Background and Design: The incidence and distribution of autoimmune subepidermal bullous diseases were estimated from prospective data (including immunoelectron microscopy) obtained from 100 cases during a mean period of 35 months in three university dermatologic centers in Amiens, Limoges, and Tours, France, that correspond to a cumulative reference population of 3.55×10 6 . Results: Using data from these regions, we found a mean annual incidence of autoimmune subepidermal bullous diseases to be 10.4 per million people and, therefore, estimated the overall number of new cases of these disorders in France to be about 590 cases per year. According to clinical and immunoelectron microscopic criteria, a precise diagnosis was established in 94 cases, distributed as follows: bullous pemphigoid, 69 cases; cicatricial pemphigoid, 12 cases; linear IgA dermatosis, five cases; herpes gestationis, four cases; epidermolysis bullosa acquisita, two cases; and vesiculobullous systemic lupus erythematosus, two cases. Conclusion: Our prospective study is the first assessing the incidence and distribution of autoimmune subepidermal bullous disorders that systematically included immunoelectron microscopic data. Our estimated incidence of bullous pemphigoid (seven new cases per million people per year) is large enough to establish bullous pemphigoid as the major autoimmune subepidermal bullous disease for the purpose of therapeutic trials. On the contrary, all other disorders, particularly epidermolysis bullosa acquisita (estimated annual incidence, 0.17 to 0.26 per million people), were very rare and reflect the paucity of patients available for shortterm clinical studies in France. (Arch Dermatol. 1995;131:48-52)

Incidence and Distribution of Subepidermal Autoimmune Bullous Skin Diseases in Three French Regions

Epitope spreading : Lessons from autoimmune skin diseases

Type VII Collagen, Anchoring Fibrils, and Epidermolysis Bullosa

Cutaneous drug reactions are the most frequently occurring adverse reactions to drugs. Among hospitalized patients, the incidence of these reactions ranges from 1 to 3%. The frequency of cutaneous reactions to specific drugs may exceed 10%. These reactions may range from mildly discomforting to those that are life-threatening. Anti-infective and anticonvulsant agents are among the drugs most commonly associated with adverse reactions in the skin. We describe and illustrate the clinical morphology of the most common cutaneous drug reactions, as well as drugs that most commonly precipitate specific reactions. The varied nature of the reactions that do occur, even with specific agents, indicates a multiplicity of mechanisms available whereby cutaneous drug reactions may be initiated. Although a variety of terms have been proposed for categorizing cutaneous drug reactions, we propose that reactions are best defined based upon mechanisms, where known. In this review, we assess the current knowledge of four categories of cutaneous drug reactions: immediate-type immune-mediated reactions, delayed-type immune-mediated reactions, photosensitivity reactions, and autoimmune syndromes. Moreover, we describe evidence that viral infection is an important predisposing factor for the development of cutaneous drug reactions upon drug administration. Finally, we review the current knowledge of the type and mechanisms of cutaneous drug reactions to several categories of drugs.

Cutaneous Drug Reactions

The 97 kDa linear IgA bullous disease antigen is identical to a portion of the extracellular domain of the 180 kDa bullous pemphigoid antigen, BPAg2

Disease-associated autoantibodies to basement membrane proteins have been used to characterize structural components of the epidermal basement membrane such as bullous pemphigoid (BP) antigen and epidermolysis bullosa acquisita (EBA) antigen (type VII collagen). The autoimmune bullous diseases characterized by IgA autoantibodies to the basement membrane zone (BMZ), i.e. linear IgA disease of adults (LAD) and chronic bullous disease of childhood (CBDC) may have circulating antibodies. Previous studies of tissue distribution and ultrastructural binding have suggested that the LAD and CBDC antigens are similar, if not identical, and differ from the target antigens of the other bullous diseases. We present the molecular characterization of the LAD/CBDC antigens by Western blotting of a large series of antisera. Seven of 33 sera (21%) were positive on immunoblotting and bound to the same antigen which has a molecular weight (MW) of 285 kDa. Using both defined polyclonal antisera to BP and LH 7.2 monoclonal antibody to type VII collagen (carboxy terminal) we have shown that the LAD and CBDC antisera both bind to an identical molecular weight protein which clearly differs from both the BP and EBA (type VII collagen) antigens. Although detectable in dermal tissue extracts like EBA, the MW of 285 kDa is heavier than type VII collagen (250 kDa, in our system, using non-collagenous standards). This study confirms the identity of LAD and CBDC antigens to be the same and to differ from previously described basement membrane proteins.

