Atopic Dermatitis

name: Atopic Dermatitis
category: Complex
parents:
- Dermatological Disease
- Chronic Inflammatory Disease
- Allergic Disease
has_subtypes:
- name: Early-Onset Atopic Dermatitis
  description: Onset in infancy or early childhood, often associated with the 
    atopic march progressing to asthma and allergic rhinitis.
- name: Adult-Onset Atopic Dermatitis
  description: First presentation in adulthood, often with different clinical 
    distribution and associations compared to childhood-onset disease.
- name: Extrinsic Atopic Dermatitis
  description: Associated with IgE-mediated sensitization to environmental 
    allergens. Elevated serum IgE and positive skin prick tests.
- name: Intrinsic Atopic Dermatitis
  description: Without IgE-mediated sensitization. Normal serum IgE levels. 
    Represents approximately 20% of cases.
pathophysiology:
- name: Epidermal Barrier Dysfunction
  description: Loss-of-function mutations in filaggrin (FLG) and other barrier 
    proteins lead to impaired skin barrier integrity, increased transepidermal 
    water loss, and enhanced allergen penetration. This is the primary 
    initiating event in many patients.
  genes:
  - preferred_term: FLG
    term:
      id: hgnc:3748
      label: FLG
  biological_processes:
  - preferred_term: Keratinization
    term:
      id: GO:0031424
      label: keratinization
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:16550169
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Filaggrin is a key protein that facilitates terminal
      differentiation of the epidermis and formation of the skin barrier. Here
      we show that two independent loss-of-function genetic variants (R510X
      [sic, correct designation is R501X] and 2282del4) in the gene encoding
      filaggrin (FLG) are very strong predisposing factors for atopic
      dermatitis.
    explanation: Landmark study establishing FLG loss-of-function as the
      strongest genetic risk factor for atopic dermatitis, with ~9% carrier
      frequency in Europeans.
  - reference: PMID:21388665
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: They are similar in that they are complex inherited diseases
      involving genes that encode immune components and structural proteins that
      regulate differentiation of epidermal cells. Each disease is characterized
      by proliferation of epidermal keratinocytes and abnormal cornification or
      terminal differentiation in the epidermis
    explanation: Describes the epidermal barrier dysfunction in atopic
      dermatitis including abnormal cornification and keratinocyte
      differentiation.
- name: Type 2 Immune Response
  description: Th2-skewed immune response drives the hallmark inflammation. 
    IL-4, IL-13, and IL-31 promote IgE production, eosinophil recruitment, and 
    pruritus. IL-4/IL-13 signaling through JAK1/STAT6 further impairs barrier 
    function by downregulating filaggrin and other barrier proteins.
  genes:
  - preferred_term: IL4
    term:
      id: hgnc:6014
      label: IL4
  - preferred_term: IL13
    term:
      id: hgnc:5973
      label: IL13
  - preferred_term: IL31
    term:
      id: hgnc:19372
      label: IL31
  - preferred_term: STAT6
    term:
      id: hgnc:11368
      label: STAT6
  downstream:
  - target: Epidermal Barrier Dysfunction
    description: IL-4 and IL-13 downregulate filaggrin expression, creating a 
      vicious cycle of barrier disruption and immune activation.
  - target: Pruritogen-Induced Neuronal Activation
    description: IL-31 signaling contributes to neuronal itch signaling in 
      lesional skin.
  biological_processes:
  - preferred_term: Type 2 immune response
    term:
      id: GO:0042092
      label: type 2 immune response
  - preferred_term: T-helper 2 cell differentiation
    term:
      id: GO:0045064
      label: T-helper 2 cell differentiation
  - preferred_term: Interleukin-4-mediated signaling pathway
    term:
      id: GO:0035771
      label: interleukin-4-mediated signaling pathway
  - preferred_term: IgE isotype switching
    term:
      id: GO:0035708
      label: interleukin-4-dependent isotype switching to IgE isotypes
  cell_types:
  - preferred_term: T-helper 2 cell
    term:
      id: CL:0000546
      label: T-helper 2 cell
  - preferred_term: Group 2 innate lymphoid cell
    term:
      id: CL:0001069
      label: group 2 innate lymphoid cell
  - preferred_term: Eosinophil
    term:
      id: CL:0000771
      label: eosinophil
  - preferred_term: Mast cell
    term:
      id: CL:0000097
      label: mast cell
  evidence:
  - reference: PMID:30819278
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Type 2 cytokines as well as interleukin 17 and interleukin 22
      contribute to skin barrier dysfunction and the development of AD.
    explanation: Confirms the role of type 2 cytokines in AD pathophysiology and
      their contribution to barrier dysfunction, supporting the Th2/type 2
      immune mechanism.
