Dermatitis herpetiformis

Background

This blistering disorder is characterized by pruritic papules and vesicles occurring in herpetiform grouping (clustering like herpes simplex). There is symmetrical involvement of the extensor surfaces and involvement of the elbows, knees, shoulders, nape of the neck, sacral area, scalp, and mucous membranes. Although this is a bullous disorder, large blisters such as seen in pemphigus vulgaris or bullous pemphigoid are distinctly uncommon. Young male adults are most commonly affected but it may occur at any age.

There is an interesting association with the gastrointestinal disorder called gluten sensitive enteropathy or celiac sprue which occurs in up to 90% of patients. These patients have circulating antibodies to gliadin, a protein present in many grains. In addition, antibodies directed against human jejunum, gastric parietal cells, endomysium, and thyroid antigens are also found. When challenged with gluten, flares of the dermatitis occur. Repeated injury to the small bowel leads to villous atrophy and malabsorption. IgA endomysial antibodies are present in 70% of patients with dermatitis herpetiformis on a normal diet and 100% of patients with villous atrophy. It is hypothesized that these IgA antibodies may cross react with proteins present within the dermal papillae. Binding leads to activation of complement with recruitment of neutrophils. This leads to further destruction of laminin and type IV collagen leading to blister formation.

Like other autoimmune diseases, there is an association with other autoimmune disorders such as thyroid diseaes, ulcerative colitis, systemic lupus erythematosus, Sjogren's syndrome, primary biliary cirrhosis, and atopic dermatitis. The skin lesions usually persist for days to weeks although recurrences are common. Iodine and non-steroidal anti-inflammatory agents may cause exacerbations. There is an association with HLA antigens B8, DR3, and DQW2.

The pathology is a subepidermal blister with collections of neutrophils present within the tips of the dermal papillae associated with edema (papillary microabscesses). Direct immunofluorescence (DIF) reveals a granular deposits of IgA at the dermal papillae of lesional and perilesional skin. It is not found in patients with celiac disease who do not have the skin disease.

The pathologist must distinguish this disorder from linear IgA bullous dermatosis, a distinction which cannot be made by routine light microscopy. DIF must be used which reveals the characteristic linear staining at the dermoepidermal junction.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/
Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/
Immunohistochemistry/
Electron Microscopy

Differential Diagnosis

Prognosis and Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

GEOGRAPHY

JAPAN

Dermatitis herpetiformis in Japan: an update.

Shibahara M, Nanko H, Shimizu M, Kanda N, Kubo M, Ikeda M, Matsumoto M, Nonaka S, Shimizu H.

Department of Dermatology, Tokyo Kousei-Nenkin Hospital, Tokyo, Japan.
Dermatology 2002;204(1):37-42 Abstract quote
BACKGROUND: Although dermatitis herpetiformis (DH) is a relatively common disease in Caucasian populations, it is rare in Asian populations including the Japanese. We encountered a Japanese case of DH which showed granular IgA and C3 deposits in the papillary dermis and which was associated with gluten-sensitive enteropathy but no HLA-B8/DR3/DQ2.

OBJECTIVE: The purpose of this study is to describe the characteristics of Japanese DH cases, since most of them have been reported in Japanese language and dermatologists outside Japan are not familiar with the characteristics of Japanese DH.

METHODS: We have reviewed all 34 Japanese DH cases reported previously.

RESULTS: We found several features of Japanese DH compared with Caucasian DH, such as a high frequency of the fibrillar pattern, rarity of gluten-sensitive enteropathy and an absence of the HLA-B8/DR3/DQ2 haplotype.

CONCLUSION: There might be significant differences in pathophysiology between Caucasian and Japanese DH cases.

DISEASE ASSOCIATIONS CHARACTERIZATION

BULLOUS PEMPHIGOID

Dermatitis herpetiformis evolving into bullous pemphigoid: a probable example of 'epitope spreading'.

Ameen M, Bhogal BS, Black MM.

St. John's Institute of Dermatology, St. Thomas' Hospital, London, UK.
Clin Exp Dermatol 2000 Jul;25(5):398-400 Abstract quote
We report a case of dermatitis herpetiformis which, 11 years after its original diagnosis, evolved into bullous pemphigoid.

Only a few similar cases supported by immunofluorescence studies have been reported previously, and we believe that they represent examples of 'epitope spreading', an increasingly recognized phenomenon used to explain the coexistence of autoimmune diseases.

CELIAC DISEASE

NEUROLOGICAL SYMPTOMS

Dermatitis herpetiformis and neurological dysfunction.

Wills AJ, Turner B, Lock RJ, Johnston SL, Unsworth DJ, Fry L.

Department of Neurology, Queen's Medical Centre, Nottingham, UK.
J Neurol Neurosurg Psychiatry 2002 Feb;72(2):259-61 Abstract quote
Dermatitis herpetiformis and coeliac disease are gluten sensitive diseases, which have common immunopathological and genetic mechanisms. Neuropsychiatric complications have been reported in up to 26% of patients with coeliac disease. This is probably an overestimate, because of the chance associations with some common neurological conditions such as epilepsy. The pathogenesis is speculative but it has been postulated that gluten is neurotoxic possibly via immune mechanisms. The frequency of neurological dysfunction in patients with dermatitis herpetiformis has not been characterised. Patients with dermatitis herpetiformis might be expected to be particularly susceptible to neuronal damage as some continue to consume gluten when their dermatological symptoms are controlled by dapsone.

Thirty five patients were recruited with dermatitis herpetiformis from dermatology clinics at St Mary's Hospital, London and Queen's Medical Centre, Nottingham and investigated for evidence of neurological abnormality. All patients underwent a full neurological examination and were asked about their neurological and general medical history by means of a structured questionnaire. Serum samples were taken and screened for the presence of anti-neuronal antibodies (anti-Hu and Yo) as well as anti-gliadin (IgA and G) anti-endomysial (IgA), and anti-tissue transglutaminase (IgA) antibodies. Neurophysiological tests were carried out where appropriate. Only two patients were identified with unexplained neurological abnormalities (one essential tremor, and one chorea). Two other patients had a history of migraine. The patient with chorea also had borderline/equivocally positive anti-Hu antibodies by immunofluorescence assay. All other samples were negative for anti-neuronal antibodies. Fifteen patients were positive for anti-gliadin antibodies (IgA and/or IgG), four for anti-endomysial antibodies (monkey oesophagus or umbilical cord), and six for anti-tissue transglutaminase antibodies.

The presence of these antibodies did not correlate with the presence of neurological abnormalities. No cases of "gluten ataxia" were identified. In conclusion, there was no convincing evidence for immune mediated neurological damage in this pilot study of dermatitis herpetiformis.

VITILIGO

Dermatitis herpetiformis and vitiligo: report of a case and review of the literature.
Amato L, Gallerani I, Fuligni A, Mei S, Fabbri P.

Department of Dermatology, University of Florence, Italy.
J Dermatol 2000 Jul;27(7):462-6 Abstract quote
We describe the case of a 53-year-old woman presenting papulous and papulovesicular lesions that were highly pruritic, localized mostly in the achromic areas of vitiligo and symmetrically distributed on the elbows, the buttocks, the shoulders and the neck.

The histopathological examination performed on the elbow's lesional skin showed the presence of neutrophils and fibrin microabscesses at the tips of dermal papillae, with a few eosinophils, and small separations between the dermis and epidermis just over the infiltrate. The overlying epidermis was uninjured. The performed tests detected IgA anti-endomysium, anti-thyrogloblin, anti-smooth muscle and anti-microsomal fraction autoantibodies; DIF showed the presence of IgA granular deposits at the dermo-epidermal junction, prevalently at the tips of dermal papillae.

This is the tenth case reported of an association between dermatitis herpetiformis and vitiligo. Although the two disorders both have immunological pathogeneses, we think that the topographic coexistence of both disorders is coincidental.

PATHOGENESIS CHARACTERIZATION

ANTI-ENDOMYSIAL ANTIBODIES

Comparison of IgA-class reticulin and endomysium antibodies in coeliac disease and dermatitis herpetiformis.

Hallstrom O.

