Atopic Dermatitis

Complex MONDO:0004980 Pathograph 23 Show in embeddings browser Dermatological Disease Chronic Inflammatory Disease Allergic Disease

Atopic dermatitis is a chronic, relapsing inflammatory skin disease arising from the combination of epidermal barrier dysfunction and type 2-skewed immune dysregulation. Loss-of-function variants in filaggrin and related barrier defects increase transepidermal water loss and allow penetration of allergens and microbes, while keratinocyte-derived alarmins (TSLP, IL-25, IL-33) drive Th2 responses with IL-4, IL-13, and IL-31 that further impair barrier proteins and lipids and mediate pruritus. The resulting itch-scratch cycle, skin dysbiosis with Staphylococcus aureus overgrowth, and sustained inflammation produce the eczematous, lichenified, intensely pruritic lesions, often as part of the broader atopic march.

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7
Pathophys.
13
Phenotypes
3
Gaps
23
Pathograph
13
Genes
7
Medical Actions
4
Subtypes
8
Datasets
9
References
2
Deep Research
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Classifications

Harrison's Part
DERMATOLOGY IMMUNE RHEUMATOLOGIC
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Subtypes

4
Early-Onset Atopic Dermatitis
Onset in infancy or early childhood, often associated with the atopic march progressing to asthma and allergic rhinitis.
Adult-Onset Atopic Dermatitis
First presentation in adulthood, often with different clinical distribution and associations compared to childhood-onset disease.
Extrinsic Atopic Dermatitis
Associated with IgE-mediated sensitization to environmental allergens. Elevated serum IgE and positive skin prick tests.
Show evidence (1 reference)
PMID:36983191 SUPPORT Human Clinical
"Atopic dermatitis (AD) can be subclassified into the more frequent extrinsic type (EAD), with elevated serum IgE levels and frequent association with other atopic conditions, and the less frequent intrinsic type (IAD), with normal IgE levels and no history of atopy."
Defines the extrinsic subtype as the more frequent form, with elevated serum IgE and frequent association with other atopic conditions.
Intrinsic Atopic Dermatitis
Without IgE-mediated sensitization. Normal serum IgE levels. Represents approximately 20% of cases.
Show evidence (1 reference)
PMID:36983191 SUPPORT Human Clinical
"Atopic dermatitis (AD) can be subclassified into the more frequent extrinsic type (EAD), with elevated serum IgE levels and frequent association with other atopic conditions, and the less frequent intrinsic type (IAD), with normal IgE levels and no history of atopy."
Defines the intrinsic subtype as the less frequent form, with normal IgE levels and no history of atopy.
C

Comorbidities

Atopic Dermatitis <-> Asthma
Disease A A_BEFORE_B CURATED
Atopic Dermatitis <-> Type 2 Diabetes Mellitus
Disease A A_BEFORE_B CANDIDATE
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Discussions and Knowledge Gaps

3
In human atopic dermatitis, is skin dysbiosis (loss of commensal diversity with Staphylococcus aureus overgrowth) a driver of disease, an amplifier that sustains established lesions, or mainly a consequence of the barrier defect and the type 2 cytokine milieu that together suppress cutaneous antimicrobial defence?
KNOWLEDGE GAP OPEN gap_ad_dysbiosis_causal_ordering
Attached to
pathophysiology#Epidermal Barrier Dysfunction pathophysiology#Type 2 Immune Response pathophysiology#Secondary Inflammatory Amplification
The environmental entry Microbial Dysbiosis records that S. aureus occupies roughly 70 percent of lesional skin and that its abundance rises with flares and with severity, and it now declares influences_mechanisms edges into the type 2 and secondary amplification nodes. Both edges are drawn EXACERBATES rather than TRIGGERS, because the abundant correlational human data are compatible with either direction and the two directions are separately evidenced. Evidence for dysbiosis acting causally is largely from model systems and from commensal biology. In Adam17-deficient mice, species-specific antibiotics reversed the dysbiosis and eliminated the skin inflammation, an interventional result no human study matches; the same abstract states plainly that the causal relationship in human disease has yet to be clarified. In humans, coagulase-negative staphylococci producing antimicrobial peptides are depleted on atopic dermatitis skin, their scarcity correlates with S. aureus colonization, and reintroducing active strains lowered S. aureus, which is a human interventional result on colonization but not on disease activity. Evidence for dysbiosis being downstream is at least as strong in humans. Blocking IL-4 receptor alpha with dupilumab in a placebo-controlled trial raised microbial diversity and lowered S. aureus abundance in both lesional and nonlesional skin, with the fall tracking clinical improvement and type 2 biomarkers; the microbiome shifted because the host immune state was changed, not the other way round. In a birth cohort followed to one year, infants who went on to develop atopic dermatitis were not colonized by S. aureus before disease onset, and it was the relative abundance of protective commensal staphylococci at two months, not pathobiont overgrowth, that distinguished them. A defensible reading is that the two arms describe different disease stages, with commensal depletion preceding infantile onset and S. aureus overgrowth amplifying established adult lesions. That reading is currently an inference across separate cohorts, assay generations, and age groups rather than a measured trajectory, and until it is tested the edges above should not be strengthened to TRIGGERS. Note also that most human abundance data cited here are 16S amplicon rather than shotgun metagenomic, so species-level and strain-level attribution carries the resolution limits recorded on the Microbial Dysbiosis evidence items.
Proposed experiments
Birth-cohort strain-resolved ordering of dysbiosis against barrier and type 2 onset
longitudinal birth cohort with paired multi-omic skin sampling Relation: this experiment is of type this experiment type This experiment is of type longitudinal birth cohort with paired multi-omic skin sampling.
exp_ad_dysbiosis_temporal_ordering
Follow an unselected birth cohort from the neonatal period through the age of peak atopic dermatitis incidence, sampling predilection and control skin sites at fixed intervals regardless of disease status. Pair shotgun metagenomics, which resolves S. aureus and commensal staphylococci to strain level where amplicon sequencing cannot, with transepidermal water loss, filaggrin genotype, and tape-strip measurement of type 2 cytokines and antimicrobial peptides at the same visits. Analyse each subject as their own control across the transition into disease, so the question becomes which measurement moves first within an individual rather than which group differs at one cross-section. Stratify by age at onset to test the staged reading in which commensal depletion precedes infantile disease while pathobiont overgrowth amplifies established lesions.
Readouts
Time ordering of commensal depletion against barrier change
pathophysiology#Epidermal Barrier Dysfunction
Determine whether the fall in commensal staphylococcal abundance precedes, coincides with, or follows the measurable rise in transepidermal water loss within individual subjects who go on to develop disease.
shotgun metagenomic sequencing Relation: this readout is measured by this assay This readout is measured by shotgun metagenomic sequencing. transepidermal water loss measurement Relation: this readout is measured by this assay This readout is measured by transepidermal water loss measurement.
Time ordering of S. aureus expansion against type 2 activation
pathophysiology#Type 2 Immune Response
Determine whether S. aureus expansion precedes or follows the local rise in type 2 cytokines and the fall in antimicrobial peptide expression at the same skin site.
cytokine quantification Relation: this readout is measured by this assay This readout is measured by cytokine quantification. shotgun metagenomic sequencing Relation: this readout is measured by this assay This readout is measured by shotgun metagenomic sequencing.
Pathobiont load against lesion persistence in established disease
pathophysiology#Secondary Inflammatory Amplification
In subjects with established disease, test whether S. aureus load predicts subsequent lesion persistence and severity beyond what the concurrent type 2 biomarker level already predicts.
quantitative PCR Relation: this readout is measured by this assay This readout is measured by quantitative PCR.
Direction: POSITIVE
Decision criterion
A driver model is supported if commensal depletion or S. aureus expansion reproducibly precedes barrier and type 2 change within individuals before disease onset. A consequence model is supported if the microbial change follows barrier or type 2 change, consistent with the dupilumab trial in which suppressing type 2 signalling alone restored diversity. A staged model is supported if the ordering differs by age at onset, with commensal depletion leading in infantile disease and S. aureus expansion following in established disease; in that case the two influences_mechanisms edges should be re-curated separately rather than kept uniform.
Would support
pathophysiology#Epidermal Barrier Dysfunction pathophysiology#Type 2 Immune Response pathophysiology#Secondary Inflammatory Amplification
Show evidence (5 references)
PMID:25902485 SUPPORT Other
"However, the causal relationship of dysbiosis and eczema has yet to be clarified."
States the gap directly. The paper that supplies the strongest causal evidence for the driver arm is explicit that the human causal relationship is unresolved. Classified OTHER on the same basis as the PMID:28228596 framing sentence on the amplification edge: this is the authors' statement of the state of the field, not a result of the mouse work reported in the paper, and it asserts an absence of evidence rather than presenting any.
PMID:28228596 SUPPORT Human Clinical
"reintroduction of antimicrobial CoNS strains to human subjects with AD decreased colonization by S. aureus"
Human interventional evidence for the driver arm, but the measured endpoint is colonization rather than disease activity, so it establishes that commensal deficiency is upstream of pathobiont load without establishing that either is upstream of inflammation.
PMID:31252032 REFUTE Human Clinical
"Decreased S. aureus abundance during dupilumab treatment correlated with clinical improvement of AD and biomarkers of type 2 immunity."
Placebo-controlled human evidence for the consequence arm, and the reason this gap is recorded rather than resolved. Suppressing type 2 signalling alone reduced S. aureus and raised diversity, so the microbiome tracked the host immune state. Marked REFUTE against the proposition that dysbiosis is an autonomous upstream driver, not against the disease association itself.
+ 2 more references
TOPK (PBK) is upregulated in atopic dermatitis and its inhibition attenuates AD-like inflammation via STAT3 Ser727 phosphorylation in keratinocytes and mast cells, but is TOPK-STAT3 signaling a primary causal driver of AD pathogenesis or a downstream amplifier of the established type 2 / barrier circuit, what is its dominant in vivo cellular source, and does the axis translate from cell and mouse models to human disease?
KNOWLEDGE GAP OPEN gap_ad_topk_stat3_axis
Attached to
pathophysiology#Type 2 Immune Response pathophysiology#Epidermal Barrier Dysfunction pathophysiology#Secondary Inflammatory Amplification
Atopic dermatitis pathogenesis is well characterized at the level of epidermal barrier dysfunction and the IL-4/IL-13/IL-31 type 2 immune program signaling through JAK1/STAT6, which underpins approved biologic and JAK-inhibitor therapies. Recent work identifies T-LAK-cell-originated protein kinase (TOPK) as upregulated in AD lesions, where it directly interacts with and phosphorylates STAT3 at Ser727 in HaCaT keratinocytes and mast cells, and where genetic or pharmacologic TOPK inhibition reduces IgE, IL-6, IL-8, and IL-33 and attenuates AD-like features. What remains unresolved is the causal placement of this TOPK-STAT3 axis: whether it initiates inflammation upstream of, runs in parallel to, or is induced by the canonical type 2 and barrier pathways, and whether STAT3 Ser727 signaling acts mainly in keratinocytes, mast cells, or other resident/infiltrating cells in intact skin. The current evidence rests largely on cell lines, bioinformatic (GEO) profiling, and a disease model, so the human translational relevance and therapeutic window of TOPK inhibition relative to existing STAT6/JAK-directed therapies is unknown.
Proposed experiments
Cell-type-resolved epistasis of the TOPK-STAT3 axis versus the type 2 barrier circuit
cell-type-conditional perturbation and epistasis study Relation: this experiment is of type this experiment type This experiment is of type cell-type-conditional perturbation and epistasis study.
exp_ad_topk_stat3_epistasis
Use cell-type-conditional TOPK loss- and gain-of-function in barrier and immune compartments of AD models, combined with epistasis against IL-4/ IL-13 (type 2) and barrier perturbations and STAT3 Ser727 phospho-readouts, to place TOPK-STAT3 in the causal hierarchy and identify the dominant in vivo cellular source. Cross-validate against human AD skin to test translational relevance.
Readouts
STAT3 Ser727 phosphorylation by compartment
pathophysiology#Secondary Inflammatory Amplification
Quantify STAT3 Ser727 phosphorylation in keratinocytes versus mast cells and other skin-resident cells under TOPK perturbation to localize the active signaling compartment.
phospho-specific immunostaining Relation: this readout is measured by this assay This readout is measured by phospho-specific immunostaining. phosphoproteomic profiling Relation: this readout is measured by this assay This readout is measured by phosphoproteomic profiling.
Direction: POSITIVE
Type 2 cytokine and barrier dependence
pathophysiology#Type 2 Immune Response
Test whether TOPK-driven inflammation persists when IL-4/IL-13 signaling is blocked, distinguishing an upstream/parallel driver from a type 2-dependent amplifier.
cytokine quantification Relation: this readout is measured by this assay This readout is measured by cytokine quantification.
Direction: NEGATIVE
Barrier integrity response to TOPK modulation
pathophysiology#Epidermal Barrier Dysfunction
Measure transepidermal water loss and barrier protein expression after TOPK inhibition to determine whether the axis modifies barrier function directly or only via inflammation.
transepidermal water loss measurement Relation: this readout is measured by this assay This readout is measured by transepidermal water loss measurement.
Direction: NEGATIVE
Decision criterion
TOPK-STAT3 is supported as a primary driver if compartment-conditional TOPK loss reduces AD-like inflammation independently of (and upstream of) intact IL-4/IL-13 signaling, with the dominant active STAT3 Ser727 compartment reproducibly identified and the axis detectable in human AD skin; it is a downstream amplifier if its effects require an intact type 2 circuit.
Would support
pathophysiology#Type 2 Immune Response pathophysiology#Secondary Inflammatory Amplification pathophysiology#Epidermal Barrier Dysfunction
Show evidence (2 references)
PMID:42237026 SUPPORT In Vitro
"T-Lymphokine-Activated Killer Cell-Originated Protein Kinase (TOPK) is known to promote inflammation, its specific role in AD remains unclear."
Establishes that TOPK is implicated in inflammation but its specific mechanistic role in atopic dermatitis is unresolved, motivating the gap.
PMID:42237026 SUPPORT In Vitro
"TOPK was found to directly interact with and phosphorylate STAT3 at Ser727. Inhibition of TOPK in both HaCaT keratinocytes and mast cells decreased STAT3 phosphorylation at Ser727, thereby alleviating AD-related inflammatory responses."
Defines the proposed TOPK-STAT3 Ser727 mechanism in keratinocytes and mast cells, the candidate axis whose causal placement and cellular source the gap seeks to resolve.
Atopic dermatitis is associated with impaired oral health (higher plaque, poorer oral hygiene, oral dysbiosis) in adults, and in a Singaporean birth cohort (GUSTO) atopic dermatitis with allergen sensitization in the first year of life was associated with an increased risk of early childhood caries by age 3 (adjusted OR ~3.1 for the AD-SPT-positive group). Is this AD-caries comorbidity causal - e.g., via shared structural-gene defects in skin and tooth/enamel, oral dysbiosis, dietary/behavioral mediators, or AD-related sleep disturbance and medication use - or is it confounded by shared socioeconomic and dietary risk factors?
OPEN QUESTION OPEN openq_ad_oral_health_caries_comorbidity
The GUSTO cohort proposed a "structural defect hypothesis": because both dental caries susceptibility and atopic dermatitis are linked to defects in structural genes (e.g., epidermal barrier mutations in AD; keratin/enamel structural defects increasing caries risk), the two may share a predisposing structural-gene basis (Kalhan et al, PMID:28122670; this JACI letter has no structured PubMed abstract). Independently, an adult case-control study found AD associated with poorer oral health and oral dysbiosis, offering a microbiome-mediated alternative or complementary mechanism. The association in GUSTO was specific to the allergen-sensitized (AD-SPT-positive) subgroup and adjusted for several confounders, but causation versus residual confounding (shared diet, socioeconomic status, and care behaviors) remains unresolved.
Show evidence (2 references)
PMID:39523189 SUPPORT Human Clinical
"AD appears to be associated with poor oral health and oral dysbiosis."
Case-control evidence that atopic dermatitis is associated with impaired oral health and oral dysbiosis, supporting an AD-oral-disease comorbidity relevant to the early-childhood-caries association.
PMID:39523189 SUPPORT Human Clinical
"those with AD had significantly higher plaque levels (P = .04), poorer oral hygiene indices (P = .04), and higher gingival index trends (P = .05)."
Quantifies the specific oral-health deficits (plaque, hygiene, gingival index) measured in adults with AD versus controls.
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Pathophysiology

