Dermatitis Herpetiformis

Autoimmune MONDO:0015614 Pathograph 18 Show in embeddings browser Autoimmune Disease Skin Disease

Dermatitis herpetiformis (DH) is the cutaneous manifestation of gluten sensitivity and a specific extraintestinal expression of celiac disease. In genetically predisposed (HLA-DQ2/DQ8) individuals, gluten-driven small-bowel autoimmunity generates IgA autoantibodies that, in DH, are of markedly higher avidity for epidermal transglutaminase (TG3) than for tissue transglutaminase. High-avidity IgA anti-TG3, together with the TG3 enzyme, forms granular immune deposits in the papillary dermis, recruits neutrophils into the dermal papillae, and produces an intensely pruritic, symmetrical papulovesicular eruption on extensor surfaces. Diagnosis rests on pathognomonic granular IgA deposits by direct immunofluorescence; a lifelong gluten-free diet is the treatment of choice, with dapsone for rapid symptom control.

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1
Inheritance
6
Pathophys.
4
Phenotypes
18
Pathograph
2
Genes
4
Medical Actions
1
Deep Research
👪

Inheritance

1
HLA-associated polygenic susceptibility HP:0010982
DH is a complex, HLA-associated autoimmune trait, not Mendelian. It shares the celiac-disease HLA-DQ2 and HLA-DQ8 haplotypes and gluten dependence.
polygenic inheritance
Show evidence (1 reference)
PMID:31244841 SUPPORT REVIEW SYNTHESIS Human Clinical
"share the same Human Leukocyte Antigen (HLA) haplotypes (DQ2 and DQ8)"
DH shares the celiac HLA-DQ2/DQ8 susceptibility haplotypes.
⚙

Pathophysiology

6
HLA-DQ2/DQ8-Restricted Gluten Presentation
Permissive HLA-DQ2 and HLA-DQ8 class II molecules present deamidated gluten peptides to CD4+ T cells, the shared genetic basis of gluten sensitivity in both DH and celiac disease.
HLA-DQA1 hgnc:4942 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves HLA-DQA1 (hgnc:4942). hgnc:4942 is a gene from the HUGO Gene Nomenclature Committee. HLA-DQB1 hgnc:4944 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves HLA-DQB1 (hgnc:4944). hgnc:4944 is a gene from the HUGO Gene Nomenclature Committee.
MHC class II peptide antigen binding GO:0042605 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves MHC class II peptide antigen binding, annotated with peptide antigen binding (GO:0042605). GO:0042605 is a molecular function from the Gene Ontology.
Downstream
Gluten-Driven Small-Bowel Autoimmunity Presentation of gluten peptides on the permissive haplotype licenses the gluten-sensitive autoimmune response.
Show evidence (1 reference)
PMID:31244841 SUPPORT REVIEW SYNTHESIS Human Clinical
"share the same Human Leukocyte Antigen (HLA) haplotypes (DQ2 and DQ8)"
Establishes the HLA-DQ2/DQ8 restriction shared with celiac disease.
Gluten-Driven Small-Bowel Autoimmunity
DH arises from latent or manifest celiac disease in the gut: gluten exposure drives an IgA autoantibody response against tissue transglutaminase, with small-bowel villous atrophy or celiac-type inflammation in most patients.
small intestine UBERON:0002108 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in small intestine (UBERON:0002108). UBERON:0002108 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Small-bowel villous atrophy The gut autoimmune response produces celiac-type villous atrophy in most DH patients.
Anti-TG3 IgA Autoantibody Response The gut autoimmune response evolves into a high-avidity IgA response against epidermal transglutaminase.
Lymphoma The chronic gluten-driven enteropathy carries a six- to tenfold increased risk of enteropathy-associated lymphoma, concentrated in the years before a gluten-free diet is established.
Show evidence (1 reference)
PMID:31093998 SUPPORT REVIEW SYNTHESIS Human Clinical
"DH and CD share a similar genetic background, small bowel mucosal alterations, and an autoimmune response against tissue transglutaminase in the serum and small bowel"
Locates the initiating anti-tissue-transglutaminase autoimmunity in the small bowel.
Anti-TG3 IgA Autoantibody Response
In DH the IgA response acquires markedly higher avidity for epidermal transglutaminase (TG3) than for tissue transglutaminase, and a TG3-specific antibody population appears. This is the molecular feature that distinguishes DH from celiac disease without skin involvement.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
immunoglobulin production GO:0002377 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased immunoglobulin production (GO:0002377). GO:0002377 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Granular IgA-TG3 Deposition in the Papillary Dermis High-avidity IgA anti-TG3 complexes with the TG3 enzyme and deposits in the papillary dermis.
Show evidence (1 reference)
PMID:11901200 SUPPORT Human Clinical
"antibodies in patients having dermatitis herpetiformis show a markedly higher avidity for epidermal transglutaminase"
The higher-avidity anti-TG3 response defines DH.
Granular IgA-TG3 Deposition in the Papillary Dermis
IgA anti-TG3 and the TG3 enzyme form tightly bound immune complexes that precipitate as pathognomonic granular IgA deposits in the papillary dermis. Passive transfer of anti-TG3 reproduces these deposits, establishing them as directly antibody-driven.
TGM3 hgnc:11779 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TGM3 (hgnc:11779). hgnc:11779 is a gene from the HUGO Gene Nomenclature Committee.
protein-glutamine gamma-glutamyltransferase activity GO:0003810 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves protein-glutamine gamma-glutamyltransferase activity (GO:0003810). GO:0003810 is a molecular function from the Gene Ontology.
papillary layer of dermis UBERON:0001992 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in papillary layer of dermis (UBERON:0001992). UBERON:0001992 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Neutrophil Recruitment and Papillary Microabscess Formation The dermal immune deposits recruit neutrophils into the dermal papillae.
Show evidence (2 references)
PMID:11901200 SUPPORT Human Clinical
"a blistering skin disease characterized by granular IgA deposits in the papillary dermis"
Granular papillary-dermis IgA deposits are the defining lesion.
PMID:21335491 SUPPORT INDIRECT Model Organism
"All mice that received goat anti-TG3 produced papillary dermal immune deposits, and these deposits reacted with both rabbit anti-TG3 and DH patient sera."
Passive transfer of anti-TG3 reproduces the deposits, showing they are antibody-driven (a human-skin-grafted mouse model).
Neutrophil Recruitment and Papillary Microabscess Formation
The dermal immune deposits drive a predominant neutrophilic infiltrate into the dermal papillae, forming the papillary microabscesses characteristic of DH histopathology. Gut-derived IL-8 primes neutrophils, which bind the deposited IgA directly through their Fc-alpha receptor (CD89, FCAR).
neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology.
FCAR hgnc:3608 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FCAR (hgnc:3608). hgnc:3608 is a gene from the HUGO Gene Nomenclature Committee.
neutrophil migration GO:1990266 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased neutrophil migration (GO:1990266). GO:1990266 is a biological process from the Gene Ontology. ↑ INCREASED
Fc-alpha (IgA) receptor activity GO:0019766 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves Fc-alpha (IgA) receptor activity, annotated with IgA receptor activity (GO:0019766). GO:0019766 is a molecular function from the Gene Ontology.
papillary layer of dermis UBERON:0001992 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in papillary layer of dermis (UBERON:0001992). UBERON:0001992 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Subepidermal Vesicle Formation Neutrophil accumulation and enzyme release at the dermal papillae detach the epidermis, forming subepidermal vesicles.
Pruritus Dermal inflammation drives the intense itch. Its mechanism (neurogenic inflammation, IL-31) is unresolved, and pruritus can precede the visible lesions by hours to months, so it is not simply a consequence of the vesicles.
Show evidence (3 references)
PMID:31244841 SUPPORT REVIEW SYNTHESIS Human Clinical
"a predominant neutrophilic infiltrate at the dermal papillae at histopathology"
The neutrophilic papillary infiltrate is a defining histopathologic feature.
PMID:31244841 SUPPORT REVIEW SYNTHESIS Human Clinical
"Circulating and skin resident neutrophils express Fc IgA receptor (CD89), suggesting a direct interaction between neutrophils and IgA."
Neutrophils bind the deposited IgA through the CD89 Fc-alpha receptor (FCAR).
PMID:31244841 SUPPORT REVIEW SYNTHESIS Human Clinical
"Activation of innate immunity in the gut leads to increased release of IL-8, which is thought to be responsible for the initial priming of neutrophils"
Gut-derived IL-8 primes the neutrophils recruited to the dermal papillae.
Subepidermal Vesicle Formation
Neutrophil-mediated damage at the dermal papillae produces subepidermal vesicles that present clinically as grouped papules and small blisters, though intense scratching often destroys the primary lesions.
epidermal-dermal junction UBERON:0008877 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in epidermal-dermal junction (UBERON:0008877). UBERON:0008877 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Pruritic papulovesicular eruption
Show evidence (1 reference)
PMID:31244841 SUPPORT REVIEW SYNTHESIS Human Clinical
"Activated neutrophils release neutrophil elastase and granzyme B, which induce subepidermal split by cleaving adhesion molecules of the BMZ, such as collagen VII"
Neutrophil elastase and granzyme B cleave basement-membrane-zone adhesion molecules to produce the subepidermal split — the node's own mechanism.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Dermatitis Herpetiformis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