  - reference: PMID:21388665
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: skin lesions contain immune infiltrates of T cells, dendritic
      cells, and other types of leukocytes. We review similarities between the
      diseases and differences in epidermal barrier defects and immune cells.
    explanation: Describes the immune cell infiltrates in AD lesions including T
      cells and dendritic cells, consistent with type 2 immune response.
- name: Th17/Th22 Inflammation
  description: In addition to the dominant Th2 response, Th17 and Th22 cells 
    contribute to inflammation, particularly in acute lesions and Asian 
    patients. IL-17 and IL-22 further disrupt epidermal differentiation.
  biological_processes:
  - preferred_term: T-helper 17 type immune response
    term:
      id: GO:0072538
      label: T-helper 17 type immune response
  cell_types:
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
- name: Pruritogen-Induced Neuronal Activation
  description: IL-31 and other pruritogens activate cutaneous sensory neurons, 
    generating persistent itch in atopic dermatitis.
  genes:
  - preferred_term: IL31
    term:
      id: hgnc:19372
      label: IL31
  downstream:
  - target: Scratching-Induced Barrier Injury
    description: Persistent itch drives repetitive scratching behavior.
  cell_types:
  - preferred_term: Sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  evidence:
  - reference: PMID:30819278
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: New insights into the pathophysiology of AD have focused on
      epidermal lipid profiles, neuroimmune interactions, and microbial
      dysbiosis.
    explanation: Supports neuroimmune signaling as a component of AD
      pathophysiology.
- name: Scratching-Induced Barrier Injury
  description: Repetitive scratching causes mechanical skin injury and worsens 
    epidermal barrier dysfunction.
  downstream:
  - target: Secondary Inflammatory Amplification
    description: Mechanical barrier injury increases local inflammatory 
      activation.
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
- name: Secondary Inflammatory Amplification
  description: Barrier injury from scratching perpetuates inflammatory signaling
    and contributes to chronic lesion persistence.
  biological_processes:
  - preferred_term: Inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
phenotypes:
- name: Eczematoid Dermatitis
  category: Dermatological
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Erythematous, pruritic patches and plaques with scaling, often in 
    flexural areas.
  phenotype_term:
    preferred_term: Eczematoid dermatitis
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
- name: Pruritus
  category: Dermatological
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Intense itching is the hallmark symptom, often worse at night.
  phenotype_term:
    preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
- name: Xerosis
  category: Dermatological
  frequency: VERY_FREQUENT
  notes: Generalized dry skin reflecting barrier dysfunction.
  phenotype_term:
    preferred_term: Xerosis
    term:
      id: HP:0000958
      label: Dry skin
- name: Lichenification
  category: Dermatological
  frequency: FREQUENT
  notes: Thickened, leathery skin from chronic scratching.
  phenotype_term:
    preferred_term: Lichenification
    term:
      id: HP:0100725
      label: Lichenification
- name: Elevated Serum IgE
  category: Immunological
  frequency: FREQUENT
  notes: Present in extrinsic subtype (~80% of patients).
  phenotype_term:
    preferred_term: Elevated serum IgE
    term:
      id: HP:0003212
      label: Increased circulating IgE concentration
genetic:
- name: FLG
  association: Associated
  notes: Loss-of-function variants are the strongest genetic risk factor. R501X 
    and 2282del4 are common in European populations.
  evidence:
  - reference: PMID:16550169
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: two independent loss-of-function genetic variants (R510X
      [sic, correct designation is R501X] and 2282del4) in the gene encoding
      filaggrin (FLG) are very strong predisposing factors for atopic
      dermatitis. These variants are carried by approximately 9% of people of
      European origin.
    explanation: Landmark Palmer et al. 2006 study establishing FLG
      loss-of-function as the major genetic predisposing factor for atopic
      dermatitis.
- name: IL4R
  association: Associated
  notes: Variants in IL-4 receptor alpha chain affect Th2 signaling intensity.
- name: IL13
  association: Associated
  notes: Variants affecting IL-13 expression or function.
- name: STAT6
  association: Associated
  notes: Transcription factor downstream of IL-4/IL-13 signaling.