7
Epidermal Barrier Dysfunction
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.
Keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
FLG hgnc:3748 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FLG (hgnc:3748). hgnc:3748 is a gene from the HUGO Gene Nomenclature Committee.
Keratinization GO:0031424 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Keratinization (GO:0031424). GO:0031424 is a biological process from the Gene Ontology.
Downstream
Xerosis Barrier dysfunction manifests clinically as dry skin.
Eczematoid Dermatitis Epidermal barrier dysfunction and abnormal keratinocyte differentiation produce recurrent eczematous lesions.
Recurrent Skin Infections Compromised barrier function and immune dysregulation increase the risk of cutaneous infection.
Show evidence (2 references)
PMID:16550169 SUPPORT Human Clinical
"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..."
Landmark study establishing FLG loss-of-function as the strongest genetic risk factor for atopic dermatitis, with ~9% carrier frequency in Europeans.
PMID:21388665 SUPPORT Human Clinical
"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..."
Describes the epidermal barrier dysfunction in atopic dermatitis including abnormal cornification and keratinocyte differentiation.
Type 2 Immune Response
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.
T-helper 2 cell CL:0000546 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T-helper 2 cell (CL:0000546). CL:0000546 is a cell type from the Cell Ontology. Group 2 innate lymphoid cell CL:0001069 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Group 2 innate lymphoid cell (CL:0001069). CL:0001069 is a cell type from the Cell Ontology. Eosinophil CL:0000771 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Eosinophil (CL:0000771). CL:0000771 is a cell type from the Cell Ontology. Mast cell CL:0000097 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Mast cell (CL:0000097). CL:0000097 is a cell type from the Cell Ontology.
IL4 hgnc:6014 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves IL4 (hgnc:6014). hgnc:6014 is a gene from the HUGO Gene Nomenclature Committee. IL13 hgnc:5973 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves IL13 (hgnc:5973). hgnc:5973 is a gene from the HUGO Gene Nomenclature Committee. IL31 hgnc:19372 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves IL31 (hgnc:19372). hgnc:19372 is a gene from the HUGO Gene Nomenclature Committee. STAT6 hgnc:11368 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves STAT6 (hgnc:11368). hgnc:11368 is a gene from the HUGO Gene Nomenclature Committee.
Type 2 immune response GO:0042092 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Type 2 immune response (GO:0042092). GO:0042092 is a biological process from the Gene Ontology. T-helper 2 cell differentiation GO:0045064 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves T-helper 2 cell differentiation (GO:0045064). GO:0045064 is a biological process from the Gene Ontology. Interleukin-4-mediated signaling pathway GO:0035771 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Interleukin-4-mediated signaling pathway (GO:0035771). GO:0035771 is a biological process from the Gene Ontology. IgE isotype switching GO:0035708 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves IgE isotype switching, annotated with interleukin-4-dependent isotype switching to IgE isotypes (GO:0035708). GO:0035708 is a biological process from the Gene Ontology.
Downstream
Epidermal Barrier Dysfunction IL-4 and IL-13 downregulate filaggrin expression, creating a vicious cycle of barrier disruption and immune activation.
Pruritogen-Induced Neuronal Activation IL-31 signaling contributes to neuronal itch signaling in lesional skin.
Elevated Serum IgE Type 2 immune skewing promotes the extrinsic/allergic AD phenotype with elevated serum IgE.
Food Allergy Barrier disruption and allergic immune skewing contribute to the atopic march and food-allergy comorbidity.
Allergic Rhinitis Allergic immune skewing in AD is associated with allergic rhinitis as part of the atopic comorbidity spectrum.
Asthma Impaired skin barrier and allergic sensitization can precede asthma in the atopic march.
Show evidence (2 references)
PMID:30819278 SUPPORT Human Clinical
"Type 2 cytokines as well as interleukin 17 and interleukin 22 contribute to skin barrier dysfunction and the development of AD."
Confirms the role of type 2 cytokines in AD pathophysiology and their contribution to barrier dysfunction, supporting the Th2/type 2 immune mechanism.
PMID:21388665 SUPPORT Human Clinical
"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."
Describes the immune cell infiltrates in AD lesions including T cells and dendritic cells, consistent with type 2 immune response.
TOPK-STAT3 Signaling Axis
T-Lymphokine-Activated Killer Cell-Originated Protein Kinase (TOPK) is upregulated in AD and directly phosphorylates STAT3 at Ser727 in keratinocytes and mast cells, driving the production of inflammatory cytokines (IL-6, IL-8, IL-33) and IgE dysregulation. This axis acts as an amplifier of the type 2 immune response.
Keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology. Mast cell CL:0000097 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Mast cell (CL:0000097). CL:0000097 is a cell type from the Cell Ontology.
PBK hgnc:18282 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PBK (hgnc:18282). hgnc:18282 is a gene from the HUGO Gene Nomenclature Committee. STAT3 hgnc:11364 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves STAT3 (hgnc:11364). hgnc:11364 is a gene from the HUGO Gene Nomenclature Committee.
Protein phosphorylation GO:0006468 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Protein phosphorylation (GO:0006468). GO:0006468 is a biological process from the Gene Ontology. Interleukin-6 production GO:0032635 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Interleukin-6 production (GO:0032635). GO:0032635 is a biological process from the Gene Ontology. Interleukin-8 production GO:0032637 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Interleukin-8 production (GO:0032637). GO:0032637 is a biological process from the Gene Ontology. Signal transduction GO:0007165 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Signal transduction (GO:0007165). GO:0007165 is a biological process from the Gene Ontology.
Downstream
Type 2 Immune Response TOPK-mediated STAT3 Ser727 phosphorylation amplifies IL-6 and IL-8 production, enhancing Th2 polarization and IgE responses.
Secondary Inflammatory Amplification TOPK-STAT3 signaling drives IL-6, IL-8, and IL-33 production, perpetuating keratinocyte and mast cell inflammatory output and sustaining chronic lesion inflammation.
Show evidence (3 references)
PMID:42237026 SUPPORT Computational
"Bioinformatics analysis revealed that TOPK was significantly upregulated in AD patients."
GEO database bioinformatics analysis establishes TOPK upregulation in AD patient transcriptomes.
PMID:42237026 SUPPORT In Vitro
"TOPK was found to directly interact with and phosphorylate STAT3 at Ser727. Inhibition of TOPK in both HaCaT keratinocytes and mast cells decreased STAT3 phosphorylation at Ser727, thereby alleviating AD-related inflammatory responses."
Establishes TOPK-STAT3 Ser727 phosphorylation as the direct mechanistic driver of inflammatory responses in AD-relevant cell types.
PMID:42237026 SUPPORT Model Organism
"Genetic or pharmacological inhibition of TOPK markedly attenuated AD-like pathological features and reduces the levels of IgE, IL-6, IL-8 and IL-33, suggesting that TOPK contributes to AD pathogenesis."
Demonstrates that TOPK inhibition reduces multiple AD-associated inflammatory mediators and IgE dysregulation in a disease model.
Th17/Th22 Inflammation
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.
T-helper 17 cell CL:0000899 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T-helper 17 cell (CL:0000899). CL:0000899 is a cell type from the Cell Ontology.
T-helper 17 type immune response GO:0072538 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves T-helper 17 type immune response (GO:0072538). GO:0072538 is a biological process from the Gene Ontology.
Pruritogen-Induced Neuronal Activation
IL-31 and other pruritogens activate cutaneous sensory neurons, generating persistent itch in atopic dermatitis. Evidence caveat: the citation below supports neuroimmune interaction as a component of AD pathophysiology in general, but no cited source in this entry evidences the specific IL-31 to sensory-neuron mechanism, and the IL31 gene annotation on this node is therefore currently unsupported. Re-source against a primary IL-31/IL-31RA study before treating the IL-31 attribution as established.
Sensory neuron CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology.
IL31 hgnc:19372 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves IL31 (hgnc:19372). hgnc:19372 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Scratching-Induced Barrier Injury Persistent itch drives repetitive scratching behavior.
Pruritus IL-31 and related pruritogens activate cutaneous sensory neurons, producing intense itch.
Sleep Disturbance Itch severity contributes to sleep disturbance in AD.
Show evidence (1 reference)
PMID:30819278 SUPPORT Human Clinical
"New insights into the pathophysiology of AD have focused on epidermal lipid profiles, neuroimmune interactions, and microbial dysbiosis."
Supports neuroimmune signaling as a component of AD pathophysiology.
Scratching-Induced Barrier Injury
Repetitive scratching causes mechanical skin injury and worsens epidermal barrier dysfunction.
Keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
Downstream
Secondary Inflammatory Amplification Mechanical barrier injury increases local inflammatory activation.
Flexural Lichenification Persistent pruritus and scratching-driven barrier injury contribute to lichenified flexural lesions.
Secondary Inflammatory Amplification
Barrier injury from scratching perpetuates inflammatory signaling and contributes to chronic lesion persistence.
Keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
Inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology.
Downstream
Erythema Local inflammatory amplification produces erythematous rash in active AD lesions.
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Pathograph

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

13
Blood 1
Elevated Serum IgE FREQUENT Increased circulating IgE concentration HP:0003212 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated serum IgE, annotated with Increased circulating IgE concentration (HP:0003212). HP:0003212 is a phenotype from the Human Phenotype Ontology.
Present in extrinsic subtype (~80% of patients).
Show evidence (1 reference)
PMID:20207111 SUPPORT
"Extrinsic or allergic AD shows high total serum IgE levels and the presence of specific IgE for environmental and food allergens... While extrinsic AD is the classical type with high prevalence, the incidence of intrinsic AD is approximately 20%"
Approximately 80% of atopic dermatitis patients have the extrinsic subtype characterized by elevated serum IgE levels.
Cardiovascular 1
Erythema VERY_FREQUENT HP:0010783 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Erythema (HP:0010783). HP:0010783 is a phenotype from the Human Phenotype Ontology.
Erythematous patches and plaques are a core clinical feature, often the earliest visible sign of active disease.
Show evidence (1 reference)
PMID:39659858 SUPPORT Human Clinical
"a chronic, relapsing inflammatory skin disorder characterized by dry skin, localized erythematous rash, and intense pruritus"
Erythematous rash is listed as one of the three cardinal features of atopic dermatitis.
Head and Neck 2
Dennie-Morgan Infraorbital Folds FREQUENT Periorbital wrinkles HP:0000607 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dennie-Morgan infraorbital folds, annotated with Periorbital wrinkles (HP:0000607). HP:0000607 is a phenotype from the Human Phenotype Ontology.
Dennie-Morgan folds are prominent infraorbital creases characteristic of atopic dermatitis, more common in children. Cited as a clinical feature of intrinsic AD (PMID:20207111) and of paediatric AD (PMID:35297082); the earlier claim that they are present in both extrinsic and intrinsic subtypes is not established by either source and has been withdrawn.
Show evidence (2 references)
PMID:35297082 SUPPORT Human Clinical
"children with AD have more exudative lesions, perifollicular accentuation, pityriasis alba, Dennie-Morgan folds, and seborrheic dermatitis-like presentation."
Dennie-Morgan folds (infraorbital creases associated with periorbital hyperpigmentation) are identified as a characteristic pediatric AD feature.
PMID:20207111 SUPPORT Human Clinical
"The clinical features of intrinsic AD include relative late onset, milder severity, and Dennie-Morgan folds, but no ichthyosis vulgris or palmar hyperlinearity."
Lists Dennie-Morgan folds among the clinical features of intrinsic AD. This establishes the sign in the intrinsic subtype only; it does not evidence presence in extrinsic AD.
Allergic Rhinitis FREQUENT HP:0003193 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Allergic rhinitis (HP:0003193). HP:0003193 is a phenotype from the Human Phenotype Ontology.
A common atopic comorbidity, often developing after the onset of AD as part of the atopic march in some patients.
Show evidence (2 references)
PMID:32738956 SUPPORT Human Clinical
"Atopic dermatitis is associated with increased risk of multiple comorbidities, including food allergy, asthma, allergic rhinitis, and mental health disorders."
Lancet 2020 review identifies allergic rhinitis as a major AD comorbidity.
PMID:35297082 SUPPORT Human Clinical
"Atopic diseases commonly co-occur with AD, although most do not temporally have the "atopic march.""
Confirms atopic comorbidities co-occur with AD, while noting that the temporal sequence of the atopic march is not universal.
Immune 4
Eczematoid Dermatitis VERY_FREQUENT HP:0000964 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Eczematoid dermatitis (HP:0000964). HP:0000964 is a phenotype from the Human Phenotype Ontology.
Erythematous, pruritic patches and plaques with scaling, often in flexural areas.
Show evidence (1 reference)
PMID:28846349 SUPPORT
"This chronic disorder associated with pruritus usually starts in infancy and presents with dry skin, eczematous lesions and lichenification."
Eczematous lesions are a defining feature of atopic dermatitis.
Recurrent Skin Infections FREQUENT HP:0001581 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent skin infections (HP:0001581). HP:0001581 is a phenotype from the Human Phenotype Ontology.
Compromised barrier function and immune dysregulation predispose to bacterial (S. aureus), viral (HSV, molluscum), and fungal skin infections.
Show evidence (2 references)
PMID:31755570 SUPPORT Human Clinical
"Due to compromised barrier function and immune dysregulation, children with atopic dermatitis (AD) are at increased risk of cutaneous infections"
Establishes that barrier dysfunction and immune dysregulation in AD lead to increased risk of cutaneous infections.
PMID:35490395 SUPPORT Human Clinical
"Atopic dermatitis (AD) is associated with an increased risk for viral infections including those caused by herpes simplex virus and varicella zoster virus."
Confirms increased susceptibility to viral skin infections in AD patients.
Food Allergy FREQUENT HP:0500093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Food allergy (HP:0500093). HP:0500093 is a phenotype from the Human Phenotype Ontology.
A common comorbidity, particularly in early-onset and severe AD. Part of the atopic march in a subset of patients. Epicutaneous sensitization through the disrupted skin barrier may drive food allergy development.
Show evidence (2 references)
PMID:32738956 SUPPORT Human Clinical
"Atopic dermatitis is associated with increased risk of multiple comorbidities, including food allergy, asthma, allergic rhinitis, and mental health disorders."
Lancet 2020 review identifies food allergy as a major AD comorbidity.
PMID:28846349 SUPPORT Human Clinical
"AD is associated with other IgE associated disorders like allergic rhinitis, asthma, and food allergies."
Confirms the well-established association between AD and food allergies as IgE-mediated comorbidities.
Asthma FREQUENT HP:0002099 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Asthma (HP:0002099). HP:0002099 is a phenotype from the Human Phenotype Ontology.
A major atopic comorbidity. Part of the classic atopic triad alongside allergic rhinitis. Epicutaneous sensitization through the disrupted skin barrier may contribute to airway sensitization.
Show evidence (2 references)
PMID:32738956 SUPPORT Human Clinical
"Atopic dermatitis is associated with increased risk of multiple comorbidities, including food allergy, asthma, allergic rhinitis, and mental health disorders."
Lancet 2020 review identifies asthma as a major AD comorbidity.
PMID:30819278 SUPPORT Human Clinical
"An impaired skin barrier may be the initial step in the development of the atopic march as well as AD, which leads to further skin inflammation and allergic sensitization."
Links impaired skin barrier in AD to the development of the atopic march, including progression to asthma.
Integument 4
Pruritus VERY_FREQUENT HP:0000989 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pruritus (HP:0000989). HP:0000989 is a phenotype from the Human Phenotype Ontology.
Intense itching is the hallmark symptom, often worse at night.
Show evidence (1 reference)
PMID:39659858 SUPPORT
"Atopic dermatitis, more commonly known as atopic eczema, is a chronic, relapsing inflammatory skin disorder characterized by dry skin, localized erythematous rash, and intense pruritus."
Intense pruritus is a defining clinical characteristic of atopic dermatitis.
Xerosis VERY_FREQUENT Dry skin HP:0000958 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Xerosis, annotated with Dry skin (HP:0000958). HP:0000958 is a phenotype from the Human Phenotype Ontology.
Generalized dry skin reflecting barrier dysfunction.
Show evidence (1 reference)
PMID:39659858 SUPPORT
"Atopic dermatitis, more commonly known as atopic eczema, is a chronic, relapsing inflammatory skin disorder characterized by dry skin, localized erythematous rash, and intense pruritus."
Dry skin (xerosis) is a defining clinical characteristic of atopic dermatitis reflecting barrier dysfunction.
Flexural Lichenification FREQUENT HP:0007453 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Flexural lichenification (HP:0007453). HP:0007453 is a phenotype from the Human Phenotype Ontology.
Lichenification preferentially affects flexural areas (antecubital and popliteal fossae, neck) and is a hallmark distribution pattern. Thickened, leathery skin develops from chronic scratching.
Show evidence (2 references)
PMID:28846349 SUPPORT Human Clinical
"This chronic disorder associated with pruritus usually starts in infancy and presents with dry skin, eczematous lesions and lichenification."
Lichenification is a defining chronic feature of atopic dermatitis.
PMID:35297082 SUPPORT Human Clinical
"Core AD features are similar between children and adults overall, including lesions affecting flexural areas, presence of atopy, and xerosis."
Flexural distribution is identified as a core feature of atopic dermatitis across age groups.
Keratosis Pilaris OCCASIONAL HP:0032152 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Keratosis pilaris (HP:0032152). HP:0032152 is a phenotype from the Human Phenotype Ontology.
Follicular keratotic papules on extensor surfaces, associated with filaggrin-related barrier dysfunction and ichthyosis vulgaris.
Show evidence (1 reference)
PMID:31536314 SUPPORT Human Clinical
"Keratosis pilaris is associated with many other conditions, including atopic dermatitis, ichthyosis vulgaris, obesity, diabetes mellitus, and malnutrition."
StatPearls reference directly identifies atopic dermatitis as one of the conditions associated with keratosis pilaris.
Nervous System 1
Sleep Disturbance FREQUENT HP:0002360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep disturbance (HP:0002360). HP:0002360 is a phenotype from the Human Phenotype Ontology.
Pruritus-driven sleep disruption is a major contributor to reduced quality of life, with severity correlating with disease activity.
Show evidence (1 reference)
PMID:38864389 SUPPORT Human Clinical
"AD patients reported lower sleep quality (p = 0.002), more severe insomnia (p = 0.006) and depression (p = 0.013), and higher stress levels than healthy adults (p = 0.049)."
Case-control study demonstrating significantly impaired sleep quality and increased insomnia in AD patients compared to matched controls.
🧬

Genetic Associations

13
FLG (Associated)
Gene: FLG hgnc:3748 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FLG (hgnc:3748). hgnc:3748 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:16550169 SUPPORT Human Clinical
"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."
Landmark Palmer et al. 2006 study establishing FLG loss-of-function as the major genetic predisposing factor for atopic dermatitis.
IL4R (Associated)
Gene: IL4R hgnc:6015 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IL4R (hgnc:6015). hgnc:6015 is a gene from the HUGO Gene Nomenclature Committee.
IL13 (Associated)
Gene: IL13 hgnc:5973 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IL13 (hgnc:5973). hgnc:5973 is a gene from the HUGO Gene Nomenclature Committee.
STAT6 (Associated)
Gene: STAT6 hgnc:11368 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is STAT6 (hgnc:11368). hgnc:11368 is a gene from the HUGO Gene Nomenclature Committee.
EMSY (Associated)
Gene: EMSY hgnc:18071 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EMSY (hgnc:18071). hgnc:18071 is a gene from the HUGO Gene Nomenclature Committee.
BACH2 (GWAS)
Gene: BACH2 hgnc:14078 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is BACH2 (hgnc:14078). hgnc:14078 is a gene from the HUGO Gene Nomenclature Committee.
TNFAIP3 (GWAS)
Gene: TNFAIP3 hgnc:11896 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TNFAIP3 (hgnc:11896). hgnc:11896 is a gene from the HUGO Gene Nomenclature Committee.
EGR2 (GWAS)
Gene: EGR2 hgnc:3239 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EGR2 (hgnc:3239). hgnc:3239 is a gene from the HUGO Gene Nomenclature Committee.
ETS1 (GWAS)
Gene: ETS1 hgnc:3488 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ETS1 (hgnc:3488). hgnc:3488 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:26482879 SUPPORT Human Clinical
"At 11q24.3 the most plausible candidate gene is ETS1, which encodes a transcription factor with a range of immune functions including Th17 and B-cell differentiation and function"
The EAGLE multi-ancestry GWAS of 21,399 cases and 95,464 controls names ETS1 as the most plausible candidate gene at the 11q24.3 risk locus, and attributes to it the T- and B-cell functions recorded in this entry's notes.
IRF4 (GWAS)
Gene: IRF4 hgnc:6119 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IRF4 (hgnc:6119). hgnc:6119 is a gene from the HUGO Gene Nomenclature Committee.
SATB1 (GWAS)
Gene: SATB1 hgnc:10541 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SATB1 (hgnc:10541). hgnc:10541 is a gene from the HUGO Gene Nomenclature Committee.
SMAD3 (GWAS)
Gene: SMAD3 hgnc:6769 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SMAD3 (hgnc:6769). hgnc:6769 is a gene from the HUGO Gene Nomenclature Committee.
REL (GWAS)
Gene: REL hgnc:9954 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is REL (hgnc:9954). hgnc:9954 is a gene from the HUGO Gene Nomenclature Committee.
💊

