Dermatitis herpetiformis: clinical guidelines

List of Abbreviations

HLA (Human Leukocyte Antigens) II – human leukocyte antigens class II

Ig (Immunoglobulin) A — immunoglobulin class A

Terms and Definitions

Celiac disease (gluten enteropathy) is a multifactorial disorder, a digestive impairment caused by damage to the villi of the small intestine by certain foods containing specific proteins: gluten and related cereal proteins (avenin, hordein, etc.) in grains such as wheat, rye, and barley. It has a mixed autoimmune, allergic, and hereditary genesis, and is inherited in an autosomal dominant manner.

Gliadin is an alcohol-soluble glycoprotein derived from wheat, which is a component of gluten.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Dermatitis herpetiformis (dermatitis herpetiformis Duhring; Duhring's disease) — an inflammatory skin disease associated with gluten-sensitive enteropathy and characterized by polymorphic pruritic eruptions, a chronic relapsing course, and granular IgA deposition in the papillary dermis.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Dermatitis herpetiformis, like gluten-sensitive enteropathy, is associated with the HLA-DQ2 and HLA-DQ8 haplotypes [1, 2]. Approximately 5% of patients with celiac disease develop dermatitis herpetiformis [3, 4].

Potential mechanisms of dermatitis herpetiformis development in celiac disease:

• Following the ingestion and digestion of gluten-containing food, gliadin is absorbed through the small intestinal mucosa.

• Gliadin is deamidated by tissue transglutaminase in the small intestinal mucosa, forming covalent cross-links between gliadin and transglutaminase.

• Deamidated gliadin peptides bind to HLA-DQ2 or HLA-DQ8 molecules on antigen-presenting cells, where they are recognized by T helper cells.

• Subsequently, activated T cells produce pro-inflammatory cytokines and matrix metalloproteinases, which stimulate mucosal damage and the production of anti-tissue transglutaminase antibodies by B cells.

• Over time, epitope spreading may occur (the formation of an immune response against an endogenous antigen or multiple endogenous antigens due to their exposure during tissue damage) and contribute to the production of antibodies capable of binding to epidermal transglutaminase.

• IgA antibodies against epidermal transglutaminase circulate in the bloodstream, eventually reaching the skin and binding to epidermal transglutaminase in the dermis.

The deposition of immune complexes in the dermis stimulates neutrophil chemotaxis and proteolytic cleavage down to the lamina lucida of the basement membrane, leading to blister formation [1].

1.3 Epidemiology of the Disease or Condition

Dermatitis herpetiformis – a rare dermatosis, more common in residents of Northern Europe. According to epidemiological studies conducted in Northern Europe, the incidence in various countries ranges from 0.4 to 3.5 cases per 100,000 population per year, and the prevalence – from 1.2 to 75.3 cases per 100,000 population [5–11]. The disease usually begins at the age of 30–40 years, but can develop in childhood and old age [12]. Men are affected more often than women; the male-to-female incidence ratio varies from 1.1:1 to 1.9:1 [2].

1.4 Features of Coding the Disease or Condition

L13.0 Dermatitis herpetiformis.

1.5 Classification of the disease or condition

There is no universally accepted classification.

1.6 Clinical presentation of the disease or condition

Patients complain of intense pruritus and rashes.

The disease is characterized by a chronic relapsing course, alternating between relapses and periods of drug-induced or spontaneous complete remissions lasting from several weeks to several years. Spontaneous remissions are possible in 10–25% of patients.

The disease is characterized by polymorphism, grouping, and symmetry of the rashes. The rashes are localized predominantly on the extensor surfaces of the extremities, scalp, shoulders, knees, elbows, sacrum, and buttocks, and are accompanied by pruritus. The rash presents as macules, wheals, papules, and blisters of various sizes. The blisters are tense, with a firm roof, filled with clear or turbid, sometimes hemorrhagic contents, and develop on an erythematous, edematous base. The blisters rupture, forming erosions that rapidly epithelialize, leaving hyperpigmentation. Occasionally, skin lesions are localized. Oral mucosa involvement is rare. The general condition of patients is satisfactory.

The occasionally observed monomorphism of rashes allowed for the identification of several clinical forms [4]:

• bullous;

• herpes-like;

• trichophitoid;

• strophuloid.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria:

The diagnosis is established based on physical examination.

2.1 Complaints and Anamnesis

Complaints and medical history are described in the section "Clinical Presentation".

2.2 Physical Examination

Physical examination findings are described in the section "Clinical Presentation".

Comments: the dermatologist evaluates the localization and nature of skin lesions and, if present, mucosal lesions.

2.3 Laboratory Diagnostics

Comments: a large number of eosinophilic leukocytes and neutrophil leukocytes are detected in the blister contents of patients.

Comments: histological examination allows for the detection of the subepidermal location of the blister containing fibrin, neutrophil and eosinophil leukocytes, and accumulations of neutrophil and eosinophil granulocytes in the tips of the dermal papillae [13–16].

Tissue fixation is performed in buffered 10% formalin. When taking a biopsy, it is desirable to capture a small vesicle entirely. If it is impossible to take an entire blister lesion, 1/3 of the obtained biopsy sample should account for the blister fragment and 2/3 for the skin/mucosal area adjacent to the blister [16].

