AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Dermatitis herpetiformis (DH) is an autoimmune blistering disorder associated with a gluten-sensitive enteropathy (GSE). The disease was described and named in 1884 by Dr. Louis Duhring at the University of Pennsylvania. It is characterized by grouped excoriations; erythematous, urticarial plaques; and papules with vesicles. These are located on the extensor surfaces of the elbows, knees, buttocks, and back. It is exquisitely pruritic, and the vesicles are often excoriated to erosions by the time of physical examination. Diagnosis requires direct immunofluorescence of a skin biopsy specimen showing deposition of immunoglobulin A (IgA) in a granular pattern in the upper papillary dermis. Although most patients are asymptomatic, more than 90% have an associated GSE upon endoscopic examination. Among patients with celiac disease, 15-25% develop DH. The mainstays of treatment are dapsone and a gluten-free diet.

Pathophysiology

DH is a disease of the skin caused by the deposition of IgA in the papillary dermis, which triggers an immunologic cascade, resulting in neutrophil recruitment and complement activation. It has been hypothesized that DH is the result of an immunologic response to chronic stimulation of the gut mucosa by dietary gluten with subsequent activation of cutaneous endothelial cells and circulating inflammatory cells, including neutrophils.

An underlying genetic predisposition to the development of DH has been demonstrated. Both DH and celiac disease (CD) show an increased expression of HLA-A1, HLA-B8, HLA-DR3, and HLA-DQ2 haplotypes. Environmental factors are also important; monozygotic twins may have DH, CD, and/or GSE with variable symptomatology.

Evidence is mounting that epidermal transglutaminase 3 (TGase3), a cytosolic enzyme involved in cell envelope formation during keratinocyte differentiation, is the autoantigen of DH. Theoretically, DH is caused by dermal deposition of circulating immune complexes containing both IgA and TGase3. This is supported by the finding that precipitates of skin-bound IgA from DH lesions contain TGase3. In addition, it has been demonstrated that serum from DH patients contains high-affinity anti-TGase IgA autoantibodies. Skin and gut TGases are both highly homologous, and serum from patients with GSE, with or without skin disease, contains IgA antibodies to both skin and gut types. The target autoantigen of TGase3 has not been demonstrated in normal papillary dermis, suggesting it is part of the circulating complex that is deposited in the papillary dermis, rather than originating from the papillary dermis.

The leading theory for DH is that a genetic predisposition for gluten sensitivity, coupled with a diet high in gluten, leads to the formation of IgA antibodies to gluten-TGase complexes. These antibodies cross-react with TGase3, and IgA/TGase3 complexes deposit within the papillary dermis to cause the lesions of DH. These IgA deposits can disappear after long-term (up to 10 y) avoidance of dietary gluten.

Cutaneous IgA deposits in DH have been shown to function in vitro as a ligand for neutrophil migration and attachment. Although IgA deposition is pivotal for disease, an increased serum IgA is not necessary for pathogenesis; in fact, case reports describe DH in patients with a partial IgA deficiency. When the disease is active, circulating neutrophils have a higher level of CD11b and an increased ability to bind IgA. In fact, the characteristic histologic finding of DH is neutrophil accumulation at the dermoepidermal junction, frequently localizing to the papillary tips of the basement membrane zone.

Collagenase and stromelysin 1 may be induced in basal keratinocytes by either cytokines released from neutrophils or by contact with keratin from damaged basement membrane matrix. Stromelysin 1 may contribute to blister formation.

One study found levels of E-selectin mRNA expression in normal-appearing skin of patients with DH to be 1271 times greater that that of controls. Additionally, the same study observed increased soluble E-selectin, IgA antitissue transglutaminase antibodies, tumor necrosis factor-alpha, and serum interleukin 8 levels in patients with DH, providing further evidence of endothelial cell activation and a systemic inflammatory response as part of the pathogenic mechanism of the disease. Mild local trauma may also induce the release of cytokines and attract the partially primed or activated neutrophils, which is consistent with the typical location of DH lesions on frequently traumatized areas, such as the knees and elbows.

Deposits of C3 also may be present in a similar pattern at the dermoepidermal junction. The membrane attack complex, C5-C9, also has been identified in perilesional skin, although it may be inactive and not contribute to cell lysis.