4
Blood 1
Lymphoma HP:0002665 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is increased lymphoma risk, annotated with Lymphoma (HP:0002665). HP:0002665 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33432477 SUPPORT REVIEW SYNTHESIS Human Clinical
"The risk in DH is increased six to tenfold."
Quantifies the increased lymphoma risk in DH.
PMID:31244841 SUPPORT REVIEW SYNTHESIS Human Clinical
"Mortality due to non-Hodgkin lymphomas was increased only during the first 5 years following the diagnosis but not thereafter"
The lymphoma-related mortality excess is confined to the first 5 years after diagnosis.
Digestive 1
Small-bowel villous atrophy FREQUENT HP:0011473 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is villous atrophy (HP:0011473). HP:0011473 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33432477 SUPPORT REVIEW SYNTHESIS Human Clinical
"three-fourths of patients with DH have villous atrophy in the small bowel, and the rest have celiac-type inflammatory changes"
Quantifies the subclinical small-bowel enteropathy in DH.
Immune 1
Pruritic papulovesicular eruption VERY_FREQUENT HP:0033700 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is papulovesicular eruption (HP:0033700), qualified as adult onset, mean 50y. HP:0033700 is a phenotype from the Human Phenotype Ontology.
Onset: ADULT; mean 50y
Show evidence (2 references)
PMID:31244841 SUPPORT REVIEW SYNTHESIS Human Clinical
"Clinically, DH presents with polymorphic lesions, including papules, vesicles, and small blisters, symmetrically distributed in typical anatomical sites including the extensor aspects of the limbs, the elbows, the sacral regions, and the buttocks."
Describes the symmetrical papulovesicular eruption on extensor surfaces.
PMID:33432477 SUPPORT REVIEW SYNTHESIS Human Clinical
"The mean age at onset is about 50 years."
Supports the adult onset (mean ~50 years) recorded on this phenotype.
Integument 1
Pruritus VERY_FREQUENT HP:0000989 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is intense pruritus, annotated with Pruritus (HP:0000989). HP:0000989 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21571167 SUPPORT REVIEW SYNTHESIS Human Clinical
"young adults present with excoriations only, as the severe pruritus effectively destroys any primary lesions"
Documents the severe pruritus characteristic of DH.
🧬

Genetic Associations

2
HLA-DQA1 (Component of the HLA-DQ2/DQ8 class II susceptibility haplotypes shared with celiac disease.)
Gene: HLA-DQA1 hgnc:4942 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HLA-DQA1 (hgnc:4942). hgnc:4942 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:31244841 SUPPORT REVIEW SYNTHESIS Human Clinical
"share the same Human Leukocyte Antigen (HLA) haplotypes (DQ2 and DQ8)"
HLA-DQ2/DQ8 haplotypes confer DH susceptibility.
HLA-DQB1 (Component of the HLA-DQ2/DQ8 class II susceptibility haplotypes shared with celiac disease.)
Gene: HLA-DQB1 hgnc:4944 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HLA-DQB1 (hgnc:4944). hgnc:4944 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (1 reference)
PMID:31244841 SUPPORT REVIEW SYNTHESIS Human Clinical
"share the same Human Leukocyte Antigen (HLA) haplotypes (DQ2 and DQ8)"
HLA-DQ2/DQ8 haplotypes confer DH susceptibility.
💊

