INTRODUCTION — Dermatitis herpetiformis (DH) is an uncommon, autoimmune, cutaneous, blistering disease that is a manifestation of gluten sensitivity. Affected patients typically develop intensely pruritic inflammatory papules and vesicles on the forearms, knees, scalp, or buttocks (picture 1A-G). The vast majority of patients with DH also have an associated gluten-sensitive enteropathy (celiac disease). In most of these patients, the enteropathy is minimally symptomatic or asymptomatic.
DH usually responds well to treatment. Dapsone and a gluten-free diet are the primary interventions for the management of this disease.
The pathogenesis, diagnosis, and treatment of DH will be discussed here. Celiac disease is reviewed separately. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults" and "Diagnosis of celiac disease in adults" and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children".)
EPIDEMIOLOGY — DH is an uncommon disorder that most frequently occurs in individuals of northern European heritage. Epidemiologic studies from northern Europe have found incidence rates between 0.4 and 3.5 per 100,000 people per year and prevalence rates between 1.2 and 75.3 per 100,000 people [1-8]. A population-based study in Utah, a location with a relatively high proportion of individuals with northern European ancestry, found incidence and prevalence rates similar to those reported in Europe . Between 1978 and 1987, the incidence of DH was 0.98 per 100,000 people per year, and the prevalence of DH in 1987 was 11.2 per 100,000 people.
The incidence of DH may be decreasing. An analysis of patient data from the Clinical Practice Research Datalink in the United Kingdom found a decline in incidence from 1.82 per 100,000 person-years in 1990 to 0.8 per 100,000 person-years in 2011 . A Finnish study that compared the incidence of DH diagnosed within a university hospital district in three successive decades, beginning in 1970, also found decreasing rates of DH . The estimated annual incidence for each decade was 5.2, 2.9, and 2.7 per 100,000 people, respectively. The reason for the observed decline in DH incidence has not been confirmed. Increased detection and treatment of mild celiac disease is a potential contributor. (See 'Pathogenesis' below.)
Epidemiologic studies have found that males are more likely to develop DH than females; reported male-to-female ratios have ranged from 1.1:1 to 1.9:1 . The reason for a male predominance in DH is unknown.
Although the mean age of disease onset is often reported to be in the fourth or fifth decade , individuals of all ages may be affected [3,11]. DH is uncommon in children. In the Finnish study mentioned above, only 18 of 477 patients with DH were children (4 percent) .
PATHOGENESIS — The pathogenesis of DH appears to be complex, involving both intrinsic and extrinsic factors. Like celiac disease, DH is considered a manifestation of gluten-sensitivity that is most likely to occur in genetically susceptible individuals. The importance of gluten in the pathogenesis of these disorders is supported by the observation that the elimination of dietary gluten results in the remission of both diseases. (See 'Gluten-free diet' below and "Management of celiac disease in adults" and "Management of celiac disease in children".)
Histologic examination of skin biopsy specimens supports an important role for the immune system in DH. Subepidermal deposition of immunoglobulin A (IgA) and neutrophilic dermal infiltrates in the superficial dermis are characteristic findings of this disease. (See 'Histopathology' below.)
Genetic predisposition — Certain human leukocyte antigen (HLA) genes predispose to the development of DH. Virtually all patients with DH carry the HLA DQ2 or HLA DQ8 haplotype . This concept was evident in a comparative study of 50 subjects with DH and 290 healthy controls . The study found that genes encoding HLA DQ2 were carried by 86 percent of the patients with DH, compared with only 25 percent of the healthy controls. In addition, six of the seven patients with DH who were negative for HLA DQ2 were positive for HLA DQ8. The importance of HLA DQ2 and HLA DQ8 is likely related to their role in the promotion of an immune response against gliadin peptides (see 'Gluten sensitivity' below). Non-HLA genetic factors may also influence the risk of developing DH .
A genetic contribution to DH is supported further by familial studies that demonstrate that first-degree relatives of patients with DH have an increased risk for both DH and celiac disease [15-17]. In a Finnish cohort of over 1000 patients with DH, 4 percent reported that they had a first-degree relative with DH, and 6 percent reported that they had a first-degree relative with celiac disease .
