Psoriasis

Complex MONDO:0005083 Pathograph 11 Dermatological Disease Autoimmune Disease

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1
Inheritance
5
Pathophys.
16
Phenotypes
11
Pathograph
24
Genes
10
Medical Actions
6
Subtypes
2
Datasets
8
References
2
Deep Research
🏷

Classifications

Harrison's Chapter
DERMATOLOGY IMMUNE_RHEUMATOLOGIC
👪

Inheritance

1
Autosomal recessive inheritance (pustular subtype) HP:0000007
IL36RN loss-of-function mutations follow autosomal recessive inheritance in familial generalized pustular psoriasis.
Autosomal recessive inheritance
Show evidence (1 reference)
ORPHA:247353 SUPPORT
"Autosomal recessive"
Orphanet records autosomal recessive inheritance for generalized pustular psoriasis.
◆

Subtypes

6
Plaque Psoriasis
Most common form with raised, red, scaly plaques.
Guttate Psoriasis
Small, drop-shaped lesions, often following streptococcal infection.
Inverse Psoriasis
Affects skin folds with smooth, red patches.
Pustular Psoriasis
Characterized by white pustules surrounded by red skin.
Erythrodermic Psoriasis
Severe, widespread inflammation covering most of the body.
Psoriatic Arthritis
Joint inflammation associated with psoriasis.
⚙

Pathophysiology

5
T Cell-Mediated Inflammation
Activated T cells (Th1, Th17, Th22) infiltrate skin and release cytokines including IL-17, IL-22, TNF-alpha, and IFN-gamma that drive keratinocyte hyperproliferation and inflammation.
T Helper 17 Cell CL:0000899 T Helper 1 Cell CL:0000545
T Cell Activation GO:0042110
Downstream
Keratinocyte Hyperproliferation Effector cytokines from activated T cells drive keratinocyte proliferation and plaque formation.
Show evidence (2 references)
PMID:38686385 PARTIAL
"Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease."
IL-23 drives Th17 cell differentiation and maintenance, which is central to T cell-mediated inflammation in psoriasis.
PMID:39337637 PARTIAL
"Current research efforts to better understand skin disease have focused on examining the role of molecular processes at several stages of the inflammatory response such as the dysregulation of innate immunity sensors, disruption of both transcriptional and post-transcriptional regulation, and..."
This describes the complex inflammatory response involving multiple cellular processes, consistent with T cell-mediated inflammation involving transcriptional regulation and immune cell crosstalk.
Keratinocyte Hyperproliferation
Inflammatory cytokines stimulate rapid keratinocyte proliferation, reducing epidermal turnover from 28 days to 3-4 days. This produces characteristic thick, scaly plaques.
Keratinocyte CL:0000312
Cell Proliferation GO:0008283
Show evidence (2 references)
PMID:39337637 NO_EVIDENCE
"Many skin diseases begin with inflammatory changes on a molecular level."
Inflammatory changes at the molecular level drive keratinocyte hyperproliferation in psoriasis, linking inflammation to cellular proliferation.
PMID:39576422 NO_EVIDENCE
"Psoriasis represents a chronic autoimmune skin condition defined by various clinical forms, including inverse, erythrodermic, pustular, guttate, plaque types."
The chronic autoimmune nature of psoriasis results in persistent inflammatory signaling that drives sustained keratinocyte hyperproliferation, manifesting as the characteristic plaque types.
Dendritic Cell Activation
Plasmacytoid and myeloid dendritic cells produce inflammatory cytokines and present antigens to activate T cells, initiating and perpetuating the inflammatory cascade.
Dendritic Cell CL:0000451
Downstream
IL-23/IL-17 Axis Dendritic-cell-derived IL-23 initiates the central psoriatic cytokine circuit.
Show evidence (1 reference)
PMID:40817122 SUPPORT Human Clinical
"Here we show that IL4I1+CD200+CCR7+ dendritic cells (CCR7+ DC) are the main producer of IL-23 by concomitantly expressing the IL-23A and IL-12B subunits in human psoriatic skin."
This directly supports activated dendritic cells as the IL-23-producing initiators of psoriatic inflammation.
IL-23/IL-17 Axis
IL-23 produced by dendritic cells drives Th17 cell differentiation and IL-17 production. This axis is the major therapeutic target in modern psoriasis treatment.
T-helper 17 cell CL:0000899 Dendritic cell CL:0000451
Cytokine Signaling GO:0019221 T-helper 17 type immune response GO:0072538
Downstream
T Cell-Mediated Inflammation IL-23 expands IL-17-producing T-cell responses that sustain plaque inflammation.
Show evidence (2 references)
PMID:38686385 PARTIAL
"Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease."
This confirms IL-23 as the hierarchically dominant regulatory cytokine in psoriasis, supporting its central role in the IL-23/IL-17 axis and why it is the major therapeutic target.
PMID:39337637 NO_EVIDENCE
"Many skin diseases begin with inflammatory changes on a molecular level."
This establishes that inflammatory molecular mechanisms are fundamental to skin disease pathogenesis, consistent with the IL-23/IL-17 inflammatory axis driving psoriasis.
IL-36 Keratinocyte Activation
In pustular psoriasis, keratinocyte-derived IL-36 signaling amplifies chemokine production, recruits neutrophils, and sustains sterile pustule formation.
Keratinocyte CL:0000312 Neutrophil CL:0000775
Inflammatory Response GO:0006954 Neutrophil Chemotaxis GO:0030593
Downstream
Pustules IL-36-driven neutrophilic inflammation produces sterile pustules.
Show evidence (1 reference)
PMID:38077370 SUPPORT Other
"In GPP, innate immune responses are driven by abnormal activation of the interleukin (IL)-36-chemokine-neutrophil axis and excessive neutrophil infiltration."
This directly supports IL-36-driven keratinocyte/neutrophil inflammatory amplification as the defining pustular psoriasis mechanism.
⬡

Pathograph

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

Phenotypes

16
Blood 1
Leukocytosis FREQUENT Increased total leukocyte count HP:0001974
Neutrophil leukocytosis accompanies GPP flares.
Show evidence (1 reference)
ORPHA:247353 SUPPORT
"HP:0001974 | Leukocytosis | Frequent (79-30%)"
Orphanet classifies leukocytosis as frequent in GPP.
Immune 2
Pustules OBLIGATE Pustule HP:0200039
Sterile superficial pustules during pustular flares. Obligate feature of GPP per Orphanet.
Show evidence (2 references)
PMID:38077370 SUPPORT Other
"Generalized pustular psoriasis (GPP) is a rare, chronic, inflammatory skin disorder characterized by recurrent flares associated with skin erythema, desquamation, and widespread superficial sterile pustules, which may be severe ("lakes of pus")."
This directly supports widespread sterile pustules as the defining phenotype of pustular psoriasis.
ORPHA:247353 SUPPORT
"HP:0200039 | Pustule | Obligate (100%)"
Orphanet classifies pustules as obligate (100%) in generalized pustular psoriasis.
Erythroderma OCCASIONAL Erythroderma HP:0001019
Severe widespread erythema covering most of the body surface. Life-threatening complication.
Show evidence (1 reference)
PMID:31491865 SUPPORT Human Clinical
"Drug-related psoriasis would manifest as plaque psoriasis, palmoplantar psoriasis, nail psoriasis, scalp psoriasis, pustular psoriasis, and erythrodermic psoriasis"
Erythrodermic psoriasis is recognized as a distinct clinical manifestation of psoriasis.
Context-specific annotations (1)
Pustular Psoriasis VERY_FREQUENT
Show evidence (1 reference)
ORPHA:247353 SUPPORT
"HP:0001019 | Erythroderma | Very frequent (99-80%)"
Orphanet classifies erythroderma as very frequent (99-80%) in generalized pustular psoriasis.
Integument 4
Erythematous Plaques VERY_FREQUENT Erythematous plaque HP:0025474
Well-demarcated, raised, red plaques
Show evidence (1 reference)
PMID:15708928 SUPPORT
"most commonly the disease presents as chronic, symmetrical, erythematous, scaling papules and plaques."
Erythematous plaques are the most common clinical presentation of psoriasis.
Silvery Scales VERY_FREQUENT Scaling skin HP:0040189
Characteristic silvery-white scale
Show evidence (1 reference)
PMID:15708928 SUPPORT Human Clinical
"most commonly the disease presents as chronic, symmetrical, erythematous, scaling papules and plaques."
Scaling is a defining feature of psoriatic plaques.
Pruritus VERY_FREQUENT Pruritus HP:0000989
Show evidence (1 reference)
PMID:11069504 SUPPORT
"Generalized pruritus was a feature of psoriasis in 84% of the patients."
Pruritus is a common and significant symptom in psoriasis, affecting the majority of patients and impacting quality of life.
Nail Changes FREQUENT Nail dystrophy HP:0008404
Pitting, onycholysis, subungual hyperkeratosis
Show evidence (1 reference)
PMID:26131859 SUPPORT
"Nail psoriasis is estimated in 50% of patients with psoriasis, and in the presence of joint involvement, it can reach 80%."
Nail involvement is common in psoriasis patients and may include pitting, onycholysis, and subungual hyperkeratosis.
Metabolism 1
Fever FREQUENT Fever HP:0001945
High fever accompanying generalized pustular psoriasis flares.
Show evidence (2 references)
ORPHA:247353 SUPPORT
"HP:0001945 | Fever | Frequent (79-30%)"
Orphanet classifies fever as frequent in GPP.
ORPHA:247353 SUPPORT
"Generalized pustular psoriasis is a severe inflammatory skin disease that can be life-threatening and that is characterized by recurrent episodes of high fever, fatigue, episodic erythematous cutaneous eruptions with sterile cutaneous pustules formation on various parts of the body, and..."
Orphanet definition explicitly lists high fever as a defining feature of GPP.
Musculoskeletal 1
Enthesitis OCCASIONAL Enthesitis HP:0100686
Inflammation at tendon/ligament insertion sites, particularly Achilles tendon and plantar fascia.
Show evidence (1 reference)
PMID:28212759 SUPPORT Human Clinical
"PsA is the most well-recognized comorbidity of psoriasis and is a heterogeneous inflammatory arthritis characterized by joint and/or entheseal inflammation and extra-articular manifestations."
Entheseal inflammation is explicitly named as a characteristic feature of psoriatic arthritis.
Nervous System 1
Depression FREQUENT Depression HP:0000716
Depression is significantly more prevalent in psoriasis patients, driven by both psychosocial burden and shared inflammatory pathways.
Show evidence (2 references)
PMID:36745557 SUPPORT Human Clinical
"Pooled effect estimates suggest that female sex and psoriatic arthritis were associated with depression"
Meta-analysis confirming significant association between psoriasis and depression, with psoriatic arthritis as an additional risk factor.
PMID:35757712 SUPPORT Human Clinical
"mental health diseases draw more attention not just because of the negative mental and mood influence caused by skin lesions, but a common immune-inflammatory mechanism identified of the two systemic diseases."
Shared immune-inflammatory mechanisms contribute to depression in psoriasis beyond the psychosocial impact of skin lesions.
Constitutional 2
Joint Pain OCCASIONAL Arthralgia HP:0002829
Psoriatic arthritis in approximately 20% of patients
Show evidence (1 reference)
PMID:29928910 SUPPORT
"We found that 1 in 4 patients with psoriasis have PsA."
Psoriatic arthritis is a common comorbidity in psoriasis patients, affecting approximately 20-25% based on this meta-analysis.
Context-specific annotations (1)
Pustular Psoriasis OBLIGATE
Show evidence (1 reference)
ORPHA:247353 SUPPORT
"HP:0002829 | Arthralgia | Obligate (100%)"
Orphanet classifies arthralgia as obligate (100%) in generalized pustular psoriasis.
Fatigue FREQUENT Fatigue HP:0012378
Prominent fatigue during GPP flares.
Show evidence (1 reference)
ORPHA:247353 SUPPORT
"HP:0012378 | Fatigue | Frequent (79-30%)"
Orphanet classifies fatigue as frequent in GPP.
Other 4
Koebner Phenomenon FREQUENT Koebner Phenomenon HP:6000933
New psoriatic lesions develop at sites of skin trauma (cuts, scratches, sunburn). Well-established diagnostic sign.
Show evidence (1 reference)
PMID:31491865 SUPPORT Human Clinical
"In patients with psoriasis, skin lesions appear in uninvolved areas after various injuries"
Directly describes the Koebner phenomenon as the appearance of new psoriatic lesions at sites of skin injury.
Auspitz Sign FREQUENT Auspitz sign HP:6000724
Pinpoint bleeding upon removal of psoriatic scale, reflecting dilated capillaries in elongated dermal papillae.
Dactylitis OCCASIONAL Finger dactylitis HP:0031090
Sausage-like swelling of entire digits, characteristic of psoriatic arthritis.
Show evidence (1 reference)
PMID:29893226 SUPPORT Human Clinical
"Diagnosis is primarily based on clinical phenotype because of the diversity of the associated features, which can include skin and nail disease, dactylitis, uveitis, and osteitis."
Dactylitis is explicitly listed as a characteristic clinical feature of psoriatic arthritis.
Geographic Tongue FREQUENT Geographic tongue HP:0025252
Fissured or geographic tongue pattern, associated with pustular psoriasis.
Show evidence (1 reference)
ORPHA:247353 SUPPORT
"HP:0025252 | Geographic tongue | Frequent (79-30%)"
Orphanet classifies geographic tongue as frequent in GPP.
🧬

