Linear IgA bullous dermatosis

INTRODUCTION — Linear IgA bullous dermatosis (LABD), also known as linear IgA disease, is a rare, idiopathic or drug-induced autoimmune blistering disease characterized by the linear deposition of IgA at the dermoepidermal junction. Although the clinical features of this disorder can be difficult to distinguish from dermatitis herpetiformis (another autoimmune blistering disease), the distinct immunopathologic findings in LABD and the absence of an associated gluten-sensitive enteropathy confirm the status of LABD as a distinct disease [1].

LABD occurs in both adults and children, and since the late 1980s, the disorder designated as chronic bullous disease of childhood has been recognized as the childhood form of LABD [2]. Children classically present with widespread annular blisters that exhibit a predilection for the lower abdomen, thighs, and groin. In adults, annular lesions are less common and the extensor extremities, face, and trunk are frequently affected. Mucosal lesions, manifesting as inflammation, erosions, or scarring, may also occur in patients with LABD.

The clinical features, diagnosis, and management of LABD in adults and children will be reviewed here. A general approach to the evaluation of patients with blistering skin lesions is reviewed separately. (See "Approach to the patient with cutaneous blisters".)

EPIDEMIOLOGY — Linear IgA bullous dermatosis (LABD) is a rare disorder. Reports of disease incidence from various countries have ranged from less than 0.5 to 2.3 cases per million individuals per year [3]. A predilection for LABD based upon ethnicity or sex has not been definitively established [3,4].

Adults frequently develop LABD in the later stages of life, with many cases occurring after the age of 60 [2,3]. In children, the disease usually presents between the ages of 6 months and 10 years; in a series of 25 affected children, the average age of onset was 4.5 years [2]. Rarely, neonates are affected [5,6].

PATHOGENESIS — Although the presence of IgA antibodies bound to the basement membrane zone is accepted as a characteristic feature of linear IgA bullous dermatosis (LABD), the mechanism of lesion formation in this disorder is not well understood. Both humoral and cellular immune responses may be involved in the pathogenesis of this disease. In particular, tissue injury resulting from an antibody-induced local inflammatory response and the release of proteolytic enzymes by neutrophils and other inflammatory cells may contribute to the development of skin and mucosal lesions [3].

Most patients with LABD have IgA1 antibodies that target a 97 kDa antigen and a 120 kDa antigen within the basement membrane zone. Both of these antigens are fragments of the extracellular portion of bullous pemphigoid antigen 2 (BP180/type XVII collagen), a transmembrane protein that plays a key role in epidermal-dermal adhesion [7,8]. Authors have detailed the process by which the cleavage of the BP180 antigen results in exposure of neoepitopes on the 15^th collagenous domain that react with IgA autoantibodies [9]. Less frequently, the NC16a epitope on BP180 has been associated with LABD [10-12]. Some patients with LABD have IgA antibodies that are directed against other basement membrane antigens, including type VII collagen (COL7), laminin-332, or laminin gamma 1. These antigenic targets are relevant when IgA antibody binding localizes to the dermal side of salt-split skin (sublamina densa) [13]. Type VII collagen appears to be the target antigen in some patients with vancomycin-induced LABD. In one study, 10 of 14 sera from patients with vancomycin-induced LABD demonstrated enhancement of reactivity to the recombinant noncollagenous (NC1) domain of type VII collagen when exposed to vancomycin [14]. (See 'Indirect immunofluorescence' below and "Approach to the patient with cutaneous blisters", section on 'Indirect immunofluorescence' and 'Risk factors' below.)

In addition, the presence of both IgA and IgG antibodies against basement membrane zone components has been detected in a subset of patients with features consistent with LABD. A Japanese review of 213 reported cases found that such findings were present in approximately 20 percent of patients [15]. Additional study is necessary to determine whether this presentation represents a distinct disorder or a variant of LABD.

RISK FACTORS — In most patients with linear IgA bullous dermatosis (LABD), the inciting factor for the disease is unknown.