Gluten sensitivity — The strong epidemiologic link between DH and celiac disease supports a shared pathogenesis involving gluten-sensitivity. More than 90 percent of patients with DH exhibit small bowel biopsy findings consistent with some degree of gluten-sensitive enteropathy [18,19]. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults" and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children".)
Both the adaptive and innate immune systems may contribute to the development of the clinical manifestations of gluten-sensitivity. Gliadin peptides (peptides derived from the digestion of gluten) and tissue transglutaminase (a calcium-dependent enzyme that catalyzes crosslinks between glutamine and lysine protein residues and forms covalent bonds with gliadin) are key antigens . Antibodies against tissue transglutaminase are present in serum from affected patients and are used to support the diagnosis of DH and celiac disease. (See 'Serology' below.)
A potential pathway through which exposure to dietary gluten could lead to DH is as follows [21-24]:
●Following the ingestion and digestion of gluten-containing food, gliadin is absorbed into the intestinal mucosa.
●Gliadin is deaminated by tissue transglutaminase in the intestinal mucosa and covalent crosslinks are formed between gliadin and tissue transglutaminase.
●Deaminated gliadin peptides bind to HLA DQ2 or HLA DQ8 molecules on antigen presenting cells, where they are recognized by helper T cells.
●The activated T cells then produce proinflammatory cytokines and matrix metalloproteinases that stimulate damage to the gut mucosa and the production of antibodies against tissue transglutaminase by B cells.
●Over time, epitope spreading (the development of an immune response against an endogenous antigen or multiple endogenous antigens due to exposure of an endogenous antigen during tissue damage) may occur and contribute to the production of antibodies that are capable of binding to epidermal transglutaminase.
●The IgA antiepidermal transglutaminase antibodies travel through the bloodstream, and upon reaching the skin, complex with epidermal transglutaminase in the dermis.
●The deposition of immune complexes in the dermis stimulates neutrophil chemotaxis and proteolytic cleavage within the lamina lucida, leading to blistering.
Other factors — In addition to genetic predisposition and dietary gluten exposure, other environmental factors may play a role in the development of DH. This concept is supported by a study that identified six patients with DH who had a monozygotic twin . Although the presence of a manifestation of gluten sensitivity (celiac disease, DH, or both disorders) was concordant in five of six twin sets, DH was present in both twins in only three twin sets. Additional study is necessary to confirm the pathogenic mechanisms of DH.
CLINICAL FINDINGS — Patients with DH may experience cutaneous, oral, and gastrointestinal manifestations related to gluten-sensitivity.
Cutaneous manifestations — The classic clinical finding in DH is the development of multiple intensely pruritic papules and vesicles that occur in grouped ("herpetiform") arrangements. The elbows, dorsal forearms, knees, scalp, back, and buttocks are among the most common sites for lesion development (picture 1A-F). The face and groin are less frequent sites of involvement .
Due to the associated pruritus, very few intact papules or vesicles are usually seen on clinical examination. Erosions and excoriations tend to be the most abundant clinical findings (picture 1G).
The extent of cutaneous involvement varies widely. Patients with mild disease present with involvement limited to a few localized areas, such as the knees or dorsal forearms, while patients with severe disease present with widely distributed lesions on the trunk and extremities. The skin lesions usually heal without scarring. However, postinflammatory pigmentary changes may develop .
Petechiae or purpuric macules on the fingers or palms are uncommon clinical features of DH. These lesions are more likely to occur in children, but may also appear in adults [27-31]. Occasionally, acral petechiae or purpura are the primary cutaneous manifestations of this disease .
Oral manifestations — Involvement of the oral mucosa is rare. Since most reports that document oral involvement in DH have not confirmed the diagnosis through direct immunofluorescence (DIF) microscopy, there is some uncertainty regarding whether some cases have actually represented aphthous stomatitis or other disorders . Oral mucosal involvement may manifest as vesicles, erosions, or erythematous macules on the oral mucosa or tongue. Discomfort may or may not be present.
As with celiac disease, tooth enamel defects may occur in patients with DH. Patients may present with horizontal grooves, pits, or discoloration . In a series of 30 adults with DH, 53 percent had enamel defects compared with only 2 percent of 66 healthy controls . A series of 10 children with DH and no clinical symptoms of celiac disease also found an elevated rate of tooth abnormalities among patients with DH; 80 percent had bilateral enamel defects, whereas similar defects were seen in only 13 percent of healthy children .