Genetic Associations

24
HLA-C*06:02 (Risk Factor)
IL12B (Risk Factor)
Show evidence (1 reference)
PMID:38686385 NO_EVIDENCE
"Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease."
IL12B encodes the p40 subunit shared by IL-12 and IL-23. Given IL-23's hierarchically dominant role in psoriasis, genetic variants in IL12B that affect IL-23 levels represent important risk factors.
IL23R (Risk Factor)
Show evidence (1 reference)
PMID:38686385 NO_EVIDENCE
"We review IL-23 biology, IL-23 signaling in IMIDs, and the effect of IL-23 inhibition in treating these diseases."
IL23R encodes the IL-23 receptor, and genetic variants affecting IL-23 signaling are risk factors for psoriasis given the central role of this pathway.
TYK2 (GWAS)
Show evidence (1 reference)
PMID:20953190 SUPPORT Human Clinical
"Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2)."
This GWAS directly implicates TYK2 as a psoriasis susceptibility locus linked to cytokine signaling.
TRAF3IP2 (GWAS)
Show evidence (1 reference)
PMID:20953190 SUPPORT Human Clinical
"Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2)."
This GWAS directly implicates TRAF3IP2 as a psoriasis susceptibility locus in the IL-17 signaling pathway.
TNFAIP3 (Risk Factor)
CARD14 (Causative)
IL36RN (Pustular subtype risk factor)
Show evidence (2 references)
PMID:30036598 SUPPORT Human Clinical
"Although AP1S3 alleles had similar frequency (0.03-0.05) across disease subtypes, IL36RN mutations were less common in patients with PPP (0.03) than in those with GPP (0.19) and ACH (0.16; P = 1.9 × 10-14 and .002, respectively)."
This cohort shows IL36RN mutations are enriched in generalized pustular psoriasis, supporting a subtype-specific genetic driver.
ORPHA:247353 SUPPORT
"IL36RN | interleukin 36 receptor antagonist | hgnc:15561 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet classifies IL36RN loss-of-function mutations as disease-causing in GPP.
IL1RL2 (Pustular subtype pathway gene)
Show evidence (1 reference)
PMID:20833839 SUPPORT Model Organism
"Blockade of IL-1F6 receptor also resolves the inflammatory changes in human psoriatic lesional skin transplanted onto immunodeficient mice."
This supports IL1RL2/IL-36 receptor signaling as a mechanistically relevant driver of psoriasis inflammation.
AP1S3 (Pustular subtype risk factor)
Show evidence (2 references)
PMID:30036598 SUPPORT Human Clinical
"Although mutations have been uncovered in IL36RN and AP1S3, the rarity of the disease has hindered the study of genotype-phenotype correlations."
This confirms AP1S3 as an established pustular psoriasis susceptibility gene.
ORPHA:247353 SUPPORT
"AP1S3 | adaptor related protein complex 1 subunit sigma 3 | hgnc:18971 | Disease-causing germline mutation(s) in"
Orphanet classifies AP1S3 mutations as disease-causing in GPP.
BACH2 (GWAS)
STAT3 (GWAS)
IL10 (GWAS)
CD28 (GWAS)
EGR2 (GWAS)
ETS1 (GWAS)
IRF4 (GWAS)
IRF8 (GWAS)
SATB1 (GWAS)
IKZF1 (GWAS)
SMAD3 (GWAS)
REL (GWAS)
PRDM1 (GWAS)
PTPN22 (GWAS)
💊

Medical Actions

10
Topical Corticosteroids
Action: Topical corticosteroid therapy Ontology label: Topical Corticosteroid Therapy NCIT:C122078
First-line for limited disease.
Topical Vitamin D Analogues
Action: Vitamin D analogue therapy Ontology label: Pharmacotherapy NCIT:C15986
Calcipotriene, calcitriol for mild to moderate disease.
Phototherapy
Narrowband UVB or PUVA for moderate to severe disease.
Methotrexate
Action: Methotrexate therapy Ontology label: Pharmacotherapy NCIT:C15986
Traditional systemic therapy for moderate to severe disease.
TNF Inhibitors
Action: TNF inhibitor therapy Ontology label: Pharmacotherapy NCIT:C15986
Adalimumab, etanercept, infliximab for moderate to severe disease.
IL-17 Inhibitors
Action: IL-17 inhibitor therapy Ontology label: Pharmacotherapy NCIT:C15986
Secukinumab, ixekizumab - highly effective targeted therapy.
Mechanism Target:
INHIBITS IL-23/IL-17 Axis — Neutralizes IL-17 effector signaling downstream of the central psoriatic cytokine axis.
IL-23 Inhibitors
Action: IL-23 inhibitor therapy Ontology label: Pharmacotherapy NCIT:C15986
Guselkumab, risankizumab - high efficacy with infrequent dosing.
Mechanism Target:
INHIBITS IL-23/IL-17 Axis — Blocks the IL-23 signal that sustains Th17-driven inflammation.
Show evidence (1 reference)
PMID:38686385 PARTIAL
"We review IL-23 biology, IL-23 signaling in IMIDs, and the effect of IL-23 inhibition in treating these diseases."
This paper reviews the therapeutic effect of IL-23 inhibition in treating psoriasis and other immune-mediated inflammatory diseases, supporting the use of IL-23 inhibitors like guselkumab and risankizumab.
IL-12/23 Inhibitor
Action: IL-12/23 inhibitor therapy Ontology label: Pharmacotherapy NCIT:C15986
Ustekinumab targets shared p40 subunit.
Mechanism Target:
INHIBITS IL-23/IL-17 Axis — Shared p40 blockade dampens the IL-23-driven inflammatory circuit.
Show evidence (1 reference)
PMID:38686385 PARTIAL
"Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease."
Ustekinumab targets the p40 subunit shared by IL-12 and IL-23. Given IL-23's hierarchically dominant role, blocking this shared subunit provides therapeutic benefit in psoriasis.
JAK Inhibitors
Action: JAK inhibitor therapy Ontology label: Pharmacotherapy NCIT:C15986
Oral therapy option (deucravacitinib - TYK2 inhibitor).
Mechanism Target:
INHIBITS IL-23/IL-17 Axis — TYK2/JAK blockade reduces cytokine signaling that maintains the IL-23/IL-17 circuit.
Spesolimab
Action: spesolimab therapy Ontology label: Pharmacotherapy NCIT:C15986
First-in-class IL-36 receptor inhibitor approved for generalized pustular psoriasis flares.
Mechanism Target:
INHIBITS IL-36 Keratinocyte Activation — IL-36R blockade dampens the IL-36-chemokine-neutrophil inflammatory loop in pustular psoriasis.
Show evidence (2 references)
PMID:38077370 SUPPORT Other
"Spesolimab is a first-in-class, humanized, monoclonal antibody that binds specifically to the IL-36R and antagonizes IL-36 signaling."
This directly supports spesolimab as a targeted therapy for the IL-36 mechanism modeled in pustular psoriasis.
PMID:38077370 SUPPORT Other
"Spesolimab was approved by the US Food and Drug Administration in September 2022 to treat GPP flares in adults and was subsequently approved for GPP flare treatment in other countries across the world."
This supports current clinical use of spesolimab for pustular psoriasis flares.
🌍

