Linear IgA bullous dermatosis

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[level-membership-for-dermatology-category]

Linear IgA bullous dermatosis

Neil J. Korman

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Linear IgA bullous dermatosis is an acquired autoimmune blistering disease of the skin and mucous membranes. The skin lesions consist of papulovesicles or blisters that may have an arcuate pattern, with a ‘cluster of jewels’ grouping of blisters along with urticarial plaques. Involvement of the oral mucous membranes is common and ocular involvement, with subsequent scarring of the conjunctiva, may uncommonly occur. Although originally believed to be a distinct entity, it is now clear that chronic bullous disease of childhood is the childhood counterpart of adult linear IgA bullous dermatosis. Direct immunofluorescence studies demonstrate that all patients have linear IgA deposits at the epidermal basement membrane zone, and the diagnosis of linear IgA bullous dermatosis is dependent upon this finding. The target antigens involved are 97 kDa and, less commonly, 290 kDa. The 97 kDa antigen is an anchoring filament protein that is part of the 180 kDa bullous pemphigoid antigen-2, and antibodies directed against the 290 kDa protein represent an IgA response directed against type VII collagen. Several reports stress the association with ulcerative colitis. Drug-induced disease is a well-recognized entity, and vancomycin is the most commonly implicated agent.

Management strategy

If drug-induced disease is considered, the suspect trigger drug must be withdrawn. Treatment of linear IgA bullous dermatosis is dictated by the severity of disease and the areas of involvement. All patients should be evaluated by an ophthalmologist to ensure the absence of ocular disease. Because linear IgA bullous dermatosis tends to be chronic it is important to be aware of the potential not only for short-term, but also for long-term, toxicities in any treatment used. In addition, treatment of children with chronic bullous disease of childhood (the childhood counterpart of linear IgA bullous dermatosis of adults) requires special consideration to ensure that any medications used have no specific contraindications in children.

The majority of patients with disease limited to the skin will respond well to treatment with dapsone, and this is the first-line therapy for patients with linear IgA bullous dermatosis. Dapsone generally works quite rapidly, with responses often occurring in the first few days of starting the drug. It is most effective for the skin lesions of linear IgA bullous dermatosis, with the mucous membrane lesions being more resistant.

Because of a dose-related oxidant stress on normal aging red blood cells, all patients treated with dapsone will experience some degree of hemolysis that is usually dose-dependent. A reduction of approximately 2–3 g of hemoglobin is often observed. As long as this decrease is relatively gradual and patients have no history of cardiovascular disease or anemia, this is usually well tolerated. It is important to measure levels of glucose-6-phosphate dehydrogenase (G6PD) in patients to be treated with dapsone because those with a deficiency in this enzyme can develop severe hemolysis. Methemoglobinemia, which is also dosage dependent, occurs in most patients but is usually asymptomatic. More worrisome toxicities include bone marrow suppression and even agranulocytosis, which usually occurs early in the course of therapy, and a dapsone-induced neuropathy, which occurs more commonly in patients treated for several years with more than 200 mg of dapsone daily. Less commonly, hepatitis, nephritis, pneumonitis, erythema multiforme, and the dapsone hypersensitivity syndrome have all been reported.

For those patients who fail to achieve satisfactory control of their disease with dapsone as first-line therapy, it is often of value to add systemic corticosteroids. This combination is considered second-line therapy. The dosage of prednisone required is often in the 20–40 mg daily range. Often the addition of prednisone will not only cause significant clinical improvement, but it may also allow the dosage of dapsone to be reduced, thereby minimizing its potential toxicity.

Other viable second-line therapies include colchicine, sulfapyridine, and the combination of tetracycline and niacinamide: sulfapyridine at doses of approximately 1–3 g daily, and colchicine has been reported to be beneficial at doses of 1.0–1.5 mg daily. The combination of tetracycline and niacinamide, usually at doses of 1.5 g of niacinamide and 2 g of tetracycline, has been used with success. Tetracycline should not be used in children under 9 years of age because it can permanently stain teeth.

Third-line therapies include sulfamethoxypyridazine, dicloxacillin, erythromycin, mycophenolate mofetil, azathioprine, cyclosporine, methotrexate, interferon-α, and intravenous immunoglobulin (IVIG). Toxicity profiles and financial considerations favor using erythromycin, dicloxacillin, or sulfamethoxypyridazine prior to treatment with the immunosuppressive agents or IVIG.

Specific investigations

Vancomycin-induced linear IgA bullous dermatosis.

Baden LA, Apovian C, Imber MJ, Dover JS. Arch Dermatol 1988; 124: 1186–8.

Litt’s Drug Eruption Reference Manual, 10th edn (Taylor and Francis, New York, 2004) implicates acetaminophen, aldesleukin, amiodarone, ampicillin, atorvastatin, candesartan, captopril, carbamazepine, cefamandole, ceftriaxone, co-trimoxazole, cyclosporine, diclofenac, furosemide, glyburide, granulocyte–macrophage colony-stimulating factor (GM–CSF), ibuprofen, interferon-α, lithium, metronidazole, naproxen, penicillins, phenytoin, piroxicam, rifampin, sulfamethoxazole, and vancomycin as drug triggers for linear IgA disease. The extent of disease may sometimes simulate toxic epidermal necrolysis.