Medical Actions

4
Gluten-free diet
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Platform: Behavioral / lifestyle
A strict, lifelong gluten-free diet is the treatment of choice for all DH patients. It heals both the rash and the small-bowel enteropathy and lowers lymphoma risk, though its effect on the rash is slow.
Mechanism Target:
INHIBITS Gluten-Driven Small-Bowel Autoimmunity — Removing gluten withdraws the trigger of the entire disease cascade.
INHIBITS Lymphoma — Strict gluten-free-diet adherence lowers the enteropathy-associated lymphoma risk.
Show evidence (1 reference)
PMID:31093998 SUPPORT REVIEW SYNTHESIS Human Clinical
"a GFD increases the quality of life for patients, and decreases the risk for lymphoma in DH"
A gluten-free diet reduces the lymphoma risk in DH.
Show evidence (1 reference)
PMID:33432477 SUPPORT REVIEW SYNTHESIS Human Clinical
"the treatment of choice for all patients is a gluten-free diet"
Gluten-free diet is the definitive treatment for DH.
Dapsone
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: dapsone CHEBI:4325 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dapsone (CHEBI:4325). CHEBI:4325 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Dapsone rapidly controls the rash and itch at onset by suppressing neutrophil function; most patients can stop it after about two years once a strict gluten-free diet controls the disease.
Mechanism Target:
INHIBITS Neutrophil Recruitment and Papillary Microabscess Formation — Dapsone suppresses the neutrophilic infiltrate that produces the rash.
Show evidence (1 reference)
PMID:33432477 SUPPORT REVIEW SYNTHESIS Human Clinical
"At onset, most patients need additional dapsone to rapidly control the rash and itching"
Dapsone is the adjunct for rapid symptom control at onset.
Sulfasalazine
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sulfasalazine CHEBI:9334 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sulfasalazine (CHEBI:9334). CHEBI:9334 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
A sulfonamide used as a dapsone alternative when dapsone is not tolerated or is contraindicated; it carries a lower monitoring burden than dapsone but can still cause hemolytic anemia and gastrointestinal upset.
Mechanism Target:
INHIBITS Neutrophil Recruitment and Papillary Microabscess Formation — As a dapsone alternative, sulfasalazine suppresses the neutrophilic infiltrate driving the rash.
Show evidence (1 reference)
PMID:31244841 SUPPORT REVIEW SYNTHESIS Human Clinical
"Possible alternatives to dapsone are the so-called sulfonamides, including sulfasalazine, sulfapyridine, and sulfamethoxypyridazine"
Names sulfasalazine among the sulfonamide dapsone alternatives.
Rituximab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: rituximab NCIT:C1702 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses rituximab (NCIT:C1702). NCIT:C1702 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
An anti-CD20 monoclonal antibody reported in a single refractory case of DH resistant to gluten-free diet, dapsone, sulfasalazine, and conventional immunosuppressants. It depletes CD20+ B cells (the autoantibody-producing lineage), not the terminally differentiated plasma cells.
Mechanism Target:
INHIBITS Anti-TG3 IgA Autoantibody Response — B-cell depletion curtails the autoantibody-producing response in refractory disease.
Show evidence (1 reference)
PMID:31244841 SUPPORT REVIEW SYNTHESIS Human Clinical
"rituximab has been proven to be effective in a patient resistant to GFD, dapsone, sulfasalazine, and conventional immunosuppressive agents such as azathioprine"
Rituximab is an option for recalcitrant DH.
🌍

Environmental Factors

2
Dietary gluten exposure
Dietary gluten is the necessary environmental trigger. It drives the small-bowel autoimmunity that underlies DH, and its removal (a gluten-free diet) heals both the rash and the enteropathy.
Show evidence (1 reference)
PMID:11901200 SUPPORT Human Clinical
"evoked and maintained by gluten"
Names gluten as the environmental factor that evokes and maintains gluten-sensitive disease.
Mechanism Target:
TRIGGERS Gluten-Driven Small-Bowel Autoimmunity — Gluten ingestion drives the gut autoimmune response that initiates DH.
Show evidence (1 reference)
PMID:31093998 SUPPORT REVIEW SYNTHESIS Human Clinical
"The treatment of choice in DH is a strict, life-long adherence to a gluten-free diet (GFD)."
Gluten removal being the definitive treatment establishes gluten as the causal exposure.
Iodide and NSAID exposure
Dietary iodide and certain NSAIDs (e.g. indomethacin) are recognized exacerbating triggers that worsen the rash and itch in established DH.
Show evidence (1 reference)
PMID:33432477 SUPPORT REVIEW SYNTHESIS Human Clinical
"Triggering factors such as taking indomethacin and inadvertent dietary iodide ingestion are known to exacerbate the rash and itching"
Documents iodide and NSAID exacerbation of the DH rash.
Mechanism Target:
EXACERBATES Neutrophil Recruitment and Papillary Microabscess Formation — These exposures worsen the neutrophil-driven rash in established DH.
Show evidence (1 reference)
PMID:33432477 SUPPORT REVIEW SYNTHESIS Human Clinical
"Triggering factors such as taking indomethacin and inadvertent dietary iodide ingestion are known to exacerbate the rash and itching"
Names indomethacin and dietary iodide as recognized exacerbating triggers.
🔬

