EBA mimics BP in 25–50 % of cases according to different authors: 25 % for Gupta [18], 40 % for Briggaman [4], and 50 % for Gammon [13]. Conversely for Gammon, 12–15 % of the patients, in whom a diagnosis of BP was done, have in fact EBA [15]. The patients usually present with a mixture of features characteristic of BP (pruritus, tense bullae on erythematous or urticarial skin, involvement of the trunk and folds) and atypical lesions for BP such as flaccid bullae, bullae on normal skin, and involvement of the face or extensor area of the limbs (Fig. 40.2). Finally, they may have a diffuse eruption, involving the entire face, trunk, and limbs.

EBA may mimic MMP (Fig. 40.2). The high frequency of mucosal lesions in EBA, in particular involvement of the tongue and lips, was highlighted by Dahl as early as 1979 in a review of ten cases [9]. All mucous membranes (MM) lined by a malpighian epithelium may be affected, namely, the oral, conjunctival, nasal, laryngeal, esophageal, genital, and anal mucosae. The lesions are identical to those initially described in the cicatricial pemphigoid, in particular the conjunctival fibrosis and the laryngeal and esophageal strictures [16, 29]. Cutaneous lesions of MMP-like EBA are on the head and trunk (Fig. 40.2). The frequency of the MMP-like form is very different from one study to another: 10 % in the series of 12 cases of Briggaman [4] and 67 % in the prospective study of Alexandre et al. [1]. A case with exclusive esophageal involvement has been published [27].

Some cases of Brunsting-Perry-like EBA have been published. The patients had only cutaneous lesions that predominate in the head and neck and heal leaving very atrophic scars [27].

In his review of 82 cases of IgA-mediated EBA, Vodegel shows that patients present clinically as LAD with few scars and milia cyst [39]. Mucosal involvement is present in 30 % of cases and severe ocular involvement in 4 %. In the series of Briggaman, this accounted for 17 % of cases [4]. However, the LAD-like EBA accounted for only 2 % of LAD in an English series of 110 cases [25].

Thirty observations have been published [3, 27]. The youngest reported case was 3 months old at the beginning of the disease [7]. This is the most common subepithelial AIBD in children (15 %) after the LAD. Clinical features are that of a form either classic or PB-like or MMP-like or LAD-like. Mucosal involvement is around 80 % and severe but long-term prognosis is generally better than in adults.

A drug induction is reported in 11 % of IgA-mediated EBA [39]. A case of IgA- and IgG-mediated EBA induced by vancomycin has also been reported in the literature [10]. Few exceptional cases of exacerbation by a combined hormonal treatment [22] or phototherapy [19] have been reported.

The severe EBA are either classical forms with extensive cutaneous lesions which look like recessive dystrophic EBH or MMP-like forms with conjunctival, ENT, or esophageal involvement. In one French series, the latter were present in, respectively, 25, 11, and 6 % of cases [26].

Many diseases have been reported in association with EBA [18]. Most of these reports are anecdotal. The only indisputable association is the chronic inflammatory bowel diseases in particular Crohn’s disease: 25 % in one French series [26] and 25 % in that of Chen et al. [8]. C7 was shown to be present in the intestinal epithelium, but elucidation of the association between EBA and inflammatory bowel disease needs further investigation. In B-cell lymphomas, the presence of circulating and in vivo tissue-bound auto-Ab to C7 has also been described in association with a frequency of 6 % in a series of 100 cases, but patients had no clinical features suggestive of EBA [2]. Finally, cases of EBA associated with systemic lupus erythematosus but not fulfilling the criteria of bullous erythematosus systemic lupus established by Camisa have been reported [6, 17].

The diagnosis of EBA should be confirmed by tests requiring skin or MM biopsies (direct IEM or serration analysis by direct IF) for study of in vivo bound auto-Ab and/or serological tests (indirect IEM, immunoblotting, or enzyme-linked immunosorbent assay (ELISA) or indirect IF on BIOCHIP with C7-NC1-expressing cells) for detection of circulating auto-Ab to C7 [27]. Routine tests such as skin standard pathology, direct IF, and indirect IF allow the diagnosis of subepithelial AIBD but do not specify a diagnosis of EBA with certainty. Specialized tests necessary to confirm EBA are available in only certain laboratories (see Part II Chaps. 3 and 5). Alternative laboratory tests including IF on SSS, IF on skin deficient in BMZ molecules, and fluorescent overlay antigen mapping (FOAM) have been described (see Part II Chaps. 2 and 4). All these tests have their limits excluding the ability to do an accurate diagnosis of EBA only based on one test.

The differential diagnosis of EBA includes non-autoimmune subepidermal bullous diseases with skin fragility: EBH, porphyria (PCT, coproporphyria, or porphyria variegata), bullous amyloidosis, pseudoporphyria, and some drug reactions. In all cases, there are no detectable immune deposits on the BMZ, except in porphyria (see below). The EBH that most closely resemble the EBA are dystrophic EBH, especially in their dominant form (see Part II Chaps. 4, 5 and 6 and Part III Chap. 20). The diagnosis of EBH can be difficult in the late-onset forms and confusing with EBA [23, 37]. The classical form of EBA may also mimic porphyria. Indeed skin fragility, tense blisters healing with scars, and milium cysts are present in porphyria. However lesions are located on photodistributed areas such as the hands and face in porphyria, while they involve also covered areas (feet, elbows, knees) in EBA. In addition, patients with EBA have no malar hypertrichosis, photosensitivity, or scleroderma-like changes. In both conditions, standard cutaneous pathology is identical, and IgG and C3 deposits are seen at the BMZ in direct IF. The direct IF features that distinguish porphyria from EBA are the additional presence of immune deposits around the vessels and dull pattern of immune deposits in porphyria. Definitive diagnosis of porphyria is confirmed by the elevation of blood and urinary and fecal porphyrins. The clinical presentation of bullous amyloidosis may also be similar to that of EBA. The diagnosis is usually suspected in patients with multiple myeloma or Waldenstrom’s disease. It is confirmed by the detection of amyloid deposits in histology or EM [34]. This diagnosis of amyloidosis may be difficult because circulating auto-Ab to C7 could be present in B-cell lymphoma [2]. Pseudoporphyria may more rarely be discussed.

All subepithelial AIBD should be discussed since there are many clinical forms of EBA misleading and especially forms that mimic BP and MMP. The diagnosis of BP may be established clinically with a positive predictive value of 95 % if three out of the four following criteria are present: age over 70 years, absence of involvement of the head and neck, absence of atrophic scarring, and absence of mucosal involvement [38]. Otherwise a diagnosis of BP is improbable, and specialized test are mandatory (see Part II Chaps. 3 and 5 and Part III Chap. 14). Lastly, several observations of border forms of AIBD with auto-Ab against several antigens of BMZ have been reported. Some patients especially children presenting clinically as EBA had auto-Ab to C7 and also BP180 and/or BP230 [11, 21, 36, 40]. Others had auto-Ab to C7 associated with auto-Ab to the alpha chain of laminin 332 [20] or p200 [12, 31, 45]. In border forms of AIBD, the definitive diagnosis needs the study by direct IEM of in vivo tissue-bound auto-Ab.

The prognosis of EBA is variable, and prognostic factors have not been established. Patients with mild disease may experience complete remission with therapy. Many patients, however, have a chronic course with episodes of exacerbations and remissions often leading to scarring. All the patients need a long-term follow-up in order to detect lesions occurring on new MM.