Environmental Factors

6
Streptococcal Infection
Triggers guttate psoriasis
Stress
Common trigger for flares
Smoking
Risk factor and worsens disease
Obesity
Associated with severity
Medications
Beta blockers, lithium, antimalarials can trigger
Skin Trauma
Koebner phenomenon
📊

Related Datasets

2
Adult human skin cells of health and psoriasis vulgaris cellxgene:b1fd6a09-eb76-44ca-822d-68318548094c
Single-cell RNA-seq atlas of adult human skin comparing healthy and psoriasis vulgaris samples, characterizing keratinocyte, immune, and stromal cell populations and their disease-associated transcriptional states.
human SINGLE CELL RNA SEQ
skin
Conditions: psoriasis normal
PMID:34131144
CZI CELLxGENE collection. DOI 10.1038/s41419-021-03724-6.
Developmental cell programs are co-opted in inflammatory skin disease cellxgene:73f82ac8-15cc-4fcd-87f8-5683723fce7f
Single-cell analysis showing that developmental cell programs are reactivated in inflammatory skin diseases including psoriasis and atopic dermatitis, providing molecular insights into pathological keratinocyte differentiation.
human SINGLE CELL RNA SEQ
skin
Conditions: psoriasis atopic dermatitis normal
PMID:32603654
CZI CELLxGENE collection. DOI 10.1126/science.aba6500. Reveals co-opted developmental programs in psoriasis.
{ }

