Dermatitis Herpetiformis

1. Disease Information

Dermatitis herpetiformis (DH, Duhring-Brocq disease) is an intensely itchy, chronic, blistering skin disease. It is the cutaneous manifestation of gluten-sensitive enteropathy (coeliac disease). Diagnosis rests on granular IgA deposits in the papillary dermis.

"DH diagnosis is confirmed by showing granular immunoglobulin A deposits in the papillary dermis" (PMID:33432477)

"The DH autoantigen, transglutaminase 3, is deposited at the same site in tightly bound immune complexes" (PMID:33432477)

• Identifiers: MONDO:0015614 comes from the template and is unchecked. OMIM, Orphanet, ICD-10 (L13.0), ICD-11 and MeSH IDs were not retrieved. ICD-10 L13.0 is from memory [unverified]. Look the rest up with just fetch-reference ORPHA:<n> or the term caches.
• Synonyms: Duhring disease, Duhring-Brocq disease, "coeliac disease of the skin". The literature also calls it "gluten-sensitive dermatopathy" [unverified].
• Data level: The resources cited are aggregated cohort, registry and review data, not EHR data from individual patients.
• Differentials with similar names: Pemphigus herpetiformis (PMID:40686696) is a different disease. The "acantholytic" (PMID:26765204) and "fibrillar-type" (PMID:31106757) variants are reported subtypes.

2. Etiology

• Causal factors: DH is a gluten-driven autoimmune disorder on the coeliac disease spectrum. Dietary gluten is the trigger. Susceptibility is HLA-DQ2/DQ8 restricted [unverified, well established].
• Genetic risk: HLA-DQ2.5 (DQA105:01/DQB102:01) and DQ8 (DQA103/DQB103:02) are present in nearly all patients [unverified]. Non-HLA coeliac loci overlap with DH. I did not retrieve DH-specific GWAS data.
• Environmental risk: Gluten ingestion is the driver. Iodine exacerbation of DH is a long-standing clinical observation [unverified].
• Protective factors: Strict gluten-free diet (GFD) induces remission and is the protective intervention. No protective genetic variants have been established.
• Gene-environment interaction: HLA-DQ2/DQ8 permits presentation of deamidated gluten peptides to T cells. Whether this leads to gut disease alone or to DH as well is poorly understood. Nothing in the retrieved material explains why only some coeliac patients develop skin disease (an open question worth a knowledge-gap entry).

3. Phenotypes

• Onset: Mean age at diagnosis was 60.9 years in Sweden (PMID:37971253). In Finland the mean age rose significantly during the study, in men from 35.3 to 51.1 years (PMID:21517799). Childhood onset occurs but is less common [unverified].
• Course: Chronic and relapsing while gluten is eaten. Skin lesions remit on a GFD, often over months to years [unverified].
• Quality of life: Quality of life and GI symptoms were studied in long-term treated patients (PMID:26267424). The extent of impairment is not quoted here because I did not read the abstract. Oats safety and quality-of-life effects are in PMID:32290504.

4. Genetic/Molecular Information

• Monogenic cause: None. DH is a complex, multifactorial condition.
• HLA: HLA-DQ2/DQ8 (HLA-DQA1/DQB1). HGNC IDs must be looked up; in this repository they use the lowercase hgnc: prefix.
• Autoantigen gene: TGM3 (epidermal transglutaminase, TG3), identified in PMID:11901200. Enzyme-substrate conformation and autoantibody binding are described in PMID:37798283. TGM2 (tissue transglutaminase) is the coeliac autoantigen.
• Modifier, epigenetic, chromosomal features: Not retrieved. Treat them as not available.

5. Environmental Information

• Dietary gluten (wheat, rye, barley) is the established trigger. Whether oats are safe is addressed in PMID:32290504. I did not read its conclusions, so check them before citing.
• Iodine and drugs: Iodide exacerbation [unverified]. Some NSAIDs are also implicated [unverified].
• Infectious agents: None established.

