Dermatitis Herpetiformis

Updated: Mar 31, 2016
  • Author: Jami L Miller, MD; Chief Editor: Dirk M Elston, MD  more...
  • Print
Overview

Background

Dermatitis herpetiformis is an exquisitely pruritic eruption classically seen on the buttocks and the extensor surfaces of the arms and legs. Severe cases may involve larger surface areas.

Dermatitis herpetiformis is an autoimmune blistering disorder that is often associated with a gluten-sensitive enteropathy (GSE). The disease was described and named in 1884 by Dr. Louis Duhring at the University of Pennsylvania. [1] It is also known as Duhring disease or Duhring-Brocq disease.

Dermatitis herpetiformis is characterized by grouped excoriations, erythematous, urticarial plaques, and papules with vesicles. The classic location for dermatitis herpetiformis lesions is on the extensor surfaces of the elbows, knees, buttocks, and back. It is extremely pruritic, and the vesicles are often excoriated to erosions by the time of physical examination, as shown in the image below.

Classic vesicles of dermatitis herpetiformis. Classic vesicles of dermatitis herpetiformis.

See Autoimmune Disorders: Making Sense of Nonspecific Symptoms, a Critical Images slideshow, to help identify several diseases that can cause a variety of nonspecific symptoms.

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, greater than 90% have an associated gluten-sensitive enteropathy upon endoscopic examination. Among patients with celiac disease, 15-25% develop dermatitis herpetiformis. The mainstays of treatment are dapsone and a gluten-free diet. A vertically oriented fibrillar staining pattern is noted in a subset of patients, with immune deposits along dermal microfibrils, creating a characteristic “picket fence” pattern of immunofluorescence. This fibrillar pattern is present in a third of Japanese patients, and this group lacks the typical distribution of skin lesions and has a low association with celiac disease. [2]

Next:

Pathophysiology

Dermatitis herpetiformis 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. Dermatitis herpetiformis is the result of an immunologic response to chronic stimulation of the gut mucosa by dietary gluten. [3]

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

The leading theory for dermatitis herpetiformis is that a genetic predisposition for gluten sensitivity, coupled with a diet high in gluten, leads to the formation of IgA antibodies against gluten-tissue transglutaminase (t-TG), which is found in the gut. These antibodies cross-react with epidermal transglutaminase (e-TG). [4] eTG is highly homologous with tTG. Serum from patients with gluten-sensitive enteropathy, with or without skin disease, contains IgA antibodies to both skin and gut types. [5] Deposition of IgA and epidermal TG complexes in the papillary dermis cause the lesions of dermatitis herpetiformis.

In patients with gluten-sensitive enteropathy, levels of circulating antibodies to tissue and epidermal transglutaminase have been found to correlate with each other, and both appear to correlate with the extent of enteropathy. [6]

Co-localized IgA and eTG deposits have been demonstrated in the papillary dermis in patients with dermatitis herpetiformis and, to lesser extent, in the healthy skin of gluten-sensitive enteropathy patients. [7] eTG 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.

Cutaneous IgA deposits in dermatitis herpetiformis 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 dermatitis herpetiformis in patients with a partial IgA deficiency. [8] When the disease is active, circulating neutrophils have a higher level of CD11b and an increased ability to bind IgA. The characteristic histologic finding of dermatitis herpetiformis is neutrophil accumulation at the dermoepidermal junction, frequently localizing to the papillary tips of the basement membrane zone.

Interleukin 8 (IL-8) is a potent neutrophil activator; gluten, UVB exposure, and trauma have all been shown to induce IL-8 production. [9] It has been demonstrated that dietary gluten increases levels of serum IL-8 in patients with dermatitis herpetiformis. A study in transgenic mice expressing IL-8 in the intestine has been shown to increase local neutrophil migration into the area.

Collagenase and stromelysin 1 may be induced in basal keratinocytes either by 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 dermatitis herpetiformis to be 1271 times greater that that of controls. [10] Additionally, the same study observed increased soluble E-selectin, IgA antitissue transglutaminase antibodies, tumor necrosis factor-alpha, and serum interleukin 8 (IL-8) levels in patients with dermatitis herpetiformis, 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 dermatitis herpetiformis 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. [11]

A recent study showed an increased expression of disintegrin and metalloproteinase (ADAMs) 8, 10, 15, and 17 in lesional skin of patients with dermatitis herpetiformis compared with controls. The high affinity of ADAMs for the basement membrane led the authors to hypothesize a role in blister formation in dermatitis herpetiformis. [12]

Hormonal factors may also play a role in the pathogenesis of dermatitis herpetiformis, and reports describe dermatitis herpetiformis induced by treatment with leuprolide acetate, a gonadotropin-releasing hormone analog. [13] Androgens have a suppressive effect on immune activity, including decreased autoimmunity, and androgen deficient states may be a potential trigger for dermatitis herpetiformis exacerbation. Exacerbation of dermatitis herpetiformis by oral contraceptives has also been reported.

Apoptosis may contribute to the pathogenesis of epidermal changes in dermatitis herpetiformis, and research demonstrates a markedly increased apoptotic rate within the epidermal compartment in dermatitis herpetiformis. [14] In addition, Bax and Bcl-2 proteins are increased in the dermal perivascular compartment and Fas proteins showed epidermal staining in dermatitis herpetiformis lesions.

Most patients with dermatitis herpetiformis have histologic evidence of enteropathy, even in the absence of symptoms of malabsorption. In one study, all dermatitis herpetiformis patients had increased intestinal permeability (as measured by the lactulose/mannitol ratio) and up-regulation of zonulin, a regulator of tight junctions. [15] Thus, increased expression of zonulin may be involved in the pathogenesis of enteropathy in patients with dermatitis herpetiformis.

Previous
Next:

Epidemiology

Frequency

United States

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

International

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

Race

Dermatitis herpetiformis occurs more frequently in individuals of Northern European ancestry and is rare in Asians and persons of African descent. Dermatitis herpetiformis is most common in Ireland and Sweden. This can be attributed to the shared HLA associations of dermatitis herpetiformis and celiac disease 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 gluten-sensitive enteropathy, 16% of the men and 9% of the women had dermatitis herpetiformis. [16]

Age

Typically, the onset of dermatitis herpetiformis is in the second to fourth decade; however, persons of any age may be affected. [17] Dermatitis herpetiformis is rare in children.

Previous