Source YAML

click to show 
name: Psoriasis
creation_date: '2025-12-18T17:01:35Z'
updated_date: '2026-04-30T12:00:00Z'
category: Complex
parents:
- Dermatological Disease
- Autoimmune Disease
disease_term:
  preferred_term: psoriasis
  term:
    id: MONDO:0005083
    label: psoriasis
has_subtypes:
- name: Plaque Psoriasis
  description: Most common form with raised, red, scaly plaques.
- name: Guttate Psoriasis
  description: Small, drop-shaped lesions, often following streptococcal infection.
- name: Inverse Psoriasis
  description: Affects skin folds with smooth, red patches.
- name: Pustular Psoriasis
  description: Characterized by white pustules surrounded by red skin.
- name: Erythrodermic Psoriasis
  description: Severe, widespread inflammation covering most of the body.
- name: Psoriatic Arthritis
  description: Joint inflammation associated with psoriasis.
prevalence:
- population: Global
  percentage: 2.0
  notes: Adult prevalence ranges from 0.91% (US) to 8.5% (Norway); higher in countries more distant from the equator. Bimodal onset with peaks at 20-30 years (Type I) and 50-60 years (Type II).
  evidence:
  - reference: PMID:23014338
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in adults it varied from 0.91% (United States) to 8.5% (Norway)."
    explanation: Systematic review of global prevalence data showing geographic variation.
- population: Pustular Psoriasis (Europe)
  subtype: Pustular Psoriasis
  percentage: 0.0002
  notes: Generalized pustular psoriasis prevalence estimated at 1-9 per million in Europe.
  evidence:
  - reference: ORPHA:247353
    supports: SUPPORT
    snippet: "1-9 / 1 000 000 | Europe | Point prevalence | ORPHANET"
    explanation: Orphanet epidemiological data for generalized pustular psoriasis.
  - reference: PMID:17229609
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Incidence and prevalence were estimated in 2004 at a minimum of 0.64 and 1.76/million respectively."
    explanation: French epidemiological survey confirming GPP rarity with prevalence of 1.76 per million.
inheritance:
- name: Autosomal recessive inheritance (pustular subtype)
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: IL36RN loss-of-function mutations follow autosomal recessive inheritance in familial generalized pustular psoriasis.
  evidence:
  - reference: ORPHA:247353
    supports: SUPPORT
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance for generalized pustular psoriasis.
pathophysiology:
- name: T Cell-Mediated Inflammation
  description: >
    Activated T cells (Th1, Th17, Th22) infiltrate skin and release
    cytokines including IL-17, IL-22, TNF-alpha, and IFN-gamma that drive
    keratinocyte hyperproliferation and inflammation.
  cell_types:
  - preferred_term: T Helper 17 Cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  - preferred_term: T Helper 1 Cell
    term:
      id: CL:0000545
      label: T-helper 1 cell
  biological_processes:
  - preferred_term: T Cell Activation
    term:
      id: GO:0042110
      label: T cell activation
  downstream:
  - target: Keratinocyte Hyperproliferation
    description: Effector cytokines from activated T cells drive keratinocyte proliferation and plaque formation.
  evidence:
  - reference: PMID:38686385
    reference_title: "IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy."
    supports: PARTIAL
    snippet: "Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease."
    explanation: "IL-23 drives Th17 cell differentiation and maintenance, which is central to T cell-mediated inflammation in psoriasis."
  - reference: PMID:39337637
    reference_title: "Pathogenesis of Inflammation in Skin Disease: From Molecular Mechanisms to Pathology."
    supports: PARTIAL
    snippet: "Current research efforts to better understand skin disease have focused on examining the role of molecular processes at several stages of the inflammatory response such as the dysregulation of innate immunity sensors, disruption of both transcriptional and post-transcriptional regulation, and crosstalk between immune and neuronal processes (neuro-immune crosstalk)."
    explanation: "This describes the complex inflammatory response involving multiple cellular processes, consistent with T cell-mediated inflammation involving transcriptional regulation and immune cell crosstalk."
- name: Keratinocyte Hyperproliferation
  description: >
    Inflammatory cytokines stimulate rapid keratinocyte proliferation,
    reducing epidermal turnover from 28 days to 3-4 days. This produces
    characteristic thick, scaly plaques.
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: Cell Proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
  evidence:
  - reference: PMID:39337637
    reference_title: "Pathogenesis of Inflammation in Skin Disease: From Molecular Mechanisms to Pathology."
    supports: NO_EVIDENCE
    snippet: "Many skin diseases begin with inflammatory changes on a molecular level."
    explanation: "Inflammatory changes at the molecular level drive keratinocyte hyperproliferation in psoriasis, linking inflammation to cellular proliferation."
  - reference: PMID:39576422
    reference_title: "Naturally derived bioactive compounds as precision modulators of immune and inflammatory mechanisms in psoriatic conditions."
    supports: NO_EVIDENCE
    snippet: "Psoriasis represents a chronic autoimmune skin condition defined by various clinical forms, including inverse, erythrodermic, pustular, guttate, plaque types."
    explanation: "The chronic autoimmune nature of psoriasis results in persistent inflammatory signaling that drives sustained keratinocyte hyperproliferation, manifesting as the characteristic plaque types."
- name: Dendritic Cell Activation
  description: >
    Plasmacytoid and myeloid dendritic cells produce inflammatory
    cytokines and present antigens to activate T cells, initiating
    and perpetuating the inflammatory cascade.
  cell_types:
  - preferred_term: Dendritic Cell
    term:
      id: CL:0000451
      label: dendritic cell
  downstream:
  - target: IL-23/IL-17 Axis
    description: Dendritic-cell-derived IL-23 initiates the central psoriatic cytokine circuit.
  evidence:
  - reference: PMID:40817122
    reference_title: "CCR7(+) dendritic cells expressing both IL-23A and IL-12B potentially contribute to psoriasis relapse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show that IL4I1+CD200+CCR7+ dendritic cells (CCR7+ DC) are the main producer of IL-23 by concomitantly expressing the IL-23A and IL-12B subunits in human psoriatic skin."
    explanation: "This directly supports activated dendritic cells as the IL-23-producing initiators of psoriatic inflammation."
- name: IL-23/IL-17 Axis
  description: >
    IL-23 produced by dendritic cells drives Th17 cell differentiation
    and IL-17 production. This axis is the major therapeutic target
    in modern psoriasis treatment.
  biological_processes:
  - preferred_term: Cytokine Signaling
    term:
      id: GO:0019221
      label: cytokine-mediated signaling pathway
  - 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
  - preferred_term: Dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  downstream:
  - target: T Cell-Mediated Inflammation
    description: IL-23 expands IL-17-producing T-cell responses that sustain plaque inflammation.
  evidence:
  - reference: PMID:38686385
    reference_title: "IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy."
    supports: PARTIAL
    snippet: "Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease."
    explanation: "This confirms IL-23 as the hierarchically dominant regulatory cytokine in psoriasis, supporting its central role in the IL-23/IL-17 axis and why it is the major therapeutic target."
  - reference: PMID:39337637
    reference_title: "Pathogenesis of Inflammation in Skin Disease: From Molecular Mechanisms to Pathology."
    supports: NO_EVIDENCE
    snippet: "Many skin diseases begin with inflammatory changes on a molecular level."
    explanation: "This establishes that inflammatory molecular mechanisms are fundamental to skin disease pathogenesis, consistent with the IL-23/IL-17 inflammatory axis driving psoriasis."
- name: IL-36 Keratinocyte Activation
  description: >
    In pustular psoriasis, keratinocyte-derived IL-36 signaling amplifies
    chemokine production, recruits neutrophils, and sustains sterile
    pustule formation.
  subtypes:
  - Pustular Psoriasis
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  - preferred_term: Neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: Inflammatory Response
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: Neutrophil Chemotaxis
    term:
      id: GO:0030593
      label: neutrophil chemotaxis
  downstream:
  - target: Pustules
    description: IL-36-driven neutrophilic inflammation produces sterile pustules.
  evidence:
  - reference: PMID:38077370
    reference_title: "The role of the interleukin-36 axis in generalized pustular psoriasis: a review of the mechanism of action of spesolimab."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In GPP, innate immune responses are driven by abnormal activation of the interleukin (IL)-36-chemokine-neutrophil axis and excessive neutrophil infiltration."
    explanation: "This directly supports IL-36-driven keratinocyte/neutrophil inflammatory amplification as the defining pustular psoriasis mechanism."
phenotypes:
- name: Erythematous Plaques
  category: Dermatological
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Well-demarcated, raised, red plaques
  phenotype_term:
    preferred_term: Erythematous plaque
    term:
      id: HP:0025474
      label: Erythematous plaque
  evidence:
  - reference: PMID:15708928
    reference_title: 'Psoriasis: epidemiology, clinical features, and quality of life.'
    supports: SUPPORT
    snippet: "most commonly the disease presents as chronic, symmetrical, erythematous, scaling papules and plaques."
    explanation: Erythematous plaques are the most common clinical presentation of psoriasis.
- name: Silvery Scales
  category: Dermatological
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Characteristic silvery-white scale
  phenotype_term:
    preferred_term: Scaling Skin
    term:
      id: HP:0040189
      label: Scaling skin
  evidence:
  - reference: PMID:15708928
    reference_title: 'Psoriasis: epidemiology, clinical features, and quality of life.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "most commonly the disease presents as chronic, symmetrical, erythematous, scaling papules and plaques."
    explanation: Scaling is a defining feature of psoriatic plaques.
- name: Pustules
  category: Dermatological
  frequency: OBLIGATE
  diagnostic: true
  subtype: Pustular Psoriasis
  notes: Sterile superficial pustules during pustular flares. Obligate feature of GPP per Orphanet.
  phenotype_term:
    preferred_term: Pustule
    term:
      id: HP:0200039
      label: Pustule
  evidence:
  - reference: PMID:38077370
    reference_title: "The role of the interleukin-36 axis in generalized pustular psoriasis: a review of the mechanism of action of spesolimab."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Generalized pustular psoriasis (GPP) is a rare, chronic, inflammatory skin disorder characterized by recurrent flares associated with skin erythema, desquamation, and widespread superficial sterile pustules, which may be severe (\"lakes of pus\")."
    explanation: "This directly supports widespread sterile pustules as the defining phenotype of pustular psoriasis."
  - reference: ORPHA:247353
    supports: SUPPORT
    snippet: "HP:0200039 | Pustule | Obligate (100%)"
    explanation: Orphanet classifies pustules as obligate (100%) in generalized pustular psoriasis.
- name: Pruritus
  category: Dermatological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: PMID:11069504
    reference_title: The prevalence and clinical characteristics of pruritus among patients with extensive psoriasis.
    supports: SUPPORT
    snippet: "Generalized pruritus was a feature of psoriasis in 84% of the patients."
    explanation: Pruritus is a common and significant symptom in psoriasis, affecting the majority of patients and impacting quality of life.
- name: Nail Changes
  category: Dermatological
  frequency: FREQUENT
  notes: Pitting, onycholysis, subungual hyperkeratosis
  phenotype_term:
    preferred_term: Nail Dystrophy
    term:
      id: HP:0008404
      label: Nail dystrophy
  evidence:
  - reference: PMID:26131859
    reference_title: 'Nail involvement in adult patients with plaque-type psoriasis: prevalence and clinical features.'
    supports: SUPPORT
    snippet: "Nail psoriasis is estimated in 50% of patients with psoriasis, and in the presence of joint involvement, it can reach 80%."
    explanation: Nail involvement is common in psoriasis patients and may include pitting, onycholysis, and subungual hyperkeratosis.
- name: Joint Pain
  category: Musculoskeletal
  frequency: OCCASIONAL
  notes: Psoriatic arthritis in approximately 20% of patients
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: PMID:29928910
    reference_title: 'Prevalence of psoriatic arthritis in patients with psoriasis: A systematic review and meta-analysis of observational and clinical studies.'
    supports: SUPPORT
    snippet: "We found that 1 in 4 patients with psoriasis have PsA."
    explanation: Psoriatic arthritis is a common comorbidity in psoriasis patients, affecting approximately 20-25% based on this meta-analysis.
  phenotype_contexts:
  - subtype: Pustular Psoriasis
    frequency: OBLIGATE
    evidence:
    - reference: ORPHA:247353
      supports: SUPPORT
      snippet: "HP:0002829 | Arthralgia | Obligate (100%)"
      explanation: Orphanet classifies arthralgia as obligate (100%) in generalized pustular psoriasis.
- name: Koebner Phenomenon
  category: Dermatological
  frequency: FREQUENT
  diagnostic: true
  notes: New psoriatic lesions develop at sites of skin trauma (cuts, scratches, sunburn). Well-established diagnostic sign.
  phenotype_term:
    preferred_term: Koebner Phenomenon
    term:
      id: HP:6000933
      label: Koebner Phenomenon
  evidence:
  - reference: PMID:31491865
    reference_title: 'Risk Factors for the Development of Psoriasis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with psoriasis, skin lesions appear in uninvolved areas after various injuries"
    explanation: Directly describes the Koebner phenomenon as the appearance of new psoriatic lesions at sites of skin injury.
- name: Auspitz Sign
  category: Dermatological
  frequency: FREQUENT
  diagnostic: true
  notes: Pinpoint bleeding upon removal of psoriatic scale, reflecting dilated capillaries in elongated dermal papillae.
  phenotype_term:
    preferred_term: Auspitz sign
    term:
      id: HP:6000724
      label: Auspitz sign
- name: Erythroderma
  category: Dermatological
  frequency: OCCASIONAL
  subtype: Erythrodermic Psoriasis
  notes: Severe widespread erythema covering most of the body surface. Life-threatening complication.
  phenotype_term:
    preferred_term: Erythroderma
    term:
      id: HP:0001019
      label: Erythroderma
  evidence:
  - reference: PMID:31491865
    reference_title: 'Risk Factors for the Development of Psoriasis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Drug-related psoriasis would manifest as plaque psoriasis, palmoplantar psoriasis, nail psoriasis, scalp psoriasis, pustular psoriasis, and erythrodermic psoriasis"
    explanation: Erythrodermic psoriasis is recognized as a distinct clinical manifestation of psoriasis.
  phenotype_contexts:
  - subtype: Pustular Psoriasis
    frequency: VERY_FREQUENT
    evidence:
    - reference: ORPHA:247353
      supports: SUPPORT
      snippet: "HP:0001019 | Erythroderma | Very frequent (99-80%)"
      explanation: Orphanet classifies erythroderma as very frequent (99-80%) in generalized pustular psoriasis.
- name: Dactylitis
  category: Musculoskeletal
  frequency: OCCASIONAL
  subtype: Psoriatic Arthritis
  notes: Sausage-like swelling of entire digits, characteristic of psoriatic arthritis.
  phenotype_term:
    preferred_term: Finger dactylitis
    term:
      id: HP:0031090
      label: Finger dactylitis
  evidence:
  - reference: PMID:29893226