Gastrointestinal disease — Nearly all patients with DH (75 to 90 percent) have associated subclinical or clinical small bowel disease related to gluten-sensitivity [11,34]. Findings on small bowel biopsy may demonstrate the villous atrophy and crypt hyperplasia classically associated with celiac disease; other cases may demonstrate only mild findings, such as an increase in intraepithelial lymphocytes in intestinal microvilli . (See "Diagnosis of celiac disease in adults", section on 'Endoscopy with small bowel biopsy'.)
Despite the common presence of histologic abnormalities in the gut, only a minority of DH patients develop clinically significant gastrointestinal symptoms. Symptomatic patients may present with abdominal bloating, cramping, pain, diarrhea, or constipation. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children", section on 'Clinical manifestations' and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Clinical manifestations'.)
Clinical course — DH is usually a life-long condition. However, the clinical course of skin disease is variable. While some patients experience intermittent eruptions that last only a few days and are separated by long asymptomatic periods, others develop continuous symptoms that wax and wane in severity . Occasionally, spontaneous remissions occur . (See 'Prognosis' below.)
ASSOCIATED DISEASES — In addition to celiac disease, other diseases may occur at increased frequencies in patients with DH. The most common associated condition is autoimmune thyroid disease . As an example, in a retrospective study of 264 adults with DH, thyroid disease was documented in 11 percent . Hypothyroidism is more likely to occur than hyperthyroidism [35,38,39].
Type I diabetes mellitus and pernicious anemia also may be more likely to develop in patients with DH. The prevalence of type 1 diabetes mellitus in patients with DH is estimated to be between 2 and 5 percent . Between 1 and 3 percent of patients with DH may have pernicious anemia . Other diseases that may occur with increased frequency in patients with DH include vitiligo, Addison disease, alopecia areata, several other autoimmune diseases, and atopic dermatitis [35,39,40].
Celiac disease has been associated with an increased risk for non-Hodgkin lymphoma  (see "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Prognosis'). An increased risk for lymphoma may also occur in association with DH, though estimates of this risk have varied [42-48]. As an example, a Swedish population-based study that included 1354 patients with DH found a slightly increased overall risk for cancer (standard incidence ratio [SIR] 1.2, 95% CI 1.0-1.4), which primarily appeared due to an increase in lymphoma and leukemia . In addition, a cohort study in the United Kingdom that included 84 patients with DH who were followed for a mean of 22 years found that the risk for non-Hodgkin lymphoma was increased in comparison to the general population (SIR 5.14, 95% CI 1.05-15.0) . In this study, the overall risk for malignancy was not increased (SIR 0.99, 95% CI 0.65-1.44).
The impact of a gluten-free diet on the risk for malignancy in patients with DH is uncertain. One retrospective study suggested a reduced risk for lymphoma among patients with a history of long-term adherence to a gluten-free diet . However, additional studies are necessary to explore the impact of a gluten-free diet on the risk for malignancy.
DIAGNOSIS — In addition to the recognition of consistent clinical findings, obtaining laboratory studies, including tissue pathology, direct immunofluorescence (DIF) microscopy, and serology can aid in the diagnosis of DH. DIF is considered the gold standard test for diagnosis.
Our initial approach to the diagnosis of DH in patients who present with suggestive clinical findings involves obtaining a lesional skin biopsy for routine hematoxylin and eosin (H&E) staining and a perilesional skin biopsy for DIF. We use serologic studies as adjunctive tests to support the diagnosis. Serology can also be useful for assessing adherence to dietary therapy. (See 'Serology' below.)
Histopathology — A 4 mm punch biopsy is usually sufficient for obtaining a tissue specimen for routine histologic examination. The biopsy specimen ideally should be taken from the site of a small, intact vesicle. If no intact vesicles are present, the biopsy should be taken from an area of intact, inflamed skin. Biopsies of excoriated lesions may yield nonspecific findings. (See "Skin biopsy techniques", section on 'Punch biopsy'.)
The histologic findings vary based upon the age of the lesion. The earliest lesions may demonstrate only collections of neutrophils (with or without eosinophils) and fibrin at the tips of the dermal papillae (papillary microabscesses) . Lesions older than 48 hours begin to demonstrate subepidermal vesiculation at the papillary tips, which eventually connect to form larger subepidermal blisters that contain neutrophils, eosinophils, and fibrin (picture 2). A perivascular lymphohistiocytic infiltrate with varying numbers of neutrophils and eosinophils is usually found in the dermis .