Diagnosis

2
Direct immunofluorescence of perilesional skin
Direct immunofluorescence of perilesional skin showing pathognomonic granular IgA deposits in the papillary dermis confirms the diagnosis.
Show evidence (1 reference)
PMID:29757210 SUPPORT REVIEW SYNTHESIS Human Clinical
"Diagnosis of DH is easily confirmed by immunofluorescence biopsy showing pathognomonic granular immunoglobulin A (IgA) deposits in the papillary dermis."
Granular papillary-dermis IgA on DIF is the diagnostic gold standard.
Serum anti-transglutaminase IgA
Circulating IgA autoantibodies against epidermal transglutaminase (TG3), and against tissue transglutaminase, support the diagnosis, though their absence does not exclude DH.
Show evidence (1 reference)
PMID:31244841 SUPPORT REVIEW SYNTHESIS Human Clinical
"assessing serum titers of autoantibodies against epidermal transglutaminase (eTG), the supposed autoantigen of DH, may also serve as a clue for the diagnosis"
Serum anti-epidermal-transglutaminase IgA is a supporting diagnostic marker.
📊

Prevalence

1
Finland
Annual Incidence 2.7 per 100,000 per year 1–9 per 100,000 per year
2.7 new cases per 100,000 per year in Finland (0.8 in the UK); the DH incidence is decreasing while celiac disease incidence rises.
Show evidence (1 reference)
PMID:29757210 SUPPORT REVIEW SYNTHESIS Human Clinical
"The annual DH incidence rate, currently 2.7 per 100,000 in Finland and 0.8 per 100,000 in the U.K."
Gives the Finnish annual incidence used for the normalized rate.
⚖️

Clinical Burden

Moderate
DH causes intense pruritus and a chronic relapsing eruption, but responds well to a gluten-free diet and dapsone, and diet-adherent patients have an excellent long-term prognosis with mortality no higher than the general population. Untreated gluten sensitivity carries an elevated lymphoma risk that the diet reduces.
Show evidence (1 reference)
PMID:31093998 SUPPORT REVIEW SYNTHESIS Human Clinical
"a GFD increases the quality of life for patients, and decreases the risk for lymphoma in DH"
Identifies the lymphoma risk and its reduction by the gluten-free diet.
{ }