Although multiple case reports have documented drug exposure as a precipitating factor [16], formal studies validating the existence of drug-induced LABD are lacking. Vancomycin is the pharmacologic agent most frequently reported as a potential inciting factor [16]. Examples of other drugs that may be linked to LABD include a variety of antibiotics, nonsteroidal anti-inflammatory agents (eg, diclofenac, naproxen, piroxicam), lithium, captopril, amiodarone, phenytoin, cyclosporine, furosemide, interferon alfa, and somatostatin (table 1) [3,17-19]. (See "Vancomycin hypersensitivity".)

Genetic factors also may contribute to the development of LABD. Associations of LABD with human leukocyte antigen (HLA) B8, HLA Cw7, HLA DR3, HLA DQ2, and the tumor necrosis factor-2 allele have been reported [20]. Further study is necessary to determine the role of both drugs and genetics in LABD.

CLINICAL MANIFESTATIONS — Linear IgA bullous dermatosis (LABD) may present with lesions on the skin, on the mucous membranes, or in both locations. Although both children and adults develop LABD, differences in the clinical characteristics of the disease are observed among these populations.

Cutaneous lesions — Since blister formation in LABD occurs subepidermally, the vesicles and bullae that form on the skin of affected patients typically have a tense, rather than flaccid, pemphigus-like quality. (See "Approach to the patient with cutaneous blisters", section on 'Blister quality'.)

A summary of the clinical characteristics of adult and childhood LABD is provided below:

●Children – LABD of childhood, also known as chronic bullous disease of childhood, most often presents with the acute development of vesicles or bullae on sites of inflamed or noninflamed skin (picture 1A-D). New blisters often form at the periphery of resolving lesions, resulting in an arciform or annular appearance (picture 2). Such lesions are frequently described as resembling strings of pearls, crowns of jewels, or rosettes [21].

The distribution of skin lesions usually is widespread, involving the trunk, face (particularly perioral area), genitalia, hands, feet, and other sites. The most intensely involved areas are often the perineum, lower abdomen, and inner thighs [2,4,22].

Affected children may be asymptomatic, but pruritus is common and may be severe. In some patients, intense pruritus heralds recurrences of the disease [7,8].

●Adults – Adult patients with LABD typically experience an abrupt onset of skin lesions; less frequently, the disease develops more slowly [23]. The tense vesicles and bullae may arise on normal skin or within inflammatory plaques (picture 3A-D). Annular lesions demonstrating peripheral vesiculation develop less frequently in adults than in children [23].

The trunk, extensor extremities, buttocks, and face (particularly the perioral area) are common sites for lesion development [3]. This distribution can make it difficult to distinguish LABD from dermatitis herpetiformis, which affects similar sites. Localized variants of LABD presenting as limited blistering eruptions or annular inflammatory plaques have also been reported [24-30]. Pruritus may be intense, and can result in the development of excoriated papules or prurigo nodularis-like lesions [31,32].

Mucosal involvement — Mucous membrane involvement can occur in both adults and children. Mucosal disease occurs in up to 80 percent of adult patients [2]. Estimates of the incidence of mucosal LABD in childhood disease vary widely. In a series of 25 children with LABD in the United Kingdom, mucosal involvement was present in 64 percent [2]. In contrast, similarly sized Japanese and Tunisian retrospective studies found mucosal disease in only 3 and 8 percent of children, respectively [15,33].

Mucosal lesions primarily present as erosions or ulcers; the detection of intact vesicles or bullae is uncommon. Any mucosal surface may be affected, including the oral cavity, conjunctiva, nose, genitalia, pharynx, larynx, anus, and esophagus [2,3,5,23].

The oral and ocular mucosa are the most commonly affected mucosal sites [2,3]. In patients with oral disease, lesions are frequently located on the palate, palatine arches, or buccal mucosa [3]. Erosive gingivitis and erosive cheilitis may also occur as manifestations of oral LABD [2,34,35]. Ocular disease may present with conjunctival redness, ocular discharge, ocular pain, or a foreign-body sensation [2].