    reference_title: 'The pathogenesis of psoriatic arthritis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis is primarily based on clinical phenotype because of the diversity of the associated features, which can include skin and nail disease, dactylitis, uveitis, and osteitis."
    explanation: Dactylitis is explicitly listed as a characteristic clinical feature of psoriatic arthritis.
- name: Enthesitis
  category: Musculoskeletal
  frequency: OCCASIONAL
  subtype: Psoriatic Arthritis
  notes: Inflammation at tendon/ligament insertion sites, particularly Achilles tendon and plantar fascia.
  phenotype_term:
    preferred_term: Enthesitis
    term:
      id: HP:0100686
      label: Enthesitis
  evidence:
  - reference: PMID:28212759
    reference_title: 'Psoriasis and comorbid diseases: Epidemiology.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PsA is the most well-recognized comorbidity of psoriasis and is a heterogeneous inflammatory arthritis characterized by joint and/or entheseal inflammation and extra-articular manifestations."
    explanation: Entheseal inflammation is explicitly named as a characteristic feature of psoriatic arthritis.
- name: Fever
  category: Constitutional
  frequency: FREQUENT
  subtype: Pustular Psoriasis
  notes: High fever accompanying generalized pustular psoriasis flares.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: ORPHA:247353
    supports: SUPPORT
    snippet: "HP:0001945 | Fever | Frequent (79-30%)"
    explanation: Orphanet classifies fever as frequent in GPP.
  - reference: ORPHA:247353
    supports: SUPPORT
    snippet: "Generalized pustular psoriasis is a severe inflammatory skin disease that can be life-threatening and that is characterized by recurrent episodes of high fever, fatigue, episodic erythematous cutaneous eruptions with sterile cutaneous pustules formation on various parts of the body, and neutrophil leukocytosis."
    explanation: Orphanet definition explicitly lists high fever as a defining feature of GPP.
- name: Fatigue
  category: Constitutional
  frequency: FREQUENT
  subtype: Pustular Psoriasis
  notes: Prominent fatigue during GPP flares.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: ORPHA:247353
    supports: SUPPORT
    snippet: "HP:0012378 | Fatigue | Frequent (79-30%)"
    explanation: Orphanet classifies fatigue as frequent in GPP.
- name: Leukocytosis
  category: Laboratory
  frequency: FREQUENT
  subtype: Pustular Psoriasis
  notes: Neutrophil leukocytosis accompanies GPP flares.
  phenotype_term:
    preferred_term: Leukocytosis
    term:
      id: HP:0001974
      label: Increased total leukocyte count
  evidence:
  - reference: ORPHA:247353
    supports: SUPPORT
    snippet: "HP:0001974 | Leukocytosis | Frequent (79-30%)"
    explanation: Orphanet classifies leukocytosis as frequent in GPP.
- name: Geographic Tongue
  category: Oral
  frequency: FREQUENT
  subtype: Pustular Psoriasis
  notes: Fissured or geographic tongue pattern, associated with pustular psoriasis.
  phenotype_term:
    preferred_term: Geographic tongue
    term:
      id: HP:0025252
      label: Geographic tongue
  evidence:
  - reference: ORPHA:247353
    supports: SUPPORT
    snippet: "HP:0025252 | Geographic tongue | Frequent (79-30%)"
    explanation: Orphanet classifies geographic tongue as frequent in GPP.
- name: Depression
  category: Psychiatric
  frequency: FREQUENT
  notes: Depression is significantly more prevalent in psoriasis patients, driven by both psychosocial burden and shared inflammatory pathways.
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:36745557
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pooled effect estimates suggest that female sex and psoriatic arthritis were associated with depression"
    explanation: Meta-analysis confirming significant association between psoriasis and depression, with psoriatic arthritis as an additional risk factor.
  - reference: PMID:35757712
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mental health diseases draw more attention not just because of the negative mental and mood influence caused by skin lesions, but a common immune-inflammatory mechanism identified of the two systemic diseases."
    explanation: Shared immune-inflammatory mechanisms contribute to depression in psoriasis beyond the psychosocial impact of skin lesions.
genetic:
- name: HLA-C*06:02
  association: Risk Factor
  notes: Strongest genetic association
- name: IL12B
  association: Risk Factor
  evidence:
  - reference: PMID:38686385
    reference_title: "IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy."
    supports: NO_EVIDENCE
    snippet: "Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease."
    explanation: "IL12B encodes the p40 subunit shared by IL-12 and IL-23. Given IL-23's hierarchically dominant role in psoriasis, genetic variants in IL12B that affect IL-23 levels represent important risk factors."
- name: IL23R
  association: Risk Factor
  evidence:
  - reference: PMID:38686385
    reference_title: "IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy."
    supports: NO_EVIDENCE
    snippet: "We review IL-23 biology, IL-23 signaling in IMIDs, and the effect of IL-23 inhibition in treating these diseases."
    explanation: "IL23R encodes the IL-23 receptor, and genetic variants affecting IL-23 signaling are risk factors for psoriasis given the central role of this pathway."
- name: TYK2
  association: GWAS
  notes: Cytokine kinase mediating IL-23 and IL-12 signaling; therapeutic target of deucravacitinib.
  evidence:
  - reference: PMID:20953190
    reference_title: "A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2)."
    explanation: "This GWAS directly implicates TYK2 as a psoriasis susceptibility locus linked to cytokine signaling."
- name: TRAF3IP2
  association: GWAS
  notes: Act1 adaptor protein for IL-17 receptor signaling.
  evidence:
  - reference: PMID:20953190
    reference_title: "A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2)."
    explanation: "This GWAS directly implicates TRAF3IP2 as a psoriasis susceptibility locus in the IL-17 signaling pathway."
- name: TNFAIP3
  association: Risk Factor
- name: CARD14
  association: Causative
  notes: Rare familial psoriasis
- name: IL36RN
  association: Pustular subtype risk factor
  subtype: Pustular Psoriasis
  notes: Encodes IL-36 receptor antagonist; enriched in generalized pustular psoriasis.
  evidence:
  - reference: PMID:30036598
    reference_title: "Clinical and genetic differences between pustular psoriasis subtypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although AP1S3 alleles had similar frequency (0.03-0.05) across disease subtypes, IL36RN mutations were less common in patients with PPP (0.03) than in those with GPP (0.19) and ACH (0.16; P = 1.9 × 10-14 and .002, respectively)."
    explanation: "This cohort shows IL36RN mutations are enriched in generalized pustular psoriasis, supporting a subtype-specific genetic driver."
  - reference: ORPHA:247353
    supports: SUPPORT
    snippet: "IL36RN | interleukin 36 receptor antagonist | hgnc:15561 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet classifies IL36RN loss-of-function mutations as disease-causing in GPP.
- name: IL1RL2
  association: Pustular subtype pathway gene
  subtype: Pustular Psoriasis
  notes: Encodes the IL-36 receptor that mediates keratinocyte-driven pustular inflammation.
  evidence:
  - reference: PMID:20833839
    reference_title: "IL-1RL2 and its ligands contribute to the cytokine network in psoriasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Blockade of IL-1F6 receptor also resolves the inflammatory changes in human psoriatic lesional skin transplanted onto immunodeficient mice."
    explanation: "This supports IL1RL2/IL-36 receptor signaling as a mechanistically relevant driver of psoriasis inflammation."
- name: AP1S3
  association: Pustular subtype risk factor
  subtype: Pustular Psoriasis
  notes: Pustular psoriasis gene linking keratinocyte autophagy defects to IL-36 overproduction.
  evidence:
  - reference: PMID:30036598
    reference_title: "Clinical and genetic differences between pustular psoriasis subtypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although mutations have been uncovered in IL36RN and AP1S3, the rarity of the disease has hindered the study of genotype-phenotype correlations."
    explanation: "This confirms AP1S3 as an established pustular psoriasis susceptibility gene."
  - reference: ORPHA:247353
    supports: SUPPORT
    snippet: "AP1S3 | adaptor related protein complex 1 subunit sigma 3 | hgnc:18971 | Disease-causing germline mutation(s) in"
    explanation: Orphanet classifies AP1S3 mutations as disease-causing in GPP.
- name: BACH2
  association: GWAS
  notes: Transcription factor regulating Treg/effector T cell balance and B cell class switching
- name: STAT3
  association: GWAS
  notes: Signal transducer mediating Th17 differentiation via JAK-STAT pathway
- name: IL10
  association: GWAS
  notes: Anti-inflammatory cytokine critical for immune tolerance
- name: CD28
  association: GWAS
  notes: T cell co-stimulatory receptor required for T cell activation
- name: EGR2
  association: GWAS
  notes: Transcription factor involved in T cell anergy and peripheral tolerance
- name: ETS1
  association: GWAS
  notes: Transcription factor regulating T and B cell development and immune cell differentiation
- name: IRF4
  association: GWAS
  notes: Transcription factor essential for Th17 and Th2 cell differentiation and plasma cell development
- name: IRF8
  association: GWAS
  notes: Interferon regulatory factor controlling myeloid cell development and type I interferon response
- name: SATB1
  association: GWAS
  notes: Chromatin organizer regulating T cell development and lineage commitment
- name: IKZF1
  association: GWAS
  notes: Ikaros transcription factor essential for lymphocyte development and differentiation
- name: SMAD3
  association: GWAS
  notes: TGF-beta signaling mediator regulating T cell differentiation and immune tolerance
- name: REL
  association: GWAS
  notes: NF-kB subunit c-Rel controlling lymphocyte activation and survival
- name: PRDM1
  association: GWAS
  notes: Blimp-1 transcription factor regulating T cell and B cell terminal differentiation
- name: PTPN22
  association: GWAS
  notes: Protein tyrosine phosphatase modulating T cell receptor signaling threshold
environmental:
- name: Streptococcal Infection
  notes: Triggers guttate psoriasis
- name: Stress
  notes: Common trigger for flares
- name: Smoking
  notes: Risk factor and worsens disease
- name: Obesity
  notes: Associated with severity
- name: Medications
  notes: Beta blockers, lithium, antimalarials can trigger
- name: Skin Trauma
  notes: Koebner phenomenon
treatments:
- name: Topical Corticosteroids
  description: First-line for limited disease.
  treatment_term:
    preferred_term: Topical corticosteroid therapy
    term:
      id: NCIT:C122078
      label: Topical Corticosteroid Therapy
- name: Topical Vitamin D Analogues
  description: Calcipotriene, calcitriol for mild to moderate disease.
  treatment_term:
    preferred_term: Vitamin D analogue therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Phototherapy
  description: Narrowband UVB or PUVA for moderate to severe disease.
- name: Methotrexate
  description: Traditional systemic therapy for moderate to severe disease.
  treatment_term:
    preferred_term: Methotrexate therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: TNF Inhibitors
  description: Adalimumab, etanercept, infliximab for moderate to severe disease.
  treatment_term:
    preferred_term: TNF inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: IL-17 Inhibitors
  description: Secukinumab, ixekizumab - highly effective targeted therapy.
  treatment_term:
    preferred_term: IL-17 inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: IL-23/IL-17 Axis
    treatment_effect: INHIBITS
    description: Neutralizes IL-17 effector signaling downstream of the central psoriatic cytokine axis.
- name: IL-23 Inhibitors
  description: Guselkumab, risankizumab - high efficacy with infrequent dosing.
  treatment_term:
    preferred_term: IL-23 inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: IL-23/IL-17 Axis
    treatment_effect: INHIBITS
    description: Blocks the IL-23 signal that sustains Th17-driven inflammation.
  evidence:
  - reference: PMID:38686385
    reference_title: "IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy."
    supports: PARTIAL
    snippet: "We review IL-23 biology, IL-23 signaling in IMIDs, and the effect of IL-23 inhibition in treating these diseases."
    explanation: "This paper reviews the therapeutic effect of IL-23 inhibition in treating psoriasis and other immune-mediated inflammatory diseases, supporting the use of IL-23 inhibitors like guselkumab and risankizumab."
- name: IL-12/23 Inhibitor
  description: Ustekinumab targets shared p40 subunit.
  treatment_term:
    preferred_term: IL-12/23 inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: IL-23/IL-17 Axis
    treatment_effect: INHIBITS
    description: Shared p40 blockade dampens the IL-23-driven inflammatory circuit.
  evidence:
  - reference: PMID:38686385
    reference_title: "IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy."
    supports: PARTIAL
    snippet: "Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease."
    explanation: "Ustekinumab targets the p40 subunit shared by IL-12 and IL-23. Given IL-23's hierarchically dominant role, blocking this shared subunit provides therapeutic benefit in psoriasis."
- name: JAK Inhibitors
  description: Oral therapy option (deucravacitinib - TYK2 inhibitor).
  treatment_term:
    preferred_term: JAK inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: IL-23/IL-17 Axis
    treatment_effect: INHIBITS
    description: TYK2/JAK blockade reduces cytokine signaling that maintains the IL-23/IL-17 circuit.
- name: Spesolimab
  description: First-in-class IL-36 receptor inhibitor approved for generalized pustular psoriasis flares.
  treatment_term:
    preferred_term: spesolimab therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: IL-36 Keratinocyte Activation
    treatment_effect: INHIBITS
    description: IL-36R blockade dampens the IL-36-chemokine-neutrophil inflammatory loop in pustular psoriasis.
  evidence:
  - reference: PMID:38077370
    reference_title: "The role of the interleukin-36 axis in generalized pustular psoriasis: a review of the mechanism of action of spesolimab."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Spesolimab is a first-in-class, humanized, monoclonal antibody that binds specifically to the IL-36R and antagonizes IL-36 signaling."
    explanation: "This directly supports spesolimab as a targeted therapy for the IL-36 mechanism modeled in pustular psoriasis."
  - reference: PMID:38077370
    reference_title: "The role of the interleukin-36 axis in generalized pustular psoriasis: a review of the mechanism of action of spesolimab."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Spesolimab was approved by the US Food and Drug Administration in September 2022 to treat GPP flares in adults and was subsequently approved for GPP flare treatment in other countries across the world."
    explanation: "This supports current clinical use of spesolimab for pustular psoriasis flares."
classifications:
  harrisons_chapter:
  - classification_value: DERMATOLOGY
  - classification_value: IMMUNE_RHEUMATOLOGIC
datasets:
# CELLxGENE - Psoriasis skin single-cell atlas
- accession: "cellxgene:b1fd6a09-eb76-44ca-822d-68318548094c"
  title: Adult human skin cells of health and psoriasis vulgaris
  description: >-
    Single-cell RNA-seq atlas of adult human skin comparing healthy and psoriasis
    vulgaris samples, characterizing keratinocyte, immune, and stromal cell
    populations and their disease-associated transcriptional states.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: skin
    tissue_term:
      preferred_term: skin of body
      term:
        id: UBERON:0002097
        label: skin of body
  conditions:
  - psoriasis
  - normal
  publication: PMID:34131144
  notes: CZI CELLxGENE collection. DOI 10.1038/s41419-021-03724-6.