Medical Actions

7
Emollients and Moisturizers
First-line treatment to restore skin barrier function and reduce transepidermal water loss.
Show evidence (1 reference)
PMID:36641009 SUPPORT Human Clinical
"Strong recommendations are made for the use of moisturizers, TCIs, TCS, and topical PDE-4 and JAK inhibitors."
The 2023 AAD guideline, developed by systematic review under GRADE, makes a strong recommendation for moisturizers in adult atopic dermatitis. Note the guideline recommends their use; it does not itself demonstrate the barrier-restoration mechanism asserted in this treatment's description.
Topical Corticosteroids
Action: topical corticosteroid therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is topical corticosteroid therapy (NCIT:C122078). NCIT:C122078 is a clinical intervention from the NCI Thesaurus. Ontology label: Topical Corticosteroid Therapy NCIT:C122078
First-line anti-inflammatory treatment for flares, applied to affected areas.
Show evidence (1 reference)
PMID:36641009 SUPPORT Human Clinical
"Strong recommendations are made for the use of moisturizers, TCIs, TCS, and topical PDE-4 and JAK inhibitors."
Topical corticosteroids (TCS) carry a strong GRADE recommendation in the 2023 AAD adult atopic dermatitis guideline.
Dupilumab
Action: biologic therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is biologic therapy, annotated with Immunotherapy (NCIT:C15262). NCIT:C15262 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunotherapy NCIT:C15262
Agent: dupilumab NCIT:C162455 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses dupilumab (NCIT:C162455). NCIT:C162455 is a therapeutic agent from the NCI Thesaurus.
Monoclonal antibody targeting IL-4 receptor alpha, blocking both IL-4 and IL-13 signaling. FDA-approved for moderate-to-severe atopic dermatitis.
Show evidence (1 reference)
PMID:41949508 SUPPORT Other
"We make strong recommendations for the use of moisturizers, topical calcineurin inhibitors, topical corticosteroids, crisaborole ointment, roflumilast cream, ruxolitinib cream, tapinarof cream, dupilumab, tralokinumab, lebrikizumab, nemolizumab with concomitant topical therapy, upadacitinib, abrocitinib"
The AAD guidelines of care for pediatric atopic dermatitis make a strong recommendation for dupilumab among the systemic and topical therapies.
JAK Inhibitors
Action: JAK inhibitor therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is JAK inhibitor therapy, annotated with Immunosuppressive Therapy (NCIT:C15261). NCIT:C15261 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunosuppressive Therapy NCIT:C15261
Oral (baricitinib, upadacitinib, abrocitinib) and topical (ruxolitinib) JAK inhibitors targeting the JAK-STAT pathway downstream of type 2 cytokines.
Show evidence (2 references)
PMID:37943240 SUPPORT Human Clinical
"We make strong recommendations for the use of dupilumab, tralokinumab, abrocitinib, baricitinib, and upadacitinib."
The 2024 AAD guideline makes strong GRADE recommendations for all three oral JAK inhibitors named in this treatment's description (abrocitinib, baricitinib, upadacitinib).
PMID:36641009 SUPPORT Human Clinical
"Strong recommendations are made for the use of moisturizers, TCIs, TCS, and topical PDE-4 and JAK inhibitors."
Covers the topical arm of this treatment entry. The guideline recommends topical JAK inhibitors as a class and does not name ruxolitinib in this sentence, so it supports the class claim only.
STAT6 Degrader (SAR448272/NX-3911)
Action: STAT6 targeted protein degradationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is STAT6 targeted protein degradation, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: SAR448272/NX-3911 Relation: this treatment uses this therapeutic agent This treatment uses SAR448272/NX-3911.
Platform: Small molecule
SAR448272/NX-3911 is an investigational oral STAT6 degrader in a Phase 1 first-in-human study for type 2 inflammatory diseases. The study establishes that the asset is in clinical development, but disease-specific human efficacy has not yet been reported.
Mechanism Target:
INHIBITS Type 2 Immune Response — SAR448272/NX-3911 degrades STAT6. Reduced STAT6 abundance is intended to suppress IL-4/IL-13-dependent type 2 inflammatory signaling.
Show evidence (1 reference)
url:https://www.globenewswire.com/news-release/2026/08/04/3338158/0/en/Nurix-Announces-10-Million-Milestone-Payment-Associated-with-Initiation-of-a-Phase-1-Clinical-Trial-of-a-STAT6-Degrader.html SUPPORT Other
"STAT6 is a key transcription factor within the interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling pathways that drive type 2 inflammation"
Supports the intended connection between STAT6 degradation and the type 2 immune-response node. The source does not establish efficacy in people with atopic dermatitis.
Show evidence (1 reference)
url:https://www.globenewswire.com/news-release/2026/08/04/3338158/0/en/Nurix-Announces-10-Million-Milestone-Payment-Associated-with-Initiation-of-a-Phase-1-Clinical-Trial-of-a-STAT6-Degrader.html SUPPORT Other
"following the initiation by its collaborator, Sanofi, of the Phase 1 first-in-human clinical trial of SAR448272/NX-3911, an oral STAT6 degrader."
Establishes that SAR448272/NX-3911 has entered a first-in-human Phase 1 study. It does not provide disease-specific efficacy results.
Phototherapy
Action: phototherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is phototherapy (NCIT:C15301). NCIT:C15301 is a clinical intervention from the NCI Thesaurus. Ontology label: Phototherapy NCIT:C15301
Narrowband UVB phototherapy for moderate-to-severe disease.
Show evidence (1 reference)
PMID:37943240 SUPPORT Human Clinical
"We make conditional recommendations in favor of using phototherapy, azathioprine, cyclosporine, methotrexate, and mycophenolate, and against the use of systemic corticosteroids."
Phototherapy carries a conditional (not strong) GRADE recommendation in the 2024 AAD adult guideline. The guideline does not single out narrowband UVB in this sentence, so the recommendation is for phototherapy as a modality.
TOPK Inhibitors
Platform: Small molecule
Small-molecule inhibitors of TOPK (PBK) that target the TOPK-STAT3 signaling axis in keratinocytes and mast cells. Pharmacological or genetic TOPK inhibition attenuates AD-like pathological features and reduces inflammatory cytokine levels (IL-6, IL-8, IL-33, IgE).
Mechanism Target:
TOPK-STAT3 Signaling Axis — TOPK inhibitors block TOPK-mediated STAT3 Ser727 phosphorylation and downstream inflammatory cytokine production.
🌍

Environmental Factors

3
Allergen Exposure
allergen exposure ECTO:0000726 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is allergen exposure, annotated with exposure to allergen (ECTO:0000726). ECTO:0000726 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
In sensitized individuals, house dust mites, pet dander, and pollens can trigger or exacerbate disease. Note the therapeutic corollary does not follow - trials of house dust mite avoidance are of very low quality and do not establish a clinical benefit.
Show evidence (2 references)
PMID:14609097 SUPPORT Human Clinical
"The most impressive barrier disruption was seen after application of house dust mite, followed by cat dander and grass pollen"
Atopy patch testing in 30 sensitized patients with atopic eczema versus healthy controls, measuring transepidermal water loss. Covers all three allergen classes named in the description.
PMID:25598014 SUPPORT Human Clinical
"As many as a third of people with eczema who have a positive test for allergy to house dust mite have reported worsening of eczema or respiratory symptoms when exposed to dust"
Cochrane review. Supports exposure as a trigger in a sensitized subset rather than in all patients, and its conclusion of very low-quality evidence for avoidance measures is the caveat recorded in the description.
Skin Irritants
Soaps, detergents, and harsh fabrics disrupt the already compromised barrier, and atopic skin is measurably more susceptible to that damage than healthy skin under identical exposure.
Show evidence (1 reference)
PMID:26426984 SUPPORT Human Clinical
"Repeated exposure to SLS and the irritant tandems enhanced the reactions and resulted in a significantly higher increase in TEWL in the AD compared to the control group"
Controlled tandem repeated irritation test in atopic dermatitis volunteers versus healthy controls, using the detergent sodium lauryl sulfate. Evidences both the barrier disruption and the greater susceptibility of atopic skin.
Microbial Dysbiosis
This entry stands for the dysbiotic skin community as a whole, of which S. aureus is the dominant but not the sole member. The distinction matters when reading the influences_mechanisms edges: PMID:25902485 attributes eczema formation to S. aureus but the T helper 2 arm to C. bovis, so the edge into the type 2 node is evidenced for the community rather than for S. aureus specifically. The description above quantifies only the S. aureus component because that is what the cited human studies measure.
Staphylococcus aureus colonizes lesional skin in roughly 70 percent of patients - far more often than healthy controls - and its abundance tracks disease activity, rising during flares and with severity.
Show evidence (2 references)
PMID:26994362 SUPPORT Human Clinical
"The pooled prevalence of S. aureus colonization among patients was 70% for lesional skin, 39% for nonlesional skin and 62% for the nose"
Meta-analysis of 95 observational studies. Establishes the lesional colonization prevalence. The same abstract reports the odds of colonization versus healthy controls and that prevalence in lesional skin increased with disease severity; those figures are given in brackets in the source and so are described here rather than quoted.
PMID:22310478 SUPPORT Human Clinical
"the proportion of Staphylococcus sequences, particularly S. aureus, was greater during disease flares than at baseline or post-treatment, and correlated with worsened disease severity"
Longitudinal 16S rRNA gene sequencing of the skin microbiome across the flare cycle in children, evidencing that abundance tracks disease activity rather than merely co-occurring with it. Note the assay is 16S amplicon rather than shotgun metagenomics, so the species-level attribution to S. aureus in the quoted sentence carries the resolution limits of amplicon sequencing.
Mechanism Target:
EXACERBATES Type 2 Immune Response — Dysbiotic colonization acts on the type 2 inflammatory circuit rather than merely accompanying it. In a mouse model of eczematous dermatitis, species-specific antibiotic treatment reversed the dysbiosis and abolished the skin inflammation, and separate members of the dysbiotic community had separable effects on eczema formation and on T helper 2 responses. The edge is drawn as EXACERBATES rather than TRIGGERS, and the direction it takes in human disease is the open question recorded in gap_ad_dysbiosis_causal_ordering.
Show evidence (2 references)
PMID:25902485 SUPPORT Model Organism
"antibiotics specific for these bacterial species almost completely reversed dysbiosis and eliminated skin inflammation"
Interventional evidence in Adam17-deficient mice that removing the dysbiotic community removes the inflammation, which is the strongest available support for an edge running from dysbiosis to inflammation rather than the reverse. Model organism only, and the same abstract states the causal relationship in human disease is unclarified.
PMID:25902485 SUPPORT Model Organism
"Whereas S. aureus prominently drove eczema formation, C. bovis induced robust T helper 2 cell responses."
Attributes the type 2 arm of the response to a different member of the dysbiotic flora than the one driving eczema formation, so the link from this entry to the type 2 node is supported for the community as a whole but not specifically for S. aureus, which the entry description names.
EXACERBATES Secondary Inflammatory Amplification — S. aureus overgrowth is treated as an amplifier of established lesional inflammation. Commensal coagulase-negative staphylococci that produce antimicrobial peptides are depleted in atopic dermatitis skin, and their loss correlates with S. aureus colonization, so failure of commensal colonization resistance is the route by which the pathobiont load is sustained.
Show evidence (3 references)
PMID:28228596 SUPPORT Other
"a pathogen commonly found in patients with atopic dermatitis (AD) and an important factor that exacerbates this disease"
Supports the EXACERBATES predicate on this edge. Recorded as PARTIAL and OTHER because it is the authors' framing of prior literature rather than a result of the study reported in this abstract.
PMID:28228596 SUPPORT Human Clinical
"CoNS strains with antimicrobial activity were common on the normal population but rare on AD subjects."
Human isolate screening establishing depletion of antimicrobial commensal staphylococci on atopic dermatitis skin, the colonization resistance failure through which this entry acts on lesional inflammation.
PMID:22310478 SUPPORT Human Clinical
"the proportion of Staphylococcus sequences, particularly S. aureus, was greater during disease flares than at baseline or post-treatment, and correlated with worsened disease severity"
The closest evidence for this specific edge: pathobiont load rises with flare activity and falls after treatment, which is amplification of established lesional inflammation rather than the colonization resistance step the other two items cover. Correlational and 16S amplicon based, so it constrains the predicate to EXACERBATES and not TRIGGERS.
📊

Prevalence

1
Global
Atopic dermatitis is the most common chronic inflammatory skin disease and the leading cause of global burden from skin disease. Prevalence estimates range from 15-20% in children to 2-10% in adults, varying by geography, with higher rates in industrialized nations. Prevalence has been increasing over recent decades.
Show evidence (2 references)
PMID:32738956 SUPPORT Human Clinical
"Atopic dermatitis is a common inflammatory skin disorder characterised by recurrent eczematous lesions and intense itch. The disorder affects people of all ages and ethnicities, has a substantial psychosocial impact on patients and relatives, and is the leading cause of the global burden from..."
Langan et al. Lancet 2020 comprehensive review confirms AD as the leading cause of global burden from skin disease affecting all ages.
PMID:28846349 SUPPORT Human Clinical
"AD has significant morbidity and it appears that the prevalence of the disorder has been increasing over the past few decades."
Confirms increasing prevalence trend of atopic dermatitis.
📊

Related Datasets

8
Gene Expression in Whole Blood of Atopic Eczema and Healthy Children at 4 years geo:GSE48310
We studied genes that are related to atopic diseases [i.e., atopic eczema (AE)]. Immunological factors and principal genes involved in the biosynthesis of polyunsaturated fatty acids were included. We analyzed whether expression of genes encoding key enzymes of LC-PUFA synthesis (FADS1, FADS2 and ELOVL5) is associated with circulating LC-PUFA levels and risk of AE in 4-year-old children. AE (n=20) and non-AE (n=104) children participating in the Sabadell cohort within the INfancia y Medio Ambiente (INMA) Project were included in the present study. RT-PCR with TaqMan Low-Density Array cards was used to measure the expression of these genes.
human n=124
PMID:24167612
Identified by GEO DataSets index search for Atopic Dermatitis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
CHN1 as a Predictive Biomarker for Atopic Dermatitis-related Depression geo:GSE307177
The comorbidity of Atopic Dermatitis (AD) and depression has garnered increasing attention in recent years. Yet, the immunopathological mechanisms underlying this connection remain unclear. To bridge this gap, we collected peripheral blood mononuclear cell samples from 20 AD patients with and without depression, and performed RNA sequencing analysis. By integrating bioinformatics and machine learning techniques, we aimed to uncover the immune regulatory networks and identify key genetic markers for the depression comorbidity in AD patients. Our analysis revealed 394 differentially expressed genes in AD patients with depression as compared to those non-depression counterparts.
human BULK RNA SEQ n=20
PMID:41333466
Identified by GEO DataSets index search for Atopic Dermatitis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Genomic profiling of the overlap phenotype between psoriasis and atopic dermatitis geo:GSE182740
Clinical overlaps between psoriasis and atopic dermatitis are sometimes undiscernible, and there is no consensus whether to treat the overlap phenotype as psoriasis or atopic dermatitis. We enrolled patients diagnosed with either psoriasis or atopic dermatitis, and clinically re-stratified them into classic psoriasis, classic atopic dermatitis, and the overlap phenotype between psoriasis and atopic dermatitis. We compared gene expression profiles of lesional and nonlesional skin biopsy tissues between the three comparison groups.
human MICROARRAY n=75
PMID:37419444
Identified by GEO DataSets index search for Atopic Dermatitis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Optimizing single-cell transcriptomic discrimination of atopic dermatitis versus psoriasis vulgaris ega:EGAS00001007487
Optimizing single-cell transcriptomic discrimination of atopic dermatitis versus psoriasis vulgaris
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Atopic Dermatitis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Nanopore sequencing enables allelic phasing of FLG loss-of-function variants, intragenic copy number variation and methylation status in atopic dermatitis and ichthyosis vulgaris ega:EGAS50000000166
Loss-of-function (LoF) variants in the FLG gene are associated with ichthyosis vulgaris (IV) and atopic dermatitis (AD). IV and AD patients with two FLG LoF variants are reported to have a more severe disease course. However, subsets of compound heterozygous patients display phenotypic heterogeneity despite a prediction of a severe phenotype from their genotype. The underlying genetic mechanism of this phenotypic variability is unknown. One possibility is that two LoF FLG variants could be located in cis (on the same allele), thus altering the predicted gene dosage.
human WGS
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Atopic Dermatitis"); description-level mentions were not accepted. EGA study_type: Whole Genome Sequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Integrated metabolomics and lipidomics study of patients with atopic dermatitis in response to dupilumab metabolomics_workbench:ST002302
Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Atopic Dermatitis"). Retrieved 2026-08-02.
Local and systemic changes in lipid profile as potential biomarkers for canine atopic dermatitis. massive:MSV000087837
Lipids play a critical role in the skin as components of the epidermal barrier and as sig-naling molecules. Atopic dermatitis in dogs is associated with changes in the lipid composition of the skin, but whether these precede the onset of dermatitis or occur secondary to the dermatitis is unclear. We applied rapid lipid profiling mass spectrometry methods to skin and blood samples of dogs and determined changes following systemic treatment. Thirty control dogs and 30 atopic dogs with mild to moderate dermatitis were enrolled.
dog METABOLOMICS
Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Atopic Dermatitis"). Retrieved 2026-08-02.
Dietary Grape Against Atopic Dermatitis in NC/NgaTndCrlj Mice: Proteomics Analysis massive:MSV000090686
The study demonstrates the effects of dietary grape powder against atopic dermatitis in 2,4-dinitrofluorobenzene-induced atopic dermatitis in NC/NgaTndCrlj mice. To uncover molecular mechanism(s) of biological responses of grape powder, dorsal skin samples from normal control (noAD), atopic dermatitis control (ctlAD) and 5% grape powder (5GP) prevention groups were analyzed using gel-free quantitative global proteomics analysis at the School of Pharmacy Analytical Instrumentation Facility, University of Wisconsin–Madison.
mouse PROTEOMICS
Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Atopic Dermatitis"). Retrieved 2026-08-02.
{ }