Hormonal factors may also play a role in the pathogenesis of DH, and 2 recent reports describe DH induced by treatment with leuprolide acetate, a gonadotropin-releasing hormone analog. Androgens have a suppressive effect on immune activity, including decreased autoimmunity, and androgen deficient states may be a potential trigger for DH exacerbation.

Apoptosis may contribute to the pathogenesis of epidermal changes in DH, and recent research demonstrates a markedly increased apoptotic rate within the epidermal compartment in DH. In addition, Bax and Bcl-2 proteins were increased in the dermal perivascular compartment and Fas proteins showed epidermal staining in DH lesions.

Most patients with DH have histologic evidence of enteropathy, even in the absence of symptoms of malabsorption. In one recent study, all DH patients had increased intestinal permeability (as measured by the lactulose/mannitol ratio) and up-regulation of zonulin, a regulator of tight junctions. Thus, increased expression of zonulin may be involved in the pathogenesis of enteropathy in patients with DH.

Frequency

United States

The only US study showed a prevalence of 11.2 cases per 100,000 population.

International

Prevalence has been reported as high as 10 cases per 100,000 population.

Mortality/Morbidity

Patients with DH were followed (152 total) from the date of diagnosis to the end of 1989 for mortality and from 1971 or the date of diagnosis (if later) to 1986 for cancer incidence. Death occurred in 38 patients younger than 85 years, slightly fewer than expected on the basis of national general population rates. Cancer incidence was significantly increased. Cancer of the small intestine caused 1 death, and lymphoma caused 1 death. A 30-year population-based study of 1147 CD and DH patients in Finland also revealed an overall good prognosis for patients with DH. The total occurrence of malignancies was equal to that of the general population in both CD and DH, but an increased incidence of non-Hodgkin lymphoma was noted among both CD and DH patients with standardized incidence ratios of 3.2 and 6.0, respectively. Overall mortality was actually decreased in DH patients compared to that in the general population.

DH lesions are extremely pruritic. Morbidity results from scarring, discomfort, and insomnia due to itching. Secondary infection may also develop, requiring antibiotic therapy.

Race

DH occurs more frequently in individuals of Northern European ancestry and is rare in Asians and persons of African descent. It is most common in Ireland and Sweden. This can be attributed to the shared HLA associations of DH and CD including DQA1*0501 and B1*-02, which encode HLA-DQ2 heterodimers.

Sex

US studies show a male-to-female ratio of 1.44:1, but international studies have demonstrated a male-to-female ratio up to 2:1. In one study of patients with GSE, 16% of the men and 9% of the women had DH.

Age

Typically, the onset of DH is in the second to fourth decade; however, persons of any age may be affected.

CLINICAL

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History

Patients typically present with a waxing and waning, pruritic eruption on the arms, knees, and buttocks. Small vesicles may have been noted. They may have associated worsening of disease with dietary intake of gluten. Many do not report any GI symptoms until prompted.

Physical

The diagnosis is suspected based on the distribution of the eruption.

• Flesh-colored–to–erythematous excoriated papules or plaques with herpetiform (ie, small, clustered) vesicles are symmetrically distributed over extensor surfaces, including the elbows, knees, buttocks, and shoulders.
• • It rarely occurs on the posterior (nuchal) scalp and face. Lesions occur infrequently on the oral mucosa, but males are more likely than females to have involvement of the oral and genital membranes. Palms and soles are spared. Digital purpura resembling vasculitis can occur. Erythematous papules and urticarialike plaques occur less frequently; bullae are rare.
  • The eruption is intensely pruritic; patients often present with erosions and crusts in the absence of vesicles, which have ruptured due to excoriation.
  • Typical symptoms include burning, stinging, and intense itching. Rarely, if ever, are patients totally asymptomatic, although the degree of itching varies.
  • DH is a lifelong disease, although periods of exacerbation and remission are common.

Causes

DH has recently been proposed as a cutaneous manifestation of asymptomatic-to-mild CD. The genetic predisposition to the development of gluten sensitivity underlies the disease.