- name: EMSY
  association: Associated
  notes: Chromatin remodeling factor identified in GWAS.
- name: BACH2
  association: GWAS
  notes: Transcription factor regulating Treg/effector T cell balance and B cell
    class switching
- name: TNFAIP3
  association: GWAS
  notes: Encodes A20, a ubiquitin-editing enzyme that negatively regulates NF-kB
    signaling
- name: EGR2
  association: GWAS
  notes: Transcription factor involved in T cell anergy and peripheral tolerance
- name: ETS1
  association: GWAS
  notes: Transcription factor regulating T and B cell development and immune 
    cell differentiation
- name: IRF4
  association: GWAS
  notes: Transcription factor essential for Th17 and Th2 cell differentiation 
    and plasma cell development
- name: SATB1
  association: GWAS
  notes: Chromatin organizer regulating T cell development and lineage 
    commitment
- name: SMAD3
  association: GWAS
  notes: TGF-beta signaling mediator regulating T cell differentiation and 
    immune tolerance
- name: REL
  association: GWAS
  notes: NF-kB subunit c-Rel controlling lymphocyte activation and survival
environmental:
- name: Allergen Exposure
  description: House dust mites, pet dander, and pollens can trigger or 
    exacerbate disease.
  effect: TRIGGERS
- name: Skin Irritants
  description: Soaps, detergents, and harsh fabrics disrupt the already 
    compromised barrier.
  effect: TRIGGERS
- name: Microbial Dysbiosis
  description: Staphylococcus aureus colonization is found in >90% of lesional 
    skin and amplifies inflammation through superantigens and biofilm formation.
  effect: WORSENS
treatments:
- name: Emollients and Moisturizers
  description: First-line treatment to restore skin barrier function and reduce 
    transepidermal water loss.
- name: Topical Corticosteroids
  description: First-line anti-inflammatory treatment for flares, applied to 
    affected areas.
- name: Dupilumab
  description: Monoclonal antibody targeting IL-4 receptor alpha, blocking both 
    IL-4 and IL-13 signaling. FDA-approved for moderate-to-severe atopic 
    dermatitis.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: dupilumab
      term:
        id: NCIT:C162455
        label: Dupilumab
- name: JAK Inhibitors
  description: Oral (baricitinib, upadacitinib, abrocitinib) and topical 
    (ruxolitinib) JAK inhibitors targeting the JAK-STAT pathway downstream of 
    type 2 cytokines.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
- name: Phototherapy
  description: Narrowband UVB phototherapy for moderate-to-severe disease.
disease_term:
  preferred_term: atopic dermatitis
  term:
    id: MONDO:0004980
    label: atopic eczema
references:
- reference: DOI:10.1007/s13555-025-01352-y
  title: 'Interleukin-4 and Atopic Dermatitis: Why Does it Matter? A Narrative Review'
  findings: []
- reference: DOI:10.1038/s41467-023-41857-8
  title: Multifaceted analysis of cross-tissue transcriptomes reveals 
    phenotype–endotype associations in atopic dermatitis
  findings: []
- reference: DOI:10.1126/sciimmunol.abi6887
  title: IL-31–dependent neurogenic inflammation restrains cutaneous type 2 
    immune response in allergic dermatitis
  findings: []
- reference: DOI:10.1186/s43556-025-00313-3
  title: 'Atopic dermatitis: diagnosis, molecular pathogenesis, and therapeutics'
  findings: []
- reference: DOI:10.14789/ejmj.jmj24-0036-r
  title: Mechanisms of Itch in Atopic Dermatitis
  findings: []
- reference: DOI:10.3390/jcm12041538
  title: 'The Role of Tight Junctions in Atopic Dermatitis: A Systematic Review'
  findings: []
- reference: DOI:10.3390/jcm14145053
  title: 'Anti-Inflammatory Therapies for Atopic Dermatitis: A New Era in Targeted
    Treatment'
  findings: []
- reference: DOI:10.64898/2026.01.10.26343854
  title: 'Protective and Susceptibility Clusters of Environmental Factors, Gene Expression,
    Antibody Responses, and Cytokines in Pediatric Atopic Dermatitis: Insights from
    Multi-Modal Data Integration'
  findings: []
- reference: DOI:10.7759/cureus.86937
  title: 'Skin Barrier Dysfunction in Chronic Dermatoses: From Pathophysiology to
    Emerging Therapeutic Strategies'
  findings: []