Approach

Consider the diagnosis of dermatitis herpetiformis in any patient with a history of a chronic, recurrent, symmetric, polymorphic, and highly pruritic vesicular skin eruption distributed in typical areas, such as the elbows, knees, shoulders, scalp, and buttocks.[2][3][11][16] Due to the extreme pruritus, the primary vesicular lesions may be masked by less specific manifestations, such as excoriations, erosions, and crusts.[2]

The most common differential diagnoses to rule out include:[2]

  • Atopic dermatitis/eczema

  • Contact/irritant dermatitis

  • Multiple folliculitis

  • Prurigo nodularis/subacuta

  • Scabies

  • Arthropod bite reactions

  • Autoimmune bullous disease (e.g., linear immunoglobulin A [IgA] bullous dermatosis, bullous pemphigoid, pemphigus herpetiformis).

Dermatitis herpetiformis is confirmed by detection of granular IgA deposits at the tips of the dermal papillae or along the basement membrane zone with direct immunofluorescence microscopy.[2][3][11][16]

History

Take a detailed clinical history from the patient, including questioning regarding:[2]

  • Description of skin symptoms, including severity, location, timing, and duration, as well as how lesions have evolved over time

  • Involvement of the gastrointestinal system, such as existence of current gastrointestinal symptoms and gastrointestinal medical history (chronic or relapsing abdominal pain, nausea, diarrhoea, constipation, weight loss)

  • General medical history, including a history of autoimmune or immune-mediated associated diseases (e.g., pernicious anaemia, Hashimoto's thyroiditis, alopecia areata, Addison's disease, or type 1 diabetes mellitus)

  • Relevant family history, such as coeliac disease, dermatitis herpetiformis, or autoimmune conditions.

Dermatitis herpetiformis usually presents with pruritic lesions that are often preceded by a burning sensation.[2][3][11][17] Pruritus is a universal feature in all patients, which often deeply affects the patient's quality of life.

Skin lesions typically appear as grouped vesicles with a symmetric distribution, most often on extensor surfaces, such as elbows and knees, as well as the shoulders, scalp, back, and buttocks, most often in areas that are frequently exposed to mechanical forces.[2] Less commonly, the posterior nuchal area and/or the hairline may be affected.[2] Patients may also describe involvement of the mouth, such as a history of oral ulcers.[18]

Occasionally, dermatitis herpetiformis may occur with atypical cutaneous presentations, including palmar or plantar petechiae, or other rarer signs such as hyperkeratotic lesions of palms and soles, leukocytoclastic vasculitis-like lesions, and prurigo-like lesions.[19] Skin lesions usually heal without scarring, but can leave post-inflammatory hyperpigmentation. The disease has a chronic recurrent course, with exacerbations that may be followed by partial remissions of the lesions.

As dermatitis herpetiformis is a specific manifestation of coeliac disease, the condition does not typically present in people who are already on a gluten-free diet for coeliac disease. Around 15% to 20% of people with dermatitis herpetiformis show gastrointestinal symptoms resembling those of coeliac disease, such as diarrhoea, constipation, abdominal bloating or pain, and weight loss. However, most people with dermatitis herpetiformis have only mild gastrointestinal involvement or are asymptomatic.[2][11] See Coeliac disease.

Children may also present with malabsorption, iron deficiency, and reduced growth rates.[2]

Physical examination

Physical examination of patients with dermatitis herpetiformis reveals the presence of symmetric, grouped, polymorphic skin lesions including:[2][11][20]

  • Erythema

  • Vesicles

  • Blisters

  • Crusts

  • Urticarial plaques

  • Papules

  • Excoriation.

Lesions are usually distributed on typical areas such as the extensor surfaces of upper and lower limbs (mainly elbows [90% of patients] and knees [30% of patients]), buttocks, shoulders, and scalp.[2][8][11][20] Less commonly, the patient may have oral mucosa involvement (oral aphthous ulcers), or lesions affecting the posterior nuchal area, and/or the hairline.[2][18][20]

The primary vesicular lesions may in some cases be masked by less specific manifestations, such as excoriations, erosions, and crusts, due to the extensively pruritic nature of the condition.[2]

[Figure caption and citation for the preceding image starts]: Characteristic pruritic papulovesicular rash of dermatitis herpetiformis, affecting the elbowsCID - ISM/Science Photo Library; used with permission [Citation ends].com.bmj.content.model.Caption@240117a0[Figure caption and citation for the preceding image starts]: Characteristic pruritic papulovesicular rash of dermatitis herpetiformis, affecting back and buttocksScience Photo Library; used with permission [Citation ends].com.bmj.content.model.Caption@4b7ae02a[Figure caption and citation for the preceding image starts]: Aphthous ulcer: a less common manifestation of dermatitis herpetiformisFrom the collection of Dr Michaell A. Huber, UTHSCSA School of Dentistry; used with permission [Citation ends].com.bmj.content.model.Caption@3ddf005b

Dermatitis herpetiformis may present atypically, with signs including palmar or plantar petechiae, or rarer signs such as hyperkeratotic lesions of palms and soles, leukocytoclastic vasculitis-like lesions, and prurigo-like lesions.[19]

Skin lesions usually heal without scarring, but can leave post-inflammatory hyperpigmentation.[2]

Around 15% to 20% of patients with dermatitis herpetiformis show gastrointestinal symptoms typical of coeliac disease; these patients may also have signs of malabsorption, which include:[2]

  • Signs of anaemia (pallor, pale conjunctiva)

  • Evidence of weight loss

  • Abdominal distension

  • Peripheral oedema.