Department of Clinical Microbiology and Immunology, University Central Hospital, Tampere, Finland.
Gut 1989 Sep;30(9):1225-32 Abstract quote
The occurrence of IgA class reticulin and endomysium antibodies was examined with the standard immunofluorescence method in coeliac disease and dermatitis herpetiformis. Similar high antibody frequencies were detected in 32 untreated adults (91%) and 18 children (100%) with coeliac disease and in 14 dermatitis herpetiformis patients with subtotal villous atrophy (reticulin antibodies 93% and endomysium antibodies 100%).

The specificity of IgA class reticulin antibodies and endomysium antibodies was high because all 45 adult patients with ulcerative colitis or Crohn's disease, 24 non-coeliac children with abdominal symptoms and 99/100 healthy blood donors were negative for these antibodies. The only positive blood donor had both IgA class reticulin antibodies and endomysium antibodies but also she was found to have coeliac disease. IgA class reticulin antibodies and endomysium antibodies declined in parallel during treatment with a gluten free diet and increased on gluten challenge. This suggests that these antibodies can be used to screen for gluten sensitive enteropathy and to monitor dietary treatment. To characterise the tissue specificity of reticulin antibodies and endomysium antibodies four positive sera were absorbed with human and several rodent liver homogenates. Absorption with rat or other rodent livers removed the rodent-specific reticulin antibodies but not the reticulin antibodies detectable with human tissues or the endomysium antibodies detectable with monkey oesophagus.

These results show that reticulin antibodies can be divided into the rat and human subtypes. The human subtype could not be separated from endomysium antibodies in the present absorption experiments.

EPIDERMAL TRANSGLUTAMINASE 3

Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis.

Sardy M, Karpati S, Merkl B, Paulsson M, Smyth N.

Department of Dermato-Venereology, Semmelweis University, H-1085 Budapest, Maria u.41, Hungary.
J Exp Med 2002 Mar 18;195(6):747-57 Abstract quote
Gluten sensitivity typically presents as celiac disease, a common chronic small intestinal disorder. However, in certain individuals it is associated with dermatitis herpetiformis, a blistering skin disease characterized by granular IgA deposits in the papillary dermis.

While tissue transglutaminase has been implicated as the major autoantigen of gluten sensitive disease, there has been no explanation as to why this condition appears in two distinct forms. Here we show that while sera from patients with either form of gluten sensitive disease react both with tissue transglutaminase and the related enzyme epidermal (type 3) transglutaminase, antibodies in patients having dermatitis herpetiformis show a markedly higher avidity for epidermal transglutaminase. Further, these patients have an antibody population specific for this enzyme. We also show that the IgA precipitates in the papillary dermis of patients with dermatitis herpetiformis, the defining signs of the disease, contain epidermal transglutaminase, but not tissue transglutaminase or keratinocyte transglutaminase.

These findings demonstrate that epidermal transglutaminase, rather than tissue transglutaminase, is the dominant autoantigen in dermatitis herpetiformis and explain why skin symptoms appear in a proportion of patients having gluten sensitive disease.

LABORATORY/
RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION

RADIOLOGIC

LABORATORY MARKERS

Tissue transglutaminase and endomysial antibodies-diagnostic markers of gluten-sensitive enteropathy in dermatitis herpetiformis.

Kumar V, Jarzabek-Chorzelska M, Sulej J, Rajadhyaksha M, Jablonska S.

IMMCO Diagnostics, Inc., Buffalo, New York, 14228, USA.
Clin Immunol 2001 Mar;98(3):378-82 Abstract quote
The association of Durhing's disease, commonly referred to as dermatitis herpetiformis (DH), with gluten-sensitive enteropathy (GSE) is supported by the presence of villous atrophy and endomysial antibodies (EMA). EMA are found to be a marker of GSE both in celiac disease (CD) and in DH. Since tissue transglutaminase (tTG) is believed to be the major autoantigen in GSE, the aim of our study was to determine the specificity and sensitivity of anti-tTG antibody ELISA compared to the EMA indirect immunofluorescence test.

We studied 44 cases of DH, confirmed by the presence of IgA immune deposits in the dermal papillae, and 58 cases of CD conforming to the International Criteria of Diagnosing CD. The control group comprised 161 sera from patients with vesiculobullous disorders other than DH and 106 sera from normal healthy blood donors. Anti-tTG antibodies were detected in 36 of 44 DH (79%) and in 32 of 58 CD (55%) patients. EMA were positive in 33 of 44 DH (74%) and in 36 of 58 CD (62%) patients. Both the EMA and the antibodies to tTG were present in the majority of patients with DH and CD when they were on a normal gluten-containing diet and were absent when on a gluten-free diet for an extended period of time. There were, however, small discrepancies in positivity and negativity in tTG antibody-positive and EMA-negative patients and vice versa. There seems to be a correlation between the EMA titers and the anti-tTG antibody levels.

This study confirms the high specificity and sensitivity of anti-tTG antibody ELISA for GSE and its strong correlation with EMA both in CD and in DH. The results of anti-tTG antibody and EMA assays were comparable; however, in DH, tTG was somewhat more sensitive than the EMA test. For screening of DH, it is advisable to perform both EMA and anti-tTG antibody tests.

Serum eosinophil cationic protein, myeloperoxidase, tryptase, eotaxin and Th2-L-like cytokines in Dermatitis herpetiformis.
Caproni M, Cardinali C, D'Agata A, Selvaggi W, Fabbri P.

Department of Dermatological Sciences, University of Florence, Italy.
Int Arch Allergy Immunol 2002 May;128(1):67-72 Abstract quote
BACKGROUND: Dermatitis herpetiformis (DH) is a subepidermal bullous disease characterized by a neutrophilic and eosinophilic infiltrate, together with activated lymphocytes that show preferential polarization towards the Th2-like phenotype. To date, the role of neither soluble mediators, such as cytokines, nor serum levels of myeloperoxidase (MPO), eosinophil cationic protein (ECP) and tryptase (TRY) have been studied in the peripheral blood of DH. In this study we investigated 40 DH subjects for possible alterations in MPO, ECP, TRY, eotaxin, interleukin (IL) 4 and IL-5 concentrations to evaluate the role of neutrophils, eosinophils and mast cells in the induction of skin lesions. Sera from 20 healthy subjects were tested as controls.

METHODS: Eotaxin, IL-4 and IL-5 serum contents were determined by a solid-phase enzyme-linked immunosorbent assay. A double antibody radioimmunoassay was used to measure serum levels of MPO, ECP and TRY. Results: Normal levels of eotaxin and IL-4 were found in all DH subjects; increased IL-5 levels were found only in 1 subject. The MPO levels were significantly higher in DH subjects than in healthy controls (p < 0.01). There was also a significant difference between the serum ECP levels of DH and healthy controls (p < 0.05). TRY was not revealed in the serum of DH subjects.

CONCLUSIONS: The determination of Th2-like cytokines and TRY serum levels is not important in quantifying the involvement of activated lymphocytes and mast cells in DH; however, the finding of high MPO and ECP serum levels seems to confirm that these products are good markers of the presence of activated neutrophils and eosinophils.

Levels of F1+2 prothrombin fragments and thrombin D antithrombin III (TAT) complexes in patients with dermatitis herpetiformis.

Wankiewicz A, Iwan-Zietek I, Gwiezdzinski Z, Kotschy M.

Chair and Clinic of Dermatology, Medical University of Bydgoszcz, Poland.
Med Sci Monit 2002 Aug;8(8):BR324-7 Abstract quote
BACKGROUND: Dermatitis herpetiformis (DH) is a rare bullous disease of autoimmune etiology. It is an intestinocutaneous syndrome, in which vesicopapular cutaneous lesions are accompanied by gluten-dependent enteropathy. The diagnosis of DH is based on immunopathological investigation of unaffected skin fragment (granular IgA deposits present at the tops of dermal papillae and IgA - EmA present in the serum).

MATERIAL/METHODS: The studied group consisted of 33 patients with dermatitis herpetiformis - 23 males and 10 females aged 22-78 (mean age 44.7). In all the patients, the following parameters of blood coagulation systems were determined in the plasma Levels of prothrombin fragments 1+2 (F1+2), levels of thrombin - antithrombin III (TAT) complexes, antithrombin III activity (AT III).

RESULTS: In patients with dermatitis herpetiformis, the main level of F1+2 fragments amounted to 9.08 nmol/l, as compared with 1.14 nmol/l in the control group (the difference statistically significant, p<0.0001). In DH patients, the levels of TAT complexes were over twice higher than among the controls and that difference also reached statistical significance (p<0.0001). Mean antithrombin III activity (AT III) in patients with DH reached 102.60% and was similar to that observed in the control group (104.68%).