Mucosal scarring may occur, and similar to patients with ocular cicatricial pemphigoid, patients with ocular LABD can develop symblepharon and ectropion [36] (see "Ocular cicatricial pemphigoid"). Examples of serious adverse consequences of cicatrizing mucosal disease include corneal damage leading to blindness, airway obstruction, and esophageal strictures [36-38].

Rarely, the mucosa is the initial or only site of LABD [34,39-41]. Mucosal-predominant LABD is considered a form of mucous membrane pemphigoid [42]. (See "Epidemiology and pathogenesis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Classification'.)

Drug-induced linear IgA — The clinical findings in drug-induced LABD usually do not differ significantly from those of idiopathic disease [16,43]. Occasionally, lesions are localized rather than widespread or resemble morbilliform drug eruptions, erythema multiforme, or toxic epidermal necrolysis (TEN) (picture 4) [44-50]. The presence of mucosal involvement varies [16].

The shared clinical features of idiopathic LABD and drug-induced LABD were demonstrated in a retrospective study of 16 patients considered to have spontaneous LABD and 12 patients considered to have drug-induced LABD that found similar frequencies of erythematous plaques, string of pearls-like configurations, target or target-like lesions, and mucosal involvement in the two groups [50]. Only the atypical features of large erosions and a positive Nikolsky sign were significantly more frequent in the drug-induced group.

Most reported cases of drug-induced LABD have occurred in adults, but LABD in association with drug exposure has also been observed in children [2,16,17]. The disease usually begins within one month of drug initiation, and often resolves within several weeks following drug cessation [17,51,52]. However, the eruption persists for longer in some patients. Antibiotic-impregnated devices (eg, cement) may contribute to delayed resolution in the setting of antibiotic-induced LABD [53]. In addition, reexposure to an inciting agent can result in the rapid recurrence of blistering [54].

The culprit medication is typically identified by the history. Use of established adverse drug algorithms to support causality is encouraged [55]. Drug-induced lymphocyte stimulation testing may provide additional information when multiple medications are temporally related to the onset of skin disease [56].

Patients with vancomycin-induced disease may have increased risk for TEN-like presentations. In a retrospective study of 69 patients with drug-induced LABD (including 39 with suspected vancomycin-induced disease), vancomycin was the suspected cause in 11 of 14 patients (79 percent) with TEN-like features [43].

Rarely, patients with LABD also develop IgA nephropathy. Resolution of drug-induced IgA nephropathy following drug withdrawal has been reported [57].

ASSOCIATED DISORDERS — Linear IgA bullous dermatosis (LABD) has occurred in the setting of ulcerative colitis, hematologic or solid organ malignancies, and other disorders:

●Ulcerative colitis – Ulcerative colitis is the most common benign disorder reported in association with LABD [15,58-62]. In a retrospective study of 70 patients with LABD referred to two dermatology departments in the United Kingdom, five patients (7 percent) had ulcerative colitis, and ulcerative colitis preceded the diagnosis of LABD by an average of six years [59]. Moreover, a Japanese review of 213 reported cases of LABD identified four patients with this disease [15].

The reason for an association between LABD and ulcerative colitis is unclear. Some authors have suggested that abnormal IgA1 production by the inflamed bowel may contribute to the development of LABD [59]. Although improvement in skin disease following surgical intervention for bowel disease has been reported [60-62], in other patients skin disease has persisted after surgery [59]. Limited data from case reports suggest that persistence of LABD may be more common after colectomy with sparing of the rectal mucosa than after proctocolectomy [63].

●Malignancy – The occurrence of LABD in association with lymphoproliferative and solid organ malignancies has been reported in multiple case reports [29,64-81]. However, further studies are necessary to confirm an association between LABD and malignancy. Thus, in the absence of signs or symptoms suggestive of a malignancy, screening beyond age-appropriate investigation is not warranted in patients with LABD.

Other disorders reported to occur in association with LABD in a few patients include a variety of infections [26,82-86], psoriasis [85,87], and systemic lupus erythematosus [15,88]. The development of LABD has also been reported following exposure to ultraviolet light [26,89,90]. Unlike dermatitis herpetiformis, which may clinically and histologically resemble LABD, gluten sensitivity is not a feature of this disorder and gluten-free diets do not improve LABD [3,91].