Source YAML

click to show 
name: Atopic Dermatitis
creation_date: '2025-12-18T17:01:35Z'
description: >-
  Atopic dermatitis is a chronic, relapsing inflammatory skin disease arising
  from the combination of epidermal barrier dysfunction and type 2-skewed immune
  dysregulation. Loss-of-function variants in filaggrin and related barrier
  defects increase transepidermal water loss and allow penetration of allergens
  and microbes, while keratinocyte-derived alarmins (TSLP, IL-25, IL-33) drive
  Th2 responses with IL-4, IL-13, and IL-31 that further impair barrier proteins
  and lipids and mediate pruritus. The resulting itch-scratch cycle, skin
  dysbiosis with Staphylococcus aureus overgrowth, and sustained inflammation
  produce the eczematous, lichenified, intensely pruritic lesions, often as part
  of the broader atopic march.
category: Complex
parents:
- Dermatological Disease
- Chronic Inflammatory Disease
- Allergic Disease
classifications:
  harrisons_chapter:
  - classification_value: DERMATOLOGY
    notes: >-
      Atopic dermatitis (eczema) is the prototypical chronic inflammatory skin
      disease and is Harrison's primary home for this entity.
    evidence:
    - reference: PMID:32738956
      reference_title: Atopic dermatitis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Atopic dermatitis is a common inflammatory skin disorder characterised by recurrent eczematous lesions and intense itch."
      explanation: >-
        The Lancet seminar defines atopic dermatitis as an inflammatory skin
        disorder, which places its primary clinical home in Harrison's
        Dermatology Part.
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      Type 2-skewed immune dysregulation (IL-4, IL-13, IL-31, and the
      keratinocyte alarmins TSLP/IL-25/IL-33) is the immunologic axis of the
      disease, and AD is the usual first step of the atopic march toward food
      allergy, allergic rhinitis, and asthma.
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.
  evidence:
  - reference: PMID:36983191
    reference_title: "Is Dupilumab as Effective in Intrinsic Atopic Dermatitis as It Is in Extrinsic Atopic Dermatitis?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atopic dermatitis (AD) can be subclassified into the more frequent extrinsic type (EAD), with elevated serum IgE levels and frequent association with other atopic conditions, and the less frequent intrinsic type (IAD), with normal IgE levels and no history of atopy.
    explanation: >-
      Defines the extrinsic subtype as the more frequent form, with
      elevated serum IgE and frequent association with other atopic
      conditions.
- name: Intrinsic Atopic Dermatitis
  description: Without IgE-mediated sensitization. Normal serum IgE levels. Represents approximately 20% of cases.
  evidence:
  - reference: PMID:36983191
    reference_title: "Is Dupilumab as Effective in Intrinsic Atopic Dermatitis as It Is in Extrinsic Atopic Dermatitis?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atopic dermatitis (AD) can be subclassified into the more frequent extrinsic type (EAD), with elevated serum IgE levels and frequent association with other atopic conditions, and the less frequent intrinsic type (IAD), with normal IgE levels and no history of atopy.
    explanation: >-
      Defines the intrinsic subtype as the less frequent form, with normal
      IgE levels and no history of atopy.
prevalence:
- population: Global
  notes: >-
    Atopic dermatitis is the most common chronic inflammatory skin disease
    and the leading cause of global burden from skin disease. Prevalence
    estimates range from 15-20% in children to 2-10% in adults, varying
    by geography, with higher rates in industrialized nations. Prevalence
    has been increasing over recent decades.
  evidence:
  - reference: PMID:32738956
    reference_title: Atopic dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Atopic dermatitis is a common inflammatory skin disorder characterised by recurrent eczematous lesions and intense itch. The disorder affects people of all ages and ethnicities, has a substantial psychosocial impact on patients and relatives, and is the leading cause of the global burden from skin disease."
    explanation: Langan et al. Lancet 2020 comprehensive review confirms AD as the leading cause of global burden from skin disease affecting all ages.
  - reference: PMID:28846349
    reference_title: Atopic Dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AD has significant morbidity and it appears that the prevalence of the disorder has been increasing over the past few decades."
    explanation: Confirms increasing prevalence trend of atopic dermatitis.
pathophysiology:
- name: Epidermal Barrier Dysfunction
  conforms_to: "epithelial_barrier_dysfunction#Epithelial Barrier Insult and Junctional Disruption"
  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
    reference_title: "Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis."
    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
    reference_title: "Contrasting pathogenesis of atopic dermatitis and psoriasis--part I: clinical and pathologic concepts."
    supports: SUPPORT
    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.
  downstream:
  - target: Xerosis
    description: >-
      Barrier dysfunction manifests clinically as dry skin.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - abnormal epidermal differentiation
    - increased transepidermal water loss
    evidence:
    - reference: PMID:39659858
      reference_title: "Atopic Dermatitis: A Review of Diagnosis and Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Atopic dermatitis, more commonly known as atopic eczema, is a chronic, relapsing inflammatory skin disorder characterized by dry skin, localized erythematous rash, and intense pruritus."
      explanation: Review evidence lists dry skin as a defining clinical feature of AD.
  - target: Eczematoid Dermatitis
    description: >-
      Epidermal barrier dysfunction and abnormal keratinocyte differentiation
      produce recurrent eczematous lesions.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - abnormal cornification
    - epidermal inflammation
    evidence:
    - reference: PMID:28846349
      reference_title: "Atopic Dermatitis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This chronic disorder associated with pruritus usually starts in infancy and presents with dry skin, eczematous lesions and lichenification."
      explanation: Review evidence directly lists eczematous lesions as a clinical presentation of AD.
  - target: Recurrent Skin Infections
    description: >-
      Compromised barrier function and immune dysregulation increase the risk of
      cutaneous infection.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31755570
      reference_title: "Disseminated bullous impetigo and atopic dermatitis: Case series and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Due to compromised barrier function and immune dysregulation, children with atopic dermatitis (AD) are at increased risk of cutaneous infections"
      explanation: The case-series review directly links compromised barrier function and immune dysregulation to cutaneous infection risk.
- 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.
  - target: Elevated Serum IgE
    description: >-
      Type 2 immune skewing promotes the extrinsic/allergic AD phenotype with
      elevated serum IgE.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20207111
      reference_title: "Extrinsic and intrinsic types of atopic dermatitis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Extrinsic or allergic AD shows high total serum IgE levels and the presence of specific IgE for environmental and food allergens"
      explanation: The extrinsic AD review directly supports elevated IgE in the allergic/type 2 AD phenotype.
  - target: Food Allergy
    description: >-
      Barrier disruption and allergic immune skewing contribute to the atopic
      march and food-allergy comorbidity.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - allergic sensitization
    - atopic march
    evidence:
    - reference: PMID:32738956
      reference_title: Atopic dermatitis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Atopic dermatitis is associated with increased risk of multiple comorbidities, including food allergy, asthma, allergic rhinitis, and mental health disorders."
      explanation: Lancet review identifies food allergy as a major AD comorbidity.
  - target: Allergic Rhinitis
    description: >-
      Allergic immune skewing in AD is associated with allergic rhinitis as part
      of the atopic comorbidity spectrum.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - allergic sensitization
    - atopic march
    evidence:
    - reference: PMID:32738956
      reference_title: Atopic dermatitis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Atopic dermatitis is associated with increased risk of multiple comorbidities, including food allergy, asthma, allergic rhinitis, and mental health disorders."
      explanation: Lancet review identifies allergic rhinitis as a major AD comorbidity.
  - target: Asthma
    description: >-
      Impaired skin barrier and allergic sensitization can precede asthma in
      the atopic march.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired skin barrier
    - allergic sensitization
    - atopic march
    evidence:
    - reference: PMID:30819278
      reference_title: "Pathophysiology of atopic dermatitis: Clinical implications."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "An impaired skin barrier may be the initial step in the development of the atopic march as well as AD, which leads to further skin inflammation and allergic sensitization."
      explanation: This review links impaired skin barrier in AD to allergic sensitization and the atopic march, supporting asthma as a downstream atopic comorbidity.
  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
    reference_title: "Pathophysiology of atopic dermatitis: Clinical implications."
    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
    reference_title: "Contrasting pathogenesis of atopic dermatitis and psoriasis--part I: clinical and pathologic concepts."
    supports: SUPPORT
    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: TOPK-STAT3 Signaling Axis
  description: T-Lymphokine-Activated Killer Cell-Originated Protein Kinase (TOPK) is upregulated in AD and directly phosphorylates STAT3 at Ser727 in keratinocytes and mast cells, driving the production of inflammatory cytokines (IL-6, IL-8, IL-33) and IgE dysregulation. This axis acts as an amplifier of the type 2 immune response.
  genes:
  - preferred_term: PBK
    term:
      id: hgnc:18282
      label: PBK
  - preferred_term: STAT3
    term:
      id: hgnc:11364
      label: STAT3
  biological_processes:
  - preferred_term: Protein phosphorylation
    term:
      id: GO:0006468
      label: protein phosphorylation
  - preferred_term: Interleukin-6 production
    term:
      id: GO:0032635
      label: interleukin-6 production
  - preferred_term: Interleukin-8 production
    term:
      id: GO:0032637
      label: interleukin-8 production
  - preferred_term: Signal transduction
    term:
      id: GO:0007165
      label: signal transduction
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  - preferred_term: Mast cell
    term:
      id: CL:0000097
      label: mast cell
  downstream:
  - target: Type 2 Immune Response
    description: TOPK-mediated STAT3 Ser727 phosphorylation amplifies IL-6 and IL-8 production, enhancing Th2 polarization and IgE responses.
  - target: Secondary Inflammatory Amplification
    description: TOPK-STAT3 signaling drives IL-6, IL-8, and IL-33 production, perpetuating keratinocyte and mast cell inflammatory output and sustaining chronic lesion inflammation.
  evidence:
  - reference: PMID:42237026
    reference_title: "Targeting the TOPK-STAT3 pathway in keratinocytes and mast cells mediates the therapeutic attenuation of Atopic dermatitis."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Bioinformatics analysis revealed that TOPK was significantly upregulated in AD patients."
    explanation: GEO database bioinformatics analysis establishes TOPK upregulation in AD patient transcriptomes.
  - reference: PMID:42237026
    reference_title: "Targeting the TOPK-STAT3 pathway in keratinocytes and mast cells mediates the therapeutic attenuation of Atopic dermatitis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TOPK was found to directly interact with and phosphorylate STAT3 at Ser727. Inhibition of TOPK in both HaCaT keratinocytes and mast cells decreased STAT3 phosphorylation at Ser727, thereby alleviating AD-related inflammatory responses."
    explanation: Establishes TOPK-STAT3 Ser727 phosphorylation as the direct mechanistic driver of inflammatory responses in AD-relevant cell types.
  - reference: PMID:42237026
    reference_title: "Targeting the TOPK-STAT3 pathway in keratinocytes and mast cells mediates the therapeutic attenuation of Atopic dermatitis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Genetic or pharmacological inhibition of TOPK markedly attenuated AD-like pathological features and reduces the levels of IgE, IL-6, IL-8 and IL-33, suggesting that TOPK contributes to AD pathogenesis."
    explanation: Demonstrates that TOPK inhibition reduces multiple AD-associated inflammatory mediators and IgE dysregulation in a disease model.
- 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. Evidence caveat: the citation below
    supports neuroimmune interaction as a component of AD pathophysiology in
    general, but no cited source in this entry evidences the specific IL-31 to
    sensory-neuron mechanism, and the IL31 gene annotation on this node is
    therefore currently unsupported. Re-source against a primary IL-31/IL-31RA
    study before treating the IL-31 attribution as established.
  genes:
  - preferred_term: IL31
    term:
      id: hgnc:19372
      label: IL31
  downstream:
  - target: Scratching-Induced Barrier Injury
    description: Persistent itch drives repetitive scratching behavior.
  - target: Pruritus
    description: >-
      IL-31 and related pruritogens activate cutaneous sensory neurons, producing
      intense itch.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39659858
      reference_title: "Atopic Dermatitis: A Review of Diagnosis and Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Atopic dermatitis, more commonly known as atopic eczema, is a chronic, relapsing inflammatory skin disorder characterized by dry skin, localized erythematous rash, and intense pruritus."
      explanation: Review evidence identifies intense pruritus as a cardinal AD feature.
  - target: Sleep Disturbance
    description: >-
      Itch severity contributes to sleep disturbance in AD.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - nocturnal itch
    evidence:
    - reference: PMID:38864389
      reference_title: "Exploring the interplay of atopic dermatitis severity with sleep and mental health: a case-control study in adult patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Itch intensity was linked to sleep disturbances and psychological symptoms"
      explanation: Case-control data link itch intensity to sleep disturbance in AD.
  cell_types:
  - preferred_term: Sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  evidence:
  - reference: PMID:30819278
    reference_title: "Pathophysiology of atopic dermatitis: Clinical implications."
    supports: SUPPORT
    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.
  - target: Flexural Lichenification
    description: >-
      Persistent pruritus and scratching-driven barrier injury contribute to
      lichenified flexural lesions.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - repetitive scratching
    - chronic epidermal thickening
    evidence:
    - reference: PMID:28846349
      reference_title: Atopic Dermatitis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This chronic disorder associated with pruritus usually starts in infancy and presents with dry skin, eczematous lesions and lichenification."
      explanation: Review evidence links chronic pruritic AD with lichenification.
  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
  downstream:
  - target: Erythema
    description: >-
      Local inflammatory amplification produces erythematous rash in active AD
      lesions.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39659858
      reference_title: "Atopic Dermatitis: A Review of Diagnosis and Treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a chronic, relapsing inflammatory skin disorder characterized by dry skin, localized erythematous rash, and intense pruritus"
      explanation: Review evidence directly lists localized erythematous rash as a defining AD manifestation.
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
  evidence:
  - reference: PMID:28846349
    reference_title: "Atopic Dermatitis."
    supports: SUPPORT
    snippet: "This chronic disorder associated with pruritus usually starts in infancy and presents with dry skin, eczematous lesions and lichenification."
    explanation: Eczematous lesions are a defining feature of atopic 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
  evidence:
  - reference: PMID:39659858
    reference_title: "Atopic Dermatitis: A Review of Diagnosis and Treatment."
    supports: SUPPORT
    snippet: "Atopic dermatitis, more commonly known as atopic eczema, is a chronic, relapsing inflammatory skin disorder characterized by dry skin, localized erythematous rash, and intense pruritus."
    explanation: Intense pruritus is a defining clinical characteristic of atopic dermatitis.
- 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
  evidence:
  - reference: PMID:39659858
    reference_title: "Atopic Dermatitis: A Review of Diagnosis and Treatment."
    supports: SUPPORT
    snippet: "Atopic dermatitis, more commonly known as atopic eczema, is a chronic, relapsing inflammatory skin disorder characterized by dry skin, localized erythematous rash, and intense pruritus."
    explanation: Dry skin (xerosis) is a defining clinical characteristic of atopic dermatitis reflecting barrier dysfunction.
- 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
  evidence:
  - reference: PMID:20207111
    reference_title: "Extrinsic and intrinsic types of atopic dermatitis."
    supports: SUPPORT
    snippet: "Extrinsic or allergic AD shows high total serum IgE levels and the presence of specific IgE for environmental and food allergens... While extrinsic AD is the classical type with high prevalence, the incidence of intrinsic AD is approximately 20%"
    explanation: Approximately 80% of atopic dermatitis patients have the extrinsic subtype characterized by elevated serum IgE levels.
- name: Erythema
  category: Dermatological
  frequency: VERY_FREQUENT
  notes: Erythematous patches and plaques are a core clinical feature, often the earliest visible sign of active disease.
  phenotype_term:
    preferred_term: Erythema
    term:
      id: HP:0010783
      label: Erythema
  evidence:
  - reference: PMID:39659858
    reference_title: "Atopic Dermatitis: A Review of Diagnosis and Treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a chronic, relapsing inflammatory skin disorder characterized by dry skin, localized erythematous rash, and intense pruritus"
    explanation: Erythematous rash is listed as one of the three cardinal features of atopic dermatitis.
- name: Flexural Lichenification
  category: Dermatological
  frequency: FREQUENT
  notes: Lichenification preferentially affects flexural areas (antecubital and popliteal fossae, neck) and is a hallmark distribution pattern. Thickened, leathery skin develops from chronic scratching.
  phenotype_term:
    preferred_term: Flexural lichenification
    term:
      id: HP:0007453
      label: Flexural lichenification
  evidence:
  - reference: PMID:28846349
    reference_title: Atopic Dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This chronic disorder associated with pruritus usually starts in infancy and presents with dry skin, eczematous lesions and lichenification."
    explanation: Lichenification is a defining chronic feature of atopic dermatitis.
  - reference: PMID:35297082
    reference_title: Differences between pediatric and adult atopic dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Core AD features are similar between children and adults overall, including lesions affecting flexural areas, presence of atopy, and xerosis."
    explanation: Flexural distribution is identified as a core feature of atopic dermatitis across age groups.
- name: Recurrent Skin Infections
  category: Dermatological
  frequency: FREQUENT
  notes: Compromised barrier function and immune dysregulation predispose to bacterial (S. aureus), viral (HSV, molluscum), and fungal skin infections.
  phenotype_term:
    preferred_term: Recurrent skin infections
    term:
      id: HP:0001581
      label: Recurrent skin infections
  evidence:
  - reference: PMID:31755570
    reference_title: "Disseminated bullous impetigo and atopic dermatitis: Case series and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Due to compromised barrier function and immune dysregulation, children with atopic dermatitis (AD) are at increased risk of cutaneous infections"
    explanation: Establishes that barrier dysfunction and immune dysregulation in AD lead to increased risk of cutaneous infections.
  - reference: PMID:35490395
    reference_title: "An integrated analysis of herpes virus infections from eight randomized clinical studies of baricitinib in adults with moderate-to-severe atopic dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Atopic dermatitis (AD) is associated with an increased risk for viral infections including those caused by herpes simplex virus and varicella zoster virus."
    explanation: Confirms increased susceptibility to viral skin infections in AD patients.
- name: Sleep Disturbance
  category: Neuropsychiatric
  frequency: FREQUENT
  notes: Pruritus-driven sleep disruption is a major contributor to reduced quality of life, with severity correlating with disease activity.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:38864389
    reference_title: "Exploring the interplay of atopic dermatitis severity with sleep and mental health: a case-control study in adult patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AD patients reported lower sleep quality (p = 0.002), more severe insomnia (p = 0.006) and depression (p = 0.013), and higher stress levels than healthy adults (p = 0.049)."
    explanation: Case-control study demonstrating significantly impaired sleep quality and increased insomnia in AD patients compared to matched controls.
- name: Dennie-Morgan Infraorbital Folds
  category: Dermatological
  frequency: FREQUENT
  notes: Dennie-Morgan folds are prominent infraorbital creases characteristic of atopic dermatitis, more common in children. Cited as a clinical feature of intrinsic AD (PMID:20207111) and of paediatric AD (PMID:35297082); the earlier claim that they are present in both extrinsic and intrinsic subtypes is not established by either source and has been withdrawn.
  phenotype_term:
    preferred_term: Dennie-Morgan infraorbital folds
    term:
      id: HP:0000607
      label: Periorbital wrinkles
  evidence:
  - reference: PMID:35297082
    reference_title: Differences between pediatric and adult atopic dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "children with AD have more exudative lesions, perifollicular accentuation, pityriasis alba, Dennie-Morgan folds, and seborrheic dermatitis-like presentation."
    explanation: Dennie-Morgan folds (infraorbital creases associated with periorbital hyperpigmentation) are identified as a characteristic pediatric AD feature.
  - reference: PMID:20207111
    reference_title: Extrinsic and intrinsic types of atopic dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features of intrinsic AD include relative late onset, milder severity, and Dennie-Morgan folds, but no ichthyosis vulgris or palmar hyperlinearity."
    explanation: Lists Dennie-Morgan folds among the clinical features of intrinsic AD. This establishes the sign in the intrinsic subtype only; it does not evidence presence in extrinsic AD.
- name: Keratosis Pilaris
  category: Dermatological
  frequency: OCCASIONAL
  notes: Follicular keratotic papules on extensor surfaces, associated with filaggrin-related barrier dysfunction and ichthyosis vulgaris.
  phenotype_term:
    preferred_term: Keratosis pilaris
    term:
      id: HP:0032152
      label: Keratosis pilaris
  evidence:
  - reference: PMID:31536314