The diagnosis of linear IgA bullous dermatosis requires routine histologic studies as well as direct and indirect immunofluorescence studies. Once the diagnosis is confirmed, laboratory studies to be obtained will depend upon the specific treatment anticipated.

Second-line therapies

image Dapsone and prednisone D
image Sulfapyridine C
image Colchicine D
image Tetracycline and niacinamide E

Third-line therapies

image Sulfamethoxypyridazine E
image Dicloxacillin E
image Flucloxacillin E
image Erythromycin E
image Trimethoprim–sulfamethoxazole E
image Methotrexate E
image Interferon-α E
image Mycophenolate mofetil E
image Azathioprine E
image Cyclosporine E
image IVIG E
image Thalidomide E
image Immunoabsorption E

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Linear IgA bullous dermatosis

Neil J. Korman

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

Linear IgA bullous dermatosis is an acquired autoimmune blistering disease of the skin and mucous membranes. The skin lesions consist of papulovesicles or blisters that may have an arcuate pattern, with a ‘cluster of jewels’ grouping of blisters along with urticarial plaques. Involvement of the oral mucous membranes is common and ocular involvement, with subsequent scarring of the conjunctiva, may uncommonly occur. Although originally believed to be a distinct entity, it is now clear that chronic bullous disease of childhood is the childhood counterpart of adult linear IgA bullous dermatosis. Direct immunofluorescence studies demonstrate that all patients have linear IgA deposits at the epidermal basement membrane zone, and the diagnosis of linear IgA bullous dermatosis is dependent upon this finding. The target antigens involved are 97 kDa and, less commonly, 290 kDa. The 97 kDa antigen is an anchoring filament protein that is part of the 180 kDa bullous pemphigoid antigen-2, and antibodies directed against the 290 kDa protein represent an IgA response directed against type VII collagen. Several reports stress the association with ulcerative colitis. Drug-induced disease is a well-recognized entity, and vancomycin is the most commonly implicated agent.

Management strategy

If drug-induced disease is considered, the suspect trigger drug must be withdrawn. Treatment of linear IgA bullous dermatosis is dictated by the severity of disease and the areas of involvement. All patients should be evaluated by an ophthalmologist to ensure the absence of ocular disease. Because linear IgA bullous dermatosis tends to be chronic it is important to be aware of the potential not only for short-term, but also for long-term, toxicities in any treatment used. In addition, treatment of children with chronic bullous disease of childhood (the childhood counterpart of linear IgA bullous dermatosis of adults) requires special consideration to ensure that any medications used have no specific contraindications in children.

The majority of patients with disease limited to the skin will respond well to treatment with dapsone, and this is the first-line therapy for patients with linear IgA bullous dermatosis. Dapsone generally works quite rapidly, with responses often occurring in the first few days of starting the drug. It is most effective for the skin lesions of linear IgA bullous dermatosis, with the mucous membrane lesions being more resistant.

Because of a dose-related oxidant stress on normal aging red blood cells, all patients treated with dapsone will experience some degree of hemolysis that is usually dose-dependent. A reduction of approximately 2–3 g of hemoglobin is often observed. As long as this decrease is relatively gradual and patients have no history of cardiovascular disease or anemia, this is usually well tolerated. It is important to measure levels of glucose-6-phosphate dehydrogenase (G6PD) in patients to be treated with dapsone because those with a deficiency in this enzyme can develop severe hemolysis. Methemoglobinemia, which is also dosage dependent, occurs in most patients but is usually asymptomatic. More worrisome toxicities include bone marrow suppression and even agranulocytosis, which usually occurs early in the course of therapy, and a dapsone-induced neuropathy, which occurs more commonly in patients treated for several years with more than 200 mg of dapsone daily. Less commonly, hepatitis, nephritis, pneumonitis, erythema multiforme, and the dapsone hypersensitivity syndrome have all been reported.

For those patients who fail to achieve satisfactory control of their disease with dapsone as first-line therapy, it is often of value to add systemic corticosteroids. This combination is considered second-line therapy. The dosage of prednisone required is often in the 20–40 mg daily range. Often the addition of prednisone will not only cause significant clinical improvement, but it may also allow the dosage of dapsone to be reduced, thereby minimizing its potential toxicity.

Other viable second-line therapies include colchicine, sulfapyridine, and the combination of tetracycline and niacinamide: sulfapyridine at doses of approximately 1–3 g daily, and colchicine has been reported to be beneficial at doses of 1.0–1.5 mg daily. The combination of tetracycline and niacinamide, usually at doses of 1.5 g of niacinamide and 2 g of tetracycline, has been used with success. Tetracycline should not be used in children under 9 years of age because it can permanently stain teeth.

Third-line therapies include sulfamethoxypyridazine, dicloxacillin, erythromycin, mycophenolate mofetil, azathioprine, cyclosporine, methotrexate, interferon-α, and intravenous immunoglobulin (IVIG). Toxicity profiles and financial considerations favor using erythromycin, dicloxacillin, or sulfamethoxypyridazine prior to treatment with the immunosuppressive agents or IVIG.