DIAGNOSIS — The clinical signs and symptoms of linear IgA bullous dermatosis (LABD) may resemble multiple mucocutaneous diseases. Thus, when available, laboratory studies are typically utilized to confirm the diagnosis. Although the findings of routine histopathologic examination of affected tissue may suggest LABD, the demonstration of linear deposits of IgA along the basement membrane zone via direct immunofluorescence (DIF) is the gold standard for diagnosis [7]. In addition, a medication history should always be reviewed to assess for the possibility of drug-induced disease. (See 'Drug-induced linear IgA' above.)

Light microscopy — The histopathologic findings of linear IgA bullous dermatosis are nonspecific and often closely resemble dermatitis herpetiformis. A subepidermal blister with an underlying neutrophil-predominant dermal infiltrate is characteristic (picture 5) [3]. Lymphocytes, eosinophils, and papillary microabscesses similar to those seen in dermatitis herpetiformis also may be present [7]. (See "Approach to the patient with cutaneous blisters", section on 'Skin biopsy'.)

Direct immunofluorescence — In order to perform direct immunofluorescence, a small biopsy (eg, 4 mm punch) is taken from perilesional skin (clinically normal appearing skin immediately adjacent to a lesion) and sent to an immunopathology laboratory in a preservative such as Michel's or Zeus medium or as a flash-frozen specimen. In situations in which the specimen can be delivered to the laboratory within minutes, transport on saline-moistened gauze is an alternative. Specimens for direct immunofluorescence should not be placed in formalin. (See "Approach to the patient with cutaneous blisters", section on 'Direct immunofluorescence'.)

The diagnostic finding of LABD via direct immunofluorescence is a linear band of IgA at the dermoepidermal junction (picture 6) [7]. Utilization of the salt-split skin technique is not particularly useful for diagnosis since testing reveals variable results [15,92]. Antibody binding to the epidermal side of the induced cleavage zone is most common; binding to the dermal side may be more likely to occur in patients who are older or who have both IgA and IgG deposits at the epidermal basement membrane zone [15]. Binding to both epidermal and dermal sides of the plane of cleavage may also occur. (See "Approach to the patient with cutaneous blisters", section on 'Basement membrane zone-split skin technique'.)

Indirect immunofluorescence — Indirect immunofluorescence can be used to detect circulating IgA antibodies against basement membrane zone components and may aid in diagnosis when a skin biopsy is not possible. This test is less likely to be positive in adults than in children (30 versus ≥75 percent of patients) [4,23]. For best results, indirect immunofluorescence should be performed on a substrate of salt-split human skin [8,92]. In the vast majority of cases, indirect immunofluorescence studies reveal antibody bound to the epidermal side of salt-split skin, a finding that is consistent with the locations of the 97 kDa antigen, 120 kDa antigen, laminin-332, and BP180 (NC16a domain) [93-95]. Type VII collagen (COL7), laminin-332, or laminin gamma 1 may be the target antigens when antibody binding localizes to the dermal side of salt-split skin (sublamina densa) [13]. (See 'Pathogenesis' above and "Approach to the patient with cutaneous blisters", section on 'Indirect immunofluorescence'.)

Other tests — Other tests such as immunoelectron microscopy and immunoblotting can also be used to confirm the diagnosis [3]. However, the cost and limited availability of these tests limit their value in the clinical setting. We do not routinely utilize these studies for diagnosis.

DIFFERENTIAL DIAGNOSIS — The acute onset of widespread annular or arcuate blisters strongly suggests the possibility of linear IgA bullous dermatosis (LABD) (picture 2). However, annular lesions are not always present, and multiple other disorders share clinical features with LABD. Examples of conditions to consider in the differential diagnosis are provided below:

●Dermatitis herpetiformis – Dermatitis herpetiformis is an autoimmune subepidermal blistering disorder with clinical and histopathologic features that can closely resemble LABD. Patients typically present with grouped vesicles or bullae on the scalp, extensor extremities, or buttocks (picture 7). Direct immunofluorescence microscopy is useful for distinguishing these disorders. (See "Dermatitis herpetiformis".)