Identification of the target antigen in chronic bullous disease of childhood and linear IgA disease of adults.

Clinical and immunopathological studies of three patients with lichen planus pemphigoides (LPP) were carried out to investigate the relationship between LPP and bullous pemphigoid (BP) and to determine whether the antigen in LPP is the classical BP antigen. LPP is usually considered to be the coexistence of lichen planus with BP. The bullae in LPP were subepidermal and indistinguishable from BP. Indirect immunofluorescence demonstrated antibody binding to the epidermal surface of 1 M NaCl-split skin and mucosae, as in BP. The tissue distribution of the LPP antigen mirrored the distribution of BP in stratified squamous epithelia but was absent from transitional epithelia (pig bladder). Immunoelectron microscopy, both direct (two cases) and indirect (one case), showed binding to the lamina lucida as with BP antigen. Western blotting of epidermal extracts using the patients' sera showed that instead of reacting with the classical bullous pemphigoid antigen (220 kDa in our series), the antisera reacted with a unique band of 200 kDa in addition to the band of 180 kDa found as a minor antigen in bullous pemphigoid, but more commonly in pemphigoid gestationis. The relationship between these antigens awaits molecular characterization. These findings suggest that the target antigen in LPP may be unique.

Lichen planus pemphigoides: its relationship to bullous pemphigoid.

SUMMARY

Using an immunoblotting technique, sera from 25 patients with pemphigoid gestationis were examined and tested against epidermal and dermal extracts of normal skin. The major antigen recognized by seven patients'sera was a molecule of 180 kDa, pemphigoid gestationis antigen, extractable only from the epidermis. Sera from 18 patients with bullous pemphigoid were studied as positive controls and the major antigen recognized was a larger molecule of 220 kDa. There was some degree of shared recognition of antigens with three patients with pemphigoid gestationis recognizing the 220 kDa bullous pemphigoid antigen. In addition one bullous pemphigoid serum recognized the 180 kDa pemphigoid gestationis antigen. The dominant pemphigoid gestationis antigen, however, differs from bullous pemphigoid antigen.

Western blot analysis of the antigen in pemphigoid gestationis.

Expression of hCG and its free subunits by non-trophoblastic tumours is well recognised. Previously we reported hCG secretion by normal and malignant bladder epithelial cells in vitro. Here we examined culture medium from 83 different cell lines derived mainly from common epithelial tumours. Thirty-two of the cell lines were found to secrete hCG-like material into their culture media. Partial immunochemical characterisation showed that of these only choriocarcinoma and fetal tissue cell lines produced intact hCG and alpha subunit. The remaining 28 hCG-expressing epithelial cell lines, which are of mucosal origin, only secreted free beta subunit. Expression of free beta hCG by non-trophoblastic nonendocrine cells would appear to be especially characteristic of mucosal epithelia from the genitourinary and oral/respiratory tracts. Furthermore, this phenomenon may be characteristic of epithelium with transitional and/or squamous cell-like properties.

http://europepmc.org/articles/PMC1971613?pdf=render

Expression of beta human chorionic gonadotrophin by non-trophoblastic non-endocrine 'normal' and malignant epithelial cells.

The sera from two patients with epidermolysis bullosa acquisita were blotted against dermal extracts in comparison with the mouse monoclonal antibody LH 7.2. This antibody reacts with carboxy terminal region of type VII collagen. The epidermolysis bullosa acquisita antisera showed binding to the same molecular weight protein as LH 7.2 confirming that the target antigen for epidermolysis bullosa acquisita antibodies is the carboxy terminal region of type VII collagen. This newly described collagen forms the major component of anchoring fibrils. These findings are consistent with established ultrastructural data which have shown that the epidermolysis bullosa acquisita antigen is located within and below the lamina densa. The monoclonal antibody LH 7.2 provides an internal standard for epidermolysis bullosa acquisita autoantisera activity. The use of immunoblotting of epidermolysis bullosa autoantisera in comparison with the monoclonal antibody LH 7.2 provides definitive investigation for the diagnosis of this disorder.

P. Whitehead

Papers

Identification of the target antigen in chronic bullous disease of childhood and linear IgA disease of adults.

Lichen planus pemphigoides: its relationship to bullous pemphigoid.

Western blot analysis of the antigen in pemphigoid gestationis.

Expression of beta human chorionic gonadotrophin by non-trophoblastic non-endocrine 'normal' and malignant epithelial cells.

Identification of the epidermolysis bullosa acquisita antigen by LH 7.2 monoclonal antibody: use in diagnosis.