blistering diseases, LSCT is playing an increasing role in treatment as techniques are advanced [8,9,54–59]. When LSCT and PKP are unsuccessful, keratoprostheses o er another option for rehabilitation of vision [1,2,50,52–59].

Linear immunoglobulin A disease

Clinical features

LAD patients commonly complain of ocular symptoms including eye pain, dry eyes, foreign-body sensation, burning, or ocular discharge. Even in the absence of ocular complaints, slit-lamp examination may reveal fine conjunctival scarring, subconjunctival fibrosis, and subsequent inner canthal architecture loss, inferior forniceal foreshortening, trichiasis, entropion, and symblepharon formation with secondary corneal opacification. The ocular changes may be clinically indistinguishable from those of MMP. Because ocular involvement is common (w50% of LAD patients) and may be asymptomatic, all LAD patients should undergo ophthalmologic examination [60].

LAD is a rare disease characterized by circulating autoimmune antibodies to the epithelial BMZ, with the prevalence estimated to be 0.6 cases per 100,000 adults in Utah [61]. Internationally, estimates include incidences of 1 case per 250,000 individuals per year in southern England, and 0.13 cases per 250,000 individuals in France [62]. Association with HLA-B8 has been noted, and LAD patients present in a bimodal age distribution, with pediatric disease presenting at a mean age of 3.3 to 4.5 years and adult cases at a mean age of 52 years [63–66]. Maleand femalepatients are equally a ected and typically present witha lengthened prodrome of a pruritus or cutaneous burning sensation before emergence of lesions classically characterized as annular tense bullae, resembling a ‘‘string of pearls’’ or ‘‘cluster of jewels’’ surrounding a patch of erythematous skin [61]. Lesions typically involve the perioral region, perineum, and extremities. In addition, mucous membrane involvement is seen in adults, with oral, genital, and conjunctival lesions that can result in scarring. These lesions may appear gradually or, in drug-associated cases, more acutely [61,63,64].

Associations between LAD and various suspected etiologies include drug-induced (most commonly vancomycin hydrochloride) cases, which are more common in adults due to treatment with multiple medical therapies for comorbid conditions [67–69]. Other suspected drugs associated with one or several cases of LAD include captopril, amiodarone, and phenytoin [70–73]. Thus, the clinician should examine the presenting patient’s medication regimen for possible iatrogenic causes. Other associations have been considered, including preceding illness, malignancy, and coexistence with other autoimmune disorders [61,64,69].

Diagnostic studies

Histopathologic examination of cutaneous blisters in LAD reveals characteristic findings including neutrophil alignment along the BMZ and

subepidermal cleavage with inflammatory cells in the upper dermis. In some cases, neutrophilic microabscesses may form within the papillary ridges. Mature lesions reveal subepidermal blistering with a predominantly neutrophilic infiltrate, although eosinophils and monocytes may be present. In patients who have atypical presentations, additional testing including bacterial culture and Gram stain of blister fluid to rule out bullous impetigo and Tzanck smear to rule out herpesvirus infection may be diagnostically informative [60,61,64,66].

As in MMP, biopsy and immunofluorescent study are the predominant modalities used to confirm the diagnosis of LAD. Direct immunofluorescent assay of involved and spared areas of skin shows corresponding linear IgA (and less frequently IgG or IgM) and complement C3 deposition along the basement membrane [60,74]. Similar deposition is observed with analysis of conjunctival and oral mucosa in a ected patients [60,74]. Addition of indirect immunofluorescence or direct immunoelectron microscopy techniques increases sensitivity, with the former identifying circulating anti-BMZ autoantibodies in approximately one half of LAD patients [60,74]. Circulating autoantibody titers are characteristically higher in children than in adults but are generally a low-frequency finding in both age groups. The use of immunoperoxidase in indirect and direct immunoelectron microscopy localizes immunoglobulin deposition to the lamina lucida and to the target antigen LAD-1, secreted by keratinocytes as a component of the anchoring filament [60,66,74]. Immunoblotting and immunoelectron microscopy studies show reactivity between LAD sera and several di erent antigenic targets [75,76]. Prediction of a particular patient’s disease course or clinical response to treatment should take this intradisease variability into account because patients are less treatment responsive in cases in which type VII collagen is the molecular target antigen [64]. Because these diseases may present with indistinguishable clinical pictures, this would explain the variation in the clinical picture and therapeutic responses seen with LAD [75,76].

Disease course and treatment

LAD typically follows an exacerbating and remitting disease course, with the possibility of progression to blindness. Overall, remission occurs in 64% of children, usually within 2 years from symptomatic onset [61,66]. Adult patients experience less frequent (48%) remission and a more prolonged disease course lasting an average of 5 to 6 years [61–66]. Drug-induced cases typically resolve quickly with identification and withdrawal of the o ending agent [67–73]. Although ocular and oral lesions may leave persistent scarring as in the case with MMP, cutaneous lesions usually heal without scarring. Involvement of the other gastrointestinal and genitourinary mucous membranes may coexist [60].

Localized treatment addresses the mucosal and cutaneous lesions, although bullae do not usually require specific care beyond hygienic dressings,