The histologic findings in DH may resemble other subepithelial blistering disorders. In particular, DH can be difficult to distinguish from linear IgA bullous dermatosis and bullous systemic lupus erythematosus. Bullous pemphigoid may also resemble DH histologically but is typically characterized by a greater abundance of eosinophils .
Direct immunofluorescence microscopy — Direct immunofluorescence (DIF) microscopy is the gold standard test for the diagnosis of DH. A 4 mm punch biopsy is typically utilized to obtain the tissue specimen. The biopsy should be taken from perilesional skin (normal-appearing skin adjacent to a lesion) because biopsies taken from lesional skin are more likely to yield falsely negative findings . Michel's medium may be used to transport the specimen. Tissue for DIF should not be placed in formalin. (See "Skin biopsy techniques", section on 'Punch biopsy' and "Approach to the patient with cutaneous blisters", section on 'Direct immunofluorescence'.)
The characteristic finding on DIF is the presence of granular deposits of IgA within the dermal papillae (picture 3). Deposits of immunoglobulin M (IgM) and C3 may also be present . Infrequently, a fibrillar, rather than granular, pattern of IgA deposition is detected [52,53].
Granular deposits of IgA along the basement membrane may also be seen in DH, and may lead to the misdiagnosis of DH as linear IgA bullous dermatosis (picture 4) [54,55]. Serologic studies are useful for clarifying the diagnosis in ambiguous cases. (See "Linear IgA bullous dermatosis", section on 'Direct immunofluorescence'.)
DIF is usually positive in DH. In a retrospective study of 264 patients with DH, DIF was positive in 244 patients (92 percent) . DIF can become negative in patients on strict gluten-free diets since adherence to the diet reduces IgA deposits in the dermis. In a retrospective series, 10 of 41 patients with DH who were on strict gluten-free diets no longer had detectable IgA deposits in the skin after an average of 13 years . IgA deposition is not affected by pharmacologic therapy .
Serology — We obtain serologic studies to confirm the diagnosis of DH in patients with consistent clinical, histologic, and DIF findings and to aid in the diagnosis of DH in cases in which DIF is negative or equivocal. Elevated levels of IgA tissue transglutaminase antibodies, IgA epidermal transglutaminase antibodies, and IgA endomysial antibodies are often present in patient serum [35,58-62].
Serology is also useful for clinical follow-up. Serum levels of these antibodies fall with gluten restriction and may be useful for monitoring the adherence and response to a gluten-free diet . (See "Management of celiac disease in adults", section on 'Monitoring the response to a gluten-free diet'.)
The serologic tests utilized in DH are generally sensitive and specific. The sensitivity of enzyme-linked immunosorbent assay (ELISA) for IgA tissue transglutaminase antibodies ranges between 47 and 95 percent, and the specificity for this test is reported to be greater than 90 percent . The sensitivity of ELISA for IgA epidermal transglutaminase antibodies ranges between 60 and 81 percent, and the specificity for this test is between 93 and 100 percent [57,63].
Endomysium is the connective tissue found in smooth muscle of the esophagus, stomach, and small intestine. The test for endomysial antibodies is performed via indirect immunofluorescence on monkey esophagus . The sensitivity of this test for celiac disease and DH ranges from 52 to 100 percent and the specificity of the test approximates 100 percent . (See "Approach to the patient with cutaneous blisters", section on 'Indirect immunofluorescence'.)
Our typical serologic work-up for patients with suspected DH includes the following:
●ELISA for IgA tissue transglutaminase antibodies
●ELISA for IgA epidermal transglutaminase antibodies (when available)
●Indirect immunofluorescence for IgA endomysial antibodies
●Total IgA level
The total IgA level is necessary because selective IgA deficiency, which decreases the likelihood of detecting IgA transglutaminase and endomysial autoantibodies, occurs at an increased frequency in patients with celiac disease . IgA deficiency appears to be less common in DH . The assessment of immunoglobulin G (IgG) antibodies against tissue transglutaminase and endomysium may be useful in this setting .