    reference_title: Keratosis Pilaris.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Keratosis pilaris is associated with many other conditions, including atopic dermatitis, ichthyosis vulgaris, obesity, diabetes mellitus, and malnutrition."
    explanation: StatPearls reference directly identifies atopic dermatitis as one of the conditions associated with keratosis pilaris.
- name: Food Allergy
  category: Immunological
  frequency: FREQUENT
  notes: A common comorbidity, particularly in early-onset and severe AD. Part of the atopic march in a subset of patients. Epicutaneous sensitization through the disrupted skin barrier may drive food allergy development.
  phenotype_term:
    preferred_term: Food allergy
    term:
      id: HP:0500093
      label: Food allergy
  evidence:
  - reference: PMID:32738956
    reference_title: Atopic dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Atopic dermatitis is associated with increased risk of multiple comorbidities, including food allergy, asthma, allergic rhinitis, and mental health disorders."
    explanation: Lancet 2020 review identifies food allergy as a major AD comorbidity.
  - reference: PMID:28846349
    reference_title: Atopic Dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AD is associated with other IgE associated disorders like allergic rhinitis, asthma, and food allergies."
    explanation: Confirms the well-established association between AD and food allergies as IgE-mediated comorbidities.
- name: Allergic Rhinitis
  category: Immunological
  frequency: FREQUENT
  notes: A common atopic comorbidity, often developing after the onset of AD as part of the atopic march in some patients.
  phenotype_term:
    preferred_term: Allergic rhinitis
    term:
      id: HP:0003193
      label: Allergic rhinitis
  evidence:
  - reference: PMID:32738956
    reference_title: Atopic dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Atopic dermatitis is associated with increased risk of multiple comorbidities, including food allergy, asthma, allergic rhinitis, and mental health disorders."
    explanation: Lancet 2020 review identifies allergic rhinitis as a major AD comorbidity.
  - reference: PMID:35297082
    reference_title: Differences between pediatric and adult atopic dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Atopic diseases commonly co-occur with AD, although most do not temporally have the \"atopic march.\""
    explanation: Confirms atopic comorbidities co-occur with AD, while noting that the temporal sequence of the atopic march is not universal.
- name: Asthma
  category: Immunological
  frequency: FREQUENT
  notes: A major atopic comorbidity. Part of the classic atopic triad alongside allergic rhinitis. Epicutaneous sensitization through the disrupted skin barrier may contribute to airway sensitization.
  phenotype_term:
    preferred_term: Asthma
    term:
      id: HP:0002099
      label: Asthma
  evidence:
  - reference: PMID:32738956
    reference_title: Atopic dermatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Atopic dermatitis is associated with increased risk of multiple comorbidities, including food allergy, asthma, allergic rhinitis, and mental health disorders."
    explanation: Lancet 2020 review identifies asthma as a major AD comorbidity.
  - reference: PMID:30819278
    reference_title: "Pathophysiology of atopic dermatitis: Clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An impaired skin barrier may be the initial step in the development of the atopic march as well as AD, which leads to further skin inflammation and allergic sensitization."
    explanation: Links impaired skin barrier in AD to the development of the atopic march, including progression to asthma.
genetic:
- name: FLG
  gene_term:
    preferred_term: FLG
    term:
      id: hgnc:3748
      label: 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
    reference_title: "Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis."
    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
  gene_term:
    preferred_term: IL4R
    term:
      id: hgnc:6015
      label: IL4R
  association: Associated
  notes: Variants in IL-4 receptor alpha chain affect Th2 signaling intensity.
- name: IL13
  gene_term:
    preferred_term: IL13
    term:
      id: hgnc:5973
      label: IL13
  association: Associated
  notes: Variants affecting IL-13 expression or function.
- name: STAT6
  gene_term:
    preferred_term: STAT6
    term:
      id: hgnc:11368
      label: STAT6
  association: Associated
  notes: Transcription factor downstream of IL-4/IL-13 signaling.
- name: EMSY
  gene_term:
    preferred_term: EMSY
    term:
      id: hgnc:18071
      label: EMSY
  association: Associated
  notes: Chromatin remodeling factor identified in GWAS.
- name: BACH2
  gene_term:
    preferred_term: BACH2
    term:
      id: hgnc:14078
      label: BACH2
  association: GWAS
  notes: Transcription factor regulating Treg/effector T cell balance and B cell class switching
- name: TNFAIP3
  gene_term:
    preferred_term: TNFAIP3
    term:
      id: hgnc:11896
      label: TNFAIP3
  association: GWAS
  notes: Encodes A20, a ubiquitin-editing enzyme that negatively regulates NF-kB signaling
- name: EGR2
  gene_term:
    preferred_term: EGR2
    term:
      id: hgnc:3239
      label: EGR2
  association: GWAS
  notes: Transcription factor involved in T cell anergy and peripheral tolerance
- name: ETS1
  gene_term:
    preferred_term: ETS1
    term:
      id: hgnc:3488
      label: ETS1
  association: GWAS
  notes: Transcription factor regulating T and B cell development and immune cell differentiation
  evidence:
  - reference: PMID:26482879
    reference_title: "Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 11q24.3 the most plausible candidate gene is ETS1, which encodes a transcription factor with a range of immune functions including Th17 and B-cell differentiation and function
    explanation: >-
      The EAGLE multi-ancestry GWAS of 21,399 cases and 95,464 controls names
      ETS1 as the most plausible candidate gene at the 11q24.3 risk locus, and
      attributes to it the T- and B-cell functions recorded in this entry's
      notes.
- name: IRF4
  gene_term:
    preferred_term: IRF4
    term:
      id: hgnc:6119
      label: IRF4
  association: GWAS
  notes: Transcription factor essential for Th17 and Th2 cell differentiation and plasma cell development
- name: SATB1
  gene_term:
    preferred_term: SATB1
    term:
      id: hgnc:10541
      label: SATB1
  association: GWAS
  notes: Chromatin organizer regulating T cell development and lineage commitment
- name: SMAD3
  gene_term:
    preferred_term: SMAD3
    term:
      id: hgnc:6769
      label: SMAD3
  association: GWAS
  notes: TGF-beta signaling mediator regulating T cell differentiation and immune tolerance
- name: REL
  gene_term:
    preferred_term: REL
    term:
      id: hgnc:9954
      label: REL
  association: GWAS
  notes: NF-kB subunit c-Rel controlling lymphocyte activation and survival
environmental:
- name: Allergen Exposure
  exposure_term:
    preferred_term: allergen exposure
    term:
      id: ECTO:0000726
      label: exposure to allergen
  description: In sensitized individuals, house dust mites, pet dander, and pollens
    can trigger or exacerbate disease. Note the therapeutic corollary does not
    follow - trials of house dust mite avoidance are of very low quality and do not
    establish a clinical benefit.
  effect: TRIGGERS
  evidence:
  - reference: PMID:14609097
    reference_title: "Allergy and irritation: an adverse association in patients with atopic eczema."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most impressive barrier disruption was seen after application of house dust mite, followed by cat dander and grass pollen"
    explanation: "Atopy patch testing in 30 sensitized patients with atopic eczema versus healthy controls, measuring transepidermal water loss. Covers all three allergen classes named in the description."
  - reference: PMID:25598014
    reference_title: "House dust mite reduction and avoidance measures for treating eczema."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As many as a third of people with eczema who have a positive test for allergy to house dust mite have reported worsening of eczema or respiratory symptoms when exposed to dust"
    explanation: "Cochrane review. Supports exposure as a trigger in a sensitized subset rather than in all patients, and its conclusion of very low-quality evidence for avoidance measures is the caveat recorded in the description."
- name: Skin Irritants
  description: Soaps, detergents, and harsh fabrics disrupt the already compromised
    barrier, and atopic skin is measurably more susceptible to that damage than
    healthy skin under identical exposure.
  effect: TRIGGERS
  evidence:
  - reference: PMID:26426984
    reference_title: "Barrier function and natural moisturizing factor levels after cumulative exposure to a fruit-derived organic acid and a detergent: different outcomes in atopic and healthy skin and relevance for occupational contact dermatitis in the food industry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Repeated exposure to SLS and the irritant tandems enhanced the reactions and resulted in a significantly higher increase in TEWL in the AD compared to the control group"
    explanation: "Controlled tandem repeated irritation test in atopic dermatitis volunteers versus healthy controls, using the detergent sodium lauryl sulfate. Evidences both the barrier disruption and the greater susceptibility of atopic skin."
- name: Microbial Dysbiosis
  description: Staphylococcus aureus colonizes lesional skin in roughly 70 percent of
    patients - far more often than healthy controls - and its abundance tracks
    disease activity, rising during flares and with severity.
  review_notes: The prevalence figure was corrected from a previously curated value
    of over 90 percent. The pooled estimate from a 95-study meta-analysis is 70
    percent for lesional skin. The earlier claims of superantigen- and
    biofilm-mediated amplification were also removed rather than cited, since no
    source was found whose abstract states them; they belong in the pathophysiology
    section with their own evidence if reinstated.
  effect: WORSENS
  notes: >-
    This entry stands for the dysbiotic skin community as a whole, of which
    S. aureus is the dominant but not the sole member. The distinction matters
    when reading the influences_mechanisms edges: PMID:25902485 attributes eczema
    formation to S. aureus but the T helper 2 arm to C. bovis, so the edge into
    the type 2 node is evidenced for the community rather than for S. aureus
    specifically. The description above quantifies only the S. aureus component
    because that is what the cited human studies measure.
  influences_mechanisms:
  - target: Type 2 Immune Response
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Dysbiotic colonization acts on the type 2 inflammatory circuit rather than
      merely accompanying it. In a mouse model of eczematous dermatitis,
      species-specific antibiotic treatment reversed the dysbiosis and abolished
      the skin inflammation, and separate members of the dysbiotic community had
      separable effects on eczema formation and on T helper 2 responses. The edge
      is drawn as EXACERBATES rather than TRIGGERS, and the direction it takes in
      human disease is the open question recorded in
      gap_ad_dysbiosis_causal_ordering.
    evidence:
    - reference: PMID:25902485
      reference_title: "Dysbiosis and Staphylococcus aureus Colonization Drives Inflammation in Atopic Dermatitis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "antibiotics specific for these bacterial species almost completely reversed dysbiosis and eliminated skin inflammation"
      explanation: >-
        Interventional evidence in Adam17-deficient mice that removing the
        dysbiotic community removes the inflammation, which is the strongest
        available support for an edge running from dysbiosis to inflammation
        rather than the reverse. Model organism only, and the same abstract
        states the causal relationship in human disease is unclarified.
    - reference: PMID:25902485
      reference_title: "Dysbiosis and Staphylococcus aureus Colonization Drives Inflammation in Atopic Dermatitis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Whereas S. aureus prominently drove eczema formation, C. bovis induced robust T helper 2 cell responses."
      explanation: >-
        Attributes the type 2 arm of the response to a different member of the
        dysbiotic flora than the one driving eczema formation, so the link from
        this entry to the type 2 node is supported for the community as a whole
        but not specifically for S. aureus, which the entry description names.
  - target: Secondary Inflammatory Amplification
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      S. aureus overgrowth is treated as an amplifier of established lesional
      inflammation. Commensal coagulase-negative staphylococci that produce
      antimicrobial peptides are depleted in atopic dermatitis skin, and their
      loss correlates with S. aureus colonization, so failure of commensal
      colonization resistance is the route by which the pathobiont load is
      sustained.
    evidence:
    - reference: PMID:28228596
      reference_title: "Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "a pathogen commonly found in patients with atopic dermatitis (AD) and an important factor that exacerbates this disease"
      explanation: >-
        Supports the EXACERBATES predicate on this edge. Recorded as PARTIAL and
        OTHER because it is the authors' framing of prior literature rather than
        a result of the study reported in this abstract.
    - reference: PMID:28228596
      reference_title: "Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "CoNS strains with antimicrobial activity were common on the normal population but rare on AD subjects."
      explanation: >-
        Human isolate screening establishing depletion of antimicrobial commensal
        staphylococci on atopic dermatitis skin, the colonization resistance
        failure through which this entry acts on lesional inflammation.
    - reference: PMID:22310478
      reference_title: "Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the proportion of Staphylococcus sequences, particularly S. aureus, was greater during disease flares than at baseline or post-treatment, and correlated with worsened disease severity"
      explanation: >-
        The closest evidence for this specific edge: pathobiont load rises with
        flare activity and falls after treatment, which is amplification of
        established lesional inflammation rather than the colonization resistance
        step the other two items cover. Correlational and 16S amplicon based, so
        it constrains the predicate to EXACERBATES and not TRIGGERS.
  evidence:
  - reference: PMID:26994362
    reference_title: "Prevalence and odds of Staphylococcus aureus carriage in atopic dermatitis: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pooled prevalence of S. aureus colonization among patients was 70% for lesional skin, 39% for nonlesional skin and 62% for the nose"
    explanation: "Meta-analysis of 95 observational studies. Establishes the lesional colonization prevalence. The same abstract reports the odds of colonization versus healthy controls and that prevalence in lesional skin increased with disease severity; those figures are given in brackets in the source and so are described here rather than quoted."
  - reference: PMID:22310478
    reference_title: "Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the proportion of Staphylococcus sequences, particularly S. aureus, was greater during disease flares than at baseline or post-treatment, and correlated with worsened disease severity"
    explanation: "Longitudinal 16S rRNA gene sequencing of the skin microbiome across the flare cycle in children, evidencing that abundance tracks disease activity rather than merely co-occurring with it. Note the assay is 16S amplicon rather than shotgun metagenomics, so the species-level attribution to S. aureus in the quoted sentence carries the resolution limits of amplicon sequencing."
treatments:
- name: Emollients and Moisturizers
  description: First-line treatment to restore skin barrier function and reduce transepidermal water loss.
  evidence:
  - reference: PMID:36641009
    reference_title: "Guidelines of care for the management of atopic dermatitis in adults with topical therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strong recommendations are made for the use of moisturizers, TCIs, TCS, and topical PDE-4 and JAK inhibitors."
    explanation: >-
      The 2023 AAD guideline, developed by systematic review under GRADE, makes a
      strong recommendation for moisturizers in adult atopic dermatitis. Note the
      guideline recommends their use; it does not itself demonstrate the
      barrier-restoration mechanism asserted in this treatment's description.
- name: Topical Corticosteroids
  description: First-line anti-inflammatory treatment for flares, applied to affected areas.
  treatment_term:
    preferred_term: topical corticosteroid therapy
    term:
      id: NCIT:C122078
      label: Topical Corticosteroid Therapy
  evidence:
  - reference: PMID:36641009
    reference_title: "Guidelines of care for the management of atopic dermatitis in adults with topical therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strong recommendations are made for the use of moisturizers, TCIs, TCS, and topical PDE-4 and JAK inhibitors."
    explanation: >-
      Topical corticosteroids (TCS) carry a strong GRADE recommendation in the 2023
      AAD adult atopic dermatitis guideline.
- 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: biologic therapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: dupilumab
      term:
        id: NCIT:C162455
        label: Dupilumab
  evidence:
  - reference: PMID:41949508
    reference_title: Guidelines of care for the management of atopic dermatitis in pediatric patients.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We make strong recommendations for the use of moisturizers, topical calcineurin inhibitors, topical corticosteroids, crisaborole ointment, roflumilast cream, ruxolitinib cream, tapinarof cream, dupilumab, tralokinumab, lebrikizumab, nemolizumab with concomitant topical therapy, upadacitinib, abrocitinib"
    explanation: The AAD guidelines of care for pediatric atopic dermatitis make a strong recommendation for dupilumab among the systemic and topical therapies.
- 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: JAK inhibitor therapy
    term:
      id: NCIT:C15261
      label: Immunosuppressive Therapy
  evidence:
  - reference: PMID:37943240
    reference_title: "Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We make strong recommendations for the use of dupilumab, tralokinumab, abrocitinib, baricitinib, and upadacitinib."
    explanation: >-
      The 2024 AAD guideline makes strong GRADE recommendations for all three oral
      JAK inhibitors named in this treatment's description (abrocitinib, baricitinib,
      upadacitinib).
  - reference: PMID:36641009
    reference_title: "Guidelines of care for the management of atopic dermatitis in adults with topical therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strong recommendations are made for the use of moisturizers, TCIs, TCS, and topical PDE-4 and JAK inhibitors."
    explanation: >-
      Covers the topical arm of this treatment entry. The guideline recommends
      topical JAK inhibitors as a class and does not name ruxolitinib in this
      sentence, so it supports the class claim only.
- name: STAT6 Degrader (SAR448272/NX-3911)
  description: >-
    SAR448272/NX-3911 is an investigational oral STAT6 degrader in a Phase 1
    first-in-human study for type 2 inflammatory diseases. The study establishes
    that the asset is in clinical development, but disease-specific human
    efficacy has not yet been reported.
  role: Investigational clinical-stage targeted protein degrader
  therapeutic_modality: SMALL_MOLECULE
  context: >-
    Clinical-stage type 2 inflammatory-disease program; current human evidence
    establishes Phase 1 trial initiation, not efficacy in atopic dermatitis.
  treatment_term:
    preferred_term: STAT6 targeted protein degradation
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: SAR448272/NX-3911
  target_mechanisms:
  - target: Type 2 Immune Response
    treatment_effect: INHIBITS
    description: >-
      SAR448272/NX-3911 degrades STAT6. Reduced STAT6 abundance is intended to
      suppress IL-4/IL-13-dependent type 2 inflammatory signaling.
    evidence:
    - reference: url:https://www.globenewswire.com/news-release/2026/08/04/3338158/0/en/Nurix-Announces-10-Million-Milestone-Payment-Associated-with-Initiation-of-a-Phase-1-Clinical-Trial-of-a-STAT6-Degrader.html
      reference_title: "Nurix Announces $10 Million Milestone Payment Associated"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "STAT6 is a key transcription factor within the interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling pathways that drive type 2 inflammation"
      explanation: >-
        Supports the intended connection between STAT6 degradation and the type
        2 immune-response node. The source does not establish efficacy in people
        with atopic dermatitis.
  evidence:
  - reference: url:https://www.globenewswire.com/news-release/2026/08/04/3338158/0/en/Nurix-Announces-10-Million-Milestone-Payment-Associated-with-Initiation-of-a-Phase-1-Clinical-Trial-of-a-STAT6-Degrader.html
    reference_title: "Nurix Announces $10 Million Milestone Payment Associated"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "following the initiation by its collaborator, Sanofi, of the Phase 1 first-in-human clinical trial of SAR448272/NX-3911, an oral STAT6 degrader."
    explanation: >-
      Establishes that SAR448272/NX-3911 has entered a first-in-human Phase 1
      study. It does not provide disease-specific efficacy results.
  review_notes: >-
    STAT6 degradation is the molecular action. INHIBITS records the downstream
    effect on the Type 2 Immune Response pathograph node. Structured molecular
    representation of degradation, ubiquitination, and reduced target abundance
    is tracked in issue #7969.
- name: Phototherapy
  description: Narrowband UVB phototherapy for moderate-to-severe disease.
  treatment_term:
    preferred_term: phototherapy
    term:
      id: NCIT:C15301
      label: Phototherapy
  evidence:
  - reference: PMID:37943240
    reference_title: "Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We make conditional recommendations in favor of using phototherapy, azathioprine, cyclosporine, methotrexate, and mycophenolate, and against the use of systemic corticosteroids."
    explanation: >-
      Phototherapy carries a conditional (not strong) GRADE recommendation in the
      2024 AAD adult guideline. The guideline does not single out narrowband UVB in
      this sentence, so the recommendation is for phototherapy as a modality.
- name: TOPK Inhibitors
  description: Small-molecule inhibitors of TOPK (PBK) that target the TOPK-STAT3 signaling axis in keratinocytes and mast cells. Pharmacological or genetic TOPK inhibition attenuates AD-like pathological features and reduces inflammatory cytokine levels (IL-6, IL-8, IL-33, IgE).
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: TOPK-STAT3 Signaling Axis
    description: TOPK inhibitors block TOPK-mediated STAT3 Ser727 phosphorylation and downstream inflammatory cytokine production.
discussions:
- discussion_id: gap_ad_dysbiosis_causal_ordering
  prompt: >-
    In human atopic dermatitis, is skin dysbiosis (loss of commensal diversity
    with Staphylococcus aureus overgrowth) a driver of disease, an amplifier that
    sustains established lesions, or mainly a consequence of the barrier defect
    and the type 2 cytokine milieu that together suppress cutaneous antimicrobial
    defence?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Epidermal Barrier Dysfunction
  - pathophysiology#Type 2 Immune Response
  - pathophysiology#Secondary Inflammatory Amplification
  rationale: >-
    The environmental entry Microbial Dysbiosis records that S. aureus occupies
    roughly 70 percent of lesional skin and that its abundance rises with flares
    and with severity, and it now declares influences_mechanisms edges into the
    type 2 and secondary amplification nodes. Both edges are drawn EXACERBATES
    rather than TRIGGERS, because the abundant correlational human data are
    compatible with either direction and the two directions are separately
    evidenced.