• Gluten is a protein present in grasses of the species Triticeae, which includes barley, rye, and wheat. Rice and oats belong to different species and are generally well tolerated. Strict compliance with a gluten-free diet results in normalization of the small bowel mucosal changes and control of the cutaneous manifestations of DH in most patients.
• The GSE does not cause symptoms in most DH patients. Less than 10% exhibit symptoms of bloating, diarrhea, or malabsorption. However, greater than 90% show abnormalities upon endoscopic examination. Two thirds have villous atrophy detected on intestinal biopsy specimens. The other third shows elevated intraepithelial lymphocyte counts, increased T-cell receptor gamma/delta intraepithelial lymphocyte counts, or both.
• • The critical role of associated GSE in the pathogenesis of DH is confirmed by the fact that resumption of a gluten-containing diet in patients with DH results in a return of the characteristic skin disease.
  • Mild steatorrhea or other signs of mild malabsorption (eg, altered D-xylose absorption, iron or folate deficiency) can be demonstrated in 20-30% of patients with DH.
  • Patients with DH and no apparent GI disease can be induced into developing DH by increasing gluten intake, which is often termed latent GSE (CD).
• IgA circulating immune complexes are present in 25-35% of patients with DH, although no association with disease severity has been noted. These immune complexes also have been noted in patients with isolated GSE and are believed to be related to the presence of the gut disease.
• • IgA antibodies to gliadin (a portion of wheat protein), reticulum, and smooth muscle endomysium have also been noted in patients with DH and in those with isolated GSE.
  • IgA endomysial antibodies are most specific for gluten sensitivity and are found in 80% of patients with DH and greater than 95% of patients with CD. The presence of IgA antiendomysial antibodies correlates with the extent of the gut disease; however, some DH patients do not have detectable IgA antiendomysial antibodies, even during episodes of active skin disease.
  • The criterion standard for the diagnosis of DH remains the presence of granular deposits of IgA in normal-appearing perilesional skin.
  • Patients with bullous pemphigoid, cicatricial pemphigoid, Henoch-Schönlein purpura, and alcoholic liver disease also may have IgA deposits in normal skin; however, the pattern of IgA deposits is different from that seen in patients with DH.
• In patients with DH, 10-15% of their first-degree relatives have DH or CD. HLA studies have conclusively established the presence of a genetic predisposition for DH. Patients with DH have an increased expression of the HLA-A1, HLA-B8, HLA-DR3, and HLA-DQ2 haplotypes. This is identical to the HLA association found in patients with isolated GSE. Most persons with these HLA types do not have DH or GSE. Associations of HLA and DH are as follows:
• • For HLA-B8, the association with DH is 58-87%, versus 20-30% for control patients.
  • For HLA-DR3, the association with DH is 90-95%, versus 23% for control patients.
  • For HLA-DQ2, the association with DH is 95-100%, versus 40% for control patients.
• Other associations include the following:
• • Associated GI conditions include gluten enteropathy, gastric atrophy, gastric hypochlorhydria, and pernicious anemia.
  • Associated autoimmune diseases include dermatomyositis, type 1 diabetes mellitus, myasthenia gravis, rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, and thyroid abnormalities. Thyroid abnormalities are present in as many as 50% of DH patients and include hypothyroidism, hyperthyroidism, thyroid nodules, and thyroid cancer.
  • Associated neoplastic conditions include GI lymphomas and non-Hodgkin lymphoma; patients are at increased risk of developing these cancers. A gluten-free diet may reduce incidence of DH-associated lymphomas.
  • CD usually involves more severe and widespread intestinal involvement. CD has been associated with genetic abnormalities, including Down syndrome, Turner syndrome, and William syndrome. Liver disease, neurologic disorders, and other skin diseases are also increased in CD, possibly due to common HLA regions on chromosome 6 or immune molecule cross-reactivity.
  • Gastric manipulation (surgery) may induce DH.
  • Several chemicals have been associated with induction of DH, including potassium iodide and cleaning solutions.
  • Case reports have described DH induced by treatment with leuprolide acetate.

DIFFERENTIALS

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Other Problems to be Considered

Eczema
Papular urticaria

WORKUP

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Lab Studies

• The diagnosis is made on the basis of skin biopsy results. However, other tests should be performed depending on the presence of symptoms of associated syndromes. Serum markers, such as IgA endomysial antibodies, are negative in up to 10-30% of patients with DH. Arguments have been made in favor of testing for tissue transglutaminase for diagnosis, but tissue transglutaminase enzyme-linked immunosorbent assay positivity can occur in many autoimmune diseases because of impurities and cross-reactivity.