CONCLUSIONS: In patients with dermatitis herpetiformis, increased levels of F1+2 prothrombin fragments and TAT complexes indicate enhanced in vivo thrombinogenesis. No statistically significant differences of F1+2, TAT and AT III levels in DH patients related to their sex, age and duration of the disease were observed

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

GENERAL

Iodine and gliadin challenge on oral mucosa in dermatitis herpetiformis.

Patinen P, Hietane J, Malmstrom M, Reunala T, Savilahti E.

Department of Oral Surgery, Institute of Dentistry, University of Helsinki, Tampere, Finland.
Acta Derm Venereol 2002;82(2):86-9 Abstract quote
Oral lesions and mucosal inflammatory changes may appear in dermatitis herpetiformis (DH).

We examined whether potassium iodine, known to initiate blisters in the DH skin, or wheat gliadin, responsible for T-cell-dependent intestinal damage, can induce visible or microscopic changes in oral mucosa. Six patients with active DH were challenged with crude gliadin and 50% potassium iodine applied in patch test chambers on buccal mucosa for 12 h. After reading, biopsies were taken from the challenged and non-challenged mucosa. No macroscopic or microscopic vesicles were seen. However, gliadin- but not iodine-challenged epithelium showed increased numbers of CD4+ lymphocytes in all 5 patients with representative specimens (p = 0.06). No marked changes were found in the numbers of CD8+ or TcR alpha/beta+ lymphocytes, and the numbers of TcR gamma/delta+ cells remained at a low level.

The results show that oral mucosa is resistant to production of macroscopic or microscopic DH lesions. It is, however, capable of reacting to locally applied gliadin by a T-cell response consisting of CD4+ lymphocytes.

VARIANTS

CHILDHOOD

Childhood dermatitis herpetiformis. Review of the new aspects and report of a case.

Safai B, Rappaport I, Matsuoka L, Sogn D, Haines K, Lewin M.
J Am Acad Dermatol 1981 Apr;4(4):435-41 Abstract quote
Dermatitis herpetiformis (DH) of linear IgA type occurred in a 6-month-old boy shortly after initiating sulfisoxazole therapy for a urinary tract infection. Generalized pruritic bullae on erythematous bases were present on his trunk and extremities. There were no clinical or laboratory findings suggestive of gastrointestinal involvement.

Direct immunofluorescent studies of skin biopsies taken early in the course of the disease and while the child was on systemic corticosteroid therapy were negative. Eventually a linear deposition of IgA at the dermoepidermal junction of involved skin on direct immunofluorescence was demonstrated. No circulating antibodies to the basement membrane were found. Because of close proximity of the initiation of sulfisoxazole (Gantrisin) therapy and the eruption of the initial bullous lesions, this case also presents an interesting diagnostic and therapeutic problem. Negative assays of lymphocyte migration inhibition factor (LMIF) to sulfisoxazole indicated that the likelihood of a hypersensitivity reaction to sulfa drugs was slight. The patient's clinical response to dapsone therapy was dramatic. The conflicting views of subepidermal bullous dermatosis of childhood and the difficulties in confirming a diagnosis of DH are discussed.

We contend that when DH is suspected in children, various laboratory tests should be repeated several times before the diagnosis can be confirmed. The case presented here is the youngest child reported with this type of DH.

PALMAR PETECHIAE

Palmar purpura: an atypical presentation of childhood dermatitis herpetiformis.

McGovern TW, Bennion SD.

Dermatology Service, Fitzsimons Army Medical Center, Aurora, Colorado 80045.

Pediatr Dermatol 1994 Dec;11(4):319-22 Abstract quote
Dermatitis herpetiformis (DH) is seen most commonly as a pruritic, papulovesicular eruption in young children or adolescents. Differentiation from other bullous diseases of childhood may be difficult.

We report the first case of an adolescent in whom pruritic, palmar, purpuric macules and papules were the only manifestations of DH. The patient later developed typical vesiculobullous extensor lesions and symptomatic gluten-sensitive enteropathy (GSE).

All lesions and GSE symptoms resolved with dapsone and a gluten-free diet. Our purpose is to illustrate an unusual presentation of pediatric DH.

TWINS

Concordance of dermatitis herpetiformis and celiac disease in monozygous twins.

Hervonen K, Karell K, Holopainen P, Collin P, Partanen J, Reunala T.

Department of Dermatology, University Hospital of Tampere, Tampere, Finland.
J Invest Dermatol 2000 Dec;115(6):990-3 Abstract quote
Celiac disease can be defined as the classical manifestation of gluten sensitivity, which primarily affects the small intestine. Gluten sensitivity has also a skin manifestation, i.e., dermatitis herpetiformis. Both diseases have a strong genetic association with HLA DQ on chromosome 6.

In this study we tried to estimate how much different clinical expressions of gluten sensitivity are determined by genetic factors, and hence how feasible they are for genetic mapping; therefore, we studied all six monozygous twin pairs found among 1292 prospectively collected patients of dermatitis herpetiformis in Finland. Three of the six twin pairs were concordant for dermatitis herpetiformis and for simultaneous enteropathy, celiac disease. Two other twin pairs were partially discordant, one of each pair had dermatitis herpetiformis and celiac disease, whereas the other had solely the gut manifestation of gluten sensitivity, i.e., celiac disease. Only one pair was found to be discordant for gluten sensitivity. All the pairs had typical risk alleles for gluten sensitivity, i.e., either HLA DQ2 or DQ8. These results demonstrate that the genetic component in gluten sensitivity as broadly defined is very strong (5/6 concordant). Genetically identical individuals can have clearly distinguished phenotypes, either dermatitis herpetiformis or celiac disease, suggesting that environmental factors determine the exact phenotype of this multifactorial disease.

These findings are of importance in genetic linkage analyses, which focus to only certain phenotypic properties of a complex trait.

HISTOLOGICAL TYPES CHARACTERIZATION

GENERAL

VARIANTS

Characterization of a subgroup of patients with dermatitis herpetiformis with nonclassical histologic features.

Warren SJ, Cockerell CJ.

Division of Dermatopathology, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A.
Am J Dermatopathol 2002 Aug;24(4):305-8 Abstract quote
Dermatitis herpetiformis (DH) is an autoimmune disease mediated by IgA antibodies. The diagnosis of DH is based on clinical presentation, biopsy for hematoxylin and eosin, and direct immunofluorescence. The chief hematoxylin and eosin finding is a subepithelial blister with neutrophils in dermal papillae. The direct immunofluorescence findings are deposition of IgA and sometimes C3 at the basement membrane with accentuation in dermal papillae. Immunofluorescence is thought to be a sensitive and specific assay in DH, and there are no other known diseases with this pattern of immunofluorescence.

The aim of this project was to determine the prevalence of nonclassical histologic findings in DH. We studied 24 cases of DH received at our institution. All cases had clinical findings of DH as well as positive direct immunofluorescence with IgA. We found that 9 of 24 cases (37.5%) had nonspecific H&E findings of a lymphocytic infiltrate only with fibrosis in the dermal papillae and ectatic capillaries. The remaining 15 cases had classic findings of multilocular neutrophilic microabscesses in the dermal papillae. These findings were reproduced on step sectioning.

These findings suggest that routine histology may be quite nonspecific in DH and direct immunofluorescence or other more specific immunologic assay is an essential adjunct to diagnosis.

SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHER CHARACTERIZATION

SPECIAL STAINS

IMMUNOPEROXIDASE

DIRECT IMMUNOFLUORESCENCE

A case of dermatitis herpetiformis with IgA endomysial antibodies but negative direct immunofluorescent findings.

Beutner EH, Baughman RD, Austin BM, Plunkett RW, Binder WL.

Beutner Laboratories and the Department of Microbiology and Dermatology, State University of New York at Buffalo, Buffalo, New York, USA.\

J Am Acad Dermatol 2000 Aug;43(2 Pt 2):329-32 Abstract quote
A patient with clinical findings of dermatitis herpetiformis (DH), negative direct immunofluorescent (DIF) findings for junctional IgA deposits in 2 biopsy specimens, and positive for IgA endomysial (AEmA) and tissue transglutaminase (tTG) antibodies responded initially to dapsone. After dapsone had to be discontinued because of side effects, a gluten-free diet and supportive therapy controlled the disease; the AEmA and tTG antibodies became negative.

