Linear IgA Bullous Dermatosis
- Linear IgA bullous dermatosis is an autoimmune, mucocutaneous blistering disorder in adults and children, characterized by linear IgA deposition on direct immunofluorescence of the skin.
- Cases may be idiopathic or drug-induced. Many other disease associations have been reported, though further studies are needed to determine their strength and significance.
- First-line treatment is oral dapsone. Systemic corticosteroids and other immunomodulators are sometimes necessary for severe or refractory cases.
Linear IgA bullous dermatosis (LABD) is an acquired, immune-mediated mucocutaneous blistering disorder. It is characterized by the linear deposition of immunoglobulin A (IgA) along the basement membrane zone on direct immunofluorescence of the skin. LABD occurs in both adults and children and can be idiopathic or drug-induced. In adults, disease tends to occur in two peaks; young adults and patients over 60 years of age.
In adults, the clinical manifestations of LABD can be varied. The classic morphology is blisters arranged in an annular or herpetiform pattern on normal, erythematous, or urticarial skin. Other less common variants include non-bullous (morbilliform or eczematous), targetoid, and a severe, toxic epidermal necrolysis (TEN)-like variant characterized by a positive Nikolsky’s sign and extensive skin denudation. Lesions are often pruritic, though they can rarely be asymptomatic. The face (especially periorally), trunk, and extensor extremities are the most commonly affected areas in adults.
Oral mucosal involvement including vesicles, erosions, and ulcerations occurs in approximately 30-45% of patients. Oral lesions are frequently located on the palate or buccal mucosa. About 10% of patients have conjunctival involvement (conjunctival injection, discharge, or a gritty sensation) that can lead to significant scarring complications including symblepharon and ectropion. Nasopharyngeal, esophageal and rarely tracheobronchial mucosal involvement have also been reported. In most patients, the disease is limited to mucocutaneous involvement, though there are rare reports of associated IgA nephropathy.
Childhood LABD, also known as chronic bullous disease of childhood (CBDC) typically presents around 4.5 years and resolves prior to puberty. Like classic adult LABD, childhood LABD typically presents with annular or arciform bullae. Crusts form over old lesions and new bullae can develop at the edge leading to an annular configuration that can resemble a “string of pearls” or “crown of jewels.” In children, bullae favor flexural areas including the lower abdomen, buttocks, genitalia, and upper thighs.
Linear IgA dermatosis is commonly a drug-induced disease. Clinical manifestations do not usually differ from idiopathic disease. Onset is typically within two weeks of drug exposure.
Culprit drugs include:
- Antibiotics: vancomycin* (most common), penicillins, cephalosporins, moxifloxacin, sulfonamide antibiotics
- Anticonvulsants: phenytoin*, carbamazepine
- Anti-hypertensives: ACE inhibitors (especially captopril), angiotensin receptor antagonists
- Others: NSAIDs, furosemide, interleukin-2, interferon-alpha, PUVA, cyclosporine, statins, amiodarone, lithium
LABD has also been reported in association with inflammatory bowel disease, especially ulcerative colitis, and gluten sensitive enteropathy (though some authors argue that these cases are actually cases of dermatitis herpetiformis). Other reported associations include internal malignancies, paraproteinemia, autoimmune diseases, and infections (upper respiratory tract infections [URIs]) and varicella zoster virus). In children, the most common associations are URIs and the use of penicillins.
Further studies are needed to confirm the strength and significance of these reported associations. In contrast to dermatitis herpetiformis, gluten-free diets do not typically improve LABD and should not be routinely recommended. In addition, in the absence of any concerning signs or symptoms, additional malignancy screening beyond an age-appropriate evaluation is not routinely recommended in LABD patients.
The natural course of disease is persistence for several years with eventual spontaneous remission in as many as two-thirds of patients. Childhood LABD typically remits prior to puberty but rarely can recur. Thus, therapeutic medications should be tapered periodically to see if spontaneous remission has occurred. In drug-induced disease, resolution typically occurs within two to six weeks of stopping the offending medication.
* Most commonly associated with TEN-like variant
As with many blistering dermatoses, initial evaluation for LABD includes a punch biopsy at the edge of a fresh blister for hematoxylin and eosin (H&E). Histology demonstrates a subepidermal bulla with a mixture of neutrophils and eosinophils. In early lesions, neutrophils lining the basement membrane zone accompanied by vacuolar changes and occasional neutrophilic microabscesses in dermal papillae are seen. The histology of adult and childhood LABD are identical.
A second punch biopsy should also be performed for direct immunofluorescence (DIF) from intact skin adjacent to a fresh blister (perilesional skin). The DIF skin specimen should be placed in Michel’s or Zeus media (not formalin) or flash frozen. In adult and childhood LABD, the DIF will show a homogenous linear pattern of IgA present at the basement membrane zone (BMZ). Sometimes IgG deposits are also seen in both adults and children.