6. Mechanism / Pathophysiology

Causal chain (steps marked inferred are not demonstrated in the retrieved sources):

1. HLA-DQ2/DQ8 genotype leads to presentation of gluten peptides to CD4+ T cells in the small intestine [unverified].
2. Dietary gluten, deamidated by tissue transglutaminase (TG2), leads to gut T-cell activation and an IgA response to TG2 [unverified].
3. Epitope spreading leads to IgA autoantibodies to epidermal transglutaminase (TG3). TG3 was identified as the DH autoantigen (PMID:11901200). Why the response spreads from TG2 to TG3 is inferred.
4. Circulating IgA-TG3 complexes or TG3 deposition at the papillary dermis leads to granular IgA-TG3 deposits (PMID:33432477).
5. The deposits lead to neutrophil recruitment and complement activation, causing dermal-epidermal separation [unverified; the neutrophil step is inferred from the histology].
6. Subepidermal vesicle formation leads to intense itch and the clinical eruption.

7. Branch: a GFD removes the antigenic drive and leads to gradual clearance of skin deposits and lesions. Dapsone controls the neutrophil-mediated inflammation faster than diet does but does not treat the underlying cause (PMID:33432477).

8. Cells and GO/CL leads: CD4+ T cells, B cells and plasma cells (IgA), neutrophils, enterocytes and keratinocytes. Terms to look up include "antibody-dependent" and "neutrophil chemotaxis" processes.

9. Protein dysfunction: Autoantibodies bind TG3 in a defined enzyme-substrate intermediate conformation (PMID:37798283).
10. Molecular profiling, single-cell, spatial and functional-genomics data: Not retrieved. I did not search GEO for DH datasets. Treat as a gap.

7. Anatomical Structures Affected

• Skin: Extensor surfaces and papillary dermis are the primary site. The lesions are symmetric and grouped.
• Gut: The small intestine often has subclinical coeliac-type enteropathy, and some patients have GI symptoms (PMID:37595955).
• UBERON leads: skin of elbow, knee and buttock; dermal papilla; small intestine.
• Cellular/subcellular: The dermal-epidermal junction is the target zone for the deposits.

8. Temporal Development

• Onset: Usually adult. Mean diagnosis age was 60.9 years in Sweden (PMID:37971253) and has risen over time in Finland (PMID:21517799).
• Course: Chronic, relapsing while gluten is eaten. Lifelong gluten sensitivity persists.
• Remission: Induced by the GFD. PMID:33432477 states "Dietary adherence offers an excellent long-term prognosis."

9. Inheritance and Population

• Inheritance: Multifactorial, with HLA-DQ2/DQ8 dependence. Bind Multifactorial inheritance (HP lead) or leave it absent if no suitable term is found.
• Finland (PMID:21517799): "The prevalence of DH was 75·3 per 100,000", "annual incidence of DH in the whole period was 3·5 per 100,000", male to female ratio "1·1:1".
• Sweden, 2005–2018 (PMID:37971253): "The mean annual incidence of dermatitis herpetiformis was 0.93/100,000", female to male ratio "1:1", "mean age at diagnosis 60.9 years".
• Geography and ethnicity: Highest in Northern Europe. Rare in East Asian and African populations [unverified].
• Trend: Incidence of DH has fallen in several countries while coeliac diagnoses have risen [unverified]. The Finnish and Swedish figures differ by several-fold, which is a methodological difference and possibly a real regional one.
• Prevalence modelling: Use measure_type: POINT_PREVALENCE for the Finnish figure and ANNUAL_INCIDENCE with an explicit rate_denominator for incidence.

10. Diagnostics

• Direct immunofluorescence (DIF) of perilesional skin is the gold standard. "Detecting granular IgA deposits at the dermal-epidermal junction by direct immunfluorescence represents the most specific diagnostic tool" (PMID:31244841).
• Histology: Neutrophilic microabscesses in dermal papillae with subepidermal blisters [unverified].
• Serology: Anti-TG2, anti-TG3 and anti-endomysial IgA. Anti-TG3 may be more DH-specific [unverified].
• Small-bowel biopsy is not always needed when DH is confirmed, but practice varies (see PMID:34441049).
• Genetic testing: HLA-DQ2/DQ8 typing can exclude coeliac disease and DH when both are negative (high negative predictive value) [unverified].
• Differential: Linear IgA bullous dermatosis, bullous pemphigoid, scabies, eczema, pemphigus herpetiformis (PMID:40686696).