Our data on 10 consecutive DH cases examined by DIF and by serum studies for AEmA and antibodies to tTG, point to frequencies of 90% DIF positive and 70% AEmA and tTG positive cases. The use of both DIF and serum tests for AEmA and tTG reveals DH cases not detected by DIF alone that respond to gluten-free diet. Findings on autoantibodies to tTG, an enzyme that metabolizes gliadin, points to a role of tTG in the immunopathology of gluten-sensitive enteropathy and helps to explain the need for a gluten-free diet in the management of DH cases.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

LINEAR IgA DISEASE

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSTIC FACTORS

Malignancy and survival in dermatitis herpetiformis: a comparison with coeliac disease.

Collin P, Pukkala E, Reunala T.

Medical School, University of Tampere, Finland.
Gut 1996 Apr;38(4):528-30 Abstract quote
BACKGROUND--Dermatitis herpetiformis is a lifelong, gluten sensitive skin disease. Patients with dermatitis herpetiformis, similar to patients with coeliac disease not adhering to a gluten free diet, seem to have increased risk for lymphoma. AIMS--This study looked at the occurrence of malignancy and survival of patients with dermatitis herpetiformis and compared the results with those seen in patients with coeliac disease or in the general population.

PATIENTS--A total of 305 adult patients with dermatitis herpetiformis diagnosed at the University Hospital of Tampere in 1970-1992 were studied. Most patients started a gluten free diet and at the end of the study 93% of the patients were adhering to the diet. A control group comprised 383 adult patients with coeliac disease, 81% of them adhered to a gluten free diet, 6% had a normal diet, and in 13% the diet history remained unknown.

METHODS--The occurrence of malignant diseases and survival of the patients were assessed up to the end of 1993. Standardised incidence ratios (SIR) with 95% confidence intervals were used for the malignant diseases. The survival of the patients was compared with that of the general population.

RESULTS--Thirteen (4.3%) patients with dermatitis herpetiformis developed 14 malignant disorders during the follow up (SIR 1.25; 95% confidence intervals 0.68 to 2.09). A non-Hodgkin's lymphoma occurred in four patients with dermatitis herpetiformis, significantly more than expected (SIR 10.3; 2.8-26.3). Thirteen (4.3%) patients with dermatitis herpetiformis died during the follow up but there was no increased general mortality. In coeliac disease, 13 (3.4%) patients developed malignancy (SIR 1.16; 0.62 to 1.97), 31 (8.1%) patients died but the survival rate did not differ from that in the general population.

CONCLUSIONS--The incidence of non-Hodgkin's lymphoma was significantly increased in patients with dermatitis herpetiformis. The results also confirm that the patients with dermatitis herpetiformis treated mainly with a gluten free diet have no increased general mortality.

TREATMENT

DAPSONE

The incidence of agranulocytosis during treatment of dermatitis herpetiformis with dapsone as reported in Sweden, 1972 through 1988.

Hornsten P, Keisu M, Wiholm BE.

Department of Hematology, University Hospital, Umea, Sweden.
Arch Dermatol 1990 Jul;126(7):919-22 Abstract quote
During the 17-year period 1972 through 1988, a total of seven cases of agranulocytosis associated with the use of dapsone for the treatment of dermatitis herpetiformis were reported in Sweden. The median age of the patients involved was 61 years; three of them were male. The median duration of dapsone treatment was 7 weeks and the daily prescribed dose was 100 mg. Based on sales and prescription data, the crude relative risk of agranulocytosis during dapsone treatment of dermatitis herpetiformis was 50, and the total risk was one case per 3000 patient years of exposure to dapsone.

In relation to the number of new cases of dermatitis herpetiformis, agranulocytosis was estimated to develop in 1 of 240 to 425 patients receiving dapsone therapy. Patients should be instructed to seek medical care immediately in case of fever.

DIET-GLUTEN FREE

Dietary treatment of dermatitis herpetiformis.

Andersson H, Mobacken H.

Department of Clinical Nutrition, University of Goteborg, Sahlgrenska Hospital, Gothenburg, Sweden.
Eur J Clin Nutr 1992 May;46(5):309-15 Abstract quote
Essentially all patients with dermatitis herpetiformis (DH) and dermal granular IgA deposits have a gluten-sensitive enteropathy as seen in coeliac disease. A gluten-free diet would normally restore mucosal morphology within months. The dapsone medication required to suppress the skin lesions could be gradually reduced and/or finally discontinued in most patients if they constantly adhere to the diet. The immunological reactions may also be reduced. The gluten-free diet could thus be successful both concerning manifestations from the skin and the gut.

Although well known in dermatological literature, diet therapy in DH has attracted little interest in journals of nutrition. A survey of this causal diet therapy for the disease therefore seems appropriate.

25 years' experience of a gluten-free diet in the treatment of dermatitis herpetiformis.

Garioch JJ, Lewis HM, Sargent SA, Leonard JN, Fry L.

Department of Dermatology, St Mary's Hospital, London, U.K.
Br J Dermatol 1994 Oct;131(4):541-5 Abstract quote
Gluten-free diets have been used in the treatment of patients with dermatitis herpetiformis in our department since 1967. Of the 212 patients with dermatitis herpetiformis attending between 1967 and 1992, 133 managed to take the diet, and 78 of these achieved complete control of their rash by diet alone. Of the remaining 55 patients taking a gluten-free diet, all but three were taking partial diets; over half of these patients managed to substantially reduce the dose of medication required. Of the 77 patients taking a normal diet, eight entered spontaneous remission, giving a remission rate of 10%; a further two patients who had been taking gluten-free diets were found to have remitted when they resumed normal diets. Loss of IgA from the skin was observed in 10 of 41 (24%) patients taking strict gluten-free diets. These patients had been taking their diets for an average of 13 years (range 5-24 years), and their rash had been controlled by diet alone for an average of 10 years (range 3-16 years).

The advantages of a gluten-free diet in the management of patients with dermatitis herpetiformis are: (i) the need for medication is reduced or abolished; (ii) there is resolution of the enteropathy, and (iii) patients experience a feeling of well-being after commencing the diet. Thus, we propose that a gluten-free diet is the most appropriate treatment for patients with dermatitis herpetiformis.

Wheat starch-containing gluten-free flour products in the treatment of coeliac disease and dermatitis herpetiformis. A long-term follow-up study.

Kaukinen K, Collin P, Holm K, Rantala I, Vuolteenaho N, Reunala T, Maki M.

Dept. of Medicine, Tampere University Hospital, Finland.
Scand J Gastroenterol 1999 Feb;34(2):163-9 Abstract quote
BACKGROUND: We investigated whether wheat starch-based gluten-free products are safe in the treatment of gluten intolerance.

METHODS: The study involved 41 children and adults with coeliac disease and 11 adults with dermatitis herpetiformis adhering to a gluten-free diet for 8 years on average. Thirty-five newly diagnosed coeliac patients at diagnosis and 6 to 24 months after the start of a gluten-free diet and 27 non-coeliac patients with dyspepsia were investigated for comparison. Daily dietary gluten and wheat starch intake were calculated. Small-bowel mucosal villous architecture, CD3+, alphabeta+, and gammadelta+ intraepithelial lymphocytes, mucosal HLA-DR expression, and serum endomysial, reticulin, and gliadin antibodies were investigated.

RESULTS: Forty of 52 long-term-treated patients adhered to a strict wheat starch-based diet and 6 to a strict naturally gluten-free diet; 6 patients had dietary lapses. In the 46 patients on a strict diet the villous architecture, enterocyte height, and density of alphabeta+ intraepithelial lymphocytes were similar to those in non-coeliac subjects and better than in short-term-treated coeliac patients. The density of gammadelta(+)cells was higher, but they seemed to decrease over time with the gluten-free diet. Wheat starch-based gluten-free flour products did not cause aberrant upregulation of mucosal HLA-DR. The mucosal integrity was not dependent on the daily intake of wheat starch in all patients on a strict diet, whereas two of the six patients with dietary lapses had villous atrophy and positive serology.

CONCLUSION: Wheat starch-based gluten-free flour products were not harmful in the treatment of coeliac disease and dermatitis herpetiformis.

Sulphamethoxypyridazine

Sulphamethoxypyridazine for dermatitis herpetiformis, linear IgA disease and cicatricial pemphigoid.

