous membranes. In pemphigus, autoantibodies recognize desmosomal proteins that connect neighbouring keratinocytes, in pemphigoid diseases, hemidesmosomal proteins are targeted, and in dermatitis herpetiformis, autoantibodies typically bind to epidermal and tissue transglutaminase.
Pemphigus and pemphigoid diseases have first been differentiated in 1953 by Lever who described intraepidermal split formation and loss of cell adherence between keratinocytes (acantholysis) as histopathological hallmarks of pemphigus whereas he coined the term “pemphigoid” for disorders in which a subepidermal split formation was typically present [1]. About 10 years later, serum and skin-bound autoantibodies were described in pemphigus and pemphigoid [2], [3] and since then, their detection is a prerequisite for the diagnosis of immunobullous disorders. Subsequently, it became clear that, in contrast to most other autoimmune disease, autoantibodies in these disorders are directly pathogenic which has been clearly demonstrated for pemphigus, bullous pemphigoid, anti-laminin 332 pemphigoid, and epidermolysis bullosa acquisita [4], [5], [6].
The incidence of pemphigus greatly varies between different geographical regions and is estimated in Central Europe and the United States between 1 and 2 new patients/1 million/year [7]. The most frequent autoimmune bullous disorder in Central Europe is bullous pemphigoid (BP) with an annual incidence of about 13 new patients/1 million followed by mucous membrane pemphigoid and pemphigoid gestationis (2 new patients/1 million) [8], [9]. Higher incidences have recently been reported in Great Britain based on a data established on the general practitioner level [10]. Interestingly, BP is the only autoimmune disease whose incidence is increasing with age with an incidence of 150–180 new patients/1 million/year in a population older than 80 years [8], [9]. Surprisingly, the incidence of BP has doubled within the last 10 years in a well-defined region of Germany [9], [11]. This may be due to the increasing age of the general population or the advances in the diagnostic tools. These advances are the focus of this review.
Section snippets
Clinical criteria
Some clinical signs are typical for specific immunobullous diseases, e.g. old age, tense blisters, and severe pruritus for BP, whereas flaccid blisters and a positive Nikolsky sign (induction of an erosion by mechanical friction) are characteristic for pemphigus vulgaris. Those clinical features that are part of the diagnostic criteria are detailed in Table 1. Nevertheless, an autoimmune bullous disease cannot be diagnosed by clinical signs alone and requires the detection of tissue-bound and
Direct immunofluorescence microscopy
The diagnostic gold standard is still the detection of autoantibodies in patients' epidermis/mucosal epithelium by direct immunofluorescence (IF) microscopy. In pemphigus, an intercellular binding of IgG and/or C3 is found in the epidermis/epithelium while in pemphigoid diseases, linear staining of IgG and/or C3 is seen at the dermal–epidermal junction. In patients with dermatitis herpetiformis, granular IgA deposits are typically observed at the dermal papillae. Importantly, cryosections of
Indirect immunofluorescence microscopy
Indirect IF microscopy is a well established screening tool for circulating autoantibodies in autoimmune blistering diseases. In pemphigus, guinea pig or monkey esophagus are the most sensitive substrates while in pemphigoid diseases, human skin, in which dermal–epidermal splitting was induced by incubation in a 1 M NaCl solution, has been identified as the optimal substrate [12]. Latter test allows the differentiation between serum autoantibodies that bind to the roof and those that stain the
Target antigen-specific serological analyses by ELISA and Western blotting
In recent years, recombinant and cell-derived forms of the target antigens have been applied in the development of sensitive and specific assays for the detection of circulating autoantibodies (Table 1). So far, 5 different ELISA systems from 2 companies are available for the diagnosis of pemphigus and pemphigoid diseases (Table 2).
Monitoring autoantibody levels during the course of the disease
In pemphigus foliaceus, pemphigus vulgaris, and BP, autoantibodies against desmoglein 1, desmoglein 3, and BP180, respectively, have been demonstrated to be of pathogenic relevance in animal models [4], [5], [6], [71] and serum autoantibody levels in patients, correlate with disease activity [18], [19], [21], [31], [33]. Since highly sensitive and specific commercial ELISA systems are available for these autoantibodies (Table 2) [18], [19], [21], [31], [33] monitoring autoantibody serum levels
Take-home messages
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Autoimmune bullous diseases are a heterogeneous group of about a dozen well-defined entities.
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The incidence of immunobullous disorders greatly varies between different geographical regions and in Central Europe, was shown to have doubled within the last decade.
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The differentiation between the various entities is important for both treatment and prognosis.
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The diagnostic gold standard is still the detection of autoantibodies in skin or mucous membranes by direct immunofluorescence microscopy of a
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