Comments: this allows for the detection of granular deposits of immunoglobulin A in the papillary dermis, which is characteristic of dermatitis herpetiformis. In contrast, linear IgA bullous dermatosis, which occurs in the absence of gluten-sensitive enteropathy, is characterized by linear IgA deposition in the basement membrane zone of the epidermis [13–15].

After collection, the material should be wrapped in a sterile gauze swab generously soaked in saline and delivered to the laboratory within 2 hours for freezing and sectioning on a cryostat microtome. Immunofluorescence examination of the patient's skin biopsy can be performed using either direct or indirect techniques.

Comments: in dermatitis herpetiformis, the blood level of anti-tissue transglutaminase antibodies is elevated.

- determination of blood levels of anti-endomysial antibodies [18];

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: in dermatitis herpetiformis, the blood level of anti-endomysial antibodies is elevated.

Comments: during systemic therapy, patients may develop adverse events that can be detected through a complete blood count. Therapy with dapsone** may lead to agranulocytosis [21–23]. Patients receiving sulfasalazine** therapy may develop hypersensitivity reactions accompanied by eosinophilia [24].

- standard clinical blood chemistry panel [21–24];

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: during systemic therapy, patients may develop adverse events that can be detected through a blood chemistry panel. Therapy with dapsone** may cause hepatotoxicity [21–24]. Nephrotoxic and hepatotoxic effects of the drug may manifest during sulfasalazine** therapy [24].

- urinalysis [21–24].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: during systemic therapy, patients may develop adverse events that can be detected through urinalysis. Adverse events that may develop during dapsone** therapy include nephritis and renal failure [21–23]. Nephrotoxic effects may manifest during sulfasalazine** therapy [24].

Comments: if dermatitis herpetiformis is associated with intestinal pathology accompanied by malabsorption syndrome, patients exhibit decreased serum iron levels.

- vitamin B12 (cyanocobalamin) level test [4, 28];

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: if dermatitis herpetiformis is associated with intestinal pathology accompanied by malabsorption syndrome, patients exhibit decreased blood levels of vitamin B12 (cyanocobalamin).

- serum folic acid test [4, 28].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: if dermatitis herpetiformis is associated with intestinal pathology accompanied by malabsorption syndrome, patients exhibit decreased serum folic acid levels.

2.4 Instrumental Diagnostics

Not applicable.

2.5 Other Procedures

Comments: gluten-sensitive enteropathy is identified in 90% of patients, although its clinical manifestations occur in only 10% of patients [12, 29]. To detect malabsorption syndrome, tests for serum iron, blood vitamin B12 (cyanocobalamin), and serum folic acid may be performed.

Comments: adherence to a gluten-free diet promotes the regression of rashes in patients [12, 25, 29, 31].

Comments: association with autoimmune diseases, including thyroid disorders, is possible [18, 30, 32]. To detect associated autoimmune thyroid involvement, thyroid-stimulating hormone (TSH) and total serum thyroxine (T4) levels are assessed [18, 30, 32].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The mainstay of patient therapy is a gluten-free diet. Patients also receive systemic and topical therapy, with the goal of treatment being partial or complete regression of the rash. To reduce itch intensity, systemic antihistamines are prescribed to patients with Duhring's dermatitis herpetiformis. Systemic antihistamines can be used to control pruritus, alternating every 10 days if necessary.

3.1 Conservative Treatment

Comments: a gluten-free diet leads to the resolution of skin lesions, elimination of enteropathy, and disappearance of IgA antibodies to gliadin, endomysium, and tissue transglutaminase.

Comments: during therapy with #dapsone**, regular blood monitoring is required (complete blood count weekly, and after a few months, monthly). In case of a significant decrease in leukocyte count, platelet count, or bone marrow suppression, #dapsone** treatment should be discontinued. In the first 4 months of pregnancy and during lactation, the drug should be prescribed only in cases of absolute necessity with extreme caution. Since #dapsone** is excreted in breast milk, women taking the drug should refrain from breastfeeding.

- #dapsone** in pediatric patients orally at a dose of 1–2 mg/kg of body weight per day [38, 39];

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: #dapsone** may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency. Therefore, before prescribing #dapsone**, to reduce the risk of hemolytic anemia, glucose-6-phosphate dehydrogenase activity in erythrocyte hemolysate may be determined. During #dapsone** therapy, anemia and agranulocytosis may develop, necessitating regular blood monitoring (complete blood count weekly, and after a few months, monthly). In case of a significant decrease in leukocyte count, platelet count, or bone marrow suppression, #dapsone** treatment should be discontinued.

or aminosalicylic acid derivatives and similar agents:

- #sulfasalazine** orally at a dose of 1–3 g per day [4, 16, 25, 26, 33, 36, 37].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: during treatment, blood alanine aminotransferase activity, blood aspartate aminotransferase activity, complete blood count (at the start of therapy: 1–2 times a month, then every 3–6 months of treatment), and urinalysis (in renal failure) are periodically performed, along with increased fluid intake. During pregnancy, prescribing the drug is possible only under strict indications and at the minimum effective dose.

