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Dermatitis Herpetiformis
Geoffrey Strider Farnsworth, MD
image BASICS
DESCRIPTION
  • Dermatitis herpetiformis (DH) presents as a chronic, relapsing, polymorphous, intensely pruritic, erythematous papulovesicular eruption with symmetrical distribution primarily involving extensor skin surfaces of the elbows, knees, buttocks, back, and scalp.
  • DH is an autoimmune disease associated with gluten sensitivity with genetic, environmental, and immunologic influences.
  • DH is distinguished from other bullous diseases by characteristic histologic and immunologic findings, as well as associated gluten-sensitive enteropathy (GSE).
  • System(s) affected: skin
  • Synonym(s): Duhring disease, Duhring-Brocq disease
EPIDEMIOLOGY
  • Occurs most frequently in those of Northern European origin
  • Rare in persons of Asian or African American origin
  • Predominant age: most common in 4th and 5th decades but may present at any age
  • Childhood DH is rare in most countries, although an Italian study showed 27% of patients were younger than the age of 10 and 36% younger than the age of 20.
  • Predominant gender: Adults: male > female (1.5:1 in the United States, 2:1 worldwide) Children: female > male
Incidence
1/100,000 persons per year in the United States
Prevalence
11/100,000 persons in the U.S. population; as high as 39/100,000 persons worldwide
ETIOLOGY AND PATHOPHYSIOLOGY
  • Evidence suggests that epidermal transglutaminase (eTG) 3, a keratinocyte enzyme involved in cell envelope formation and maintenance, is the autoantigen in DH.
  • eTG is highly homologous with tissue transglutaminase (tTG), which is the antigenic target in celiac disease and GSE.
  • The initiating event for DH is presumed to be the interaction of wheat peptides with tTGs, which results in the formation of an autoantigen with high affinity for particular class II major histocompatibility complex (MHC) molecules.
  • Presentation of the autoantigen leads to activation of T cells and the humoral immune system.
  • IgA antibodies against tTG cross-react with eTG and result in IgA-eTG immune complexes that are deposited in the papillary dermis. Subsequent activation of complement and recruitment of neutrophils to the area result in inflammation and microabscesses.
  • Skin eruption may be delayed up to 5 to 6 weeks after exposure to gluten.
  • Gluten applied directly to the skin does not result in the eruption, whereas gluten taken by mouth or rectum does. This implies necessary processing by the GI system.
  • Thought to be immune complex-mediated disease
Genetics
  • High association with human leukocyte antigen DQ2 (95%), with remaining patients being positive for DQ8, DR4, or DR3
  • Strong association with combination of alleles DQA1*0501 and DQB1*0201/0202, DRB1*03 and DRB1*05/07, or DQA1*0301 and DQB1*0302
RISK FACTORS
  • GSE: >90% of those with DH will have GSE, which may be asymptomatic.
  • Family history of DH or celiac disease
GENERAL PREVENTION
Gluten-free diet (GFD) results in improvement of DH and reduces dependence on medical therapy. GFD also may reduce the risk of lymphomas associated with DH.
COMMONLY ASSOCIATED CONDITIONS
  • Hypothyroidism is the most common autoimmune condition associated with DH.
  • GSE, gluten ataxia
  • Gastric atrophy, hypochlorhydria, pernicious anemia
  • GI lymphoma, non-Hodgkin lymphoma
  • Hyperthyroidism, thyroid nodules, thyroid cancer
  • IgA nephropathy
  • Autoimmune disorders, including systemic lupus erythematosus, dermatomyositis, Sjögren syndrome, rheumatoid arthritis, sarcoidosis, Raynaud phenomenon, insulin-dependent diabetes mellitus, myasthenia gravis, Addison disease, vitiligo, alopecia areata, primary biliary cirrhosis, and psoriasis
image DIAGNOSIS
Diagnosis of DH involves a clinicopathologic correlation among clinical presentation, histologic and direct immunofluorescence evaluation, serology, and response to therapy or dietary restriction.
PHYSICAL EXAM
  • Classic lesions described as symmetric, grouped, erythematous papules and vesicles
  • More commonly presents with erosions, excoriations, lichenification, hypopigmentation, and/or hyperpigmentation secondary to scratching and healing of old lesions
  • Areas involved include extensor surfaces of elbows (90%), knees (30%), shoulders, buttocks, and sacrum. The scalp is also frequently affected. Oral lesions are rare.
  • In children, purpura may be visible on digits and palmoplantar surfaces.
  • Adults with associated enteropathy are most often asymptomatic, with about 20% experiencing steatorrhea and <10% with findings of bloating, diarrhea, or malabsorption.
  • Children with associated enteropathy may present with abdominal pain, diarrhea, iron deficiency, and reduced growth rate.
DIFFERENTIAL DIAGNOSIS
  • In adults
    • Bullous pemphigoid: linear deposition of C3 and IgG at the basement membrane zone
    • Linear IgA disease: homogeneous and linear deposition of IgA at the basement membrane zone, absence of GSE
    • Prurigo nodularis
    • Urticaria: wheals, angioedema, dermal edema
    • Erythema multiforme
  • In children
    • Atopic dermatitis: face and flexural areas
    • Scabies: interdigital areas, axillae, genital region
    • Papular urticaria: dermal edema
    • Impetigo
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Serum IgA tTG antibodies: Detection of tTG antibodies was noted to be up to 95% sensitive and >90% specific for DH in patients on unrestricted diets (1,2)[A].