ADDITIONAL TESTS — Since DH is considered a cutaneous manifestation of celiac disease and the treatment for both disorders is similar (a gluten-free diet), performance of a small bowel biopsy to confirm bowel pathology is not indicated [57,65]. (See "Diagnosis of celiac disease in adults" and "Diagnosis of celiac disease in children".)
Due to the association of DH with thyroid disease, we typically obtain thyroid function tests in patients with DH . We also screen patients for diabetes. Additional tests may be ordered based upon clinical suspicion for other autoimmune diseases. (See 'Associated diseases' above and "Laboratory assessment of thyroid function".)
DIFFERENTIAL DIAGNOSIS — The clinical features of DH can resemble the clinical findings of other dermatologic disorders. Intensely pruritic conditions that present with excoriations and inflammatory papules, such as atopic dermatitis, prurigo nodularis, scabies, and arthropod bites, should be considered.
Other subepidermal blistering diseases, such as bullous pemphigoid (picture 5), linear IgA bullous dermatosis (picture 6A-B), and bullous systemic lupus erythematosus, are also included in the differential diagnosis. Blistering tends to be more prominent in these conditions than in DH. However, in the prodromal phase of bullous pemphigoid, blistering may be minimal or absent (picture 7). (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid" and "Linear IgA bullous dermatosis" and "Bullous systemic lupus erythematosus".)
The careful assessment of the patient history as well as the clinical, histopathologic, immunopathologic, and serologic findings usually successfully distinguishes DH from other disorders. (See 'Diagnosis' above.)
TREATMENT — The two most important therapeutic interventions for DH include a strict gluten-free diet and dapsone therapy [66-68]. A gluten-free diet is effective for both DH and the often associated gluten-sensitive enteropathy. However, several months to a few years may be required to achieve complete remission of DH with a gluten-free diet as monotherapy [11,66].
In contrast to a gluten-free diet, dapsone is rapidly effective for DH, resulting in the resolution of active skin lesions within days of the start of therapy. Disadvantages of dapsone therapy include the potential for drug-related adverse events and its lack of effect on the gastrointestinal manifestations of gluten-sensitivity . (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults".)
Our preferred approach to the treatment of DH consists of a combination regimen that allows patients to benefit from the favorable features of both interventions. At the start of treatment, we prescribe dapsone to induce rapid clearance of symptoms and simultaneously strongly encourage patients to eliminate gluten in their diets. We then slowly taper dapsone as tolerated, with a goal of eventually maintaining clinical improvement only on dietary therapy.
Indications for referral — Patients are usually managed by a dermatologist (for the management of DH) and a nutritionist (for dietary counseling) . Additional specialists are added as needed based upon patient comorbidities (eg, thyroid disease, diabetes).
First-line therapy — First-line therapy for DH consists of both dapsone and the elimination of gluten from the diet.
Dapsone — The efficacy of dapsone in DH is well-accepted based upon extensive clinical experience and the clear correlation with rapid clinical improvement immediately after the initiation of treatment [11,57,65,66,68,69]. Pruritus usually improves within 72 hours, and the skin manifestations typically resolve within days . No randomized trials have evaluated the efficacy of dapsone in DH.
In adults with DH, treatment with dapsone is typically begun at 25 to 50 mg per day. The dose is slowly titrated upward (eg, a 25 mg increase in the daily dose every one to two weeks up to a dose of 2 mg/kg per day) based upon patient tolerance and the response to therapy. Our experience suggests that most adult patients on unrestricted diets respond fully to doses between 50 and 150 mg per day . Mild eruptions (eg, one to two new lesions per week) are expected at optimum dosing and are not an indication for increasing the dose of dapsone. Symptoms from these mild outbreaks can be treated with application of a potent topical corticosteroid. (See 'Corticosteroids' below.)