- On DIF, granular deposition of IgA at BMZ
- Less likely to see intact vesicles given highly pruritic
- Very high association with gluten sensitive enteropathy
- On H&E, typically more eosinophils and less neutrophils
- On DIF, linear IgG and C3 at BMZ
- Bulla typically more localized
- Wound culture from blister fluid is often positive for bacteria
Epidermolysis bullosa acquisita
- On DIF, IgG at BMZ
- Patients meet criteria for systemic lupus
- On DIF, granular IgG (sometimes IgA and/or IgM) along the BMZ
Mucous membrane pemphigoid
- Primarily mucosal involvement with limited, if any, skin involvement
- Mucosal predominate LABD may be considered a form of mucous membrane pemphigoid
In some cases, both linear IgG and IgA are present along the BMZ making clinical distinction between LABD, BP, and EBA difficult. Most experts agree that classification should be based on the predominate immunoglobulin present at the BMZ.
The therapeutic strategy is control of blister formation and relief of symptoms.
- For drug-induced disease, discontinue the culprit drug.
- For idiopathic disease and more extensive drug-induced disease, first-line treatment is oral dapsone usually starting at 50 mg per day (0.5 mg/kg daily for children). Expect a clinical response within 48-72 hours.
- CBC with differential, LFTs, and glucose-6-phosphate dehydrogenase (G6PD) should be obtained at baseline. CBC and LFTs should then be followed closely especially when escalating the dose.
- If blistering is not controlled, increase dapsone every one to two weeks in 25-50 mg increments (max 200-300 mg daily in adults, 2 mg/kg in children).
- Oral corticosteroids may be necessary for rapid control of severe disease (prednisone 0.5-1 mg/kg per day or equivalent).
- Medium and high potency topical corticosteroids can be used for localized disease or as adjunct. Topical calcineurin inhibitors have also been used for a steroid sparing effect.
- Colchicine may be used to supplement the dapsone dose (0.6 mg twice to three times a day in adults).
- Small case series and reports have suggested systemic antibiotics may be helpful in LABD.
- Oxacillin, dicloxacillin, and erythromycin given at doses of 50 mg per day have been used in childhood LABD.
- Tetracycline 1000-1500 mg/day plus nicotinamide 500 mg two to three times a day have been used in adults. Tetracyclines should be avoided in children given the potential damage to developing teeth.
- Rarely, steroid sparing agents such as azathioprine, mycophenolate mofetil, and IVIG have been required in patients with refractory disease.
- Sulfapyridine has been used historically alone or in combination with dapsone (1000-1500 mg per day in adults). This medication can have limited availability in the US and may require a compounding pharmacy.
Taper dapsone by 50 mg increments every two weeks until the appropriate maintenance dose is achieved. The maintenance dose should be the level at which the patient gets an occasional blister. Many cases may spontaneously remit, thus, medications should be tapered periodically.
- Patients should be screened for G6PD deficiency, as dapsone causes severe acute hemolysis in these individuals.
- Caution should be used with dapsone given risk of hemolysis (occurs to some degree in all patients), methemoglobinemia, and hypersensitivity syndromes.
- If a patient does not respond to dapsone, the diagnosis should be reevaluated, especially for a potential inciting medication.
- A 55-year-old female is admitted to the hospital for refractory lower extremity cellulitis and started on intravenous vancomycin
- One week after the initiation of the medication, the patient notes pruritus and a few urticarial lesions scattered on the arms and trunk
- She is treated with anti-histamines with minimal improvement
- Two days later, many small, tense blisters are noted within the urticarial plaques
- Dermatology is consulted. A skin biopsy is performed and shows a subepidermal bulla with neutrophils and eosinophils. A DIF is also performed which shows characteristic linear IgA along the BMZ
Linear IgA bullous dermatosis
Her skin manifestations developed within one week of starting vancomycin, a medication associated with drug-induced cases of LABD, and thus a suspected diagnosis of vancomycin-induced linear IgA bullous dermatosis is made.
- Vancomycin is immediately discontinued
- A G6PD is ordered which is within the normal range and the patient’s recent CBC and LFT are reviewed
- Dapsone is started at a dose of 50 mg daily
- The patient continues to have new bullae after one week of dapsone 50 mg daily and the dose is increased to 100 mg daily with close monitoring of the patient’s CBC
- Within 14 days, no new blisters have developed and all of her old lesions are crusted and healing
- At week four, dapsone taper is initiated. By six weeks, her skin is clear with only mild post inflammatory hyperpigmentation at previously involved sites
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