Dermatitis herpetiformis

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Dermatitis herpetiformis

John J. Zone

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

Dermatitis herpetiformis (DH) is a cutaneous manifestation of celiac disease. Rare exceptions have been reported in the Japanese population. More than 85% of patients have an associated gluten-sensitive enteropathy that varies in severity. Both the skin disease and the histological intestinal inflammatory process respond to dietary gluten restriction. DH patients present with a spectrum of severity, ranging from minimal pruritic papules on the elbows and knees to severe, intensely pruritic vesicular lesions over multiple extensor surfaces. The prevalence of DH is approximately 10–39 per 100 000 persons in the Caucasian population. One in six patients diagnosed with celiac disease has DH. DH is distinguished from other bullous diseases by characteristic histologic, immunologic, and associated gastrointestinal findings. Histologically, vesicle formation at the dermal–epidermal junction and infiltration of dermal papillary tips with neutrophils are seen. Direct immunofluorescence shows granular or fibrillar IgA localized in the dermal papillary tips or along the basement membrane of perilesional skin.

Management strategy

The course of DH depends on the therapeutic choices that are made at the time of diagnosis. If patients choose a strict gluten-free diet and adopt a conscientious change in eating habits and lifestyle, they are likely to have a long-term remission and not be bothered by the skin disease. Associated intestinal symptoms are also minimized. In such situations relapses are usually associated with dietary indiscretions. Elevated levels of IgA antibodies to tissue transglutaminase are characteristic of celiac disease, correlate with the degree of intestinal inflammation, and decrease with gluten restriction. Elevated levels of IgA epidermal transglutaminase antibodies are characteristic of DH and are responsible for the diagnostic IgA deposits in skin. If medical therapy with dapsone or sulfapyridine is chosen, the cutaneous lesions can be well controlled. However, attention must be paid to potential side effects of medications. Intestinal symptoms, if present, will continue unabated. Occasionally, some patients (10–20%) will enjoy a spontaneous remission without medication or dietary restriction. The reason for such remission is unclear.

Dapsone is the drug of choice for DH and is currently the only drug approved by the US Food and Drug Administration (FDA) for use in this disease. Initial treatment with dapsone 25 mg daily will usually improve pruritus within 24–48 hours and the papulovesicular lesions within 1 week in adults. Correspondingly smaller doses (0.5–1 mg/kg) should be used in children. Maintenance therapy is then adjusted on a weekly basis to maintain adequate suppression of symptoms. The average maintenance dose is 0.5–1.0 mg/kg daily. Despite adequate dapsone dosages, outbreaks of facial and scalp lesions are common.

Adherence to a gluten-free diet (GFD) improves clinical symptoms in patients with DH. The advantages of gluten restriction include a reduction of dapsone dosage and its attendant complications, improvement of gastrointestinal symptoms (which range from cramping pain to overt diarrhea), and a therapy aimed at the cause rather than the symptoms of the disease. The increased risk of lymphoma incident to DH and celiac disease is also reduced with a GFD, but not with dapsone. Dapsone improves the cutaneous lesions, but has no effect on intestinal disease. Strict adherence to a GFD is, however, challenging, and re-introduction of gluten can exacerbate symptoms of DH. Rare patients will not respond to gluten restriction. It is not possible to predict with certainty which patients will respond to a GFD. In the author’s opinion, a useful therapeutic strategy is the initial control of DH symptoms with dapsone coincident with a GFD with subsequent tapering of dapsone. Oats have been found to be non-toxic in most patients with DH and may broaden the dietary options in an otherwise restrictive GFD.

Sulfapyridine is an alternative choice in patients who are intolerant to dapsone and has been shown to result in significant therapeutic efficacy. Sulfapyridine is started at 500 mg three times a day and is usually increased to a maximum maintenance dose of 1.5 g three times a day.

Other agents that have been reported to have a therapeutic benefit in DH include nicotinamide, tetracycline (or a combination of the two), heparin, cyclosporine, colchicine, and systemic corticosteroids. Topical corticosteroid application is generally inadequate when used alone to control DH symptoms. However, potent corticosteroids in gel form applied frequently may provide relief for occasional lesions that develop on otherwise adequate dapsone or GFD therapy. This allows patients to treat lesions without increasing the dosage of dapsone.

Specific investigations

First-line therapies

imageDapsone B
imageGluten-free diet B

Suggested guidelines for patient monitoring: hepatic and hematologic toxicity attributable to systemic dermatologic drugs.

Wolverton SE, Remlinger K. Dermatol Clin 2007; 25: 195–205.

Dapsone may produce a drug hypersensitivity syndrome with liver toxicity in the first three to 12 weeks. Monitoring of the aspartate transaminase (AST), alanine transaminase (ALT), and eosinophil count is indicated. Hepatocellular toxicity may also occur in a dose-related fashion especially with doses greater than 2 mg/kg. AST and ALT should be monitored when the dosage is increased. There are three main hematologic toxicities of dapsone: hemolysis, methoglobinemia and agranulocytosis. Methoglobinemia is usually mild and not problematic unless the patient has underlying cardiopulmonary problems. Agranulocytosis is rare and usually occurs in the first three to 12 weeks of therapy. Symptoms demanding attention include pharyngitis, fever, and oral ulcerations. Virtually all patients have at least some degree of hemolysis and a fall of the hemoglobin of 1–3 g/dL is to be expected. A compensatory reticulocytosis occurs and may be monitored with a reticulocyte count. Hemolysis may be severe in patients with glucose-6-phosphate dehydrogenase deficiency. Glucose-6-phosphate dehydrogenase levels should be evaluated in blacks and those of Southern Mediterranean origin prior to the initiation of therapy to avoid potentially catastrophic hemolytic anemia.