Comments: clemastine tablets are contraindicated in children under 6 years of age.

or

- #chloropyramine** orally for adults 1 tablet 3–4 times a day (75–100 mg per day), pediatric patients aged 3 to 6 years – 1/2 tablet (12.5 mg) 2 times a day (total daily dose – 25 mg); children aged 6 to 14 years – 1/2 tablet (12.5 mg) 2–3 times a day (total daily dose – 25–37.5 mg); aged 14 to 18 years: 1 tablet (25 mg) 3–4 times a day (total daily dose – 75–100 mg) [4, 33, 36, 37];

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: chloropyramine** tablets are contraindicated, depending on the drug manufacturer, in children under 3 years or under 14 years of age.

or

- loratadine** orally for adults and children over 12 years with a body weight of more than 30 kg, 10 mg once daily; children aged 3 to 12 years with a body weight of less than 30 kg, 5 mg (1/2 tablet) once daily (total daily dose – 5 mg) for 7–10 days [4, 33, 36, 37];

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: loratadine** is contraindicated in children under 3 years of age.

Comments: a contraindication to prescribing clobetasol is the age under 1 year.

or

- betamethasone** 0.05% ointment to lesion sites 2 times a day [4, 33, 35, 36, 37].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: a contraindication to prescribing betamethasone** 0.05% ointment is the age under 1 year.

Dermatological corticosteroids can be used for severe pruritus to reduce it. When a secondary infection occurs, topical corticosteroids combined with antibiotics or corticosteroids combined with antiseptics can be used for topical therapy [16, 18, 35].

Comments: should not be used by women during pregnancy and breastfeeding period.

or

- brilliant green 1% solution for topical application [alcoholic] is applied directly to the damaged surface, capturing the surrounding healthy tissue 2–3 times a day for 5–14 days.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: blister and erosion areas are treated with aniline dye solutions; in the presence of secondary infection, low-potency corticosteroids combined with antibiotics or moderate-potency corticosteroids combined with antibiotics in the form of a topical aerosol are used.

3.2 Other Treatment

Not applicable.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Not applicable.

5. Prevention and Dispensary Observation

Primary prevention has not been developed.

Comments: a gluten-free diet prevents the development of relapses. Out of 38 patients who followed a gluten-free diet for an average of 8 years and then stopped, relapse developed within an average of 2 months in 31 patients [25].

Comments: during patient therapy, regular evaluation of the efficacy and safety of ongoing systemic therapy is necessary.

6. Organization of Medical Care

Indications for hospitalization in a medical organization:

1) lack of response to treatment administered in an outpatient setting;

2) appearance of new rashes;

3) presence of secondary infection in the lesion foci.

Indications for patient discharge from a medical organization:

1) stabilization of the process (absence of new rashes);

2) epithelialization of 70% of erosions;

3) disappearance of pruritus.

7. Additional Information

In cases of strict adherence to a gluten-free diet, the prognosis for patients with dermatitis herpetiformis is favorable [35]. Provided that a gluten-free diet is followed, 47% of patients with dermatitis herpetiformis were able to discontinue dapsone** therapy, 38% managed to reduce their daily dose of dapsone** by 50% or more, and only 15% of patients could not reduce the dose of dapsone** [41]. It has been found that the quality of life of patients with dermatitis herpetiformis who adhere to a gluten-free diet long-term is comparable to that of the general population [42].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Kubanov Alexey Alekseevich – Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

2. Makhneva Nataliya Vit ́evna – Doctor of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

3. Znamenskaya Lyudmila Fedorovna – Doctor of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

4. Karamova Arfenya Eduardovna – Candidate of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

5. Chikin Vadim Viktorovich – Doctor of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.

6. Nefedova Maria Andreevna – Member of the Russian Society of Dermatovenereologists and Cosmetologists.

Conflict of interest: the authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Specialist physicians: dermatovenereologist, cosmetologist.

2. Residents and trainees of continuing professional education programs in the specified specialties.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for grading levels of evidence (LoE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitative interventions)

Table 3. Scale for grading grades of recommendation (GoR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. Order of the Russian Ministry of Health No. 924n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to the Population in the Profile 'Dermatovenereology'."

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

1. To prevent exacerbations and relapses of the disease, dietary compliance is necessary. Wheat, barley, rye, oats, and other cereals must be completely eliminated from the diet. Foods containing iodine (seafood, feijoa, persimmon, etc.) must also be avoided.

2. A gluten-free diet leads to regression of rashes in 1–2 years; however, dermatitis herpetiformis invariably relapses within 12 weeks after the reintroduction of dietary gluten, which is why patients must adhere to the diet for life. Only 10–20% of patients develop immune tolerance and are able to resume a normal diet after several years of a strict gluten-free diet; this is most frequently observed in cases of disease onset in childhood and in patients treated with dapsone**.

3. Strict adherence to a gluten-free diet over a long period leads to a reduced need for medications, a lower risk of intestinal lymphomas, resolution of skin rashes, and improvement of enteropathy/malabsorption symptoms.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Special assessment scales, indices, and questionnaires are not used during patient examination.