edema within the papilla in addition to edema and vacuolar alteration along the dermal-epidermal junction. A subepidermal blister forms as the disease progresses. Neutrophilic inflammation along with eosinophils and monocytes within the dermis can be seen histologically, revealing little inflammatory infiltrate, unlike bullous pemphigoid [98]. The infiltrate can be found perivascularly, around follicles, and in the interstitium and can lead to fibrosis in older lesions. Autoantibodies to type VII collagen have also been found to activate complement in both in vivo and in vitro studies. The complement components C3, C5b, and the membrane attack complex have been found in patients who have EBA. Passive transfer of IgG into mice from a patient who had EBA was shown to induce dermal edema and a granulocytic infiltrate in the superficial dermis, with immune deposits at the BMZ localized by direct immunofluorescence and by direct immunoelectron microscopy to anchoring fibrils; however, no clinical disease was observed [99].

Disease course and treatment

EBA has a protracted course and is usually resistant to treatment. EBA persists for several years in most patients, and the likelihood of remission is unpredictable. The primary therapeutic choices include immunosuppressive or anti-inflammatory agents. Systemic immunosuppressive drugs including prednisone, azathioprine, cyclophosphamide, methotrexate, and cyclosporine are used in various dosages. A group of anti-inflammatory drugs including dapsone, sulfapyridine, and colchicine appear to be e ective and may decrease inflammation because of their antineutrophil e ect [100,101]. Children who have EBA respond better with dapsone and prednisone, whereas patients who have bullous systemic lupus erythematosus usually respond rapidly and completely to dapsone [102]. Photochemotherapy was reported to be e ective in one study but resulted in only partial improvement in two of three patients in another study [103]. IVIG has also recently been reported to be e ective as a sole therapeutic agent and when used in combination with other immunomodulatory agents such as rituxamab [93,97]. The basis for treatment with rituximab is to deplete pre-, immature, and mature B lymphocytes; cases of dramatically improved symptoms within a few weeks and a decrease in steroid requirements have been noted [97]. Of note, the patients who respond best to rituximab are those who have pem- phigoid-type EBA [79].

Ocular pemphigus vulgaris

Clinical features

OPV is an autoimmune blistering disease localized to the skin and mucous membranes. The hallmark of the disease is acantholysis, and patients present with flaccid blisters on an erythematous base as opposed to the bulging, tense blisters seen in bullous pemphigoid [104]. The blisters may present

with Nikolsky’s sign (describing the separation of the epithelium with tangential pressure on the skin surface), which o ers a moderately sensitive but highly specific tool for the diagnosis of pemphigus [105,106]. The skin lesions can be found on the trunk, groin, axilla, scalp, face, and other pressure points. Oral and mucosal lesions are seen in 80% to 90% of cases and may be the initial presentation, although the disease can present with an early urticarial, nonblistering phase. A ected mucosal surfaces include the conjunctiva, esophagus, vulva, cervix, anus, and larynx [104,106]. Ocular involvement in pemphigus vulgaris is rare, is limited to the conjunctiva and eyelids, and does not typically progress to scarring. Lid margin erosions can appear in lower and upper lids, and lid margin erosions in the medial aspect of the lower eyelid may be pathognomonic of OPV [107]. OPV does not appear to a ect visual acuity, and patients have a full recovery without sequelae [108]. Even more uncommonly, eyes are a ected by pemphigus erythematosus, a pemphigus variant characterized by erythematous and crusted lesions in seborrheic areas of the head and trunk. This di erence is due to di erential expression of the OPV and pemphigus erythematosus autoantigens desmoglein 3 and 1, respectively, throughout squamous epithelia, leading to a distinct antibody profile against targeted tissues [109].

Diagnostic studies

Perilesional biopsy demonstrating IgG deposits in the intracellular space with direct and indirect immunofluorescence confirms the diagnosis of OPV [106]. The pemphigus antigens include the desmosomal cadherins desmoglein 1 and 3 and the epithelial acetylcholine receptors alpha 9 and pemphaxin [110,111]. Direct immunofluorescence demonstrates in vivo intercellular deposits of antibodies, primarily IgG, on the surface of keratinocytes in and around lesions throughout the epidermis, with IgG1 and IgG4 as the most common subclasses [112]. Other immunoreactants such as complement C3 and IgM can be deposited less frequently than IgG [113]. This pattern of intracellular deposition throughout the dermis is not specific for OPV and may be seen in pemphigus vegetans, pemphigus foliaceus, and pemphigus erythematosus. Indirect immunofluorescence demonstrates the presence of circulating IgG autoantibodies that bind to the epidermis in 80% to 90% of patients who have OPV and that correlate with disease course [110]. Laboratory use of ELISA to reveal desmoglein 1 and 3 antibodies provides objective, quantitative, and reproducible data that allow di erentiation of OPV from pemphigus foliaceus. Due to these diagnostic advantages, ELISA is likely to become a routine technique in diagnostic laboratories [114].

Histopathology demonstrates an intradermal blister, with changes consisting of intercellular edema with loss of intercellular attachments in the basal layer. The blisters are formed from suprabasal epidermal cells that subsequently separate from the basal cells that remain attached to the