Source YAML

click to show 
name: Dermatitis Herpetiformis
creation_date: "2026-09-30T23:45:00Z"
category: Autoimmune
description: >-
  Dermatitis herpetiformis (DH) is the cutaneous manifestation of gluten
  sensitivity and a specific extraintestinal expression of celiac disease. In
  genetically predisposed (HLA-DQ2/DQ8) individuals, gluten-driven small-bowel
  autoimmunity generates IgA autoantibodies that, in DH, are of markedly higher
  avidity for epidermal transglutaminase (TG3) than for tissue transglutaminase.
  High-avidity IgA anti-TG3, together with the TG3 enzyme, forms granular immune
  deposits in the papillary dermis, recruits neutrophils into the dermal
  papillae, and produces an intensely pruritic, symmetrical papulovesicular
  eruption on extensor surfaces. Diagnosis rests on pathognomonic granular IgA
  deposits by direct immunofluorescence; a lifelong gluten-free diet is the
  treatment of choice, with dapsone for rapid symptom control.
disease_term:
  preferred_term: dermatitis herpetiformis
  term:
    id: MONDO:0015614
    label: dermatitis herpetiformis
synonyms:
- Duhring's disease
- Duhring-Brocq disease
- dermatosis herpetiformis
parents:
- Autoimmune Disease
- Skin Disease
notes: >-
  DH and celiac disease (curated separately in Celiac_Disease) are two cutaneous
  and intestinal expressions of the same gluten-sensitive autoimmunity; this
  entry models the skin disease and the gut origin that drives it, not the full
  enteropathy. The distinguishing molecular feature is the higher-avidity IgA
  response to epidermal transglutaminase (TG3, gene TGM3) versus the tissue
  transglutaminase (TG2, gene TGM2) response shared with celiac disease. No
  GeneReviews chapter exists (complex HLA-associated autoimmune disease, not
  Mendelian). Gluten is recorded as an environmental trigger without an ECTO
  exposure_term: ECTO was searched (l~gluten, l~wheat) and has no gluten or
  wheat dietary-exposure class.
prevalence:
- population: Finland
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 2.7
  rate_denominator: POPULATION_PER_YEAR
  notes: >-
    2.7 new cases per 100,000 per year in Finland (0.8 in the UK); the DH
    incidence is decreasing while celiac disease incidence rises.
  evidence:
  - reference: PMID:29757210
    reference_title: 'Dermatitis Herpetiformis: A Common Extraintestinal Manifestation of Coeliac Disease.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The annual DH incidence rate, currently 2.7 per 100,000 in Finland and 0.8
      per 100,000 in the U.K.
    explanation: >-
      Gives the Finnish annual incidence used for the normalized rate.
clinical_burden:
  burden_level: MODERATE
  rationale: >-
    DH causes intense pruritus and a chronic relapsing eruption, but responds
    well to a gluten-free diet and dapsone, and diet-adherent patients have an
    excellent long-term prognosis with mortality no higher than the general
    population. Untreated gluten sensitivity carries an elevated lymphoma risk
    that the diet reduces.
  evidence:
  - reference: PMID:31093998
    reference_title: Dermatitis herpetiformis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      a GFD increases the quality of life for patients, and decreases the risk
      for lymphoma in DH
    explanation: >-
      Identifies the lymphoma risk and its reduction by the gluten-free diet.
inheritance:
- name: HLA-associated polygenic susceptibility
  inheritance_term:
    preferred_term: polygenic inheritance
    term:
      id: HP:0010982
      label: Polygenic inheritance
  description: >-
    DH is a complex, HLA-associated autoimmune trait, not Mendelian. It shares
    the celiac-disease HLA-DQ2 and HLA-DQ8 haplotypes and gluten dependence.
  evidence:
  - reference: PMID:31244841
    reference_title: 'Dermatitis Herpetiformis: Novel Perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      share the same Human Leukocyte Antigen (HLA) haplotypes (DQ2 and DQ8)
    explanation: >-
      DH shares the celiac HLA-DQ2/DQ8 susceptibility haplotypes.
pathophysiology:
- name: HLA-DQ2/DQ8-Restricted Gluten Presentation
  biological_scale: MOLECULAR
  description: >-
    Permissive HLA-DQ2 and HLA-DQ8 class II molecules present deamidated gluten
    peptides to CD4+ T cells, the shared genetic basis of gluten sensitivity in
    both DH and celiac disease.
  genes:
  - preferred_term: HLA-DQA1
    term:
      id: hgnc:4942
      label: HLA-DQA1
  - preferred_term: HLA-DQB1
    term:
      id: hgnc:4944
      label: HLA-DQB1
  molecular_functions:
  - preferred_term: MHC class II peptide antigen binding
    term:
      id: GO:0042605
      label: peptide antigen binding
  downstream:
  - target: Gluten-Driven Small-Bowel Autoimmunity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Presentation of gluten peptides on the permissive haplotype licenses the
      gluten-sensitive autoimmune response.
  evidence:
  - reference: PMID:31244841
    reference_title: 'Dermatitis Herpetiformis: Novel Perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      share the same Human Leukocyte Antigen (HLA) haplotypes (DQ2 and DQ8)
    explanation: >-
      Establishes the HLA-DQ2/DQ8 restriction shared with celiac disease.
- name: Gluten-Driven Small-Bowel Autoimmunity
  biological_scale: ORGANISM
  description: >-
    DH arises from latent or manifest celiac disease in the gut: gluten exposure
    drives an IgA autoantibody response against tissue transglutaminase, with
    small-bowel villous atrophy or celiac-type inflammation in most patients.
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  downstream:
  - target: Small-bowel villous atrophy
    causal_link_type: DIRECT
    description: >-
      The gut autoimmune response produces celiac-type villous atrophy in most
      DH patients.
  - target: Anti-TG3 IgA Autoantibody Response
    causal_link_type: DIRECT
    description: >-
      The gut autoimmune response evolves into a high-avidity IgA response
      against epidermal transglutaminase.
    evidence:
    - reference: PMID:29757210
      reference_title: 'Dermatitis Herpetiformis: A Common Extraintestinal Manifestation of Coeliac Disease.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        it starts from latent or manifest coeliac disease in the gut and evolves
        into an immune complex deposition of high avidity IgA epidermal
        transglutaminase (TG3) antibodies, together with the TG3 enzyme, in the
        papillary dermis
      explanation: >-
        States the gut-origin-to-skin causal sequence.
  - target: Lymphoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The chronic gluten-driven enteropathy carries a six- to tenfold increased
      risk of enteropathy-associated lymphoma, concentrated in the years before
      a gluten-free diet is established.
    evidence:
    - reference: PMID:33432477
      reference_title: 'Dermatitis Herpetiformis: An Update on Diagnosis and Management.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Lymphomas are of enteropathy-associated T-cell or B-cell origin, and
        patients not adhering to a GFD are at special risk
      explanation: >-
        Ties the lymphoma risk to the enteropathy and to continued gluten
        exposure.
  evidence:
  - reference: PMID:31093998
    reference_title: Dermatitis herpetiformis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      DH and CD share a similar genetic background, small bowel mucosal
      alterations, and an autoimmune response against tissue transglutaminase in
      the serum and small bowel
    explanation: >-
      Locates the initiating anti-tissue-transglutaminase autoimmunity in the
      small bowel.
- name: Anti-TG3 IgA Autoantibody Response
  biological_scale: CELLULAR
  description: >-
    In DH the IgA response acquires markedly higher avidity for epidermal
    transglutaminase (TG3) than for tissue transglutaminase, and a TG3-specific
    antibody population appears. This is the molecular feature that distinguishes
    DH from celiac disease without skin involvement.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
    modifier: INCREASED
  downstream:
  - target: Granular IgA-TG3 Deposition in the Papillary Dermis
    causal_link_type: DIRECT
    description: >-
      High-avidity IgA anti-TG3 complexes with the TG3 enzyme and deposits in the
      papillary dermis.
    evidence:
    - reference: PMID:11901200
      reference_title: Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the IgA precipitates in the papillary dermis of patients with dermatitis
        herpetiformis, the defining signs of the disease, contain epidermal
        transglutaminase
      explanation: >-
        The papillary-dermis IgA deposits contain epidermal transglutaminase.
  evidence:
  - reference: PMID:11901200
    reference_title: Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      antibodies in patients having dermatitis herpetiformis show a markedly
      higher avidity for epidermal transglutaminase
    explanation: >-
      The higher-avidity anti-TG3 response defines DH.
- name: Granular IgA-TG3 Deposition in the Papillary Dermis
  biological_scale: TISSUE
  description: >-
    IgA anti-TG3 and the TG3 enzyme form tightly bound immune complexes that
    precipitate as pathognomonic granular IgA deposits in the papillary dermis.
    Passive transfer of anti-TG3 reproduces these deposits, establishing them as
    directly antibody-driven.
  genes:
  - preferred_term: TGM3
    term:
      id: hgnc:11779
      label: TGM3
  molecular_functions:
  - preferred_term: protein-glutamine gamma-glutamyltransferase activity