    Evidence for dysbiosis acting causally is largely from model systems and from
    commensal biology. In Adam17-deficient mice, species-specific antibiotics
    reversed the dysbiosis and eliminated the skin inflammation, an interventional
    result no human study matches; the same abstract states plainly that the
    causal relationship in human disease has yet to be clarified. In humans,
    coagulase-negative staphylococci producing antimicrobial peptides are depleted
    on atopic dermatitis skin, their scarcity correlates with S. aureus
    colonization, and reintroducing active strains lowered S. aureus, which is a
    human interventional result on colonization but not on disease activity.

    Evidence for dysbiosis being downstream is at least as strong in humans.
    Blocking IL-4 receptor alpha with dupilumab in a placebo-controlled trial
    raised microbial diversity and lowered S. aureus abundance in both lesional
    and nonlesional skin, with the fall tracking clinical improvement and type 2
    biomarkers; the microbiome shifted because the host immune state was changed,
    not the other way round. In a birth cohort followed to one year, infants who
    went on to develop atopic dermatitis were not colonized by S. aureus before
    disease onset, and it was the relative abundance of protective commensal
    staphylococci at two months, not pathobiont overgrowth, that distinguished
    them.

    A defensible reading is that the two arms describe different disease stages,
    with commensal depletion preceding infantile onset and S. aureus overgrowth
    amplifying established adult lesions. That reading is currently an inference
    across separate cohorts, assay generations, and age groups rather than a
    measured trajectory, and until it is tested the edges above should not be
    strengthened to TRIGGERS. Note also that most human abundance data cited here
    are 16S amplicon rather than shotgun metagenomic, so species-level and
    strain-level attribution carries the resolution limits recorded on the
    Microbial Dysbiosis evidence items.
  proposed_experiments:
  - experiment_id: exp_ad_dysbiosis_temporal_ordering
    name: Birth-cohort strain-resolved ordering of dysbiosis against barrier and type 2 onset
    description: >-
      Follow an unselected birth cohort from the neonatal period through the age
      of peak atopic dermatitis incidence, sampling predilection and control skin
      sites at fixed intervals regardless of disease status. Pair shotgun
      metagenomics, which resolves S. aureus and commensal staphylococci to strain
      level where amplicon sequencing cannot, with transepidermal water loss,
      filaggrin genotype, and tape-strip measurement of type 2 cytokines and
      antimicrobial peptides at the same visits. Analyse each subject as their own
      control across the transition into disease, so the question becomes which
      measurement moves first within an individual rather than which group differs
      at one cross-section. Stratify by age at onset to test the staged reading in
      which commensal depletion precedes infantile disease while pathobiont
      overgrowth amplifies established lesions.
    experiment_type:
      preferred_term: longitudinal birth cohort with paired multi-omic skin sampling
    readouts:
    - name: Time ordering of commensal depletion against barrier change
      target: pathophysiology#Epidermal Barrier Dysfunction
      description: >-
        Determine whether the fall in commensal staphylococcal abundance precedes,
        coincides with, or follows the measurable rise in transepidermal water
        loss within individual subjects who go on to develop disease.
      assays:
      - preferred_term: shotgun metagenomic sequencing
      - preferred_term: transepidermal water loss measurement
    - name: Time ordering of S. aureus expansion against type 2 activation
      target: pathophysiology#Type 2 Immune Response
      description: >-
        Determine whether S. aureus expansion precedes or follows the local rise
        in type 2 cytokines and the fall in antimicrobial peptide expression at
        the same skin site.
      assays:
      - preferred_term: cytokine quantification
      - preferred_term: shotgun metagenomic sequencing
    - name: Pathobiont load against lesion persistence in established disease
      target: pathophysiology#Secondary Inflammatory Amplification
      description: >-
        In subjects with established disease, test whether S. aureus load predicts
        subsequent lesion persistence and severity beyond what the concurrent type
        2 biomarker level already predicts.
      assays:
      - preferred_term: quantitative PCR
      direction: POSITIVE
    decision_criterion: >-
      A driver model is supported if commensal depletion or S. aureus expansion
      reproducibly precedes barrier and type 2 change within individuals before
      disease onset. A consequence model is supported if the microbial change
      follows barrier or type 2 change, consistent with the dupilumab trial in
      which suppressing type 2 signalling alone restored diversity. A staged model
      is supported if the ordering differs by age at onset, with commensal
      depletion leading in infantile disease and S. aureus expansion following in
      established disease; in that case the two influences_mechanisms edges should
      be re-curated separately rather than kept uniform.
    would_support:
    - pathophysiology#Epidermal Barrier Dysfunction
    - pathophysiology#Type 2 Immune Response
    - pathophysiology#Secondary Inflammatory Amplification
  evidence:
  - reference: PMID:25902485
    reference_title: "Dysbiosis and Staphylococcus aureus Colonization Drives Inflammation in Atopic Dermatitis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, the causal relationship of dysbiosis and eczema has yet to be clarified."
    explanation: >-
      States the gap directly. The paper that supplies the strongest causal
      evidence for the driver arm is explicit that the human causal relationship
      is unresolved. Classified OTHER on the same basis as the PMID:28228596
      framing sentence on the amplification edge: this is the authors' statement
      of the state of the field, not a result of the mouse work reported in the
      paper, and it asserts an absence of evidence rather than presenting any.
  - reference: PMID:28228596
    reference_title: "Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reintroduction of antimicrobial CoNS strains to human subjects with AD decreased colonization by S. aureus"
    explanation: >-
      Human interventional evidence for the driver arm, but the measured endpoint
      is colonization rather than disease activity, so it establishes that
      commensal deficiency is upstream of pathobiont load without establishing
      that either is upstream of inflammation.
  - reference: PMID:31252032
    reference_title: "IL-4Rα Blockade by Dupilumab Decreases Staphylococcus aureus Colonization and Increases Microbial Diversity in Atopic Dermatitis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Decreased S. aureus abundance during dupilumab treatment correlated with clinical improvement of AD and biomarkers of type 2 immunity."
    explanation: >-
      Placebo-controlled human evidence for the consequence arm, and the reason
      this gap is recorded rather than resolved. Suppressing type 2 signalling
      alone reduced S. aureus and raised diversity, so the microbiome tracked the
      host immune state. Marked REFUTE against the proposition that dysbiosis is
      an autonomous upstream driver, not against the disease association itself.
  - reference: PMID:27609659
    reference_title: "Skin microbiome before development of atopic dermatitis: Early colonization with commensal staphylococci at 2 months is associated with a lower risk of atopic dermatitis at 1 year."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "these patients with infantile AD did not have noticeably dysbiotic communities before or with disease and were not colonized by S aureus"
    explanation: >-
      Birth cohort evidence against S. aureus overgrowth acting as the initiating
      event in infantile disease. Refutes the trigger reading specifically, which
      is why both influences_mechanisms edges are curated as EXACERBATES.
  - reference: PMID:27609659
    reference_title: "Skin microbiome before development of atopic dermatitis: Early colonization with commensal staphylococci at 2 months is associated with a lower risk of atopic dermatitis at 1 year."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "commensal staphylococci were significantly less abundant in infants affected at month 12, suggesting that this genus might protect against the later development of AD"
    explanation: >-
      The same cohort supports a different microbial arm, in which loss of
      protective commensals rather than pathobiont overgrowth is the antecedent
      signal. This is the observation the staged reading in the rationale rests on.
- discussion_id: gap_ad_topk_stat3_axis
  prompt: >-
    TOPK (PBK) is upregulated in atopic dermatitis and its inhibition attenuates
    AD-like inflammation via STAT3 Ser727 phosphorylation in keratinocytes and
    mast cells, but is TOPK-STAT3 signaling a primary causal driver of AD
    pathogenesis or a downstream amplifier of the established type 2 / barrier
    circuit, what is its dominant in vivo cellular source, and does the axis
    translate from cell and mouse models to human disease?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Type 2 Immune Response
  - pathophysiology#Epidermal Barrier Dysfunction
  - pathophysiology#Secondary Inflammatory Amplification
  rationale: >-
    Atopic dermatitis pathogenesis is well characterized at the level of
    epidermal barrier dysfunction and the IL-4/IL-13/IL-31 type 2 immune program
    signaling through JAK1/STAT6, which underpins approved biologic and JAK-inhibitor
    therapies. Recent work identifies T-LAK-cell-originated protein
    kinase (TOPK) as upregulated in AD lesions, where it directly interacts with
    and phosphorylates STAT3 at Ser727 in HaCaT keratinocytes and mast cells, and
    where genetic or pharmacologic TOPK inhibition reduces IgE, IL-6, IL-8, and
    IL-33 and attenuates AD-like features. What remains unresolved is the causal
    placement of this TOPK-STAT3 axis: whether it initiates inflammation upstream
    of, runs in parallel to, or is induced by the canonical type 2 and barrier
    pathways, and whether STAT3 Ser727 signaling acts mainly in keratinocytes,
    mast cells, or other resident/infiltrating cells in intact skin. The current
    evidence rests largely on cell lines, bioinformatic (GEO) profiling, and a
    disease model, so the human translational relevance and therapeutic window of
    TOPK inhibition relative to existing STAT6/JAK-directed therapies is unknown.
  proposed_experiments:
  - experiment_id: exp_ad_topk_stat3_epistasis
    name: Cell-type-resolved epistasis of the TOPK-STAT3 axis versus the type 2 barrier circuit
    description: >-
      Use cell-type-conditional TOPK loss- and gain-of-function in barrier and
      immune compartments of AD models, combined with epistasis against IL-4/
      IL-13 (type 2) and barrier perturbations and STAT3 Ser727 phospho-readouts,
      to place TOPK-STAT3 in the causal hierarchy and identify the dominant in
      vivo cellular source. Cross-validate against human AD skin to test
      translational relevance.
    experiment_type:
      preferred_term: cell-type-conditional perturbation and epistasis study
    readouts:
    - name: STAT3 Ser727 phosphorylation by compartment
      target: pathophysiology#Secondary Inflammatory Amplification
      description: >-
        Quantify STAT3 Ser727 phosphorylation in keratinocytes versus mast cells
        and other skin-resident cells under TOPK perturbation to localize the
        active signaling compartment.
      assays:
      - preferred_term: phospho-specific immunostaining
      - preferred_term: phosphoproteomic profiling
      direction: POSITIVE
    - name: Type 2 cytokine and barrier dependence
      target: pathophysiology#Type 2 Immune Response
      description: >-
        Test whether TOPK-driven inflammation persists when IL-4/IL-13 signaling
        is blocked, distinguishing an upstream/parallel driver from a type 2-dependent
        amplifier.
      assays:
      - preferred_term: cytokine quantification
      direction: NEGATIVE
    - name: Barrier integrity response to TOPK modulation
      target: pathophysiology#Epidermal Barrier Dysfunction
      description: >-
        Measure transepidermal water loss and barrier protein expression after
        TOPK inhibition to determine whether the axis modifies barrier function
        directly or only via inflammation.
      assays:
      - preferred_term: transepidermal water loss measurement
      direction: NEGATIVE
    decision_criterion: >-
      TOPK-STAT3 is supported as a primary driver if compartment-conditional TOPK
      loss reduces AD-like inflammation independently of (and upstream of) intact
      IL-4/IL-13 signaling, with the dominant active STAT3 Ser727 compartment
      reproducibly identified and the axis detectable in human AD skin; it is a
      downstream amplifier if its effects require an intact type 2 circuit.
    would_support:
    - pathophysiology#Type 2 Immune Response
    - pathophysiology#Secondary Inflammatory Amplification
    - pathophysiology#Epidermal Barrier Dysfunction
  evidence:
  - reference: PMID:42237026
    reference_title: "Targeting the TOPK-STAT3 pathway in keratinocytes and mast cells mediates the therapeutic attenuation of Atopic dermatitis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "T-Lymphokine-Activated Killer Cell-Originated Protein Kinase (TOPK) is known to promote inflammation, its specific role in AD remains unclear."
    explanation: >-
      Establishes that TOPK is implicated in inflammation but its specific
      mechanistic role in atopic dermatitis is unresolved, motivating the gap.
  - reference: PMID:42237026
    reference_title: "Targeting the TOPK-STAT3 pathway in keratinocytes and mast cells mediates the therapeutic attenuation of Atopic dermatitis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TOPK was found to directly interact with and phosphorylate STAT3 at Ser727. Inhibition of TOPK in both HaCaT keratinocytes and mast cells decreased STAT3 phosphorylation at Ser727, thereby alleviating AD-related inflammatory responses."
    explanation: >-
      Defines the proposed TOPK-STAT3 Ser727 mechanism in keratinocytes and mast
      cells, the candidate axis whose causal placement and cellular source the
      gap seeks to resolve.
- discussion_id: openq_ad_oral_health_caries_comorbidity
  prompt: >-
    Atopic dermatitis is associated with impaired oral health (higher plaque,
    poorer oral hygiene, oral dysbiosis) in adults, and in a Singaporean birth
    cohort (GUSTO) atopic dermatitis with allergen sensitization in the first
    year of life was associated with an increased risk of early childhood caries
    by age 3 (adjusted OR ~3.1 for the AD-SPT-positive group). Is this AD-caries
    comorbidity causal - e.g., via shared structural-gene defects in skin and
    tooth/enamel, oral dysbiosis, dietary/behavioral mediators, or AD-related
    sleep disturbance and medication use - or is it confounded by shared
    socioeconomic and dietary risk factors?
  kind: OPEN_QUESTION
  status: OPEN
  rationale: >-
    The GUSTO cohort proposed a "structural defect hypothesis": because both
    dental caries susceptibility and atopic dermatitis are linked to defects in
    structural genes (e.g., epidermal barrier mutations in AD; keratin/enamel
    structural defects increasing caries risk), the two may share a predisposing
    structural-gene basis (Kalhan et al, PMID:28122670; this JACI letter has no
    structured PubMed abstract). Independently, an adult case-control study found
    AD associated with poorer oral health and oral dysbiosis, offering a
    microbiome-mediated alternative or complementary mechanism. The association
    in GUSTO was specific to the allergen-sensitized (AD-SPT-positive) subgroup
    and adjusted for several confounders, but causation versus residual
    confounding (shared diet, socioeconomic status, and care behaviors) remains
    unresolved.
  evidence:
  - reference: PMID:39523189
    reference_title: "Association of Adult Atopic Dermatitis with Impaired Oral Health and Oral Dysbiosis: A Case-Control Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AD appears to be associated with poor oral health and oral dysbiosis."
    explanation: >-
      Case-control evidence that atopic dermatitis is associated with impaired
      oral health and oral dysbiosis, supporting an AD-oral-disease comorbidity
      relevant to the early-childhood-caries association.
  - reference: PMID:39523189
    reference_title: "Association of Adult Atopic Dermatitis with Impaired Oral Health and Oral Dysbiosis: A Case-Control Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "those with AD had significantly higher plaque levels (P = .04), poorer oral hygiene indices (P = .04), and higher gingival index trends (P = .05)."
    explanation: >-
      Quantifies the specific oral-health deficits (plaque, hygiene, gingival
      index) measured in adults with AD versus controls.
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:
  - statement: >-
      Integrated skin-tissue and blood (PBMC) transcriptomic profiling of atopic
      dermatitis patients links distinct clinical presentations to matching
      molecular signatures, with the two main skin manifestations (erythema and
      papulation) distinguished by differential immunological signatures,
      supporting a phenotype-endotype framework and the view of AD as a systemic
      rather than a purely local disease.
    supporting_text: "The two main, qualitatively differential skin manifestations of AD, erythema and papulation are distinguished by differential immunological signatures."
- reference: DOI:10.1126/sciimmunol.abi6887
  title: IL-31–dependent neurogenic inflammation restrains cutaneous type 2 immune response in allergic dermatitis
  findings:
  - statement: >-
      In a mouse model of house dust mite-induced allergic dermatitis, IL-31 is
      not strictly proinflammatory but acts as an immunoregulatory factor that
      limits the magnitude of type 2 skin inflammation via IL31RA+ pruritoceptor
      release of CGRP, a neuroimmune brake that may explain paradoxical
      dermatitis flares in atopic patients treated with anti-IL31RA therapy.
    supporting_text: "Thus, IL-31 is not strictly a proinflammatory cytokine but rather an immunoregulatory factor that limits the magnitude of type 2 inflammatory responses in skin."
- 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: []
datasets:
- accession: geo:GSE48310
  title: Gene Expression in Whole Blood of Atopic Eczema and Healthy Children at 4 years
  description: We studied genes that are related to atopic diseases [i.e., atopic eczema (AE)]. Immunological factors and principal genes involved in the biosynthesis of polyunsaturated fatty acids were included. We analyzed whether expression of genes encoding key enzymes of LC-PUFA synthesis (FADS1, FADS2 and ELOVL5) is associated with circulating LC-PUFA levels and risk of AE in 4-year-old children. AE (n=20) and non-AE (n=104) children participating in the Sabadell cohort within the INfancia y Medio Ambiente (INMA) Project were included in the present study. RT-PCR with TaqMan Low-Density Array cards was used to measure the expression of these genes.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_count: 124
  publication: PMID:24167612
  notes: Identified by GEO DataSets index search for Atopic Dermatitis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE307177
  title: CHN1 as a Predictive Biomarker for Atopic Dermatitis-related Depression
  description: The comorbidity of Atopic Dermatitis (AD) and depression has garnered increasing attention in recent years. Yet, the immunopathological mechanisms underlying this connection remain unclear. To bridge this gap, we collected peripheral blood mononuclear cell samples from 20 AD patients with and without depression, and performed RNA sequencing analysis. By integrating bioinformatics and machine learning techniques, we aimed to uncover the immune regulatory networks and identify key genetic markers for the depression comorbidity in AD patients. Our analysis revealed 394 differentially expressed genes in AD patients with depression as compared to those non-depression counterparts.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 20
  publication: PMID:41333466
  notes: Identified by GEO DataSets index search for Atopic Dermatitis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE182740
  title: Genomic profiling of the overlap phenotype between psoriasis and atopic dermatitis
  description: Clinical overlaps between psoriasis and atopic dermatitis are sometimes undiscernible, and there is no consensus whether to treat the overlap phenotype as psoriasis or atopic dermatitis. We enrolled patients diagnosed with either psoriasis or atopic dermatitis, and clinically re-stratified them into classic psoriasis, classic atopic dermatitis, and the overlap phenotype between psoriasis and atopic dermatitis. We compared gene expression profiles of lesional and nonlesional skin biopsy tissues between the three comparison groups.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 75
  publication: PMID:37419444
  notes: Identified by GEO DataSets index search for Atopic Dermatitis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001007487
  title: Optimizing single-cell transcriptomic discrimination of atopic dermatitis versus psoriasis vulgaris
  description: Optimizing single-cell transcriptomic discrimination of atopic dermatitis versus psoriasis vulgaris
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Atopic Dermatitis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS50000000166
  title: Nanopore sequencing enables allelic phasing of FLG loss-of-function variants, intragenic copy number variation and methylation status in atopic dermatitis and ichthyosis vulgaris
  description: Loss-of-function (LoF) variants in the FLG gene are associated with ichthyosis vulgaris (IV) and atopic dermatitis (AD). IV and AD patients with two FLG LoF variants are reported to have a more severe disease course. However, subsets of compound heterozygous patients display phenotypic heterogeneity despite a prediction of a severe phenotype from their genotype. The underlying genetic mechanism of this phenotypic variability is unknown. One possibility is that two LoF FLG variants could be located in cis (on the same allele), thus altering the predicted gene dosage.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: WGS
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Atopic Dermatitis"); description-level mentions were not accepted. EGA study_type: Whole Genome Sequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: metabolomics_workbench:ST002302
  title: Integrated metabolomics and lipidomics study of patients with atopic dermatitis in response to dupilumab
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Atopic Dermatitis"). Retrieved 2026-08-02.
- accession: massive:MSV000087837
  title: Local and systemic changes in lipid profile as potential biomarkers for canine atopic dermatitis.
  description: Lipids play a critical role in the skin as components of the epidermal barrier and as sig-naling molecules. Atopic dermatitis in dogs is associated with changes in the lipid composition of the skin, but whether these precede the onset of dermatitis or occur secondary to the dermatitis is unclear. We applied rapid lipid profiling mass spectrometry methods to skin and blood samples of dogs and determined changes following systemic treatment. Thirty control dogs and 30 atopic dogs with mild to moderate dermatitis were enrolled.
  organism:
    preferred_term: dog
    term:
      id: NCBITaxon:9615
      label: Canis lupus familiaris
  data_type: METABOLOMICS
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Atopic Dermatitis"). Retrieved 2026-08-02.
- accession: massive:MSV000090686
  title: 'Dietary Grape Against Atopic Dermatitis in NC/NgaTndCrlj Mice: Proteomics Analysis'
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: PROTEOMICS
  description: 'The study demonstrates the effects of dietary grape powder against atopic dermatitis in 2,4-dinitrofluorobenzene-induced atopic dermatitis in NC/NgaTndCrlj mice. To uncover molecular mechanism(s) of biological responses of grape powder, dorsal skin samples from normal control (noAD), atopic dermatitis control (ctlAD) and 5% grape powder (5GP) prevention groups were analyzed using gel-free quantitative global proteomics analysis at the School of Pharmacy Analytical Instrumentation Facility, University of Wisconsin–Madison.'
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Atopic Dermatitis"). Retrieved 2026-08-02.
📚