McFadden JP, Leonard JN, Powles AV, Rutman AJ, Fry L.

Department of Dermatology, St Mary's Hospital, London, U.K.
Br J Dermatol 1989 Dec;121(6):759-62 Abstract quote
One-hundred and sixty-eight cases of dermatitis herpetiformis were reviewed to compare the clinical response to and incidence of side-effects from dapsone and sulphamethoxypyridazine.

Thirty-seven received sulphamethoxypyridazine (0.25-1.5 g/day) as a single agent therapy at some stage during their care and 161 had dapsone only (50-450 mg/day). Thirty of these patients received both drugs, but at different times. Both were highly effective in controlling the skin disease in 97% of patients on dapsone and 89% on sulphamethoxypyridazine. While 36 (22%) of dapsone-treated subjects had intolerable side effects warranting a change in therapy, this occurred in only five (13.5%) of those treated with sulphamethoxypyridazine.

Sulphamethoxypyridazine was also effective as a single agent in three patients with linear IgA disease who had suffered adverse effects from dapsone, and in 10 out of 15 patients with oral and cutaneous lesions of cicatricial pemphigoid.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Commonly Used Terms

Collagen VII-Collagen variant present in the skin basement membrane within the anchoring fibrils.

Salt split skin assay-Normal skin incubated with 1M NaCl which separates the epidermis from dermis. The epidermal half contains the upper lamina lucida, hemidesmosomes, and BP antigen. The dermal half contains laminin 5, lamina densa, and anchoring fibrils.

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LABORATORY/ RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
LABORATORY MARKERS
Tissue transglutaminase and endomysial antibodies-diagnostic markers of gluten-sensitive enteropathy in dermatitis herpetiformis. Kumar V, Jarzabek-Chorzelska M, Sulej J, Rajadhyaksha M, Jablonska S. IMMCO Diagnostics, Inc., Buffalo, New York, 14228, USA.	Clin Immunol 2001 Mar;98(3):378-82 Abstract quote The association of Durhing's disease, commonly referred to as dermatitis herpetiformis (DH), with gluten-sensitive enteropathy (GSE) is supported by the presence of villous atrophy and endomysial antibodies (EMA). EMA are found to be a marker of GSE both in celiac disease (CD) and in DH. Since tissue transglutaminase (tTG) is believed to be the major autoantigen in GSE, the aim of our study was to determine the specificity and sensitivity of anti-tTG antibody ELISA compared to the EMA indirect immunofluorescence test. We studied 44 cases of DH, confirmed by the presence of IgA immune deposits in the dermal papillae, and 58 cases of CD conforming to the International Criteria of Diagnosing CD. The control group comprised 161 sera from patients with vesiculobullous disorders other than DH and 106 sera from normal healthy blood donors. Anti-tTG antibodies were detected in 36 of 44 DH (79%) and in 32 of 58 CD (55%) patients. EMA were positive in 33 of 44 DH (74%) and in 36 of 58 CD (62%) patients. Both the EMA and the antibodies to tTG were present in the majority of patients with DH and CD when they were on a normal gluten-containing diet and were absent when on a gluten-free diet for an extended period of time. There were, however, small discrepancies in positivity and negativity in tTG antibody-positive and EMA-negative patients and vice versa. There seems to be a correlation between the EMA titers and the anti-tTG antibody levels. This study confirms the high specificity and sensitivity of anti-tTG antibody ELISA for GSE and its strong correlation with EMA both in CD and in DH. The results of anti-tTG antibody and EMA assays were comparable; however, in DH, tTG was somewhat more sensitive than the EMA test. For screening of DH, it is advisable to perform both EMA and anti-tTG antibody tests.
Serum eosinophil cationic protein, myeloperoxidase, tryptase, eotaxin and Th2-L-like cytokines in Dermatitis herpetiformis. Caproni M, Cardinali C, D'Agata A, Selvaggi W, Fabbri P. Department of Dermatological Sciences, University of Florence, Italy.	Int Arch Allergy Immunol 2002 May;128(1):67-72 Abstract quote BACKGROUND: Dermatitis herpetiformis (DH) is a subepidermal bullous disease characterized by a neutrophilic and eosinophilic infiltrate, together with activated lymphocytes that show preferential polarization towards the Th2-like phenotype. To date, the role of neither soluble mediators, such as cytokines, nor serum levels of myeloperoxidase (MPO), eosinophil cationic protein (ECP) and tryptase (TRY) have been studied in the peripheral blood of DH. In this study we investigated 40 DH subjects for possible alterations in MPO, ECP, TRY, eotaxin, interleukin (IL) 4 and IL-5 concentrations to evaluate the role of neutrophils, eosinophils and mast cells in the induction of skin lesions. Sera from 20 healthy subjects were tested as controls. METHODS: Eotaxin, IL-4 and IL-5 serum contents were determined by a solid-phase enzyme-linked immunosorbent assay. A double antibody radioimmunoassay was used to measure serum levels of MPO, ECP and TRY. Results: Normal levels of eotaxin and IL-4 were found in all DH subjects; increased IL-5 levels were found only in 1 subject. The MPO levels were significantly higher in DH subjects than in healthy controls (p < 0.01). There was also a significant difference between the serum ECP levels of DH and healthy controls (p < 0.05). TRY was not revealed in the serum of DH subjects. CONCLUSIONS: The determination of Th2-like cytokines and TRY serum levels is not important in quantifying the involvement of activated lymphocytes and mast cells in DH; however, the finding of high MPO and ECP serum levels seems to confirm that these products are good markers of the presence of activated neutrophils and eosinophils.
Levels of F1+2 prothrombin fragments and thrombin D antithrombin III (TAT) complexes in patients with dermatitis herpetiformis. Wankiewicz A, Iwan-Zietek I, Gwiezdzinski Z, Kotschy M. Chair and Clinic of Dermatology, Medical University of Bydgoszcz, Poland.	Med Sci Monit 2002 Aug;8(8):BR324-7 Abstract quote BACKGROUND: Dermatitis herpetiformis (DH) is a rare bullous disease of autoimmune etiology. It is an intestinocutaneous syndrome, in which vesicopapular cutaneous lesions are accompanied by gluten-dependent enteropathy. The diagnosis of DH is based on immunopathological investigation of unaffected skin fragment (granular IgA deposits present at the tops of dermal papillae and IgA - EmA present in the serum). MATERIAL/METHODS: The studied group consisted of 33 patients with dermatitis herpetiformis - 23 males and 10 females aged 22-78 (mean age 44.7). In all the patients, the following parameters of blood coagulation systems were determined in the plasma Levels of prothrombin fragments 1+2 (F1+2), levels of thrombin - antithrombin III (TAT) complexes, antithrombin III activity (AT III). RESULTS: In patients with dermatitis herpetiformis, the main level of F1+2 fragments amounted to 9.08 nmol/l, as compared with 1.14 nmol/l in the control group (the difference statistically significant, p<0.0001). In DH patients, the levels of TAT complexes were over twice higher than among the controls and that difference also reached statistical significance (p<0.0001). Mean antithrombin III activity (AT III) in patients with DH reached 102.60% and was similar to that observed in the control group (104.68%). CONCLUSIONS: In patients with dermatitis herpetiformis, increased levels of F1+2 prothrombin fragments and TAT complexes indicate enhanced in vivo thrombinogenesis. No statistically significant differences of F1+2, TAT and AT III levels in DH patients related to their sex, age and duration of the disease were observed