    term:
      id: GO:0003810
      label: protein-glutamine gamma-glutamyltransferase activity
  locations:
  - preferred_term: papillary layer of dermis
    term:
      id: UBERON:0001992
      label: papillary layer of dermis
  downstream:
  - target: Neutrophil Recruitment and Papillary Microabscess Formation
    causal_link_type: DIRECT
    description: >-
      The dermal immune deposits recruit neutrophils into the dermal papillae.
  evidence:
  - reference: PMID:11901200
    reference_title: Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a blistering skin disease characterized by granular IgA deposits in the
      papillary dermis
    explanation: >-
      Granular papillary-dermis IgA deposits are the defining lesion.
  - reference: PMID:21335491
    reference_title: Dermatitis herpetiformis sera or goat anti-transglutaminase-3 transferred to human skin-grafted mice mimics dermatitis herpetiformis immunopathology.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      All mice that received goat anti-TG3 produced papillary dermal immune
      deposits, and these deposits reacted with both rabbit anti-TG3 and DH
      patient sera.
    explanation: >-
      Passive transfer of anti-TG3 reproduces the deposits, showing they are
      antibody-driven (a human-skin-grafted mouse model).
- name: Neutrophil Recruitment and Papillary Microabscess Formation
  biological_scale: TISSUE
  description: >-
    The dermal immune deposits drive a predominant neutrophilic infiltrate into
    the dermal papillae, forming the papillary microabscesses characteristic of
    DH histopathology. Gut-derived IL-8 primes neutrophils, which bind the
    deposited IgA directly through their Fc-alpha receptor (CD89, FCAR).
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  genes:
  - preferred_term: FCAR
    term:
      id: hgnc:3608
      label: FCAR
  biological_processes:
  - preferred_term: neutrophil migration
    term:
      id: GO:1990266
      label: neutrophil migration
    modifier: INCREASED
  molecular_functions:
  - preferred_term: Fc-alpha (IgA) receptor activity
    term:
      id: GO:0019766
      label: IgA receptor activity
  locations:
  - preferred_term: papillary layer of dermis
    term:
      id: UBERON:0001992
      label: papillary layer of dermis
  downstream:
  - target: Subepidermal Vesicle Formation
    causal_link_type: DIRECT
    description: >-
      Neutrophil accumulation and enzyme release at the dermal papillae detach
      the epidermis, forming subepidermal vesicles.
    evidence:
    - reference: PMID:33432477
      reference_title: 'Dermatitis Herpetiformis: An Update on Diagnosis and Management.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        neutrophilic micro-abscesses in the dermal papillae with or without
        subepidermal blistering
      explanation: >-
        Links the papillary neutrophilic microabscesses to the subepidermal
        blister.
  - target: Pruritus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Dermal inflammation drives the intense itch. Its mechanism (neurogenic
      inflammation, IL-31) is unresolved, and pruritus can precede the visible
      lesions by hours to months, so it is not simply a consequence of the
      vesicles.
  evidence:
  - reference: PMID:31244841
    reference_title: 'Dermatitis Herpetiformis: Novel Perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      a predominant neutrophilic infiltrate at the dermal papillae at
      histopathology
    explanation: >-
      The neutrophilic papillary infiltrate is a defining histopathologic
      feature.
  - reference: PMID:31244841
    reference_title: 'Dermatitis Herpetiformis: Novel Perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Circulating and skin resident neutrophils express Fc IgA receptor (CD89),
      suggesting a direct interaction between neutrophils and IgA.
    explanation: >-
      Neutrophils bind the deposited IgA through the CD89 Fc-alpha receptor
      (FCAR).
  - reference: PMID:31244841
    reference_title: 'Dermatitis Herpetiformis: Novel Perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Activation of innate immunity in the gut leads to increased release of
      IL-8, which is thought to be responsible for the initial priming of
      neutrophils
    explanation: >-
      Gut-derived IL-8 primes the neutrophils recruited to the dermal papillae.
- name: Subepidermal Vesicle Formation
  biological_scale: TISSUE
  description: >-
    Neutrophil-mediated damage at the dermal papillae produces subepidermal
    vesicles that present clinically as grouped papules and small blisters,
    though intense scratching often destroys the primary lesions.
  locations:
  - preferred_term: epidermal-dermal junction
    term:
      id: UBERON:0008877
      label: epidermal-dermal junction
  downstream:
  - target: Pruritic papulovesicular eruption
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11901200
      reference_title: Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This is a bullous skin disease with polymorphic papules and blisters
        typically located over the extensor surfaces of the major joints
      explanation: >-
        The blistering eruption on extensor surfaces is the clinical outcome.
  evidence:
  - reference: PMID:31244841
    reference_title: 'Dermatitis Herpetiformis: Novel Perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Activated neutrophils release neutrophil elastase and granzyme B, which
      induce subepidermal split by cleaving adhesion molecules of the BMZ, such
      as collagen VII
    explanation: >-
      Neutrophil elastase and granzyme B cleave basement-membrane-zone adhesion
      molecules to produce the subepidermal split — the node's own mechanism.
phenotypes:
- category: Cutaneous
  name: Pruritic papulovesicular eruption
  description: >-
    Symmetrical grouped papules and vesicles on extensor surfaces (elbows,
    knees, buttocks, sacral region); the clinical hallmark of DH.
  phenotype_term:
    preferred_term: papulovesicular eruption
    term:
      id: HP:0033700
      label: Papulovesicular eruption
    onset:
      onset_category: ADULT
      mean_age_years: 50
      notes: >-
        DH presents mainly in adults; the mean age at onset is about 50 years
        (PMID:33432477).
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:31244841
    reference_title: 'Dermatitis Herpetiformis: Novel Perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Clinically, DH presents with polymorphic lesions, including papules,
      vesicles, and small blisters, symmetrically distributed in typical
      anatomical sites including the extensor aspects of the limbs, the elbows,
      the sacral regions, and the buttocks.
    explanation: >-
      Describes the symmetrical papulovesicular eruption on extensor surfaces.
  - reference: PMID:33432477
    reference_title: 'Dermatitis Herpetiformis: An Update on Diagnosis and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The mean age at onset is about 50 years.
    explanation: >-
      Supports the adult onset (mean ~50 years) recorded on this phenotype.
- category: Cutaneous
  name: Pruritus
  description: >-
    Intense itch, often so severe that scratching destroys the primary lesions
    and leaves excoriations.
  phenotype_term:
    preferred_term: intense pruritus
    term:
      id: HP:0000989
      label: Pruritus
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:21571167
    reference_title: Dermatitis herpetiformis. Part I. Epidemiology, pathogenesis, and clinical presentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      young adults present with excoriations only, as the severe pruritus
      effectively destroys any primary lesions
    explanation: >-
      Documents the severe pruritus characteristic of DH.
- category: Gastrointestinal
  name: Small-bowel villous atrophy
  description: >-
    Most DH patients have celiac-type small-bowel changes, ranging from villous
    atrophy to increased intraepithelial lymphocytes, usually without overt
    gastrointestinal symptoms.
  phenotype_term:
    preferred_term: villous atrophy
    term:
      id: HP:0011473
      label: Villous atrophy
  frequency: FREQUENT
  evidence:
  - reference: PMID:33432477
    reference_title: 'Dermatitis Herpetiformis: An Update on Diagnosis and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      three-fourths of patients with DH have villous atrophy in the small bowel,
      and the rest have celiac-type inflammatory changes
    explanation: >-
      Quantifies the subclinical small-bowel enteropathy in DH.
- category: Neoplasm
  name: Lymphoma
  description: >-
    Like celiac disease, DH carries a six- to tenfold increased risk of lymphoma
    (enteropathy-associated T-cell and B-cell types / non-Hodgkin lymphoma). The
    excess risk is concentrated in the first years after diagnosis and is reduced
    by strict gluten-free-diet adherence; overall DH mortality is not elevated.
  phenotype_term:
    preferred_term: increased lymphoma risk
    term:
      id: HP:0002665
      label: Lymphoma
  evidence:
  - reference: PMID:33432477
    reference_title: 'Dermatitis Herpetiformis: An Update on Diagnosis and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The risk in DH is increased six to tenfold.
    explanation: >-
      Quantifies the increased lymphoma risk in DH.
  - reference: PMID:31244841
    reference_title: 'Dermatitis Herpetiformis: Novel Perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Mortality due to non-Hodgkin lymphomas was increased only during the first