Initial investigations

Order the following investigations in a patient with suspected dermatitis herpetiformis:[2][11][20][21]

  • Skin biopsy of lesional skin for histopathological examination and of perilesional skin for direct immunofluorescence microscopy.

    • The optimal biopsy site is perilesional, uninvolved skin because direct immunofluorescence microscopy performed on lesional biopsies rather than perilesional skin often leads to false-negative results.[2][22]

  • Blood tests to detect immunoglobulin A-tissue transglutaminase (IgA-tTG), and if this is negative, test for the presence of endomysial antibody (EMA).

Direct immunofluorescence microscopy is the definitive investigation for the diagnosis of dermatitis herpetiformis and almost universally shows granular deposition of IgA at the tips of dermal papillae and/or along the dermal-epidermal junction.[2][11][16][20]

If a patient with high suspicion of dermatitis herpetiformis tests negative at direct immunofluorescence microscopy, request a repeat skin biopsy; false-negative results after repeated biopsies are very rare.[23]

Histopathological examination usually shows accumulation of neutrophils at the dermal papillae and a dermal-epidermal detachment; however, in about one third of patients, histopathological examination is not specific, showing only perivascular infiltration of lymphocytes.[24]

Use serological testing to aid the diagnosis, but it should not be used alone to diagnose the disease.[2]

  • IgA-tTG detected by enzyme-linked immunosorbent assay (ELISA) is present in up to 95% of patients and should be ordered as the initial serological test.[25]

Order EMA, detected by indirect immunofluorescence, if IgA-tTG antibody testing is negative.

  • EMA testing has a sensitivity ranging from 60% to 90%.[26][27][28]

However, these autoantibodies are specific for the diagnosis of coeliac disease rather than of dermatitis herpetiformis; moreover, up to 10% of patients with dermatitis herpetiformis do not have detectable autoantibodies.[7]

Other investigations

Order genetic testing for human leukocyte antigen (HLA)-DQ2 and HLA-DQ8 if dermatitis herpetiformis is not confirmed by initial investigations.[2][11][21]

  • This test cannot confirm the diagnosis, but a negative test can be used to rule out the condition in these patients due to its high negative predictive rate.[2]

  • The HLA-DQ2 and HLA-DQ8 haplotypes are present in 95% and 5%, respectively, of people with dermatitis herpetiformis.[10][11]

Perform a full blood count with or without ferritin levels to assess for anaemia in patients with confirmed dermatitis herpetiformis and to obtain baseline levels prior to commencement of treatment.[2] Patients with bowel involvement may have reduced haemoglobin levels and associated microcytic hypochromic red cells.

Consider referral for gastrological consultation once the diagnosis of dermatitis herpetiformis is confirmed to assess gastrointestinal status and for consideration of gastroscopy with duodenal biopsy (unless a diagnosis of coeliac disease has been confirmed).[2]

  • The majority of patients with dermatitis herpetiformis (up to 70%) have a mild enteropathy with mild villous atrophy; the remainder may show severe intestinal involvement or, in few cases, the presence of normal bowel mucosa.[15]

Also consider assessment for associated conditions such as:[2]

  • Thyroid disease

  • Malignancies (lymphoma and leukaemia)

  • Diabetes.

Other associated conditions to be aware of include Addison's disease, vitiligo, alopecia areata, and several other autoimmune diseases.[2][29]

Pitfalls in diagnosis

Although the diagnosis of dermatitis herpetiformis can easily be confirmed by direct immunofluorescence microscopy, clinical suspicion may not arise in the first instance due to the rarity of the condition as well as the polymorphic clinical appearance. This can lead to delays in diagnosis, with the condition often being overlooked in favour of more common skin diseases.

Moreover, if serological testing for IgA-tTG or EMA is performed before direct immunofluorescence microscopy and results are negative, the diagnosis of dermatitis herpetiformis may be wrongly excluded.

It is also worth noting that some patients with coeliac disease who have skin manifestations other than dermatitis herpetiformis (e.g., psoriasis, eczema, and granuloma annulare) may demonstrate granular IgA deposits in perilesional skin.[30] In these cases, misdiagnosis of dermatitis herpetiformis can occur.

It is important to give only symptomatic therapy until all diagnostic steps have been carried out, as gluten-free diet and dapsone treatment may modify diagnostic results.[2]

  • Gluten-free diet can alter the presence of granular IgA deposits detected by direct immunofluorescence microscopy.

  • Dapsone may clear clinical lesions, therefore making histology unreliable at confirming the diagnosis.

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