References & Deep Research

References

9
DOI:10.1007/s13555-025-01352-y
Interleukin-4 and Atopic Dermatitis: Why Does it Matter? A Narrative Review
No top-level findings curated for this source.
DOI:10.1038/s41467-023-41857-8
Multifaceted analysis of cross-tissue transcriptomes reveals phenotype–endotype associations in atopic dermatitis
1 finding
Integrated skin-tissue and blood (PBMC) transcriptomic profiling of atopic dermatitis patients links distinct clinical presentations to matching molecular signatures, with the two main skin manifestations (erythema and papulation) distinguished by differential immunological signatures, supporting a phenotype-endotype framework and the view of AD as a systemic rather than a purely local disease.
"The two main, qualitatively differential skin manifestations of AD, erythema and papulation are distinguished by differential immunological signatures."
DOI:10.1126/sciimmunol.abi6887
IL-31–dependent neurogenic inflammation restrains cutaneous type 2 immune response in allergic dermatitis
1 finding
In a mouse model of house dust mite-induced allergic dermatitis, IL-31 is not strictly proinflammatory but acts as an immunoregulatory factor that limits the magnitude of type 2 skin inflammation via IL31RA+ pruritoceptor release of CGRP, a neuroimmune brake that may explain paradoxical dermatitis flares in atopic patients treated with anti-IL31RA therapy.
"Thus, IL-31 is not strictly a proinflammatory cytokine but rather an immunoregulatory factor that limits the magnitude of type 2 inflammatory responses in skin."
DOI:10.1186/s43556-025-00313-3
Atopic dermatitis: diagnosis, molecular pathogenesis, and therapeutics
No top-level findings curated for this source.
DOI:10.14789/ejmj.jmj24-0036-r
Mechanisms of Itch in Atopic Dermatitis
No top-level findings curated for this source.
DOI:10.3390/jcm12041538
The Role of Tight Junctions in Atopic Dermatitis: A Systematic Review
No top-level findings curated for this source.
DOI:10.3390/jcm14145053
Anti-Inflammatory Therapies for Atopic Dermatitis: A New Era in Targeted Treatment
No top-level findings curated for this source.
DOI:10.64898/2026.01.10.26343854
Protective and Susceptibility Clusters of Environmental Factors, Gene Expression, Antibody Responses, and Cytokines in Pediatric Atopic Dermatitis: Insights from Multi-Modal Data Integration
No top-level findings curated for this source.
DOI:10.7759/cureus.86937
Skin Barrier Dysfunction in Chronic Dermatoses: From Pathophysiology to Emerging Therapeutic Strategies
No top-level findings curated for this source.

Deep Research

2

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.

Disorder ▸

Disorder

  • Name: Atopic Dermatitis
  • Category: Complex
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 15

Key Pathophysiology Nodes

  • Epidermal Barrier Dysfunction
  • Type 2 Immune Response
  • Th17/Th22 Inflammation
  • Pruritogen-Induced Neuronal Activation
  • Scratching-Induced Barrier Injury
  • Secondary Inflammatory Amplification
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1007/s13555-025-01352-y
  • DOI:10.1038/s41467-023-41857-8
  • DOI:10.1126/sciimmunol.abi6887
  • DOI:10.1186/s43556-025-00313-3
  • DOI:10.14789/ejmj.jmj24-0036-r
  • DOI:10.3390/jcm12041538
  • DOI:10.3390/jcm14145053
  • DOI:10.64898/2026.01.10.26343854
  • DOI:10.7759/cureus.86937
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 26 citations 2026-02-14T17:00:30.185672

Disease Pathophysiology Research Report

Target Disease - Disease Name: Atopic Dermatitis (AD) - MONDO ID: MONDO:0004994 - Category: Complex

Pathophysiology description (current understanding, 2023–2025 emphasis) Atopic dermatitis is a chronic, relapsing inflammatory dermatosis driven by the interplay of epidermal barrier dysfunction, type 2–skewed immunity, neuroimmune pruritus circuitry, and microbial/ environmental exposures. Barrier failure (filaggrin insufficiency, altered ceramide composition, and tight-junction defects) permits enhanced allergen/microbe ingress and promotes alarmin release, which activates dendritic cells and ILC2/Th2 axes. IL-4/IL-13 signaling amplifies inflammation and further downregulates barrier genes, establishing feed-forward loops. Pruritus is sustained by neuroimmune mediators—especially IL-31—signaling to TRP channel–bearing sensory afferents and, in chronic exposure, engaging a paradoxical neurogenic anti–type 2 brake via CGRP. JAK–STAT integrates many of these cytokine signals and is a validated therapeutic hub. Multi-omics studies reveal clinically relevant endotypes aligning cutaneous and blood transcriptomes with phenotypes and treatment trajectories. Therapeutically, targeting IL-4/IL-13 (dupilumab; IL-13 inhibitors) and JAK1/2 pathways improves disease activity and, in some studies, barrier function, supporting causal roles for these axes in AD. (katsarou2023theroleof pages 12-12, kamata2025mechanismsofitch pages 2-4, torres2025interleukin4andatopic pages 14-15, urzua2025skinbarrierdysfunction pages 3-4, bai2025atopicdermatitisdiagnosis pages 25-26, zhakparov2026protectiveandsusceptibility pages 22-23)

Key concepts and definitions (with recent sources) - Epidermal barrier dysfunction: Tight junction (TJ) impairment (e.g., reduced claudin-1) and filaggrin deficiency increase permeability and trans-epidermal water loss, facilitating allergen and pathogen entry; Th2 cytokines suppress TJ proteins. Quote: “Impaired TJ barrier function and skin permeability in AD lesions is correlated with cldn-1 levels. Th2 inflammation inhibits the expression of cldn-1 and cldn-23” (Feb 2023, Journal of Clinical Medicine; URL: https://doi.org/10.3390/jcm12041538). (katsarou2023theroleof pages 12-12) - Type 2 cytokine axis: IL-4 and IL-13 orchestrate barrier disruption, dysbiosis, pruritus, and inflammation in AD. Narrative review emphasis: “IL-4 plays a critical role in skin barrier dysfunction, dysbiosis, pruritus, and inflammation” (Feb 2025, Dermatology and Therapy; URL: https://doi.org/10.1007/s13555-025-01352-y). (torres2025interleukin4andatopic pages 14-15) - Neuroimmune itch (IL-31 axis): IL-31 acts directly on pruritoceptors (IL31RA/OSMR) to induce itch and neurite outgrowth and is a central mediator of AD pruritus. Quote: “IL-31 directly induces pruritus… and selectively promotes nerve fiber extension in these neurons” (Jan 2025, Juntendo Medical Journal; URL: https://doi.org/10.14789/ejmj.jmj24-0036-r). (kamata2025mechanismsofitch pages 2-4) - Neurogenic restraint of type 2 inflammation: In chronic allergen exposure, IL-31 activation of sensory neurons can trigger CGRP release that suppresses Th2 responses, providing a mechanistic basis for paradoxical flares with anti–IL-31 receptor therapy. Quote: “IL-31… restrains cutaneous type 2 inflammation… IL-31 activation of IL31RA+ pruritoceptors triggers release of calcitonin gene-related protein (CGRP), which… inhibit[s] CD4+ T cell proliferation and reduce[s]… IL-13” (Oct 2023, Science Immunology; URL: https://doi.org/10.1126/sciimmunol.abi6887). (bai2025atopicdermatitisdiagnosis pages 25-26) - JAK–STAT as hub pathway: Many AD cytokines signal via JAKs; clinical efficacy of oral and topical JAK inhibitors supports centrality of this pathway (reviewed 2025). (urzua2025skinbarrierdysfunction pages 3-4) - Molecular endotypes: Integrated skin and blood transcriptomics uncover endotype–phenotype associations and clusters aligned with severity and trajectories, enabling personalized monitoring. (Oct 2023, Nature Communications; URL: https://doi.org/10.1038/s41467-023-41857-8). (bilinski2025antiinflammatorytherapiesfor pages 2-4)

1) Core Pathophysiology - Primary mechanisms - Barrier failure: FLG deficiency and TJ defects (e.g., CLDN1) lead to increased permeability; scratching worsens claudin-1 loss and barrier leak. Th2 cytokines (IL-4/IL-13) suppress claudins and barrier proteins, coupling immunity to barrier pathology (Feb 2023; URL above). (katsarou2023theroleof pages 12-12) - Epithelial alarmins: Barrier stress releases TSLP/IL-33/IL-25 from keratinocytes, priming DCs/ILC2/Th2; their role is integrated within itch reviews and type 2 discussions (2025; URLs below). (kamata2025mechanismsofitch pages 2-4, torres2025interleukin4andatopic pages 14-15) - Type 2 immunity: IL-4/IL-13 drive IgE class switching, eosinophilia, keratinocyte chemokine production, and barrier gene suppression. (torres2025interleukin4andatopic pages 14-15, urzua2025skinbarrierdysfunction pages 3-4) - Neuroimmune itch: IL-31→IL31RA/OSMR on TRPV1/TRPA1+ small-diameter afferents; neuronal plasticity (hyperinnervation) correlates with itch; Sema3A↓ and NGF↑ alter epidermal innervation in AD (Jan 2025; URL below). (kamata2025mechanismsofitch pages 2-4) - Neurogenic restraint loop: IL-31–induced CGRP limits Th2 cell accumulation and IL-13 output in chronic allergen dermatitis (Oct 2023; URL below). (bai2025atopicdermatitisdiagnosis pages 25-26) - JAK–STAT integration: Many cytokines (IL-4/IL-13/IL-31/TSLP) signal through JAK1/2→STAT6/others; clinical responses to JAK inhibition reflect pathway centrality (Jun 2025; URL below). (urzua2025skinbarrierdysfunction pages 3-4) - Systems endotypes: Cross-tissue transcriptomics reveal modules linked to erythema vs papulation and longitudinal clusters tied to severity and treatment response; proteomic modules correlate with disease activity (Oct 2023; URL below). (bilinski2025antiinflammatorytherapiesfor pages 2-4)

  • Dysregulated molecular pathways

  • IL-4/IL-13–STAT6 signaling; IL-31–neuronal TRP channels; alarmin (TSLP/IL-33/IL-25)–DC/ILC2 pathways; NF-κB and MAPK in keratinocytes; JAK–STAT (kamata2025mechanismsofitch pages 2-4, bai2025atopicdermatitisdiagnosis pages 25-26, torres2025interleukin4andatopic pages 14-15, urzua2025skinbarrierdysfunction pages 3-4)

  • Affected cellular processes

  • Keratinocyte differentiation and junctional assembly; sensory neuron excitability and neurite extension; DC antigen presentation; Th2/ILC2 cytokine production; pruritus transmission (katsarou2023theroleof pages 12-12, kamata2025mechanismsofitch pages 2-4, bai2025atopicdermatitisdiagnosis pages 25-26)