Procedures

• The diagnosis is made after observing characteristic findings from skin biopsy specimens. The biopsy sample should be taken from the edge of a lesion for hematoxylin and eosin staining and from normal-appearing perilesional skin for direct immunofluorescence staining.
• Direct immunofluorescence of lesional skin is often falsely negative. The vigorous immune response degrades the IgA antibody at the site. Therefore, biopsy specimens for the direct immunofluorescence studies should be taken from healthy-appearing skin.

Histologic Findings

Biopsy specimens of lesional skin reveal neutrophils in the dermal papillae, with fibrin deposition, neutrophil fragments, and edema. Eosinophils may be present. Papillary microabscesses form and progress to subepidermal vacuolization and vesicle formation. Vesicles form in the lamina lucida, the weakest portion of the dermoepidermal junction, due to neutrophil lysosomal enzymes (see Media File 2).

The histologic differential diagnosis of early skin lesions includes bullous lupus erythematosus, bullous pemphigoid, epidermolysis bullosa acquisita, and linear IgA disease. The histologic differential diagnosis of late skin lesions includes bullous drug eruption, bullous pemphigoid, erythema multiforme, and herpes gestationis.

Granular IgA deposits in dermal papillae of perilesional skin observed by direct immunofluorescence is the criterion standard of diagnosis. Inflammation in lesional skin degrades the immunoreactants and is usually negative for the diagnostic granular pattern. Because deposits are found throughout normal-appearing skin, the standard practice is to obtain biopsy specimens from normal-appearing perilesional skin for direct immunofluorescent staining.

TREATMENT

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Medical Care

Control of the skin disease can be achieved with medications, dietary avoidance of gluten, or both.

• A gluten-free diet is very difficult to achieve; however, limiting intake of wheat, barley, or rye products can lessen the symptoms.
• Dapsone (diaminodiphenyl sulfone) and sulfapyridine are the primary medications used to treat DH.
• • Before easy availability of direct immunofluorescence, rapid improvement after dapsone therapy was a chief diagnostic criterion for the disease. However, many diseases respond to dapsone, and this should not be used as the only diagnostic criterion. Dapsone is readily available at most pharmacies and is the first-line drug therapy.
  • For patients unable to tolerate dapsone, particularly those who develop hemolysis, sulfapyridine may be substituted.
  • The mechanism for therapeutic effect of dapsone in DH is unclear. It may be related to the inhibition of neutrophil migration into the area, thus, decreasing the inflammatory response.
  • Improvement may be dramatic; symptomatic improvement of skin lesions often begins within hours. No new lesions form for up to 2 days after a dose of dapsone; however, dapsone does not improve GI mucosal pathology.
• Other, less effective treatments for DH include colchicine, cyclosporine, azathioprine, and prednisone. UV light may provide some symptomatic relief. Cyclosporine should be used with caution in patients with DH because of a potential increase in the risk of developing intestinal lymphomas.
• One case report described resolution of DH after initiation of the Atkins diet.
• Nonsteroidal anti-inflammatory drugs may exacerbate DH; however, ibuprofen appears to be safe.
• Iodides may elicit or exacerbate DH.

Consultations

• Consider consultation with a gastroenterologist for evaluation and for recommendations regarding GSE.
• Consult with a dietitian regarding patients who are modifying dietary intake to avoid gluten or who are instituting an elemental diet.

Diet

Dietary intake of gluten causes the disease, and elimination improves it.

• Most patients (as many as 80%) respond to gluten-free diet with control of their skin disease. Some patients are able to totally discontinue dapsone therapy. Compliance with a gluten-free diet is difficult and requires a motivated patient, and the best treatment response occurs with absolute gluten restriction in the diet.
• Strict dietary vigilance may be required for 5-12 months before the dapsone dose can be reduced.
• Maintaining a gluten-free diet is the only sustainable method of eliminating the disease, not only from the skin, but also from the GI mucosa.
• Patients on a gluten-reduced diet may experience a decrease in symptoms; therefore, diet reduces the dosage of dapsone required for disease control.
• Neither IgA deposition nor circulating antibodies correlate with gluten intake in short-duration studies; however, some studies have suggested a correlation with complement deposition. Avoidance of dietary gluten for 10 years or more has resulted in loss of cutaneous IgA deposits, which then return upon reinstitution of gluten in the diet.
• Elemental diets may improve the disease within weeks. These diets consist of free amino acids, small amounts of triglycerides, and short-chain polysaccharides; they are marketed by pharmaceutical companies. One report has suggested that this improvement may be independent of gluten ingestion; however, this finding has not been confirmed.