●Bullous impetigo – Bullous impetigo is a Staphylococcus aureus infection that most commonly occurs in young children. Multiple, easily-ruptured bullae with clear or yellow fluid are typically present on the face, trunk, or extremities (picture 8). A collarette of scale often remains at the site of ruptured lesions. A culture of the fluid from an intact blister can be used to detect S. aureus. (See "Impetigo", section on 'Bullous impetigo'.)

●Bullous pemphigoid – Bullous pemphigoid is an autoimmune subepidermal blistering disorder that typically affects older adults and manifests as pruritic inflammatory plaques and bullae that are primarily distributed on the trunk and extremities (picture 9A-C). Histopathologic examination usually reveals a higher proportion of eosinophils than are present in LABD. Direct immunofluorescence in bullous pemphigoid usually reveals linear IgG and C3 deposits at the basement membrane zone. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Clinical features of bullous pemphigoid'.)

●Pemphigoid gestationis – Pemphigoid gestationis is an autoimmune subepidermal blistering disorder that occurs in pregnant women. The pruritic eruption frequently begins around the umbilicus and subsequently spreads elsewhere (picture 10A-C). Direct immunofluorescence microscopy reveals the deposition of C3 in a linear pattern at the basement membrane zone. (See "Dermatoses of pregnancy", section on 'Pemphigoid gestationis'.)

●Bullous lupus erythematosus – Bullous lupus erythematosus is a rare subepidermal blistering disorder. The presence of a bullous disorder in a patient with systemic lupus erythematosus suggests the possibility of this disease. (See "Overview of cutaneous lupus erythematosus", section on 'Bullous cutaneous lupus erythematosus'.)

●Epidermolysis bullosa acquisita – Epidermolysis bullosa acquisita is a rare acquired subepidermal blistering disorder of the skin and mucous membranes (picture 11). Scarring and milia are common associated features. On direct immunofluorescence, deposits of IgG are most commonly detected at the basement membrane zone; however, less commonly, other immunoglobulins (including IgA) may be present. (See "Epidermolysis bullosa acquisita".)

●Mucous membrane pemphigoid – Mucous membrane pemphigoid consists of a group of subepidermal blistering disorders in which mucosal surfaces are the primary site of involvement. Mucosal-predominant LABD may be considered a form of mucous membrane pemphigoid. The immunofluorescence findings distinguish this subtype from other disorders. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Clinical features of mucous membrane pemphigoid'.)

Infrequently, LABD may resemble prurigo nodularis [31], morbilliform drug eruptions [46], erythema multiforme [47], or toxic epidermal necrolysis (TEN) [44,45]. In addition, LABD in children may be mistaken for child abuse. (See 'Cutaneous lesions' above and 'Drug-induced linear IgA' above.)

THERAPY — Data on the treatment options for linear IgA bullous dermatosis (LABD) are limited. The approach to treatment is primarily based upon case reports and case series.

First-line therapy — Dapsone, an immunomodulatory sulfone that has been successfully utilized for the treatment of multiple dermatologic disorders characterized by neutrophilic infiltrates, is considered first-line treatment for LABD [3,4,7,8,96]. Dapsone has a long history of successful use in LABD and dermatitis herpetiformis, and is well tolerated by most patients.

Dapsone — Although no controlled trials have evaluated the efficacy of dapsone in children and adults with LABD, based upon case series, case reports, and clinical observations, the drug appears to be effective in many patients [15,31,33,97-101]. As an example, in a retrospective study in which 19 children received dapsone (1 to 2 mg/kg per day) as monotherapy, 11 patients (61 percent) attained lesion regression within 8 to 15 days [33].

Dapsone is started at a low dose (eg, <0.5 mg/kg per day in children or 25 or 50 mg per day in adults) that is titrated upward over several weeks as tolerated and in accordance with treatment response [102]. In LABD, the response to treatment can be dramatic, with signs of improvement noted within the first few days of therapy.