Dapsone therapy is associated with a variety of potential adverse effects (table 1). Some degree of hemolysis occurs in essentially all patients. Although this is tolerated by most patients, individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency are at increased risk for severe hemolytic anemia. Examples of additional side effects include methemoglobinemia, agranulocytosis, and a dapsone hypersensitivity reaction. When it occurs, agranulocytosis usually appears 2 to 12 weeks after the initiation of dapsone therapy. Dapsone-associated hypersensitivity syndrome classically presents with flu-like symptoms, a morbilliform cutaneous eruption, fever, lymphadenopathy, hepatitis, and eosinophilia. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Acute hemolytic anemia' and "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)
Careful laboratory monitoring is necessary during dapsone therapy. We typically obtain a complete blood count (CBC), liver function tests, and renal function tests prior to the start of therapy. A G6PD screen is also recommended since dapsone therapy is contraindicated in patients with G6PD deficiency. We repeat a CBC every one to three weeks for one month, and every one to three months during the first six months of therapy. Subsequently, we obtain a CBC every three to six months provided the dose of dapsone is not increased. Liver and renal function tests are performed every three to four months. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)
Slow, progressive tapering of dapsone can be attempted after the patient has been on a strict gluten-free diet for at least two to three months  (see 'Gluten-free diet' below). Tapering too rapidly can result in disease flares. The best regimen for reducing the dose of dapsone has not been determined. We usually attempt to taper the drug by 25 mg every four to six weeks. In one study, tapering of dapsone to treatment cessation required an average of two years .
Gluten-free diet — The designation of a gluten-free diet as a first-line treatment for DH is based upon uncontrolled studies and extensive clinical experience that support its benefit in DH and the dual efficacy of the diet for the cutaneous and gastrointestinal manifestations of gluten-sensitivity [56,66,72-76]. Although dapsone is highly effective for inducing clinical remissions of DH, a gluten-free diet is our preferred option for long-term therapy. (See "Management of celiac disease in adults" and "Management of celiac disease in children".)
Patients who adhere to a gluten-free diet are usually able to reduce the requirement for dapsone and eventually may be able to discontinue dapsone therapy. As an example, in a 36-month study of 81 patients with DH who were on a gluten-free diet for 6 to 36 months and 49 patients with DH who maintained a normal diet, reductions in the dose of dapsone were achieved in 93 versus 16 percent of patients, respectively . After one year, the average reduction in the dose of dapsone in patients on a gluten-free diet was 60 percent; the percentage reduction increased to 80 percent after three years. During the study period, 28 percent of patients on the gluten-free diet were able to discontinue dapsone completely. Among these patients, the mean amount of time required to discontinue dapsone was two years.
Strict adherence to a gluten-free diet is challenging. Counseling with a dietician is recommended to help patients to identify and eliminate both obvious and hidden sources of dietary gluten and to assist patients with finding alternatives to gluten-containing foods. Multiple resources that provide information on gluten-free diets are available. Examples include the Celiac Disease Foundation and the Gluten Intolerance Group. Whether a gluten-free diet reduces the risk for autoimmune diseases and malignancy in patients with DH is not clear. (See "Management of celiac disease in adults", section on 'Is strict gluten avoidance necessary?'.)
If a relapse of DH occurs in a patient on a strict gluten-free diet, the possibility of exposure to hidden sources of gluten or other triggers (iodide, medications) should be considered. Close review of the diet with a dietician may identify unintentional sources of gluten intake. For severe recurrences, dapsone can be reinstituted with the same regimen used for initial therapy. (See 'Dapsone' above.)
Other sulfa-based drugs — In patients who cannot tolerate treatment with dapsone, other sulfonamide drugs are options for pharmacotherapy. However, there is much less experience with the use of these therapies.
Case reports document successful treatment of DH with sulfapyridine [77,78] and sulfasalazine [79-82]. Although sulfasalazine is metabolized to sulfapyridine in the intestine, the absorption of sulfapyridine (the active drug) is more predictable when sulfapyridine is administered [79,83]. Thus, our preference is to use sulfapyridine. Sulfapyridine may be given to adults at a starting dose of 0.5 g three times per day, which may be increased to up to 6 g per day if necessary to control patient symptoms. Sulfasalazine has been reported to be effective in doses between 1 and 2 g per day .
Of these two agents, only sulfasalazine is commercially available in the United States. Sulfapyridine may be obtained through compounding pharmacies.
Although sulfapyridine and sulfasalazine do not cause the hemolysis seen with dapsone therapy, agranulocytosis and hypersensitivity reactions are potential adverse effects. In addition, adequate fluid intake is recommended during treatment with these drugs to reduce the risk for drug-induced nephrolithiasis. As with dapsone, laboratory monitoring should be performed periodically. We typically follow a CBC, liver function panel, and urinalysis.