      5 years following the diagnosis but not thereafter
    explanation: >-
      The lymphoma-related mortality excess is confined to the first 5 years
      after diagnosis.
genetic:
- name: HLA-DQA1
  gene_term:
    preferred_term: HLA-DQA1
    term:
      id: hgnc:4942
      label: HLA-DQA1
  relationship_type: SUSCEPTIBILITY
  association: >-
    Component of the HLA-DQ2/DQ8 class II susceptibility haplotypes shared with
    celiac disease.
  evidence:
  - reference: PMID:31244841
    reference_title: 'Dermatitis Herpetiformis: Novel Perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      share the same Human Leukocyte Antigen (HLA) haplotypes (DQ2 and DQ8)
    explanation: >-
      HLA-DQ2/DQ8 haplotypes confer DH susceptibility.
- name: HLA-DQB1
  gene_term:
    preferred_term: HLA-DQB1
    term:
      id: hgnc:4944
      label: HLA-DQB1
  relationship_type: SUSCEPTIBILITY
  association: >-
    Component of the HLA-DQ2/DQ8 class II susceptibility haplotypes shared with
    celiac disease.
  evidence:
  - reference: PMID:31244841
    reference_title: 'Dermatitis Herpetiformis: Novel Perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      share the same Human Leukocyte Antigen (HLA) haplotypes (DQ2 and DQ8)
    explanation: >-
      HLA-DQ2/DQ8 haplotypes confer DH susceptibility.
environmental:
- name: Dietary gluten exposure
  description: >-
    Dietary gluten is the necessary environmental trigger. It drives the
    small-bowel autoimmunity that underlies DH, and its removal (a gluten-free
    diet) heals both the rash and the enteropathy.
  effect: Necessary dietary trigger; removal is disease-modifying
  chemicals:
  - gluten
  influences_mechanisms:
  - target: Gluten-Driven Small-Bowel Autoimmunity
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Gluten ingestion drives the gut autoimmune response that initiates DH.
    evidence:
    - reference: PMID:31093998
      reference_title: Dermatitis herpetiformis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The treatment of choice in DH is a strict, life-long adherence to a
        gluten-free diet (GFD).
      explanation: >-
        Gluten removal being the definitive treatment establishes gluten as the
        causal exposure.
  evidence:
  - reference: PMID:11901200
    reference_title: Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      evoked and maintained by gluten
    explanation: >-
      Names gluten as the environmental factor that evokes and maintains
      gluten-sensitive disease.
- name: Iodide and NSAID exposure
  description: >-
    Dietary iodide and certain NSAIDs (e.g. indomethacin) are recognized
    exacerbating triggers that worsen the rash and itch in established DH.
  effect: Exacerbating exposures in established disease
  chemicals:
  - iodide
  - indomethacin
  influences_mechanisms:
  - target: Neutrophil Recruitment and Papillary Microabscess Formation
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      These exposures worsen the neutrophil-driven rash in established DH.
    evidence:
    - reference: PMID:33432477
      reference_title: 'Dermatitis Herpetiformis: An Update on Diagnosis and Management.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Triggering factors such as taking indomethacin and inadvertent dietary
        iodide ingestion are known to exacerbate the rash and itching
      explanation: >-
        Names indomethacin and dietary iodide as recognized exacerbating
        triggers.
  evidence:
  - reference: PMID:33432477
    reference_title: 'Dermatitis Herpetiformis: An Update on Diagnosis and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Triggering factors such as taking indomethacin and inadvertent dietary
      iodide ingestion are known to exacerbate the rash and itching
    explanation: >-
      Documents iodide and NSAID exacerbation of the DH rash.
treatments:
- name: Gluten-free diet
  description: >-
    A strict, lifelong gluten-free diet is the treatment of choice for all DH
    patients. It heals both the rash and the small-bowel enteropathy and lowers
    lymphoma risk, though its effect on the rash is slow.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Gluten-Driven Small-Bowel Autoimmunity
    treatment_effect: INHIBITS
    description: >-
      Removing gluten withdraws the trigger of the entire disease cascade.
  - target: Lymphoma
    treatment_effect: INHIBITS
    description: >-
      Strict gluten-free-diet adherence lowers the enteropathy-associated
      lymphoma risk.
    evidence:
    - reference: PMID:31093998
      reference_title: Dermatitis herpetiformis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        a GFD increases the quality of life for patients, and decreases the risk
        for lymphoma in DH
      explanation: >-
        A gluten-free diet reduces the lymphoma risk in DH.
  evidence:
  - reference: PMID:33432477
    reference_title: 'Dermatitis Herpetiformis: An Update on Diagnosis and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      the treatment of choice for all patients is a gluten-free diet
    explanation: >-
      Gluten-free diet is the definitive treatment for DH.
- name: Dapsone
  description: >-
    Dapsone rapidly controls the rash and itch at onset by suppressing neutrophil
    function; most patients can stop it after about two years once a strict
    gluten-free diet controls the disease.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dapsone
      term:
        id: CHEBI:4325
        label: dapsone
  target_mechanisms:
  - target: Neutrophil Recruitment and Papillary Microabscess Formation
    treatment_effect: INHIBITS
    description: >-
      Dapsone suppresses the neutrophilic infiltrate that produces the rash.
  evidence:
  - reference: PMID:33432477
    reference_title: 'Dermatitis Herpetiformis: An Update on Diagnosis and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      At onset, most patients need additional dapsone to rapidly control the
      rash and itching
    explanation: >-
      Dapsone is the adjunct for rapid symptom control at onset.
- name: Sulfasalazine
  description: >-
    A sulfonamide used as a dapsone alternative when dapsone is not tolerated or
    is contraindicated; it carries a lower monitoring burden than dapsone but can
    still cause hemolytic anemia and gastrointestinal upset.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sulfasalazine
      term:
        id: CHEBI:9334
        label: sulfasalazine
  target_mechanisms:
  - target: Neutrophil Recruitment and Papillary Microabscess Formation
    treatment_effect: INHIBITS
    description: >-
      As a dapsone alternative, sulfasalazine suppresses the neutrophilic
      infiltrate driving the rash.
  evidence:
  - reference: PMID:31244841
    reference_title: 'Dermatitis Herpetiformis: Novel Perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Possible alternatives to dapsone are the so-called sulfonamides, including
      sulfasalazine, sulfapyridine, and sulfamethoxypyridazine
    explanation: >-
      Names sulfasalazine among the sulfonamide dapsone alternatives.
- name: Rituximab
  description: >-
    An anti-CD20 monoclonal antibody reported in a single refractory case of DH
    resistant to gluten-free diet, dapsone, sulfasalazine, and conventional
    immunosuppressants. It depletes CD20+ B cells (the autoantibody-producing
    lineage), not the terminally differentiated plasma cells.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  target_mechanisms:
  - target: Anti-TG3 IgA Autoantibody Response
    treatment_effect: INHIBITS
    description: >-
      B-cell depletion curtails the autoantibody-producing response in
      refractory disease.
  evidence:
  - reference: PMID:31244841
    reference_title: 'Dermatitis Herpetiformis: Novel Perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      rituximab has been proven to be effective in a patient resistant to GFD,
      dapsone, sulfasalazine, and conventional immunosuppressive agents such as
      azathioprine
    explanation: >-
      Rituximab is an option for recalcitrant DH.
diagnosis:
- name: Direct immunofluorescence of perilesional skin
  description: >-
    Direct immunofluorescence of perilesional skin showing pathognomonic granular
    IgA deposits in the papillary dermis confirms the diagnosis.
  evidence:
  - reference: PMID:29757210
    reference_title: 'Dermatitis Herpetiformis: A Common Extraintestinal Manifestation of Coeliac Disease.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Diagnosis of DH is easily confirmed by immunofluorescence biopsy showing
      pathognomonic granular immunoglobulin A (IgA) deposits in the papillary
      dermis.
    explanation: >-
      Granular papillary-dermis IgA on DIF is the diagnostic gold standard.
- name: Serum anti-transglutaminase IgA
  description: >-
    Circulating IgA autoantibodies against epidermal transglutaminase (TG3),
    and against tissue transglutaminase, support the diagnosis, though their
    absence does not exclude DH.
  evidence:
  - reference: PMID:31244841
    reference_title: 'Dermatitis Herpetiformis: Novel Perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      assessing serum titers of autoantibodies against epidermal transglutaminase
      (eTG), the supposed autoantigen of DH, may also serve as a clue for the
      diagnosis
    explanation: >-
      Serum anti-epidermal-transglutaminase IgA is a supporting diagnostic
      marker.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Dermatitis_Herpetiformis · 2026-09-30T23:44:33Z · View source