Typical dose ranges for dapsone therapy for LABD are listed below:

●Children: 0.5 to 2 mg/kg per day [21,33,103]

●Adults: 50 to 150 mg per day [8,96]

Although most patients tolerate the drug well, dapsone must be administered with caution, since potential serious adverse effects, such as hemolysis, methemoglobinemia, agranulocytosis, hypersensitivity syndrome, and peripheral motor neuropathy may occur as a result of therapy. Hemolysis occurs to some degree in all patients, and frequent hematologic monitoring during the early stages of treatment is recommended.

A complete blood count (CBC) with differential, liver function tests and glucose-6-phosphate dehydrogenase (G6PD) level should be obtained prior to the initiation of dapsone. We typically follow the CBC with differential weekly for one month, and then decrease the frequency to every two weeks for an additional eight weeks. Liver function tests should be monitored monthly for first three months. For long-term monitoring we recommend obtaining a CBC with differential, renal function tests, and liver function tests every three to four months.

Screening for glucose-6-phosphate (G6PD) deficiency should be performed prior to the initiation of dapsone therapy. The administration of dapsone should be avoided in patients with G6PD deficiency since this disorder is associated with an elevated risk for the development of severe hemolytic anemia. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Acute hemolytic anemia' and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Screening tests'.)

Topical corticosteroids — Although some authors have suggested that topical corticosteroids may be sufficient for disease control in patients with mild or localized LABD [96,104], most patients require systemic therapy to adequately control the disease. Thus, topical corticosteroids are primarily used as adjunctive therapy.

High potency or superpotent topical corticosteroids applied to individual lesions once or twice daily for up to two weeks may be utilized to accelerate improvement in lesions on the trunk or extremities. Low potency agents are preferred for lesions on the face, genital, or intertriginous regions due to an increased risk for corticosteroid-induced cutaneous atrophy in these areas. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)

Second-line therapy — Patients who cannot tolerate dapsone may benefit from treatment with sulfapyridine or sulfamethoxypyridazine, sulfonamide agents that have structural similarities with dapsone [7]. Colchicine is an additional therapeutic option.

Sulfonamides — Evidence for the efficacy of sulfapyridine and sulfamethoxypyridazine are primarily limited to reports of expert clinical experience [3,7,8,102,105]. Formal therapeutic trials of these agents to confirm efficacy in LABD have not been performed. In one series, sulfamethoxypyridazine monotherapy (1000 mg per day) was associated with the attainment of disease control in three patients with LABD who discontinued dapsone due to a failure to tolerate therapy [105]. None of these patients were young children.

Adults with LABD may be treated with 1000 to 1500 mg per day of sulfapyridine or sulfamethoxypyridazine [8]. Children have been treated with 15 to 60 mg/kg per day of sulfapyridine [3,7]. An appropriate dose range has not been established for sulfamethoxypyridazine treatment in children [3]. These agents have also been used in combination with dapsone in patients with LABD [7,105,106].

The availability of these agents is limited in some countries. In the United States, sulfapyridine can be obtained through compounding pharmacies, and sulfamethoxypyridazine is not available. The side effect profile of sulfapyridine is similar to dapsone, but the toxicity is less, a feature that makes use of this agent possible in patients with dapsone intolerance [107]. Alveolitis is an additional side effect that has been reported in patients treated with sulfamethoxypyridazine [105,108].

Monitoring guidelines for sulfapyridine and sulfamethoxypyridazine have not been established. During treatment with sulfapyridine, we typically obtain a CBC every three to six months to evaluate for leukopenia.

Colchicine — Successful treatment of childhood LABD with colchicine has been documented in case reports and small case series and this agent may be another reasonable option for children who cannot tolerate dapsone [98,109-112]. In a series of eight children with systemic glucocorticoid-refractory LABD, the addition of colchicine to glucocorticoid therapy led to dramatic responses to therapy in five patients within four to six weeks. In addition, these patients tolerated tapering and discontinuation of glucocorticoid therapy.

