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Dermatitis herpetiformis
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Dermatitis herpetiformis (DH) is a cutaneous manifestation of celiac disease (CD). More than 85% of patients with DH have a gluten-sensitive enteropathy (CD) that varies in clinical and histologic severity. The skin and intestinal disease both respond to gluten restriction. DH symptoms range from minimally pruritic papules on the elbows and knees to severe, intensely pruritic vesicles over multiple extensor surfaces (see figure). The prevalence of DH is 10–39 per 100,000 persons in the Caucasian population and occurs most frequently in those of northern European descent. CD is rare in those with DH in the Japanese population. One in six patients diagnosed with CD has DH. DH is distinguished from other bullous diseases by characteristic histologic, immunologic, and gastrointestinal findings. Histologically, vesicle formation at the dermal–epidermal junction and infiltration of dermal papillary tips with neutrophils occurs in two-thirds of cases; however, non-specific inflammation is also frequent. Direct immunofluorescence shows granular or fibrillar IgA localized in the dermal papillary tips or along the basement membrane of perilesional skin.
Management Strategy
If patients adhere to a strict gluten-free diet, they are likely to undergo long-term remission. Associated intestinal symptoms are minimized and relapses are usually associated with dietary indiscretions. Elevated levels of IgA antibodies to tissue transglutaminase (TG2) are characteristic of CD. Levels correlate with the degree of intestinal inflammation and decrease with gluten restriction. Elevated levels of IgA epidermal transglutaminase (TG3) antibodies are characteristic of DH and are responsible for the diagnostic IgA deposits in skin. Serum levels of both antibodies correlate with response to a gluten-free diet but are not affected by dapsone. DH can be well controlled with medical therapies such as dapsone or sulfapyridine alone, but intestinal symptoms, if present, will continue unabated and contribute to the risk of small intestine lymphoma. Cutaneous disease recurs in 24–72 hours if dapsone is discontinued. Rare patients will enjoy spontaneous DH remission without medical therapy or dietary restriction.
Dapsone is the drug of choice for DH and is currently the only drug approved by the US Food and Drug Administration for DH. We recommend initial treatment with low-dose dapsone at 25 mg daily. Pruritus will usually improve within 24–48 hours and the papulovesicular lesions within 1 week. 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. Gluten restriction targets the cause of disease as well as the symptoms. Advantages include a reduction in dapsone dosage, improvement in gastrointestinal symptoms, and reduced risk of lymphoma incident to DH and CD, a benefit not seen with dapsone. Strict adherence to a GFD is challenging, and reintroduction of gluten can exacerbate DH. Rare patients will not respond to gluten restriction. 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 gluten-free dietary options.
Sulfapyridine is an alternative in patients intolerant to dapsone and offers significant therapeutic efficacy. Sulfapyridine is started at 500 mg three times a day and is increased to a maximum maintenance dose of 1.5 g three times a day. Virtually all DH patients respond to dapsone, but some patients may not respond to sulfapyridine at any dose.
Nicotinamide, tetracycline (or a combination of the two), heparin, ciclosporin, colchicine, rituximab, and systemic corticosteroids have been reported to provide therapeutic benefit in DH. Topical corticosteroid application is generally inadequate when used alone to control DH symptoms. Potent corticosteroids in gel form applied frequently may provide relief for occasional lesions that develop on otherwise adequate dapsone or GFD therapy. Ultraviolet light may provide symptomatic relief. Patients with refractory disease should be screened for iodide ingestion, which can exacerbate DH and has been found in medications, contrast media, dental packing strips, food sources, and dietary supplements.
Specific Investigations
Deposition of granular IgA relative to clinical lesions in dermatitis herpetiformis
Zone JJ, Meyer LJ, Petersen MJ. Arch Dermatol 1996; 132: 912–8.
Granular IgA deposition in perilesional, clinically normal-appearing skin is the most reliable diagnostic criterion for DH. The diagnosis of DH should not be made without identification of granular IgA in dermal papillae. Linear IgA disease demonstrates identical histology but does not respond to a GFD. These disorders can only be separated on direct immunofluorescence. If direct immunofluorescence is negative and histology is suggestive of DH, a repeat biopsy for direct immunofluorescence is recommended.
Dermatitis herpetiformis: from the genetics to the development of skin lesions
Bonciani D, Verdelli A, Bonciolini V, et al. Clin Dev Immunol 2012; 2012: 239691.
DH is a cutaneous manifestation of CD. The pathogenesis involves an immune response in genetically susceptible individuals (HLA-DQ2 and -DQ8) to dietary gliadin peptides complexed with tissue transglutaminase (TG2). IgA TG2 antibodies are an index of the severity of intestinal involvement and correlate with response to gluten restriction. IgA epidermal transglutaminase (TG3) antibodies are present in the serum of new DH patients and are complexed with TG3 to form the diagnostic immune complexes in the skin of DH patients.
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 3–12 weeks. Monitoring of the aspartate transaminase (AST), alanine transaminase (ALT), and eosinophil count is indicated. Hepatocellular toxicity may occur in a dose-related fashion, especially with doses greater than 2 mg/kg. AST and ALT should be monitored when dapsone dosage is increased. There are three main hematologic toxicities of dapsone: hemolysis, methemoglobinemia, and agranulocytosis. Methemoglobinemia is usually mild and not problematic unless the patient has underlying cardiopulmonary problems. Agranulocytosis is rare and usually occurs in the first 3–12 weeks of therapy. Symptoms demanding attention include pharyngitis, fever, and oral ulcerations. Virtually all patients have some degree of hemolysis and a decrease in hemoglobin of 1–3 g/dL is expected. Initiation of small doses of dapsone (25 mg daily) and gradual dose increases will minimize these symptoms. A compensatory reticulocytosis occurs. Hemolysis may be severe in patients with glucose-6-phosphate dehydrogenase deficiency. Glucose-6-phosphate dehydrogenase levels should be evaluated prior to the initiation of therapy to avoid catastrophic hemolytic anemia.
Complete blood count and liver function tests should be checked every 2–3 weeks for the first 3 months, then every 3–6 months thereafter.
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