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
Iodine and gliadin challenge on oral mucosa in dermatitis herpetiformis. Patinen P, Hietane J, Malmstrom M, Reunala T, Savilahti E. Department of Oral Surgery, Institute of Dentistry, University of Helsinki, Tampere, Finland.	Acta Derm Venereol 2002;82(2):86-9 Abstract quote Oral lesions and mucosal inflammatory changes may appear in dermatitis herpetiformis (DH). We examined whether potassium iodine, known to initiate blisters in the DH skin, or wheat gliadin, responsible for T-cell-dependent intestinal damage, can induce visible or microscopic changes in oral mucosa. Six patients with active DH were challenged with crude gliadin and 50% potassium iodine applied in patch test chambers on buccal mucosa for 12 h. After reading, biopsies were taken from the challenged and non-challenged mucosa. No macroscopic or microscopic vesicles were seen. However, gliadin- but not iodine-challenged epithelium showed increased numbers of CD4+ lymphocytes in all 5 patients with representative specimens (p = 0.06). No marked changes were found in the numbers of CD8+ or TcR alpha/beta+ lymphocytes, and the numbers of TcR gamma/delta+ cells remained at a low level. The results show that oral mucosa is resistant to production of macroscopic or microscopic DH lesions. It is, however, capable of reacting to locally applied gliadin by a T-cell response consisting of CD4+ lymphocytes.
VARIANTS
CHILDHOOD
Childhood dermatitis herpetiformis. Review of the new aspects and report of a case. Safai B, Rappaport I, Matsuoka L, Sogn D, Haines K, Lewin M.	J Am Acad Dermatol 1981 Apr;4(4):435-41 Abstract quote Dermatitis herpetiformis (DH) of linear IgA type occurred in a 6-month-old boy shortly after initiating sulfisoxazole therapy for a urinary tract infection. Generalized pruritic bullae on erythematous bases were present on his trunk and extremities. There were no clinical or laboratory findings suggestive of gastrointestinal involvement. Direct immunofluorescent studies of skin biopsies taken early in the course of the disease and while the child was on systemic corticosteroid therapy were negative. Eventually a linear deposition of IgA at the dermoepidermal junction of involved skin on direct immunofluorescence was demonstrated. No circulating antibodies to the basement membrane were found. Because of close proximity of the initiation of sulfisoxazole (Gantrisin) therapy and the eruption of the initial bullous lesions, this case also presents an interesting diagnostic and therapeutic problem. Negative assays of lymphocyte migration inhibition factor (LMIF) to sulfisoxazole indicated that the likelihood of a hypersensitivity reaction to sulfa drugs was slight. The patient's clinical response to dapsone therapy was dramatic. The conflicting views of subepidermal bullous dermatosis of childhood and the difficulties in confirming a diagnosis of DH are discussed. We contend that when DH is suspected in children, various laboratory tests should be repeated several times before the diagnosis can be confirmed. The case presented here is the youngest child reported with this type of DH.
PALMAR PETECHIAE
Palmar purpura: an atypical presentation of childhood dermatitis herpetiformis. McGovern TW, Bennion SD. Dermatology Service, Fitzsimons Army Medical Center, Aurora, Colorado 80045.	Pediatr Dermatol 1994 Dec;11(4):319-22 Abstract quote Dermatitis herpetiformis (DH) is seen most commonly as a pruritic, papulovesicular eruption in young children or adolescents. Differentiation from other bullous diseases of childhood may be difficult. We report the first case of an adolescent in whom pruritic, palmar, purpuric macules and papules were the only manifestations of DH. The patient later developed typical vesiculobullous extensor lesions and symptomatic gluten-sensitive enteropathy (GSE). All lesions and GSE symptoms resolved with dapsone and a gluten-free diet. Our purpose is to illustrate an unusual presentation of pediatric DH.
TWINS
Concordance of dermatitis herpetiformis and celiac disease in monozygous twins. Hervonen K, Karell K, Holopainen P, Collin P, Partanen J, Reunala T. Department of Dermatology, University Hospital of Tampere, Tampere, Finland.	J Invest Dermatol 2000 Dec;115(6):990-3 Abstract quote Celiac disease can be defined as the classical manifestation of gluten sensitivity, which primarily affects the small intestine. Gluten sensitivity has also a skin manifestation, i.e., dermatitis herpetiformis. Both diseases have a strong genetic association with HLA DQ on chromosome 6. In this study we tried to estimate how much different clinical expressions of gluten sensitivity are determined by genetic factors, and hence how feasible they are for genetic mapping; therefore, we studied all six monozygous twin pairs found among 1292 prospectively collected patients of dermatitis herpetiformis in Finland. Three of the six twin pairs were concordant for dermatitis herpetiformis and for simultaneous enteropathy, celiac disease. Two other twin pairs were partially discordant, one of each pair had dermatitis herpetiformis and celiac disease, whereas the other had solely the gut manifestation of gluten sensitivity, i.e., celiac disease. Only one pair was found to be discordant for gluten sensitivity. All the pairs had typical risk alleles for gluten sensitivity, i.e., either HLA DQ2 or DQ8. These results demonstrate that the genetic component in gluten sensitivity as broadly defined is very strong (5/6 concordant). Genetically identical individuals can have clearly distinguished phenotypes, either dermatitis herpetiformis or celiac disease, suggesting that environmental factors determine the exact phenotype of this multifactorial disease. These findings are of importance in genetic linkage analyses, which focus to only certain phenotypic properties of a complex trait.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
Malignancy and survival in dermatitis herpetiformis: a comparison with coeliac disease. Collin P, Pukkala E, Reunala T. Medical School, University of Tampere, Finland.	Gut 1996 Apr;38(4):528-30 Abstract quote BACKGROUND--Dermatitis herpetiformis is a lifelong, gluten sensitive skin disease. Patients with dermatitis herpetiformis, similar to patients with coeliac disease not adhering to a gluten free diet, seem to have increased risk for lymphoma. AIMS--This study looked at the occurrence of malignancy and survival of patients with dermatitis herpetiformis and compared the results with those seen in patients with coeliac disease or in the general population. PATIENTS--A total of 305 adult patients with dermatitis herpetiformis diagnosed at the University Hospital of Tampere in 1970-1992 were studied. Most patients started a gluten free diet and at the end of the study 93% of the patients were adhering to the diet. A control group comprised 383 adult patients with coeliac disease, 81% of them adhered to a gluten free diet, 6% had a normal diet, and in 13% the diet history remained unknown. METHODS--The occurrence of malignant diseases and survival of the patients were assessed up to the end of 1993. Standardised incidence ratios (SIR) with 95% confidence intervals were used for the malignant diseases. The survival of the patients was compared with that of the general population. RESULTS--Thirteen (4.3%) patients with dermatitis herpetiformis developed 14 malignant disorders during the follow up (SIR 1.25; 95% confidence intervals 0.68 to 2.09). A non-Hodgkin's lymphoma occurred in four patients with dermatitis herpetiformis, significantly more than expected (SIR 10.3; 2.8-26.3). Thirteen (4.3%) patients with dermatitis herpetiformis died during the follow up but there was no increased general mortality. In coeliac disease, 13 (3.4%) patients developed malignancy (SIR 1.16; 0.62 to 1.97), 31 (8.1%) patients died but the survival rate did not differ from that in the general population. CONCLUSIONS--The incidence of non-Hodgkin's lymphoma was significantly increased in patients with dermatitis herpetiformis. The results also confirm that the patients with dermatitis herpetiformis treated mainly with a gluten free diet have no increased general mortality.
TREATMENT
DAPSONE
The incidence of agranulocytosis during treatment of dermatitis herpetiformis with dapsone as reported in Sweden, 1972 through 1988. Hornsten P, Keisu M, Wiholm BE. Department of Hematology, University Hospital, Umea, Sweden.	Arch Dermatol 1990 Jul;126(7):919-22 Abstract quote During the 17-year period 1972 through 1988, a total of seven cases of agranulocytosis associated with the use of dapsone for the treatment of dermatitis herpetiformis were reported in Sweden. The median age of the patients involved was 61 years; three of them were male. The median duration of dapsone treatment was 7 weeks and the daily prescribed dose was 100 mg. Based on sales and prescription data, the crude relative risk of agranulocytosis during dapsone treatment of dermatitis herpetiformis was 50, and the total risk was one case per 3000 patient years of exposure to dapsone. In relation to the number of new cases of dermatitis herpetiformis, agranulocytosis was estimated to develop in 1 of 240 to 425 patients receiving dapsone therapy. Patients should be instructed to seek medical care immediately in case of fever.
DIET-GLUTEN FREE
Dietary treatment of dermatitis herpetiformis. Andersson H, Mobacken H. Department of Clinical Nutrition, University of Goteborg, Sahlgrenska Hospital, Gothenburg, Sweden.	Eur J Clin Nutr 1992 May;46(5):309-15 Abstract quote Essentially all patients with dermatitis herpetiformis (DH) and dermal granular IgA deposits have a gluten-sensitive enteropathy as seen in coeliac disease. A gluten-free diet would normally restore mucosal morphology within months. The dapsone medication required to suppress the skin lesions could be gradually reduced and/or finally discontinued in most patients if they constantly adhere to the diet. The immunological reactions may also be reduced. The gluten-free diet could thus be successful both concerning manifestations from the skin and the gut. Although well known in dermatological literature, diet therapy in DH has attracted little interest in journals of nutrition. A survey of this causal diet therapy for the disease therefore seems appropriate.
25 years' experience of a gluten-free diet in the treatment of dermatitis herpetiformis. Garioch JJ, Lewis HM, Sargent SA, Leonard JN, Fry L. Department of Dermatology, St Mary's Hospital, London, U.K.	Br J Dermatol 1994 Oct;131(4):541-5 Abstract quote Gluten-free diets have been used in the treatment of patients with dermatitis herpetiformis in our department since 1967. Of the 212 patients with dermatitis herpetiformis attending between 1967 and 1992, 133 managed to take the diet, and 78 of these achieved complete control of their rash by diet alone. Of the remaining 55 patients taking a gluten-free diet, all but three were taking partial diets; over half of these patients managed to substantially reduce the dose of medication required. Of the 77 patients taking a normal diet, eight entered spontaneous remission, giving a remission rate of 10%; a further two patients who had been taking gluten-free diets were found to have remitted when they resumed normal diets. Loss of IgA from the skin was observed in 10 of 41 (24%) patients taking strict gluten-free diets. These patients had been taking their diets for an average of 13 years (range 5-24 years), and their rash had been controlled by diet alone for an average of 10 years (range 3-16 years). The advantages of a gluten-free diet in the management of patients with dermatitis herpetiformis are: (i) the need for medication is reduced or abolished; (ii) there is resolution of the enteropathy, and (iii) patients experience a feeling of well-being after commencing the diet. Thus, we propose that a gluten-free diet is the most appropriate treatment for patients with dermatitis herpetiformis.
Wheat starch-containing gluten-free flour products in the treatment of coeliac disease and dermatitis herpetiformis. A long-term follow-up study. Kaukinen K, Collin P, Holm K, Rantala I, Vuolteenaho N, Reunala T, Maki M. Dept. of Medicine, Tampere University Hospital, Finland.	Scand J Gastroenterol 1999 Feb;34(2):163-9 Abstract quote BACKGROUND: We investigated whether wheat starch-based gluten-free products are safe in the treatment of gluten intolerance. METHODS: The study involved 41 children and adults with coeliac disease and 11 adults with dermatitis herpetiformis adhering to a gluten-free diet for 8 years on average. Thirty-five newly diagnosed coeliac patients at diagnosis and 6 to 24 months after the start of a gluten-free diet and 27 non-coeliac patients with dyspepsia were investigated for comparison. Daily dietary gluten and wheat starch intake were calculated. Small-bowel mucosal villous architecture, CD3+, alphabeta+, and gammadelta+ intraepithelial lymphocytes, mucosal HLA-DR expression, and serum endomysial, reticulin, and gliadin antibodies were investigated. RESULTS: Forty of 52 long-term-treated patients adhered to a strict wheat starch-based diet and 6 to a strict naturally gluten-free diet; 6 patients had dietary lapses. In the 46 patients on a strict diet the villous architecture, enterocyte height, and density of alphabeta+ intraepithelial lymphocytes were similar to those in non-coeliac subjects and better than in short-term-treated coeliac patients. The density of gammadelta(+)cells was higher, but they seemed to decrease over time with the gluten-free diet. Wheat starch-based gluten-free flour products did not cause aberrant upregulation of mucosal HLA-DR. The mucosal integrity was not dependent on the daily intake of wheat starch in all patients on a strict diet, whereas two of the six patients with dietary lapses had villous atrophy and positive serology. CONCLUSION: Wheat starch-based gluten-free flour products were not harmful in the treatment of coeliac disease and dermatitis herpetiformis.
Sulphamethoxypyridazine
Sulphamethoxypyridazine for dermatitis herpetiformis, linear IgA disease and cicatricial pemphigoid. McFadden JP, Leonard JN, Powles AV, Rutman AJ, Fry L. Department of Dermatology, St Mary's Hospital, London, U.K.	Br J Dermatol 1989 Dec;121(6):759-62 Abstract quote One-hundred and sixty-eight cases of dermatitis herpetiformis were reviewed to compare the clinical response to and incidence of side-effects from dapsone and sulphamethoxypyridazine. Thirty-seven received sulphamethoxypyridazine (0.25-1.5 g/day) as a single agent therapy at some stage during their care and 161 had dapsone only (50-450 mg/day). Thirty of these patients received both drugs, but at different times. Both were highly effective in controlling the skin disease in 97% of patients on dapsone and 89% on sulphamethoxypyridazine. While 36 (22%) of dapsone-treated subjects had intolerable side effects warranting a change in therapy, this occurred in only five (13.5%) of those treated with sulphamethoxypyridazine. Sulphamethoxypyridazine was also effective as a single agent in three patients with linear IgA disease who had suffered adverse effects from dapsone, and in 10 out of 15 patients with oral and cutaneous lesions of cicatricial pemphigoid.