Colchicine has also been reported to be effective in a few adults with generalized or localized LABD [27,113]. However, the clinical experiences of some authors with adult patients have been less favorable [8].

The typical dosage for colchicine is 0.6 mg twice daily in children and 0.6 to 1 mg two to three times daily in adults [3,4,109,110].

Severe and refractory disease — Immunosuppressive agents may be beneficial in patients with severe clinical manifestations or refractory disease.

Immunosuppressants — Systemic glucocorticoids (eg, 0.5 to 1 mg/kg per day of prednisone) may be used during the initial few weeks of treatment to accelerate improvement in patients with severe involvement while awaiting the response to dapsone [8,33,96,98].

Patients who fail to respond sufficiently to dapsone may also derive benefit from the addition of systemic glucocorticoids to dapsone therapy [8,99-102,114]. However, due to the potential adverse effects of systemic glucocorticoids, these agents are not recommended for long-term use. Glucocorticoid-sparing agents, such as mycophenolate mofetil [115-119], cyclophosphamide, and cyclosporine [120], have been reported to be effective in small numbers of patients and can be utilized. Cyclophosphamide may be considered in patients with severe mucosal involvement [121]. (See "Major side effects of systemic glucocorticoids".)

Other interventions — Intravenous immunoglobulin [24,122-127] and immunoadsorption [128] have been reported to be effective in a few patients with LABD. Rituximab and anti-tumor necrosis factor (TNF)-alpha inhibitors have been used for patients with recalcitrant disease unresponsive to standard treatment [121]. In addition, benefit of omalizumab in a patient with LABD and chronic idiopathic urticaria has been reported [129]. Further studies are necessary to evaluate the efficacy of these interventions prior to a recommendation for their routine use in severe or refractory LABD.

Additional therapeutic options — Antibiotic therapy, tetracycline in combination with nicotinamide, and topical tacrolimus are utilized less frequently than dapsone for the treatment of LABD, but have been reported to be effective in small numbers of patients. Additional studies are necessary to confirm the efficacy of these therapies.

Systemic antibiotics — Case reports and small case series suggest that systemic antibiotics may be of benefit for childhood LABD. Whether anti-inflammatory, antibacterial, or other properties of these agents contribute to treatment efficacy is unknown.

In a series of seven children with LABD treated with flucloxacillin, disease clearance was achieved in all patients, but only four patients who received treatment early in the course of the disease (within one month of disease onset) had long-lasting remission off of therapy [82]. Oxacillin [33], dicloxacillin [130], erythromycin [99], and miocamycin [131], all given at doses of 50 mg/kg per day, have additionally been reported to be of benefit in individual children [132]. Erythromycin may also have been effective in an adult [133]. Trimethoprim-sulfamethoxazole has been associated with both the induction and remission of LABD [18,134-136].

Tetracycline and nicotinamide — Tetracycline (1000 to 1500 mg per day) plus nicotinamide (900 to 2000 mg per day), a drug combination that has been used for the treatment of bullous pemphigoid, was reported to induce disease clearance within a few weeks in three adult patients with LABD [137-139]. Of note, tetracycline cannot be utilized in children under the age of nine due to the drug's adverse effects on developing teeth.

Topical tacrolimus — Treatment with tacrolimus ointment, a topical calcineurin inhibitor, has been attempted in LABD. Disease resolution was observed in a child on dapsone therapy two weeks after her adjunctive topical therapy was changed from betamethasone dipropionate 0.05% to tacrolimus 0.03% ointment applied twice daily [140]. However, spontaneous resolution may also have accounted for the resolution of the disease.

Drug-induced disease — Drug-induced LABD typically resolves with withdrawal of the offending agent (see 'Prognosis and cessation of therapy' below). In severe or persistent cases, treatment with prednisone and/or dapsone may be beneficial. Therapy should be tapered or discontinued early in the course of treatment (eg, within the first four to six weeks) to confirm the presence of active disease that necessitates the continuation of systemic treatment. Prolonged systemic treatment is rarely needed. A report describes a patient with severe drug-induced LABD with toxic epidermal necrolysis (TEN)-like presentation who improved with cessation of the offending medication and initiation of etanercept, an anti-TNF agent [141].