# CELLxGENE - Developmental programs in inflammatory skin
- accession: "cellxgene:73f82ac8-15cc-4fcd-87f8-5683723fce7f"
  title: Developmental cell programs are co-opted in inflammatory skin disease
  description: >-
    Single-cell analysis showing that developmental cell programs are reactivated
    in inflammatory skin diseases including psoriasis and atopic dermatitis,
    providing molecular insights into pathological keratinocyte differentiation.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: skin
    tissue_term:
      preferred_term: skin of body
      term:
        id: UBERON:0002097
        label: skin of body
  conditions:
  - psoriasis
  - atopic dermatitis
  - normal
  publication: PMID:32603654
  notes: CZI CELLxGENE collection. DOI 10.1126/science.aba6500. Reveals co-opted developmental programs in psoriasis.

references:
- reference: DOI:10.1007/s10787-024-01602-z
  title: Naturally derived bioactive compounds as precision modulators of immune and inflammatory mechanisms in psoriatic conditions
  findings: []
- reference: DOI:10.31661/gmj.vi.3854
  title: Advances in the Molecular Pathogenesis and  Targeted Therapy of Psoriasis
  findings: []
- reference: DOI:10.3389/fimmu.2024.1331217
  title: 'IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy'
  findings: []
- reference: DOI:10.3389/fimmu.2025.1573905
  title: 'Interventions in cytokine signaling: novel horizons for psoriasis treatment'
  findings: []
- reference: DOI:10.3389/fimmu.2025.1643418
  title: 'Skin immune microenvironment in psoriasis: from bench to bedside'
  findings: []
- reference: DOI:10.3390/ijms251810152
  title: 'Pathogenesis of Inflammation in Skin Disease: From Molecular Mechanisms to Pathology'
  findings: []
- reference: DOI:10.3390/jpm14050535
  title: 'Review: A Contemporary, Multifaced Insight into Psoriasis Pathogenesis'
  findings: []
- reference: DOI:10.7759/cureus.68569
  title: 'Shared Pathophysiology of Inflammatory Bowel Disease and Psoriasis: Unraveling the Connection'
  findings: []
📚

References & Deep Research

References

8
DOI:10.1007/s10787-024-01602-z
Naturally derived bioactive compounds as precision modulators of immune and inflammatory mechanisms in psoriatic conditions
No top-level findings curated for this source.
DOI:10.31661/gmj.vi.3854
Advances in the Molecular Pathogenesis and Targeted Therapy of Psoriasis
No top-level findings curated for this source.
DOI:10.3389/fimmu.2024.1331217
IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy
No top-level findings curated for this source.
DOI:10.3389/fimmu.2025.1573905
Interventions in cytokine signaling: novel horizons for psoriasis treatment
No top-level findings curated for this source.
DOI:10.3389/fimmu.2025.1643418
Skin immune microenvironment in psoriasis: from bench to bedside
No top-level findings curated for this source.
DOI:10.3390/ijms251810152
Pathogenesis of Inflammation in Skin Disease: From Molecular Mechanisms to Pathology
No top-level findings curated for this source.
DOI:10.3390/jpm14050535
Review: A Contemporary, Multifaced Insight into Psoriasis Pathogenesis
No top-level findings curated for this source.
DOI:10.7759/cureus.68569
Shared Pathophysiology of Inflammatory Bowel Disease and Psoriasis: Unraveling the Connection
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Psoriasis
  • Category: Complex
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 21

Key Pathophysiology Nodes

  • T Cell-Mediated Inflammation
  • Keratinocyte Hyperproliferation
  • Dendritic Cell Activation
  • IL-23/IL-17 Axis
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1007/s10787-024-01602-z
  • DOI:10.31661/gmj.vi.3854
  • DOI:10.3389/fimmu.2024.1331217
  • DOI:10.3389/fimmu.2025.1573905
  • DOI:10.3389/fimmu.2025.1643418
  • DOI:10.3390/ijms251810152
  • DOI:10.3390/jpm14050535
  • DOI:10.3399/fimmu.2025.1573905
  • DOI:10.7759/cureus.68569
Falcon ▸
Pathophysiology description
Edison Scientific Literature 29 citations 2025-12-17T19:02:33.119965

Pathophysiology description Psoriasis is a chronic, immune-mediated inflammatory disease of the skin with systemic manifestations driven by a self-amplifying cytokine network centered on the IL-23/IL-17 axis, keratinocyte–immune cell feedback loops, and genetically primed dysregulation of innate and adaptive immunity. Dendritic cells, mononuclear phagocytes, and keratinocytes orchestrate Th17/Tc17 responses that sustain epidermal hyperproliferation and barrier dysfunction; in parallel, IL-36–mediated innate inflammation underlies pustular variants. Single-cell and translational studies highlight the persistence of tissue-resident memory T cells and circuit-level reinforcement of inflammation that guide current targeted therapies against IL‑23, IL‑17, and TYK2 signaling (deucravacitinib), with emerging modulators of AHR and other pathways under investigation (krueger2024il23pastpresent pages 5-5, yao2025skinimmunemicroenvironment pages 6-7, li2025interventionsincytokine pages 5-6, shirley2024pathogenesisofinflammation pages 7-9).

1) Core Pathophysiology - Central cytokine axis and feedback: Antigen-presenting cells in lesional skin produce IL‑23 (p19/p40) and TNF-α, driving Th17/Tc17 effectors that secrete IL‑17A/F and IL‑22; IL‑17 acts on keratinocytes to induce chemokines, AMPs, and further cytokines, establishing a positive feedback loop that sustains chronic inflammation and epidermal hyperplasia. Selective IL‑23p19 and IL‑17 inhibitors achieve high and durable clinical clearance in moderate–severe plaque psoriasis, underscoring the axis’ pathogenic dominance (URL: https://doi.org/10.3389/fimmu.2024.1331217; Apr 2024) (krueger2024il23pastpresent pages 5-5). Single-cell and microenvironment-focused reviews emphasize that keratinocyte exposure to IL‑17/IL‑22 triggers additional IL‑23/Th17 axis signaling and tissue-resident memory T-cell persistence that predisposes to recurrence (URL: https://doi.org/10.3389/fimmu.2025.1643418; Aug 2025) (yao2025skinimmunemicroenvironment pages 6-7). - Keratinocyte signaling programs: Keratinocyte hyperproliferation and aberrant differentiation are potentiated by STAT3 and NF‑κB activation downstream of IL‑22/IL‑17/TNF; genetic and pharmacologic evidence link TYK2/JAK signaling to Th17 biology and keratinocyte responses. Loss-of-function TYK2 variants reduce risk, and JAK/TYK2 inhibitors show efficacy. AHR dysregulation modulates epidermal hyperplasia and cytokine balance, indicating a role for xenobiotic and photometabolic pathways in epidermal control (URL: https://doi.org/10.3390/ijms251810152; Sep 2024) (shirley2024pathogenesisofinflammation pages 7-9). Oxidative stress and cGAS–STING/type I IFN pathways can augment these signals and couple innate sensing to Th17 responses (URL: https://doi.org/10.3389/fimmu.2025.1573905; Apr 2025) (li2025interventionsincytokine pages 5-6). - Dendritic cell–T cell crosstalk: Plasmacytoid DCs release type I IFNs that activate myeloid DCs, which produce IL‑12 and IL‑23 to drive Th1/Th17 polarization; the resulting IL‑17/IL‑22 milieu drives keratinocyte proliferation and neutrophil recruitment, with LL37/AMPs further amplifying DC activation (URL: https://doi.org/10.3389/fimmu.2025.1573905; Apr 2025; URL: https://doi.org/10.7759/cureus.68569; Sep 2024) (li2025interventionsincytokine pages 5-6, jauregui2024sharedpathophysiologyof pages 3-5). - Innate IL‑36 pathway in pustular disease: Keratinocyte‑derived IL‑36 cytokines activate IL‑36R→NF‑κB signaling to induce chemokines, inhibit differentiation, and recruit neutrophils. Genetic or functional imbalance between IL‑36 agonists and IL‑36RN (IL‑36Ra) is a hallmark of pustular psoriasis; clinical targeting of IL‑36R has shown benefit in generalized pustular psoriasis (URL: https://doi.org/10.3389/fimmu.2025.1643418; Aug 2025) (yao2025skinimmunemicroenvironment pages 6-7).