Complete blood count and liver function tests should be checked every 2 to 3 weeks for the first 3 months and then every 3 to 6 months thereafter.

Second-line therapies

imageSulfapyridine and sulfasalazine E
imageElemental diet C

Third-line therapies

imageTetracycline and nicotinamide E
imageHeparin E
imageCyclosporine E
imageColchicine E
imageSystemic corticosteroids E

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Dermatitis herpetiformis

John J. Zone

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

Dermatitis herpetiformis (DH) is a cutaneous manifestation of celiac disease. Rare exceptions have been reported in the Japanese population. More than 85% of patients have an associated gluten-sensitive enteropathy that varies in severity. Both the skin disease and the histological intestinal inflammatory process respond to dietary gluten restriction. DH patients present with a spectrum of severity, ranging from minimal pruritic papules on the elbows and knees to severe, intensely pruritic vesicular lesions over multiple extensor surfaces. The prevalence of DH is approximately 10–39 per 100 000 persons in the Caucasian population. One in six patients diagnosed with celiac disease has DH. DH is distinguished from other bullous diseases by characteristic histologic, immunologic, and associated gastrointestinal findings. Histologically, vesicle formation at the dermal–epidermal junction and infiltration of dermal papillary tips with neutrophils are seen. Direct immunofluorescence shows granular or fibrillar IgA localized in the dermal papillary tips or along the basement membrane of perilesional skin.

Management strategy

The course of DH depends on the therapeutic choices that are made at the time of diagnosis. If patients choose a strict gluten-free diet and adopt a conscientious change in eating habits and lifestyle, they are likely to have a long-term remission and not be bothered by the skin disease. Associated intestinal symptoms are also minimized. In such situations relapses are usually associated with dietary indiscretions. Elevated levels of IgA antibodies to tissue transglutaminase are characteristic of celiac disease, correlate with the degree of intestinal inflammation, and decrease with gluten restriction. Elevated levels of IgA epidermal transglutaminase antibodies are characteristic of DH and are responsible for the diagnostic IgA deposits in skin. If medical therapy with dapsone or sulfapyridine is chosen, the cutaneous lesions can be well controlled. However, attention must be paid to potential side effects of medications. Intestinal symptoms, if present, will continue unabated. Occasionally, some patients (10–20%) will enjoy a spontaneous remission without medication or dietary restriction. The reason for such remission is unclear.

Dapsone is the drug of choice for DH and is currently the only drug approved by the US Food and Drug Administration (FDA) for use in this disease. Initial treatment with dapsone 25 mg daily will usually improve pruritus within 24–48 hours and the papulovesicular lesions within 1 week in adults. Correspondingly smaller doses (0.5–1 mg/kg) should be used in children. Maintenance therapy is then adjusted on a weekly basis to maintain adequate suppression of symptoms. The average maintenance dose is 0.5–1.0 mg/kg daily. Despite adequate dapsone dosages, outbreaks of facial and scalp lesions are common.

Adherence to a gluten-free diet (GFD) improves clinical symptoms in patients with DH. The advantages of gluten restriction include a reduction of dapsone dosage and its attendant complications, improvement of gastrointestinal symptoms (which range from cramping pain to overt diarrhea), and a therapy aimed at the cause rather than the symptoms of the disease. The increased risk of lymphoma incident to DH and celiac disease is also reduced with a GFD, but not with dapsone. Dapsone improves the cutaneous lesions, but has no effect on intestinal disease. Strict adherence to a GFD is, however, challenging, and re-introduction of gluten can exacerbate symptoms of DH. Rare patients will not respond to gluten restriction. It is not possible to predict with certainty which patients will respond to a GFD. In the author’s opinion, a useful therapeutic strategy is the initial control of DH symptoms with dapsone coincident with a GFD with subsequent tapering of dapsone. Oats have been found to be non-toxic in most patients with DH and may broaden the dietary options in an otherwise restrictive GFD.

Sulfapyridine is an alternative choice in patients who are intolerant to dapsone and has been shown to result in significant therapeutic efficacy. Sulfapyridine is started at 500 mg three times a day and is usually increased to a maximum maintenance dose of 1.5 g three times a day.

Other agents that have been reported to have a therapeutic benefit in DH include nicotinamide, tetracycline (or a combination of the two), heparin, cyclosporine, colchicine, and systemic corticosteroids. Topical corticosteroid application is generally inadequate when used alone to control DH symptoms. However, potent corticosteroids in gel form applied frequently may provide relief for occasional lesions that develop on otherwise adequate dapsone or GFD therapy. This allows patients to treat lesions without increasing the dosage of dapsone.

Specific investigations

image Biopsy for histology and direct immunofluorescence

image Complete blood count and liver function tests

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