Differential diagnosis

Manifestations of BP may resemble those of a variety of dermatoses, including drug reactions, contact dermatitis, prurigo, fixed urticaria, vasculitis, arthropod reaction and scabies. Clinical history, pathologic features and negative immunofluorescence microscopy findings are essential to distinguish these disorders from BP. Diseases within the pemphigus group can be easily differentiated on the basis of distinctive immunopathological features. In dermatitis herpetiformis IF microscopy findings, the clinical setting with associated (clinical aor subclinical) coeliac disease and the serological profile (see Dermatitis herpetiformis chapter) are peculiar. In contrast, the distinction of BP from certain autoimmune blistering disorders is difficult. However, a recent study has found that in patients with a blistering disorder associated with linear deposits of IgG or C3 in the epidermal basement membrane the presence of certain clinical criteria (that is, absence of skin atrophy, absence of mucosal involvement, absence of head and neck involvement and age greater than 70 years) indicates to a diagnosis of BP with high sensitivity and specificity (Vaillant et al. 1998, Joly et al. 2004). Paraneoplastic pemphigus, a recently described autoimmune blistering disorder associated with neoplasia, might present with clinical features reminiscent of BP. However, its immunopathological features are peculiar enough to allow its differentiation from BP. The distinction of the following subepidermal blistering disorders may be challenging:

1) Epidermolysis bullosa acquisita (EBA) shows a wide spectrum of presentations (Briggaman et al. 1985; Gammon 1988; Gammon and Briggaman 1993)(see EBA chapter). The classical "non-inflammatory" form includes skin fragility, blistering, erosions, with milia formation, skin atrophy and scarring that typically develop over trauma-exposed sites, such as arms, elbows, hands and feet. Occasionally, nail dystrophy and scarring alopecia are observed. While the features of this classical form are suggestive, a substantial number of patients have an "inflammatory" form of EBA mimicking BP, characterized by a widespread eruption with blisters involving intertriginous and flexural areas that heal without milia or atrophic scar. In addition, in the course of the disease, a mixture of inflammatory and non inflammatory features may be observed. Mucosal involvement can occur and potentially results in significant morbidity. Diagnosis of EBA relies on the detection of autoantibodies that bind to the dermal side of 1 M NaCl separated skin and specifically react with type VII collagen, the major component of anchoring fibrils (Briggaman et al. 1985; Woodley et al. 1984). Correct diagnosis of EBA is important for at least two reasons: the disease might be associated with other conditions, such as Crohn's disease, rheumatoid arthritis, and systemic lupus erythematosus, and second, EBA is thought to be more resistant to treatment than BP.

2) Linear IgA bullous dermatosis (LABD) was originally considered a distinct entity defined on the basis of the immunopathological finding of linear

IgA deposits in the cutaneous BMZ (Chorzelski et al. 1979; Wojnarowska et al. 1988). The condition, thought to represent the most common autoimmune blistering disorder of childhood, is associated with urticated, annular and or polycyclic lesions, with development of vesicles and bul-lae. The latter might be distributed in "jewel-like" clusters or "string of pearls" patterns. Involvement of mucosae is not unusual. Childhood features of LABD are often peculiar,with involvement of the genital area or around the mouth, whereas adulthood LABD is more polymorphic. The autoantigens of LABD are heterogeneous. The two most characteristic target antigens are a protein of 97kDand a120 kDa protein, termed the LABD antigen 1 (LABD97) and LAD-1 respectively. These two molecules-correspond to the cleaved, shedded ectodomain of BP180 (Zone et al. 1998; Pas et al. 1997; Hirako et al. 1998 and 2003; Schacke et al. 1998). It is thought that extracellular processing of BP180, which is catalyzed by members of the ADAMs family (a disintegrin and metalloprotease) (Franzke et al. 2004), results in the formation of neoepitopes which are specifically targeted by patients' IgA and, occasionally IgG, autoantibodies. Nevertheless, some patients with bona fide LABD have been found to possess IgA (and IgG) autoantibodies that recognize BP180 and BP230 (Ghohestani et al. 1997), type VII collagen (Hashimoto et al. 1996) or other, as yet uncharacterized antigens (Wojnarowska et al. 1991). Some of these LABD patients therefore fulfill the diagnostic criteria for BP or EBA. In summary, LABD most likely comprises a group of subepidermal blistering disorders rather than a single nosologic entity.

3) Cicatricial pemphigoid (CP) includes a heterogeneous group of blistering diseases, which have in common the involvement of the mucosae, a chronic course and a scarring tendency (Mutasim et al. 1993; Chan et al. 1993). In contrast to BP, CP skin lesions generally involve the scalp, head, and the upper trunk, and they are found in up to 25% of patients. The oral mucosa and the conjunctiva, and, less frequently, nose, esophagus, larynx and genitals are affected. Subsets of patients with either pure ocular involvement, predominant oral mucosal involvement without cutaneous lesions, or with both oral and cutaneous lesions have been identified (Chan et al. 1993). Erosions and scarring of the mucosae might result in significant morbidity. Ocular disease can lead to symblepharon formation, entropion, and trichiasis. In addition, stenoses of the nasopharynx, larynx, esophagus and urethra are observed. Patients with a CP pheno-type might exhibit IgG and/or IgA autoantibodies of different specificity, that recognize BP180 and BP230 (Bernard et al. 1990a), the 97/120 kDa LABD antigen, laminin-5 and laminin-6 (Domloge-Hultsch et al. 1992; Chan et al. 1997), type VII collagen (Luke et al. 2000) or the p4 integrin subunit (Tyagi et al. 1996). Importantly, in the context of the so called anti-epiligrin cicatricial pemphigoid characterized by the presence of autoantibodies directed against laminin 5, there is apparently an increased relative risk for solid cancer (adenocarcinomas), especially in the first year after blister onset (Egan et al. 2003). The latter observation probably accounts for the high incidence of mortality observed among these patients.

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