New entry for dermatitis herpetiformis (MONDO:0015614), the cutaneous IgA/epidermal-transglutaminase (TG3) manifestation of gluten sensitivity. Deep research: claude_code (research/Dermatitis_Herpetiformis-deep-research-claude_code.md); report used as a coverage lead only. All 22 evidence snippets were taken from independently PubMed-fetched, cached abstracts and verified. Causal chain: HLA-DQ2/DQ8 gluten presentation -> gut small-bowel autoimmunity (anti-tTG) -> high-avidity anti-TG3 IgA -> granular IgA-TG3 papillary-dermis deposition -> neutrophil recruitment/microabscess -> subepidermal vesicles -> pruritic papulovesicular eruption; all 3 phenotypes causally connected. Key PMIDs: 11901200 (TG3 as DH autoantigen, Sardy), 29757210/31093998/33432477/31244841/21571167 (reviews), 21335491 (anti-TG3 passive transfer, human-skin-grafted mouse). Gluten environmental trigger left without ECTO term (searched l~gluten, l~wheat; none). No GeneReviews chapter (complex HLA disease). Validated: just validate (schema/terms/22 snippets), check-entity-refs, check-causal-targets, gene-grounding, list-disconnected-phenotypes (3/3).

Claude Code ▸
1. Disease Information
claude-haiku-4-5-20251001, claude-sonnet-5-5 2026-09-30T23:37:34.918037

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

Phenotype Notes HPO lead (verify)
Intense pruritus Burning or itching often precedes lesions Pruritus
Grouped papulovesicles on extensor surfaces Elbows, knees, buttocks, scalp, sacrum; symmetric Vesicular/bullous eruption
Excoriations and erosions Vesicles are usually scratched off, so intact blisters are uncommon Excoriation
Granular IgA deposits (laboratory/histologic) Pathognomonic finding Skin IgA deposition lead
Associated gluten-sensitive enteropathy Often subclinical in DH Villous atrophy
Gastrointestinal symptoms Reported at diagnosis and persist in some patients on GFD (PMID:37595955) Abdominal pain, diarrhea leads
  • 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.

Outcome Count
References checked 18
Resolved 18
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 6
Quoted claims found in source 5
Quoted claims not found in source 1
References weighed for topical relevance 18
On topic 8
Off topic 0

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.

Outcome Count
Terms checked 2
Resolved 2
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0

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