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/ Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms
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EPIDEMIOLOGY	CHARACTERIZATION
GEOGRAPHY
JAPAN
Dermatitis herpetiformis in Japan: an update. Shibahara M, Nanko H, Shimizu M, Kanda N, Kubo M, Ikeda M, Matsumoto M, Nonaka S, Shimizu H. Department of Dermatology, Tokyo Kousei-Nenkin Hospital, Tokyo, Japan.	Dermatology 2002;204(1):37-42 Abstract quote BACKGROUND: Although dermatitis herpetiformis (DH) is a relatively common disease in Caucasian populations, it is rare in Asian populations including the Japanese. We encountered a Japanese case of DH which showed granular IgA and C3 deposits in the papillary dermis and which was associated with gluten-sensitive enteropathy but no HLA-B8/DR3/DQ2. OBJECTIVE: The purpose of this study is to describe the characteristics of Japanese DH cases, since most of them have been reported in Japanese language and dermatologists outside Japan are not familiar with the characteristics of Japanese DH. METHODS: We have reviewed all 34 Japanese DH cases reported previously. RESULTS: We found several features of Japanese DH compared with Caucasian DH, such as a high frequency of the fibrillar pattern, rarity of gluten-sensitive enteropathy and an absence of the HLA-B8/DR3/DQ2 haplotype. CONCLUSION: There might be significant differences in pathophysiology between Caucasian and Japanese DH cases.

DISEASE ASSOCIATIONS	CHARACTERIZATION
BULLOUS PEMPHIGOID
Dermatitis herpetiformis evolving into bullous pemphigoid: a probable example of 'epitope spreading'. Ameen M, Bhogal BS, Black MM. St. John's Institute of Dermatology, St. Thomas' Hospital, London, UK.	Clin Exp Dermatol 2000 Jul;25(5):398-400 Abstract quote We report a case of dermatitis herpetiformis which, 11 years after its original diagnosis, evolved into bullous pemphigoid. Only a few similar cases supported by immunofluorescence studies have been reported previously, and we believe that they represent examples of 'epitope spreading', an increasingly recognized phenomenon used to explain the coexistence of autoimmune diseases.
CELIAC DISEASE
NEUROLOGICAL SYMPTOMS
Dermatitis herpetiformis and neurological dysfunction. Wills AJ, Turner B, Lock RJ, Johnston SL, Unsworth DJ, Fry L. Department of Neurology, Queen's Medical Centre, Nottingham, UK.	J Neurol Neurosurg Psychiatry 2002 Feb;72(2):259-61 Abstract quote Dermatitis herpetiformis and coeliac disease are gluten sensitive diseases, which have common immunopathological and genetic mechanisms. Neuropsychiatric complications have been reported in up to 26% of patients with coeliac disease. This is probably an overestimate, because of the chance associations with some common neurological conditions such as epilepsy. The pathogenesis is speculative but it has been postulated that gluten is neurotoxic possibly via immune mechanisms. The frequency of neurological dysfunction in patients with dermatitis herpetiformis has not been characterised. Patients with dermatitis herpetiformis might be expected to be particularly susceptible to neuronal damage as some continue to consume gluten when their dermatological symptoms are controlled by dapsone. Thirty five patients were recruited with dermatitis herpetiformis from dermatology clinics at St Mary's Hospital, London and Queen's Medical Centre, Nottingham and investigated for evidence of neurological abnormality. All patients underwent a full neurological examination and were asked about their neurological and general medical history by means of a structured questionnaire. Serum samples were taken and screened for the presence of anti-neuronal antibodies (anti-Hu and Yo) as well as anti-gliadin (IgA and G) anti-endomysial (IgA), and anti-tissue transglutaminase (IgA) antibodies. Neurophysiological tests were carried out where appropriate. Only two patients were identified with unexplained neurological abnormalities (one essential tremor, and one chorea). Two other patients had a history of migraine. The patient with chorea also had borderline/equivocally positive anti-Hu antibodies by immunofluorescence assay. All other samples were negative for anti-neuronal antibodies. Fifteen patients were positive for anti-gliadin antibodies (IgA and/or IgG), four for anti-endomysial antibodies (monkey oesophagus or umbilical cord), and six for anti-tissue transglutaminase antibodies. The presence of these antibodies did not correlate with the presence of neurological abnormalities. No cases of "gluten ataxia" were identified. In conclusion, there was no convincing evidence for immune mediated neurological damage in this pilot study of dermatitis herpetiformis.
VITILIGO
Dermatitis herpetiformis and vitiligo: report of a case and review of the literature. Amato L, Gallerani I, Fuligni A, Mei S, Fabbri P. Department of Dermatology, University of Florence, Italy.	J Dermatol 2000 Jul;27(7):462-6 Abstract quote We describe the case of a 53-year-old woman presenting papulous and papulovesicular lesions that were highly pruritic, localized mostly in the achromic areas of vitiligo and symmetrically distributed on the elbows, the buttocks, the shoulders and the neck. The histopathological examination performed on the elbow's lesional skin showed the presence of neutrophils and fibrin microabscesses at the tips of dermal papillae, with a few eosinophils, and small separations between the dermis and epidermis just over the infiltrate. The overlying epidermis was uninjured. The performed tests detected IgA anti-endomysium, anti-thyrogloblin, anti-smooth muscle and anti-microsomal fraction autoantibodies; DIF showed the presence of IgA granular deposits at the dermo-epidermal junction, prevalently at the tips of dermal papillae. This is the tenth case reported of an association between dermatitis herpetiformis and vitiligo. Although the two disorders both have immunological pathogeneses, we think that the topographic coexistence of both disorders is coincidental.