  • Serum IgA eTG antibodies: Antibodies to eTG, the primary autoantigen in DH, were shown to be more sensitive than antibodies to tTG in the diagnosis of patients with DH on unrestricted diets (95% vs. 79%) but is not widely available in all labs (1,2)[A].
  • Serum IgA endomysial antibodies: have a sensitivity between 50% and 100% and a specificity close to 100% in patients on unrestricted diets but is more expensive, time-consuming, and operator-dependent than tTG (2)
Follow-Up Tests & Special Considerations
Serologic assessment of anti-tTG and anti-eTG correlate with intestinal involvement of disease and in conjunction with antiendomysial antibodies (EMA) may be useful in monitoring major deviations from GFD (1,2).
Diagnostic Procedures/Other
The “gold standard” for diagnosing DH is a skin biopsy of perilesional skin evaluated via direct immunofluorescence, which demonstrates granular IgA deposited in dermal papillae and/or basement membrane (1,2)[A],(3)[C].
Test Interpretation
  • Direct immunofluorescence of perilesional skin reveals a granular pattern of IgA deposition in the dermal papillae (1,2).
  • Histopathology of lesion with routine staining reveals neutrophilic microabscesses in the tips of the dermal papillae and may show subepidermal blistering (1,2).
image TREATMENT
GENERAL MEASURES
  • GFD is the mainstay of treatment and can lead to complete resolution of symptoms (1,2)[A].
  • Typically requires 18 to 24 months of strict adherence to GFD prior to resolution of skin lesions without other treatment.
  • Lesions can recur within 12 weeks of reintroduction of gluten.
MEDICATION
Medication is useful for immediate symptom management but should be used as an adjunct to dietary modification (2).
First Line
  • Dapsone is approved by the FDA for use in DH and is the most widely used medication (2,4)[A]. Initial dosing of 50 mg/day typically results in improvement of symptoms within 24 to 48 hours; can increase dose to 200 mg to obtain control (1)[C]. Use minimum effective dose with slow titration based on patient response and tolerability. Average maintenance dose is 1 mg/kg/day (50 to 150 mg/day). Minor outbreaks on the face and scalp are common even with treatment. Not ideal for long-term use in DH.
  • P.281

  • Dapsone works by inhibiting neutrophil recruitment and IL-8 release, inhibiting the respiratory burst of neutrophils, and protecting cells from neutrophil-mediated injury, thereby suppressing the skin reaction. It has no role in preventing IgA deposition or mitigating the immune reaction in the gut (2,4).
  • Precautions
    • Common side effects include nausea, vomiting, headache, dizziness, weakness, and hemolysis.
    • A drop in hemoglobin of 1 to 2 g is characteristic with dapsone 100 mg/day.
    • G6PD deficiency increases severity of hemolytic stress. Dapsone should be avoided, if possible, in those who are G6PD-deficient.
    • Dose-related methemoglobinemia may occur with doses >100 mg/day. Cimetidine may reduce the severity of this side effect.
    • Risk of distal motor neuropathy
Pediatric Considerations
  • <2 years: Dosing is not established.
  • >2 years: 0.5 to 1.0 mg/kg/day
Pregnancy Considerations
  • Category C: Safety during pregnancy is not established.
  • Secreted in breast milk and will produce hemolytic anemia in infants
  • Adherence to a strict GFD 6 to 12 months before conception should be considered with the hope of eliminating need for dapsone during pregnancy.
Second Line
  • High-potency topical steroids can be used acutely to control symptoms until dapsone becomes effective (1)[C].
  • Sulfapyridine (1 to 2 g/day) is FDA approved for use in DH and is thought to be the active metabolite in sulfasalazine (2 to 4 g/day) (2,5)[B]. Common side effects include nausea, vomiting, and anorexia. Enteric-coated form may reduce side effects. Other side effects include agranulocytosis, hypersensitivity reactions, hemolytic anemia, proteinuria, and crystalluria (2,5).
ISSUES FOR REFERRAL
Over time, interdisciplinary treatment may involve a dermatologist, gastroenterologist, and registered dietician. Genetic counseling and testing should be considered on diagnosis (1,2).
ADDITIONAL THERAPIES
A single case report describes topical dapsone therapy as potential alternative treatment or as an adjunct to oral dapsone to decrease systemic exposure and risk of severe side effects. However, it has not been studied extensively (6)[C].
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Every 6 to 12 months by physician and dietician to evaluate GFD adherence and recurrence of symptoms
  • Adherence to GFD can be monitored with serologic levels of anti-tTG, anti eTG, and EMA levels (1).
  • Patients on dapsone require lab monitoring weekly for the 1st month, biweekly for 2 months, then every 3 months for the duration of medication use (1,4).