MEDICATION

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Drug Category: Antibiotics

Drug Name	Sulfapyridine
Description	Competitive antagonist of PABA. May be better tolerated in older patients, patients with cardiopulmonary problems, and patients who cannot tolerate dapsone. Hemolysis and methemoglobinemia are not as great a concern as with dapsone. Not available in pharmacies. To obtain it, contact Jacobus Pharmaceuticals.
Adult Dose	1-1.5 g/d PO; 500 mg PO bid initially; increase by 1 g q1-2wk until disease is controlled; control may require 1-4 g/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; slow acetylators may require smaller doses or more gradual initial dosage adjustment
Interactions	Reduces bioavailability of digoxin; (2- to 3-h interval between administrations recommended); may inhibit metabolism of methotrexate (may enhance toxic effects; adjust dose); local PACA anesthetic derivatives (benzocaine, procaine, tetracaine) may antibacterial activity of sulfonamides; may use local anesthetics that are not PABA derivatives (lidocaine, dibucaine)
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Idiosyncratic reactions (eg, hypersensitivity pneumonitis, lupuslike syndrome, pancreatitis, toxic hepatitis) may occur; agranulocytosis occurs rarely; both immune and nonimmune hemolytic anemia may develop (latter is more common in G-6-PD–deficient patients); folate deficiency may occur secondary to impaired absorption; nephrolithiasis may occur as with other sulfa drugs; toxic epidermal necrolysis has been reported with medications containing sulfa groups; check CBC counts and LFTs qmo for 5 mo then q6wk thereafter; may increase bleeding time (use caution during dental procedures or routine oral hygiene)

FOLLOW-UP

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Further Outpatient Care

• Dietitians and gastroenterologists are helpful in addressing the GSE.

Complications

• Complications are related to the GSE, the risk of developing lymphomas, and the potential adverse effects of medications (dapsone).

Prognosis

• DH is an ongoing disease process of variable severity.
• The prognosis is good for patients who can tolerate dapsone and the few who can maintain a gluten-free diet (which may decrease the risk of lymphoma).

Patient Education

• Educate patients regarding the use of a gluten-free diet as well as the adverse effects and complications of dapsone.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to consider and diagnose DH can result in the continuation of a distressing disease in a patient who can be treated successfully with dapsone.
• Failure to mention the association of DH with gluten sensitivity and the association with lymphoma can result in further distress to the patient. Although maintenance of a gluten-free diet demands a motivated patient, it should always be offered as an option.
• Failure to diagnose DH with immunofluorescence can result in an erroneous diagnosis and the concomitant associated adverse effects of medications (eg, dapsone) used ineffectively.
• Patients must be monitored when using dapsone or sulfapyridine. Very commonly, patients' hemoglobin levels drop by 1-2 g/dL while taking dapsone. Larger decreases may be seen. Patients should be counseled regarding the signs of a pronounced hemolytic anemia or methemoglobinemia, including malaise, shortness of breath, tachycardia, or jaundice. Most patients can continue the dapsone if the anemia is mild and they are asymptomatic.

Special Concerns

• Polymorphic lesions and an atypical presentation, including a paucity of the characteristic vesicles may make clinical diagnosis difficult.
• Histopathologic and immunologic confirmation of clinically suspected disease is mandatory for diagnosis.

MULTIMEDIA

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Media file 1:  Light micrograph shows neutrophils in the dermal papillae, with fibrin deposition, neutrophil fragments, and edema (hematoxylin and eosin stain).
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Media file 2:  Papillary microabscesses form and progress to subepidermal vacuolization and vesicle formation in the lamina lucida, the weakest portion of the dermoepidermal junction (hematoxylin and eosin stain).
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Media type:  Photo

Media file 3:  Classic vesicles of dermatitis herpetiformis.
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Media file 4:  Immunofluorescence showing immunoglobulin A at the dermoepidermal junction (direct immunofluorescence stain).
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Media file 5:  Polymorphic lesions on extensor surface of arm.
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REFERENCES

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Article Last Updated: May 18, 2007