2) Key Molecular Players - Genes/Proteins (HGNC symbols): - IL23A (IL‑23p19), IL12B (p40), IL23R: genetic and mechanistic contributors to Th17 maintenance; protective and risk alleles identified across GWAS; central therapeutic targets (krueger2024il23pastpresent pages 5-5, radu2025naturallyderivedbioactive pages 3-5). - IL17A/IL17F, IL17RA: effector cytokines/receptor mediating keratinocyte activation and neutrophil mobilization (krueger2024il23pastpresent pages 5-5, li2025interventionsincytokine pages 5-6). - TYK2: kinase transducing IL‑23/IL‑12 signals; LoF variants protective; therapeutic target of deucravacitinib (shirley2024pathogenesisofinflammation pages 7-9, li2025interventionsincytokine pages 5-6). - CARD14: keratinocyte NF‑κB adaptor; rare variants cause PSORS2 and promote keratinocyte‑intrinsic inflammation (radu2025naturallyderivedbioactive pages 3-5). - TRAF3IP2 (Act1): adaptor for IL‑17 receptor signaling; GWAS locus for Th17 signaling (radu2025naturallyderivedbioactive pages 3-5). - IL36RN, IL1RL2 (IL‑36R), IL1RAP, AP1S3: IL‑36 pathway and autophagy adaptor genes implicated in pustular forms and innate amplification (yao2025skinimmunemicroenvironment pages 6-7, radu2025naturallyderivedbioactive pages 3-5, li2025interventionsincytokine pages 5-6). - HLA‑C*06:02 (PSORS1): strongest MHC class I risk allele; associated with early-onset/guttate phenotypes and treatment response heterogeneity (krueger2024il23pastpresent pages 5-5, li2025interventionsincytokine pages 5-6, jauregui2024sharedpathophysiologyof pages 3-5). - LCE3B/C deletions, ERAP1, IFIH1: barrier and antigen processing/IFN pathway contributors (radu2025naturallyderivedbioactive pages 3-5). - Chemical entities/classes: - Biologics targeting IL‑23 (risankizumab, guselkumab, tildrakizumab) and IL‑17/IL‑17RA (secukinumab, ixekizumab, brodalumab) demonstrate high clearance rates and durable control; IL‑23 inhibitors often provide superior long-term durability with slower onset versus IL‑17A inhibitors (krueger2024il23pastpresent pages 5-5). - Oral TYK2 inhibitor deucravacitinib modulates IL‑23/IL‑12 signaling; benefits reported in plaque psoriasis (li2025interventionsincytokine pages 5-6). - AHR pathway modulators under investigation; AHR dysregulation affects epidermal hyperplasia and cytokines (shirley2024pathogenesisofinflammation pages 7-9). - Cell types (CL terms): - Keratinocytes (epidermal): primary responders/amplifiers of IL‑17/IL‑22/TNF; source of IL‑36 and AMPs (shirley2024pathogenesisofinflammation pages 7-9, yao2025skinimmunemicroenvironment pages 6-7). - Dendritic cells: plasmacytoid and myeloid DCs initiate and sustain Th17 responses (li2025interventionsincytokine pages 5-6, jauregui2024sharedpathophysiologyof pages 3-5). - Th17/Tc17 cells and tissue-resident memory T cells: key effectors and persistence drivers (yao2025skinimmunemicroenvironment pages 6-7, krueger2024il23pastpresent pages 5-5). - Neutrophils: downstream of IL‑17/IL‑36, prominent in pustular forms (yao2025skinimmunemicroenvironment pages 6-7, li2025interventionsincytokine pages 5-6). - Anatomical locations (UBERON): epidermis and dermis of skin; lesional niches enriched for DCs and TRM T cells with keratinocyte–immune crosstalk (krueger2024il23pastpresent pages 5-5, yao2025skinimmunemicroenvironment pages 6-7).

3) Biological Processes (candidate GO terms; evidence-linked) - Th17 cell differentiation and maintenance by IL‑23 signaling; JAK/TYK2–STAT pathways (krueger2024il23pastpresent pages 5-5, shirley2024pathogenesisofinflammation pages 7-9, li2025interventionsincytokine pages 5-6). - Response to interleukin‑17; chemokine-mediated neutrophil chemotaxis; antimicrobial peptide production by keratinocytes (krueger2024il23pastpresent pages 5-5, li2025interventionsincytokine pages 5-6, jauregui2024sharedpathophysiologyof pages 3-5). - NF‑κB signaling in keratinocytes; regulation of keratinocyte proliferation and differentiation; STAT3 activation by IL‑22 (shirley2024pathogenesisofinflammation pages 7-9, li2025interventionsincytokine pages 5-6). - IL‑36 signaling and neutrophil recruitment; innate immune activation (yao2025skinimmunemicroenvironment pages 6-7). - Type I interferon signaling and cGAS–STING activation downstream of oxidative DNA damage (li2025interventionsincytokine pages 5-6).

4) Cellular Components (candidate GO-CC terms) - Plasma membrane/cytokine receptor complexes (IL‑23R/IL‑12R/IL‑17RA complexes) in T cells and keratinocytes (krueger2024il23pastpresent pages 5-5, li2025interventionsincytokine pages 5-6). - Cytosol and nucleus for STAT3/NF‑κB transcriptional programs in keratinocytes (shirley2024pathogenesisofinflammation pages 7-9). - Extracellular space for cytokines/chemokines and antimicrobial peptides; epidermal/dermal interstitial microenvironment of lesions (krueger2024il23pastpresent pages 5-5, li2025interventionsincytokine pages 5-6, jauregui2024sharedpathophysiologyof pages 3-5).

5) Disease Progression - Initiation: Environmental triggers (infection, trauma, stress) and genetic predisposition activate innate sensors (TLRs, cGAS–STING) and plasmacytoid DCs → type I IFN and TNF; myeloid DC activation produces IL‑23/IL‑12 (shirley2024pathogenesisofinflammation pages 7-9, li2025interventionsincytokine pages 5-6). - Amplification: IL‑23 sustains Th17/Tc17; IL‑17A/F and IL‑22 drive keratinocyte proliferation, AMP and chemokine release; keratinocytes feed back to immune cells, reinforcing IL‑23/Th17 axis; TRM cells persist and predispose to relapse after therapy (yao2025skinimmunemicroenvironment pages 6-7, krueger2024il23pastpresent pages 5-5). - Chronicity: Circuit-level reinforcement via NF‑κB/STAT3 in keratinocytes, oxidative stress/type I IFN, and continued DC–T cell crosstalk sustains plaques; in pustular forms, IL‑36 dysregulation produces neutrophilic inflammation (li2025interventionsincytokine pages 5-6, yao2025skinimmunemicroenvironment pages 6-7).

6) Phenotypic Manifestations and Comorbidities - Clinical phenotypes (HP terms): - Chronic plaque psoriasis (erythematous scaly plaques; acanthosis; neutrophils in stratum corneum) linked to IL‑23/IL‑17 dominance (krueger2024il23pastpresent pages 5-5, jauregui2024sharedpathophysiologyof pages 3-5). - Guttate psoriasis often associated with HLA‑Cw6 and heightened Th17 signatures (li2025interventionsincytokine pages 5-6, jauregui2024sharedpathophysiologyof pages 3-5). - Generalized pustular psoriasis characterized by IL‑36 pathway activation, keratinocyte-derived IL‑36, and neutrophilia (yao2025skinimmunemicroenvironment pages 6-7, li2025interventionsincytokine pages 5-6). - Systemic inflammation and comorbidities: Psoriasis is systemic with links to psoriatic arthritis, IBD, and cardiovascular/metabolic disease; IL‑23/Th17 biology and chronic inflammation are implicated. IL‑23 inhibitors show durable efficacy and systemic benefits in psoriatic disease management frameworks (URL: https://doi.org/10.3389/fimmu.2024.1331217; Apr 2024) (krueger2024il23pastpresent pages 5-5).

7) Microbiome in Pathogenesis - Gut–skin axis: Psoriasis associates with gut dysbiosis, including Firmicutes/Bacteroidetes imbalance and SCFA depletion; dysbiosis modulates immune tone (Th17/Treg balance) and may exacerbate systemic inflammation and lesions (URL: https://doi.org/10.7759/cureus.68569; Sep 2024) (jauregui2024sharedpathophysiologyof pages 3-5). Narrative mechanistic synthesis reports increased Prevotella and reduced SCFAs in psoriasis, and highlights adjunctive microbiome-modulating strategies as areas of investigation (URL: https://doi.org/10.3389/fimmu.2025.1573905; Apr 2025) (li2025interventionsincytokine pages 5-6). - Skin microbiome: Dysbiosis with increased streptococci and decreased commensals reported; keratinocyte AMP overexpression (LL37/β-defensins/S100s) links microbial signals to DC activation and type I IFN (URL: https://doi.org/10.7759/cureus.68569; Sep 2024) (jauregui2024sharedpathophysiologyof pages 3-5).

8) Current Applications and Therapeutic Implications (2023–2024 priority) - IL‑23 selective inhibition: Guselkumab, risankizumab, and tildrakizumab are approved for moderate–severe plaque psoriasis; head‑to‑head trials and long-term extensions show superior durability to TNF and some IL‑17 agents, with potential for sustained responses after withdrawal, although onset can be slower than IL‑17A blockers (URL: https://doi.org/10.3389/fimmu.2024.1331217; Apr 2024) (krueger2024il23pastpresent pages 5-5). - IL‑17 pathway inhibition: IL‑17A (secukinumab, ixekizumab) and IL‑17RA (brodalumab) rapidly suppress keratinocyte inflammatory programs and neutrophilic signatures; highly effective for plaque disease (krueger2024il23pastpresent pages 5-5). - TYK2 inhibition: Deucravacitinib (selective TYK2 allosteric inhibitor) addresses IL‑23/IL‑12 signaling with demonstrated efficacy in plaque psoriasis; genetic TYK2 LoF supports target validity (URL: https://doi.org/10.3399/fimmu.2025.1573905; Apr 2025; URL: https://doi.org/10.3390/ijms251810152; Sep 2024) (li2025interventionsincytokine pages 5-6, shirley2024pathogenesisofinflammation pages 7-9). - IL‑36 pathway targeting: The IL‑36 axis is pivotal in generalized pustular psoriasis; clinical proof-of-concept with IL‑36R blockade aligns with mechanistic role (yao2025skinimmunemicroenvironment pages 6-7). - AHR modulators: AHR dysregulation contributes to epidermal hyperplasia and cytokine balance; antagonists/ligands are under investigation as keratinocyte-directed therapies (URL: https://doi.org/10.3390/ijms251810152; Sep 2024) (shirley2024pathogenesisofinflammation pages 7-9).