Sulfamethoxypyridazine has also been reported to be effective for DH [84,85]. This agent is not available in the United States.
Corticosteroids — Topical superpotent corticosteroids may help alleviate pruritus (table 2). These agents are not sufficient for the management of DH, and should be used in conjunction with dapsone and a gluten-free diet. Systemic glucocorticoids are usually ineffective for DH.
Treatment of children — As with adults, the treatment of children with DH typically consists of dapsone and a gluten-free diet. Dapsone is usually initiated at a low dose (<0.5 mg/kg per day) and titrated upward as tolerated; the therapeutic dose is typically between 0.5 and 2 mg/kg per day . As the gluten-free diet begins to take effect, dapsone is tapered as tolerated .
The duration of time to improvement without dapsone therapy was evaluated in a study in which 41 children with DH were treated with only a gluten-free diet . The study found that 33 of 41 children (80 percent) treated with a gluten-free diet alone had resolution of their symptoms within one to six months. However, since the relief attained with dapsone is almost immediate, we typically use combination therapy.
PROGNOSIS — Most often, DH is a life-long condition that requires continued treatment with dapsone and/or a gluten-free diet to maintain remission. Symptoms can recur within two days after the discontinuation of dapsone, and within three months after the resumption of gluten intake [65,69]. However, 10 to 15 percent of patients may develop remissions that persist despite the discontinuation of both pharmacologic and dietary therapy [37,56].
ln contrast to celiac disease, which may be associated with an increased risk for mortality compared with the general population, patients with DH may have a reduced mortality rate [48,88]. A Finnish cohort study of 476 patients with DH found a lower than expected mortality rate for all causes despite a significant increase in the standardized mortality rate due to lymphoproliferative malignancies in the first five years of follow-up . Further studies are necessary to clarify the factors that may contribute to a reduction in mortality.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dermatitis herpetiformis".)
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●Basics topic (see "Patient education: Gluten-free diet (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Overview – Dermatitis herpetiformis (DH) is an uncommon, cutaneous disorder that occurs as a manifestation of gluten sensitivity. DH is usually accompanied by a gluten-sensitive enteropathy (celiac disease). (See 'Introduction' above and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults" and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children".)
●Epidemiology – DH most frequently occurs in individuals of northern European ancestry. Both children and adults may be affected. (See 'Epidemiology' above.)
●Pathogenesis – Genetic predisposition and gluten-sensitivity are key factors in the pathogenesis of DH. Virtually all patients with DH carry the HLA DQ2 or HLA DQ8 haplotype. Antibodies against epidermal transglutaminase produced in association with an immune response to ingested gluten play a key role in the disease pathogenesis. (See 'Pathogenesis' above.)
●Clinical findings – DH classically presents as an intensely pruritic skin eruption characterized by the development of inflammatory papules and vesicles (picture 1A-G). Due to the pruritus, excoriations and erosions are often the most prominent clinical manifestations. The elbows, forearms, knees, buttocks, back, and scalp are common sites for lesion development. (See 'Clinical findings' above.)
●Associated diseases – Patients with DH may have an increased risk for the development of other autoimmune diseases. Thyroid disease is the most common autoimmune disorder associated with DH. Patients with DH may also have an increased risk for lymphoma. (See 'Associated diseases' above.)
●Diagnosis – The diagnosis of DH is made based on both the clinical findings and laboratory studies. The gold standard test for diagnosis is direct immunofluorescence (DIF) of perilesional skin. DIF classically demonstrates granular deposits of immunoglobulin A (IgA) within the papillary dermis (picture 3). Serologic studies that identify circulating IgA antibodies against tissue transglutaminase, epidermal transglutaminase, and endomysium are useful for confirming the diagnosis. (See 'Diagnosis' above.)
●Treatment – Our preferred approach to the treatment of DH consists of both pharmacotherapy and dietary therapy. For children and adults with DH, we suggest treatment with both dapsone and a gluten-free diet as initial therapy (Grade 2A). Subsequently, dapsone may be slowly tapered with the goal of sustaining remission with dietary therapy. (See 'Treatment' above.)
●Prognosis – DH is usually a life-long condition that requires continued treatment. Spontaneous remission may occur in a minority of patients. (See 'Prognosis' above.)
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