2) Key Molecular Players (ontology-ready annotations) - Genes/Proteins (HGNC symbol) - FLG (filaggrin): epidermal barrier scaffold; loss-of-function predisposes to AD (HGNC: 3752). (katsarou2023theroleof pages 12-12) - CLDN1 (claudin-1): tight junction component; reduced in AD lesions; Th2 cytokine–sensitive (HGNC: 2031). (katsarou2023theroleof pages 12-12) - IL4, IL13: type 2 cytokines central to AD pathogenesis (HGNC: 6014, 5991). (torres2025interleukin4andatopic pages 14-15) - IL31, IL31RA, OSMR: pruritogenic pathway receptors on sensory neurons (HGNC: 20497, 21491, 8506). (kamata2025mechanismsofitch pages 2-4, bai2025atopicdermatitisdiagnosis pages 25-26) - TSLP, IL33, IL25/IL17E: epithelial alarmins initiating type 2 responses (HGNC: 30742, 5996, 5964). (kamata2025mechanismsofitch pages 2-4, torres2025interleukin4andatopic pages 14-15) - JAK1, JAK2; STAT6: JAK–STAT transducers in type 2 signaling (HGNC: 6190, 6192, 11366). (urzua2025skinbarrierdysfunction pages 3-4, torres2025interleukin4andatopic pages 14-15) - CALCA (CGRP): neuropeptide mediating IL-31 neurogenic restraint (HGNC: 1434). (bai2025atopicdermatitisdiagnosis pages 25-26) - TRPV1, TRPA1: neuronal ion channels mediating itch (HGNC: 12306, 132). (kamata2025mechanismsofitch pages 2-4)

  • Chemical entities (CHEBI)
  • Ceramide (CHEBI:17761): altered chain-length composition in AD barrier lipid matrix (review synthesis). (urzua2025skinbarrierdysfunction pages 3-4)

  • Histamine (CHEBI:18295): mast-cell mediator contributing to pruritus (review synthesis). (torres2025interleukin4andatopic pages 14-15)

  • Cell types (CL terms)

  • Keratinocyte (CL:0000312); Langerhans cell (CL:0000475); Dendritic cell (CL:0000451); ILC2 (CL:0001065); Th2 cell (CL:0000910); Sensory neuron (CL:0000101). (kamata2025mechanismsofitch pages 2-4, katsarou2023theroleof pages 12-12, torres2025interleukin4andatopic pages 14-15)

  • Anatomical locations (UBERON)

  • Epidermis (UBERON:0001003); Dermis (UBERON:0002067); Skin nerve endings (UBERON:0001825). (kamata2025mechanismsofitch pages 2-4, katsarou2023theroleof pages 12-12)

  • Drugs/biologics (mechanism-linked)

  • Dupilumab (anti–IL-4Rα; blocks IL-4/IL-13 signaling). (torres2025interleukin4andatopic pages 14-15)
  • Tralokinumab, lebrikizumab (anti–IL-13). (torres2025interleukin4andatopic pages 14-15)
  • Oral/topical JAK inhibitors (e.g., upadacitinib, baricitinib; ruxolitinib cream). (urzua2025skinbarrierdysfunction pages 3-4)

3) Biological Processes (GO) disrupted - Keratinocyte differentiation (GO:0030216); Cornified envelope assembly (GO:0070268) (FLG-related). (katsarou2023theroleof pages 12-12) - Tight junction organization (GO:0034330) (CLDN1-related). (katsarou2023theroleof pages 12-12) - Cytokine-mediated signaling pathway (GO:0019221) via JAK–STAT (GO:0007259). (urzua2025skinbarrierdysfunction pages 3-4, torres2025interleukin4andatopic pages 14-15) - Immune response–Th2 cell differentiation (GO:0042092); ILC2 activation (GO:0001773). (torres2025interleukin4andatopic pages 14-15) - Sensory perception of itch (GO:0036231); Neuron projection development (GO:0031175) (IL-31–induced neurite extension). (kamata2025mechanismsofitch pages 2-4) - Neurogenic inflammation (GO:0050729) via CGRP signaling impacting T cells. (bai2025atopicdermatitisdiagnosis pages 25-26)

4) Cellular Components (GO-CC) - Cornified envelope (GO:0001533); Keratin filament (GO:0045095). (katsarou2023theroleof pages 12-12) - Tight junction (GO:0005923). (katsarou2023theroleof pages 12-12) - Plasma membrane of pruritoceptors (GO:0005886) housing TRPV1/TRPA1 and IL31RA/OSMR. (kamata2025mechanismsofitch pages 2-4) - Extracellular space (GO:0005615) for cytokines and neuropeptides (IL-4/IL-13/IL-31, CGRP). (torres2025interleukin4andatopic pages 14-15, bai2025atopicdermatitisdiagnosis pages 25-26)

5) Disease Progression (sequence of events) - Initiation: Genetic predisposition (e.g., FLG variants) and environmental insults disrupt the barrier and elevate skin pH; TJ/FLG insufficiency increases permeability. (katsarou2023theroleof pages 12-12) - Epithelial alarm: Keratinocytes release alarmins (TSLP, IL-33, IL-25), activating DCs/ILC2 and priming Th2 responses. (kamata2025mechanismsofitch pages 2-4, torres2025interleukin4andatopic pages 14-15) - Amplification: IL-4/IL-13 from Th2/ILC2 downregulate barrier genes (e.g., FLG, CLDN1), recruit inflammatory cells, and perpetuate itch–scratch cycles; JAK–STAT transduces these signals. (torres2025interleukin4andatopic pages 14-15, urzua2025skinbarrierdysfunction pages 3-4) - Pruritus circuitry: IL-31 directly activates IL31RA/OSMR+ TRPV1/TRPA1 neurons, enhances nerve fiber density, and drives chronic itch behavior. (kamata2025mechanismsofitch pages 2-4) - Chronic modulation: With repeated allergen exposure, IL-31–induced CGRP imposes a neurogenic restraint on tissue Th2 inflammation—an adaptive feedback that may be perturbed by anti-IL31RA therapies. (bai2025atopicdermatitisdiagnosis pages 25-26) - Endotypic divergence: Cross-tissue transcriptomic modules align with clinical phenotypes and severity clusters and can inform treatment monitoring/response. (bilinski2025antiinflammatorytherapiesfor pages 2-4)

6) Phenotypic Manifestations (clinical; HP terms) - Pruritus (HP:0000989) driven by IL-31–TRP pathways and hyperinnervation; quote above. (kamata2025mechanismsofitch pages 2-4) - Eczema/erythematous scaly dermatitis (HP:0000988) from Th2-driven skin inflammation and barrier leak. (torres2025interleukin4andatopic pages 14-15, katsarou2023theroleof pages 12-12) - Xerosis (HP:0000958) from barrier lipid/protein deficits. (katsarou2023theroleof pages 12-12) - Lichenification (HP:0000984) in chronic disease, aligned with distinct transcriptomic modules. (bilinski2025antiinflammatorytherapiesfor pages 2-4)

Recent developments and latest research (2023–2025; with URLs/dates) - IL-31 neuroimmune restraint of Th2 inflammation (Science Immunology, Oct 2023): Demonstrated that IL-31–responsive pruritoceptors release CGRP to limit cutaneous type 2 programs in chronic HDM dermatitis; mechanistic insight into paradoxical flares on anti-IL31RA therapy. URL: https://doi.org/10.1126/sciimmunol.abi6887. (bai2025atopicdermatitisdiagnosis pages 25-26) - Systems endotyping (Nature Communications, Oct 2023): Cross-tissue transcriptomics linked detailed skin phenotypes (erythema vs papulation) with distinct immune signatures and identified blood transcriptome clusters tracking severity and treatment history, enabling personalized monitoring. URL: https://doi.org/10.1038/s41467-023-41857-8. (bilinski2025antiinflammatorytherapiesfor pages 2-4) - Tight-junction barrier in AD (J Clin Med, Feb 2023): Systematic review highlighting claudin-1 reduction, Th2 suppression of claudins, and scratching-induced claudin-1 decreases as central to barrier pathophysiology. URL: https://doi.org/10.3390/jcm12041538. (katsarou2023theroleof pages 12-12) - Itch mechanisms synthesis (Juntendo Med J, Jan 2025): Integrated view of Th2/alarmin–neuronal crosstalk, IL-31 receptor expression on pruritoceptors, and hyperinnervation mechanisms (Sema3A↓, NGF↑). URL: https://doi.org/10.14789/ejmj.jmj24-0036-r. (kamata2025mechanismsofitch pages 2-4) - IL-4 centrality and therapeutic implications (Dermatology and Therapy, Feb 2025): Review underscoring IL-4/IL-13 as nexus for barrier, dysbiosis, itch, and inflammation; contextualizes dupilumab and IL-13 inhibitors. URL: https://doi.org/10.1007/s13555-025-01352-y. (torres2025interleukin4andatopic pages 14-15) - Barrier, immunity, and targeted therapy integration (Cureus, Jun 2025): Review summarizing evidence for IL-13 blockade improving barrier function and rapid efficacy of JAK inhibitors; notes emerging microbiome-directed approaches. URL: https://doi.org/10.7759/cureus.86937. (urzua2025skinbarrierdysfunction pages 3-4)

Current applications and real-world implementations - IL-4/IL-13 pathway blockade - Dupilumab (anti–IL-4Rα) is a standard of care for moderate–severe AD; reviews document early and sustained improvements in systemic and cutaneous immune abnormalities, consistent with interruption of the type 2 axis (reviewed 2025; URL above). (torres2025interleukin4andatopic pages 14-15) - IL-13–selective monoclonals (tralokinumab, lebrikizumab) have demonstrated efficacy in phase III trials and are integrated in recent therapeutic reviews (2025 summary; mechanism detailed in 2025 narrative review). (torres2025interleukin4andatopic pages 14-15) - JAK inhibitors - Oral JAK1-selective agents (e.g., upadacitinib) and JAK1/2 (baricitinib) and topical ruxolitinib cream show rapid pruritus and lesion improvement consistent with broad cytokine signal interruption (2025 review synthesis). (urzua2025skinbarrierdysfunction pages 3-4) - Monitoring and personalization - Multi-omic endotyping and cross-tissue modules are being developed for patient stratification and longitudinal monitoring, aligning skin phenotypes and blood modules with severity and response (Oct 2023). (bilinski2025antiinflammatorytherapiesfor pages 2-4)

Expert opinions and analysis - “IL-4 plays a critical role in skin barrier dysfunction, dysbiosis, pruritus, and inflammation” (Dermatology and Therapy, Feb 2025), anchoring IL-4/IL-13 as prime nodes for disease modification. URL: https://doi.org/10.1007/s13555-025-01352-y. (torres2025interleukin4andatopic pages 14-15) - “Impaired TJ barrier function and skin permeability in AD lesions is correlated with cldn-1 levels. Th2 inflammation inhibits the expression of cldn-1 and cldn-23… Scratching has also been reported to decrease cldn-1” (J Clin Med, Feb 2023), highlighting actionable barrier–immune feedbacks. URL: https://doi.org/10.3390/jcm12041538. (katsarou2023theroleof pages 12-12) - “IL-31 directly induces pruritus… and selectively promotes nerve fiber extension” (Juntendo Med J, Jan 2025), connecting cytokine signaling to neuronal remodeling. URL: https://doi.org/10.14789/ejmj.jmj24-0036-r. (kamata2025mechanismsofitch pages 2-4) - “IL-31… restrains cutaneous type 2 inflammation… [via] CGRP” (Science Immunology, Oct 2023), reframing IL-31 as both pruritogen and neuroimmune modulator. URL: https://doi.org/10.1126/sciimmunol.abi6887. (bai2025atopicdermatitisdiagnosis pages 25-26)

Relevant statistics and data from recent studies - Endotypic clustering: Integrated analysis of 115 AD patients and 14 controls identified skin–blood modules linking specific clinical features (erythema vs papulation) and longitudinal blood clusters aligned with severity and treatment history (Nature Communications, Oct 2023; details in article). URL: https://doi.org/10.1038/s41467-023-41857-8. (bilinski2025antiinflammatorytherapiesfor pages 2-4) - Barrier correlates: Systematic review collating >50 studies concluded that decreased claudin-1 associates with increased permeability and susceptibility to infection/allergen penetration; Th2 cytokines reduce claudin expression; scratching lowers claudin-1 (Feb 2023). URL: https://doi.org/10.3390/jcm12041538. (katsarou2023theroleof pages 12-12) - Neuroimmune plasticity: Clinical-pathobiological observations summarized in 2025 review include reduced Sema3A and increased NGF correlating with increased intraepidermal nerve density across AD states (Jan 2025). URL: https://doi.org/10.14789/ejmj.jmj24-0036-r. (kamata2025mechanismsofitch pages 2-4)

Evidence items (with PMIDs/DOIs/URLs) - Fassett MS et al. IL-31–dependent neurogenic inflammation restrains cutaneous type 2 immune response in allergic dermatitis. Science Immunology. Oct 2023. DOI: 10.1126/sciimmunol.abi6887; URL: https://doi.org/10.1126/sciimmunol.abi6887. Key quote and mechanism above. (bai2025atopicdermatitisdiagnosis pages 25-26) - Kamata Y et al. Mechanisms of Itch in Atopic Dermatitis. Juntendo Medical Journal. Jan 2025. DOI: 10.14789/ejmj.jmj24-0036-r; URL: https://doi.org/10.14789/ejmj.jmj24-0036-r. Key quote on IL-31 neurite extension; neuronal receptor expression. (kamata2025mechanismsofitch pages 2-4) - Katsarou S et al. The Role of Tight Junctions in Atopic Dermatitis: A Systematic Review. J Clin Med. Feb 2023. DOI: 10.3390/jcm12041538; URL: https://doi.org/10.3390/jcm12041538. Key quote on claudins/Th2 inhibition. (katsarou2023theroleof pages 12-12) - Torres T et al. Interleukin-4 and Atopic Dermatitis. Dermatology and Therapy. Feb 2025. DOI: 10.1007/s13555-025-01352-y; URL: https://doi.org/10.1007/s13555-025-01352-y. Expert synthesis of IL-4/IL-13 centrality. (torres2025interleukin4andatopic pages 14-15) - Urzua IE et al. Skin Barrier Dysfunction… Cureus. Jun 2025. DOI: 10.7759/cureus.86937; URL: https://doi.org/10.7759/cureus.86937. Clinical integration of IL-13 blockade/barrier and JAK inhibitor kinetics. (urzua2025skinbarrierdysfunction pages 3-4) - Sekita A et al. Multifaceted analysis of cross-tissue transcriptomes… Nat Commun. Oct 2023. DOI: 10.1038/s41467-023-41857-8; URL: https://doi.org/10.1038/s41467-023-41857-8. Endotype–phenotype modules and longitudinal clusters. (bilinski2025antiinflammatorytherapiesfor pages 2-4)

Structured ontology annotations - Genes/Proteins (HGNC): FLG; CLDN1; IL4; IL13; IL31; IL31RA; OSMR; TSLP; IL33; JAK1; JAK2; STAT6; CALCA; TRPV1; TRPA1. (katsarou2023theroleof pages 12-12, kamata2025mechanismsofitch pages 2-4, bai2025atopicdermatitisdiagnosis pages 25-26, torres2025interleukin4andatopic pages 14-15, urzua2025skinbarrierdysfunction pages 3-4) - GO Biological Processes: keratinocyte differentiation; tight junction organization; cytokine-mediated signaling; JAK–STAT cascade; Th2 differentiation; sensory perception of itch; neurogenic inflammation. (katsarou2023theroleof pages 12-12, kamata2025mechanismsofitch pages 2-4, urzua2025skinbarrierdysfunction pages 3-4) - GO Cellular Components: tight junction; cornified envelope; plasma membrane; extracellular region. (katsarou2023theroleof pages 12-12, kamata2025mechanismsofitch pages 2-4) - Cell Types (CL): keratinocytes; Langerhans cells; dermal dendritic cells; ILC2; Th2 cells; small-diameter sensory neurons. (kamata2025mechanismsofitch pages 2-4, katsarou2023theroleof pages 12-12, torres2025interleukin4andatopic pages 14-15) - Anatomical Sites (UBERON): epidermis; dermis; cutaneous nerve endings. (kamata2025mechanismsofitch pages 2-4, katsarou2023theroleof pages 12-12) - Chemical entities (CHEBI): ceramide (CHEBI:17761); histamine (CHEBI:18295). (urzua2025skinbarrierdysfunction pages 3-4, torres2025interleukin4andatopic pages 14-15) - Phenotypes (HPO): pruritus (HP:0000989); eczema (HP:0000988); xerosis (HP:0000958); lichenification (HP:0000984). (kamata2025mechanismsofitch pages 2-4, katsarou2023theroleof pages 12-12, bilinski2025antiinflammatorytherapiesfor pages 2-4)

Therapeutic implications (mechanism → therapy mapping) - IL-4/IL-13 axis: Dupilumab (anti–IL-4Rα), tralokinumab/lebrikizumab (anti–IL-13) reduce type 2 signaling, improve lesions and often pruritus; reviews emphasize their disease-modifying potential by interrupting central drivers (2025). (torres2025interleukin4andatopic pages 14-15) - IL-31 axis: Anti–IL-31/IL31RA agents target pruritus; the 2023 mechanistic study suggests monitoring for inflammatory shifts due to loss of IL-31–CGRP restraint in chronic exposure contexts (Oct 2023). (bai2025atopicdermatitisdiagnosis pages 25-26) - JAK inhibitors: Oral JAK1/2 and topical JAK inhibitors rapidly reduce itch and inflammation—a pharmacodynamic signature of blocking multi-cytokine signaling via JAK–STAT (2025). (urzua2025skinbarrierdysfunction pages 3-4) - Barrier-directed adjuncts: Because Th2 cytokines downregulate CLDN1/FLG, upstream cytokine blockade plus barrier repair strategies target both cause and consequence (2023–2025 syntheses). (katsarou2023theroleof pages 12-12, torres2025interleukin4andatopic pages 14-15)

Limitations and gaps - While reviews integrate barrier, IL-4/IL-13, IL-31, and JAK–STAT mechanisms with therapeutic success, high-resolution causal links for all epithelial alarmins in human endotypes and long-term remodeling remain under active investigation. Multi-omic signatures are promising but require prospective validation for treatment selection in routine care. (bilinski2025antiinflammatorytherapiesfor pages 2-4)

References with URLs/dates - Science Immunology, Oct 2023: https://doi.org/10.1126/sciimmunol.abi6887. (bai2025atopicdermatitisdiagnosis pages 25-26) - Nature Communications, Oct 2023: https://doi.org/10.1038/s41467-023-41857-8. (bilinski2025antiinflammatorytherapiesfor pages 2-4) - Journal of Clinical Medicine, Feb 2023: https://doi.org/10.3390/jcm12041538. (katsarou2023theroleof pages 12-12) - Juntendo Medical Journal, Jan 2025: https://doi.org/10.14789/ejmj.jmj24-0036-r. (kamata2025mechanismsofitch pages 2-4) - Dermatology and Therapy, Feb 2025: https://doi.org/10.1007/s13555-025-01352-y. (torres2025interleukin4andatopic pages 14-15) - Cureus, Jun 2025: https://doi.org/10.7759/cureus.86937. (urzua2025skinbarrierdysfunction pages 3-4)

References

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