Expert opinions and analysis - “IL‑23…is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis…Selective IL‑23p19 inhibitors…are approved…show superior efficacy versus adalimumab, secukinumab, and ustekinumab in head‑to‑head trials, achieve high durable responses… and can maintain benefit after treatment withdrawal” (Krueger et al., 2024; URL: https://doi.org/10.3389/fimmu.2024.1331217) (krueger2024il23pastpresent pages 5-5). - “IL‑17A/F are pivotal effectors and IL‑23 (p19/p40) drives Th17/Tc17 populations…TRM cells are long-lived pathogenic drivers…The IL‑36 family…links to pustular phenotypes” (Yao et al., 2025; URL: https://doi.org/10.3389/fimmu.2025.1643418) (yao2025skinimmunemicroenvironment pages 6-7). - “JAK–STAT pathway is central: IL‑22 activates TYK2/JAK1, IL‑23 activates JAK2/TYK2…TYK2 loss‑of‑function decreases disease risk…AHR dysregulation…modulates epidermal hyperplasia and cytokine balance” (Shirley et al., 2024; URL: https://doi.org/10.3390/ijms251810152) (shirley2024pathogenesisofinflammation pages 7-9).

Relevant statistics and data - Dominant therapeutic axis: Multiple head-to-head clinical comparisons summarized in expert roadmap show IL‑23 inhibitors’ superior durability and high PASI90/100 rates vs TNF and some IL‑17 agents in moderate–severe plaque psoriasis, with responses maintained up to 5 years and post-withdrawal durability in subsets (Krueger et al., 2024) (krueger2024il23pastpresent pages 5-5). - Genetic architecture: GWAS and exome studies implicate HLA‑C*06:02 (PSORS1), IL23/IL12 pathways (IL12B, IL23A/IL23R), TYK2, TRAF3IP2, CARD14, barrier genes (LCE3B/C), ERAP1, and interferon signaling (IFIH1), consistent with Th17/keratinocyte–NF‑κB biology (Radu et al., 2025) (radu2025naturallyderivedbioactive pages 3-5). - Microbiome patterns: Reviews synthesize Firmicutes/Bacteroidetes imbalance, increased Streptococcus on skin, and reduced SCFAs in gut, collectively supporting a Th17‑skewing milieu (Jauregui et al., 2024; Li et al., 2025) (jauregui2024sharedpathophysiologyof pages 3-5, li2025interventionsincytokine pages 5-6).

Evidence items (primary texts; URLs and dates) - Krueger JG et al. IL‑23 past, present, and future: a roadmap… Frontiers in Immunology. Apr 2024. https://doi.org/10.3389/fimmu.2024.1331217 (krueger2024il23pastpresent pages 5-5) - Yao Y et al. Skin immune microenvironment in psoriasis: from bench to bedside. Frontiers in Immunology. Aug 2025. https://doi.org/10.3389/fimmu.2025.1643418 (yao2025skinimmunemicroenvironment pages 6-7) - Shirley SN et al. Pathogenesis of inflammation in skin disease: IJMS. Sep 2024. https://doi.org/10.3390/ijms251810152 (shirley2024pathogenesisofinflammation pages 7-9) - Li L et al. Interventions in cytokine signaling: novel horizons… Frontiers in Immunology. Apr 2025. https://doi.org/10.3389/fimmu.2025.1573905 (li2025interventionsincytokine pages 5-6) - Radu A et al. Naturally derived bioactives… Inflammopharmacology. Nov 2025. https://doi.org/10.1007/s10787-024-01602-z (radu2025naturallyderivedbioactive pages 3-5) - Jauregui W et al. Shared pathophysiology of IBD and psoriasis. Cureus. Sep 2024. https://doi.org/10.7759/cureus.68569 (jauregui2024sharedpathophysiologyof pages 3-5) - Shokoufa P, Aghaei M. Advances in molecular pathogenesis and therapy. GMJ. May 2025. https://doi.org/10.31661/gmj.vi.3854 (shokoufa2025advancesinthe pages 1-3) - Dascălu RC et al. Contemporary insight into psoriasis pathogenesis. J Pers Med. May 2024. https://doi.org/10.3390/jpm14050535 (dascalu2024reviewacontemporary pages 14-16)

Structured annotations for knowledge-base integration - Genes/proteins (HGNC): IL23A; IL12B; IL23R; IL17A/IL17F; IL17RA; TYK2; CARD14; TRAF3IP2; IL36RN; IL1RL2; IL1RAP; AP1S3; HLA‑C (krueger2024il23pastpresent pages 5-5, radu2025naturallyderivedbioactive pages 3-5, li2025interventionsincytokine pages 5-6, yao2025skinimmunemicroenvironment pages 6-7, jauregui2024sharedpathophysiologyof pages 3-5). - Biological processes (GO BP): Th17 cell differentiation; response to interleukin‑17; keratinocyte proliferation; NF‑κB signaling; JAK–STAT cascade; cytokine-mediated signaling; neutrophil chemotaxis; type I interferon signaling; IL‑36 signaling pathway (krueger2024il23pastpresent pages 5-5, shirley2024pathogenesisofinflammation pages 7-9, li2025interventionsincytokine pages 5-6, yao2025skinimmunemicroenvironment pages 6-7). - Cellular components (GO CC): plasma membrane cytokine receptor complexes (IL‑23R/IL‑12R/IL‑17RA); cytosol and nucleus (STAT3/NF‑κB transcriptional machinery); extracellular space (cytokines/chemokines/AMPs) (shirley2024pathogenesisofinflammation pages 7-9, krueger2024il23pastpresent pages 5-5, li2025interventionsincytokine pages 5-6). - Cell types (CL): keratinocyte; plasmacytoid dendritic cell; conventional/myeloid dendritic cell; Th17/Tc17 cell; tissue-resident memory T cell; neutrophil (yao2025skinimmunemicroenvironment pages 6-7, li2025interventionsincytokine pages 5-6, jauregui2024sharedpathophysiologyof pages 3-5, krueger2024il23pastpresent pages 5-5). - Anatomical locations (UBERON): skin epidermis and dermis; lesional microenvironments enriched for DCs/TRM (krueger2024il23pastpresent pages 5-5, yao2025skinimmunemicroenvironment pages 6-7). - Chemical entities (classes; CHEBI mapping where appropriate): IL‑23/IL‑17 biological antagonists; TYK2 inhibitor (deucravacitinib); experimental AHR modulators (krueger2024il23pastpresent pages 5-5, li2025interventionsincytokine pages 5-6, shirley2024pathogenesisofinflammation pages 7-9). - Phenotypes (HP): psoriasiform dermatitis; chronic plaque psoriasis; guttate psoriasis; generalized pustular psoriasis; nail and scalp involvement (mechanistic mapping emphasized for plaque/pustular) (yao2025skinimmunemicroenvironment pages 6-7, li2025interventionsincytokine pages 5-6, krueger2024il23pastpresent pages 5-5, jauregui2024sharedpathophysiologyof pages 3-5).

Quotable excerpts supporting key statements - “IL‑23…is a hierarchically dominant regulatory cytokine in…psoriasis…Selective IL‑23p19 inhibitors…show superior efficacy…achieve high durable responses…and can maintain benefit after treatment withdrawal” (krueger2024il23pastpresent pages 5-5). - “IL‑17A/F are pivotal effectors and IL‑23 (p19/p40) drives Th17/Tc17…TRM cells are long-lived pathogenic drivers…The IL‑36 family…links to pustular phenotypes” (yao2025skinimmunemicroenvironment pages 6-7). - “The JAK–STAT pathway is central: IL‑22 activates TYK2/JAK1, IL‑23 activates JAK2/TYK2…TYK2 loss-of-function decreases disease risk…AHR dysregulation…modulates epidermal hyperplasia” (shirley2024pathogenesisofinflammation pages 7-9). - “pDCs release TNF and type I IFNs and activate mDCs to produce IL‑12/IL‑23 that drive Th1/Th17 responses” with oxidative stress and cGAS–STING augmenting type I IFN and Th17 pathways (li2025interventionsincytokine pages 5-6). - “Genome-wide…link susceptibility to…HLA‑C, ERAP1…Th17 activation (TRAF3IP2, IL12B, IL23R, IL23A)… and type I interferon signaling (IFIH1, TYK2)” (radu2025naturallyderivedbioactive pages 3-5).

Limitations and evidence gaps - While single-cell and spatial studies are rapidly refining stromal/immune states and lesion dynamics, high-resolution fibroblast-state data and early on-treatment cellular kinetics—crucial for precision stratification—are still being generalized from limited cohorts and were only partially represented in the sources reviewed here (yao2025skinimmunemicroenvironment pages 6-7, shokoufa2025advancesinthe pages 1-3). Additional integration with large longitudinal scRNA-seq/spatial datasets will improve cellular ontologies and therapeutic response prediction.

Summary Psoriasis pathophysiology centers on an IL‑23→Th17→IL‑17/IL‑22 axis that drives keratinocyte NF‑κB/STAT3 activation, epidermal hyperproliferation, and multi-cellular feedback involving DCs, TRM T cells, and neutrophils; pustular variants feature IL‑36–dominated innate cascades. Genetic architecture maps strongly to MHC class I (HLA‑C*06:02), Th17 signaling (IL12B/IL23A/IL23R/TYK2/TRAF3IP2), keratinocyte NF‑κB (CARD14), and innate IL‑36/autophagy circuits (IL36RN, AP1S3). Dysbiosis of skin and gut microbiota likely skews immune tone toward Th17. These insights rationalize current first-line targeted interventions (IL‑23/IL‑17 biologics, TYK2 inhibition) and motivate investigation of keratinocyte‑directed AHR modulation and IL‑36 blockade for pustular disease (krueger2024il23pastpresent pages 5-5, yao2025skinimmunemicroenvironment pages 6-7, shirley2024pathogenesisofinflammation pages 7-9, li2025interventionsincytokine pages 5-6, radu2025naturallyderivedbioactive pages 3-5, jauregui2024sharedpathophysiologyof pages 3-5).

References

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