PROGNOSIS AND CESSATION OF THERAPY — Idiopathic linear IgA bullous dermatosis (LABD) typically persists for months to several years prior to spontaneous resolution, and resolves in most children prior to puberty [2,4,114]. However, disease may persist for a decade or longer, and relapses after long periods of remission may occur [114]. A review of 72 adults with LABD found that older patients (>70 years) without mucosal involvement were most likely to experience a complete remission [121]. Even within this group relapses are common, and a chronic course was seen in 64 percent of all LABD patients [121]. In contrast, in drug-induced LABD, cessation of new lesion formation typically occurs within three days of removal of the inciting agent and disease resolution usually occurs within several weeks [52].

The duration of treatment required for idiopathic LABD is variable. It is important to recognize patients at high risk for a chronic, recalcitrant course (those with mucosal involvement and less than 70 years of age) when selecting treatment and determining treatment duration. Treatment with an effective agent is usually continued for several weeks after complete remission is attained. A negative direct immunofluorescence in areas of prior involvement may provide further support that a gradual tapering towards treatment cessation is reasonable [8,114,121]. If relapse occurs after treatment cessation, treatment should be reinitiated [114].

Although cutaneous lesions usually heal without permanent scars, patients with mucosal involvement may experience morbidity and functional limitations due to stricture formation or conjunctival and corneal scarring. Consequences related to poor oral hygiene and alimentation may also occur in patients with oral disease. (See 'Mucosal involvement' above.)

INDICATIONS FOR REFERRAL — A dermatologist or another clinician familiar with the management of LABD should be involved in the care of these patients. Patients with signs or symptoms of ocular disease should be referred to an ophthalmologist. In addition, consultation with an otolaryngologist or gastroenterologist is appropriate for patients with symptoms suggestive of pharyngeal, laryngeal, or esophageal disease.

SUMMARY AND RECOMMENDATIONS

●Linear IgA bullous dermatosis (LABD) is a rare autoimmune blistering disorder that usually presents with the abrupt onset of tense bullae and inflammatory lesions on the skin. Both children and adults may be affected. (See 'Epidemiology' above.)

●Most cases of LABD are idiopathic. However, LABD has also been reported in association with drug exposure. Vancomycin is the pharmacologic agent most frequently associated with LABD. (See 'Risk factors' above and 'Drug-induced linear IgA' above.)

●Children with LABD frequently develop widespread annular or arciform blisters that are often most abundant on the groin, lower abdomen, and medial thighs. In adults, the annular lesions are less commonly detected, and the trunk and extremities are typical sites of involvement. Pruritus is a common symptom of LABD. (See 'Cutaneous lesions' above.)

●Mucosal involvement in LABD may affect any mucosal site. Examples of potential serious consequences of mucosal involvement include blindness, airway obstruction, and esophageal strictures. (See 'Mucosal involvement' above.)

●The gold standard for the diagnosis of LABD is the detection of linear deposits of IgA with direct immunofluorescence microscopy. The tissue specimen for direct immunofluorescence should be taken from perilesional skin. The specimen must not be placed in formalin. (See 'Diagnosis' above and "Approach to the patient with cutaneous blisters", section on 'Direct immunofluorescence'.)

●Data on the treatment options for LABD are primarily limited to case reports and case series. For children and adults with LABD, we suggest the use of dapsone as first-line therapy (Grade 2C). The response to therapy is usually evident within days. Sulfapyridine, sulfamethoxypyridazine, and colchicine are additional options for patients who cannot tolerate dapsone therapy. (See 'Therapy' above.)

●Immunosuppressive therapy may be employed for patients with LABD that is refractory to dapsone or sulfonamide therapy. Use of a glucocorticoid-sparing agent such as mycophenolate mofetil is recommended when long-term immunosuppression is required. (See 'Severe and refractory disease' above.)