11. Outcome/Prognosis

• Mortality and malignancy (PMID:42256615, 2026 matched cohort): "566/6768 (8.36%) died, compared with 443/6770 (6.54%) matched comparators (aHR = 1.25; 1.10-1.42)" and "non-Hodgkin lymphoma (aHR = 2.58; 1.47-4.51)". I retrieved only the DH-specific sentences, so I can't confirm which group each figure belongs to. Re-read the abstract before curating, because it covers both coeliac disease and DH.
• Lymphoma: Risk is elevated in DH (see above). Earlier cohort data on this are not verified here.
• Complications: Associated autoimmune disease (thyroid disease, type 1 diabetes) [unverified]; osteoporosis and GFD-related nutritional issues.
• Prognosis on diet: "Dietary adherence offers an excellent long-term prognosis" (PMID:33432477).

12. Treatment

• Gluten-free diet: "the treatment of choice for all patients is a gluten-free diet" (PMID:33432477). Lesions clear slowly, over months to years. NCIT lead: Dietary Intervention (NCIT:C15447 in this repository's table, re-check). therapeutic_modality: BEHAVIORAL.
• Dapsone: "most patients need additional dapsone" (PMID:33432477). It gives rapid control of itch and new lesions, typically within days [unverified]. Use the pharmacotherapy action term with therapeutic_agent bound to dapsone (look up in CHEBI). Reviews: PMID:39078587, PMID:31909480. therapeutic_modality: SMALL_MOLECULE.
• Dapsone adverse effects: Dose-related hemolysis, methemoglobinemia, agranulocytosis, neuropathy [unverified]. G6PD testing before starting is standard [unverified]. Pancreatitis and overdose are documented in case reports, which the literature search surfaced but I did not review.
• Alternatives when dapsone is not tolerated: sulfapyridine, sulfasalazine [unverified]. Topical steroids for symptoms.
• Oats: Safety and quality-of-life effects are addressed in PMID:32290504.
• Reviews of management: PMID:22560140, PMID:21925009, PMID:34441049.
• Clinical trials: Not searched. Run just discover-datasets and search ClinicalTrials.gov before adding any.

13. Prevention

• Primary prevention: None known.
• Secondary prevention and tertiary prevention: Lifelong strict GFD. It prevents skin flares and is believed to reduce lymphoma risk, but the protective effect on lymphoma needs confirmation [unverified].
• Monitoring: Periodic dietary review and check-ups for associated autoimmune and malignancy risk (see PMID:34441049).
• Counseling: Family screening for coeliac disease in first-degree relatives [unverified].

14. Other Species / Natural Disease

I did not search OMIA. The only possibly relevant naturally occurring analogue is gluten-sensitive enteropathy in Irish Setters [unverified], and I know of no established DH equivalent. Treat species, breed and orthologous-gene fields as not available.

15. Model Organisms

I did not retrieve model-organism data. From memory, [unverified] there is no widely accepted faithful animal model of DH. Humanized HLA-DQ8 transgenic mice exist for gluten sensitivity, and some work on DH-like skin deposition in such mice has been reported. Flag this as a knowledge gap (HUMAN_MODEL_MISMATCH or KNOWLEDGE_GAP discussion) rather than inventing a model entry.

Gaps and Next Steps for the Curator

1. Unretrieved identifiers: OMIM, Orphanet, ICD-11, MeSH, and the MONDO ID check.
2. Unsourced claims: Every item marked [unverified] needs a PMID with an exact snippet. Start with the HLA-DQ2/DQ8 frequency, the TG2-to-TG3 epitope spreading concept, and the neutrophil/complement steps.
3. Quote check: Quotes above came from abstract text returned by a summarizing fetch. Re-verify them against the references_cache copies before using them as snippets.
4. Suggested next fetches: just fetch-reference PMID:11901200 PMID:33432477 PMID:21517799 PMID:37971253 PMID:31244841 PMID:42256615.
5. Search gaps: GEO and other omics datasets, ClinicalTrials.gov, and OMIA were not searched.

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

• PMID:31244841: "Detecting granular IgA deposits at the dermal-epidermal junction by direct immunfluorescence represents the most specific diagnostic tool"
• closest text in source: "Detecting granular IgA deposits at the dermal-epidermal junction by direct immunofluorescence (DIF) from perilesional skin represents the most specific diagnostic tool"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Every term resolved, and every label the report gave matched.