PATHOGENESIS	CHARACTERIZATION
ANTI-ENDOMYSIAL ANTIBODIES
Comparison of IgA-class reticulin and endomysium antibodies in coeliac disease and dermatitis herpetiformis. Hallstrom O. Department of Clinical Microbiology and Immunology, University Central Hospital, Tampere, Finland.	Gut 1989 Sep;30(9):1225-32 Abstract quote The occurrence of IgA class reticulin and endomysium antibodies was examined with the standard immunofluorescence method in coeliac disease and dermatitis herpetiformis. Similar high antibody frequencies were detected in 32 untreated adults (91%) and 18 children (100%) with coeliac disease and in 14 dermatitis herpetiformis patients with subtotal villous atrophy (reticulin antibodies 93% and endomysium antibodies 100%). The specificity of IgA class reticulin antibodies and endomysium antibodies was high because all 45 adult patients with ulcerative colitis or Crohn's disease, 24 non-coeliac children with abdominal symptoms and 99/100 healthy blood donors were negative for these antibodies. The only positive blood donor had both IgA class reticulin antibodies and endomysium antibodies but also she was found to have coeliac disease. IgA class reticulin antibodies and endomysium antibodies declined in parallel during treatment with a gluten free diet and increased on gluten challenge. This suggests that these antibodies can be used to screen for gluten sensitive enteropathy and to monitor dietary treatment. To characterise the tissue specificity of reticulin antibodies and endomysium antibodies four positive sera were absorbed with human and several rodent liver homogenates. Absorption with rat or other rodent livers removed the rodent-specific reticulin antibodies but not the reticulin antibodies detectable with human tissues or the endomysium antibodies detectable with monkey oesophagus. These results show that reticulin antibodies can be divided into the rat and human subtypes. The human subtype could not be separated from endomysium antibodies in the present absorption experiments.
EPIDERMAL TRANSGLUTAMINASE 3
Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis. Sardy M, Karpati S, Merkl B, Paulsson M, Smyth N. Department of Dermato-Venereology, Semmelweis University, H-1085 Budapest, Maria u.41, Hungary.	J Exp Med 2002 Mar 18;195(6):747-57 Abstract quote Gluten sensitivity typically presents as celiac disease, a common chronic small intestinal disorder. However, in certain individuals it is associated with dermatitis herpetiformis, a blistering skin disease characterized by granular IgA deposits in the papillary dermis. While tissue transglutaminase has been implicated as the major autoantigen of gluten sensitive disease, there has been no explanation as to why this condition appears in two distinct forms. Here we show that while sera from patients with either form of gluten sensitive disease react both with tissue transglutaminase and the related enzyme epidermal (type 3) transglutaminase, antibodies in patients having dermatitis herpetiformis show a markedly higher avidity for epidermal transglutaminase. Further, these patients have an antibody population specific for this enzyme. We also show that the IgA precipitates in the papillary dermis of patients with dermatitis herpetiformis, the defining signs of the disease, contain epidermal transglutaminase, but not tissue transglutaminase or keratinocyte transglutaminase. These findings demonstrate that epidermal transglutaminase, rather than tissue transglutaminase, is the dominant autoantigen in dermatitis herpetiformis and explain why skin symptoms appear in a proportion of patients having gluten sensitive disease.

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
VARIANTS
Characterization of a subgroup of patients with dermatitis herpetiformis with nonclassical histologic features. Warren SJ, Cockerell CJ. Division of Dermatopathology, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A.	Am J Dermatopathol 2002 Aug;24(4):305-8 Abstract quote Dermatitis herpetiformis (DH) is an autoimmune disease mediated by IgA antibodies. The diagnosis of DH is based on clinical presentation, biopsy for hematoxylin and eosin, and direct immunofluorescence. The chief hematoxylin and eosin finding is a subepithelial blister with neutrophils in dermal papillae. The direct immunofluorescence findings are deposition of IgA and sometimes C3 at the basement membrane with accentuation in dermal papillae. Immunofluorescence is thought to be a sensitive and specific assay in DH, and there are no other known diseases with this pattern of immunofluorescence. The aim of this project was to determine the prevalence of nonclassical histologic findings in DH. We studied 24 cases of DH received at our institution. All cases had clinical findings of DH as well as positive direct immunofluorescence with IgA. We found that 9 of 24 cases (37.5%) had nonspecific H&E findings of a lymphocytic infiltrate only with fibrosis in the dermal papillae and ectatic capillaries. The remaining 15 cases had classic findings of multilocular neutrophilic microabscesses in the dermal papillae. These findings were reproduced on step sectioning. These findings suggest that routine histology may be quite nonspecific in DH and direct immunofluorescence or other more specific immunologic assay is an essential adjunct to diagnosis.

SPECIAL STAINS/ IMMUNOPEROXIDASE/ OTHER	CHARACTERIZATION
SPECIAL STAINS
IMMUNOPEROXIDASE
DIRECT IMMUNOFLUORESCENCE
A case of dermatitis herpetiformis with IgA endomysial antibodies but negative direct immunofluorescent findings. Beutner EH, Baughman RD, Austin BM, Plunkett RW, Binder WL. Beutner Laboratories and the Department of Microbiology and Dermatology, State University of New York at Buffalo, Buffalo, New York, USA.\	J Am Acad Dermatol 2000 Aug;43(2 Pt 2):329-32 Abstract quote A patient with clinical findings of dermatitis herpetiformis (DH), negative direct immunofluorescent (DIF) findings for junctional IgA deposits in 2 biopsy specimens, and positive for IgA endomysial (AEmA) and tissue transglutaminase (tTG) antibodies responded initially to dapsone. After dapsone had to be discontinued because of side effects, a gluten-free diet and supportive therapy controlled the disease; the AEmA and tTG antibodies became negative. Our data on 10 consecutive DH cases examined by DIF and by serum studies for AEmA and antibodies to tTG, point to frequencies of 90% DIF positive and 70% AEmA and tTG positive cases. The use of both DIF and serum tests for AEmA and tTG reveals DH cases not detected by DIF alone that respond to gluten-free diet. Findings on autoantibodies to tTG, an enzyme that metabolizes gliadin, points to a role of tTG in the immunopathology of gluten-sensitive enteropathy and helps to explain the need for a gluten-free diet in the management of DH cases.

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
LINEAR IgA DISEASE