DIET
GFD
  • Grains that should be avoided: wheat (includes spelt, kamut, semolina, and triticale), rye, and barley (including malt)
  • Safe grains (gluten-free): rice, amaranth, buckwheat, corn, millet, quinoa, sorghum, teff (an Ethiopian cereal grain), and oats
  • Care should be taken to avoid gluten-free grains that are contaminated with sources of gluten during processing such as oats.
  • Sources of gluten-free starches that can be used as flour alternatives
    • Cereal grains: amaranth, buckwheat, corn, millet, quinoa, sorghum, teff, rice (white, brown, wild, basmati, jasmine), and montina
    • Tubers: arrowroot, jicama, taro, potato, and tapioca
    • Legumes: chickpeas, lentils, kidney beans, navy beans, pea beans, peanuts, and soybeans
    • Nuts: almonds, walnuts, chestnuts, hazelnuts, and cashews
    • Seeds: sunflower, flax, and pumpkin
PATIENT EDUCATION
  • Patients on dapsone should be made aware of potential hemolytic anemia and the signs associated with methemoglobinemia.
  • American Academy of Dermatology, 930 N. Meacham Road, P.O. Box 4014, Schaumberg, IL 60168-4014; (708)330-0230
  • The University of Chicago Celiac Disease Center, 5841 S. Maryland Ave., Mail Code 4069, Chicago, IL 60637; (773) 702-7593; www.celiacdisease.net or http://www.cureceliacdisease.org/
  • Gluten Intolerance Group of North America, 31214-124 Ave. SE, Auburn, WA 98092; (206) 246-6652; fax (206) 246-6531; https://www.gluten.org/
  • The Celiac Disease Foundation, 13251 Ventura Blvd., #1, Studio City, CA 9160; (818) 990-2354; fax (818) 990-2379
PROGNOSIS
  • Lifelong disease with favorable prognosis
  • 10- to 15-year survival rates do not seem to differ from general population.
  • Remission in 10-15%
  • Skin disease responds readily to dapsone. Occasional new lesions (2 to 3 per week) are to be expected and are not an indication for altering daily dosage.
  • Strict adherence to a GFD improves clinical symptoms and decreases dapsone requirement. GFD is the only sustainable method of eliminating cutaneous and GI disease.
  • Risk of lymphoma may be decreased in those who maintain a GFD.
REFERENCES
1. Antiga E, Caproni M. The diagnosis and treatment of dermatitis herpetiformis. Clin Cosmet Investig Dermatol. 2015;8:257-265.
2. Bolotin D, Petronic-Rosic V. Dermatitis herpetiformis. Part II. Diagnosis, management, and prognosis. J Am Acad Dermatol. 2011;64(6):1027-1033.
3. Junkins-Hopkins JM. Dermatitis herpetiformis: pearls and pitfalls in diagnosis and management. J Am Acad Dermatol. 2010;63(3):526-528.
4. Wozel G, Blasum C. Dapsone in dermatology and beyond. Arch Dermatol Res. 2014;306(2):103-124.
5. Willsteed E, Lee M, Wong LC, et al. Sulfasalazine and dermatitis herpetiformis. Australas J Dermatol. 2005;46(2):101-103.
6. Handler MZ, Chacon AH, Shiman MI, et al. Letter to the editor: application of dapsone 5% gel in a patient with dermatitis herpetiformis. J Dermatol Case Rep. 2012;6(4):132-133.
Additional Reading
&NA;
  • Bolotin D, Petronic-Rosic V. Dermatitis herpetiformis. Part I. Epidemiology, pathogenesis, and clinical presentation. J Am Acad Dermatol. 2011;64(6):1017-1024.
  • Cardones AR, Hall RP III. Management of dermatitis herpetiformis. Immunol Allergy Clin North Am. 2012;32(2):275-281.
  • Cardones AR, Hall RP III. Pathophysiology of dermatitis herpetiformis: a model for cutaneous manifestations of gastrointestinal inflammation. Immunol Allergy Clin North Am. 2012;32(2):263-274.
  • Kárpáti S. An exception within the group of autoimmune blistering diseases: dermatitis herpetiformis, the gluten-sensitive dermopathy. Immunol Allergy Clin North Am. 2012;32(2):255-262.
  • Paek SY, Steinberg SM, Katz SI. Remission in dermatitis herpetiformis: a cohort study. Arch Dermatol. 2011;147(3):301-305.
See Also
&NA;
  • Celiac Disease
  • Algorithm: Rash, Focal
Codes
&NA;
ICD10
L13.0 Dermatitis herpetiformis
Clinical Pearls
&NA;
  • DH is a chronic, relapsing, intensely pruritic rash that often presents with erosions, excoriations, lichenification, and pigmentary changes secondary to scratching and healing of old papulovesicular lesions.
  • Strong association with gluten-sensitive enteropathy
  • Diagnosis established with perilesional skin biopsy showing direct immunofluorescence demonstrating granular IgA deposits in the dermal papillae.
  • Serologic levels of IgA transglutaminase aid in diagnosis and monitoring of deviations from GFD.
  • Mainstay of treatment is a GFD with dapsone used primarily for short-term symptom relief.