Psoriasis 14, Pustular (Mendelian) — Disease Characteristics Research Report

Executive overview

“Pustular psoriasis” is a clinically heterogeneous spectrum of inflammatory skin disorders characterized by erythematous plaques bearing sterile pustules, with major subtypes including generalized pustular psoriasis (GPP), acrodermatitis continua of Hallopeau (ACH), and palmoplantar pustular psoriasis/palmoplantar pustulosis (PPP/PPPP). (akiyama2022pustularpsoriasisas pages 1-2) Among these, GPP is a severe autoinflammatory disease with episodic or persistent sterile pustulation that can be life-threatening and is increasingly understood as driven by innate immune activation centered on the IL-36 axis. (akiyama2022pustularpsoriasisas pages 1-2, gwillim2024spesolimabforgeneralized pages 1-2)

“Psoriasis 14, pustular” corresponds to a Mendelian disease concept in MONDO (MONDO_0013626) and is linked to genes that predispose to pustular psoriasis, including AP1S3, IL36RN, and CARD14 in Open Targets disease–target associations. (OpenTargets Search: pustular psoriasis)

1. Disease information

1.1 What is the disease?

Psoriasis 14, pustular is best interpreted operationally as a monogenic/Mendelian entity within the pustular psoriasis spectrum, in which rare high-impact variants (especially in AP1S3 and IL-36 pathway genes) predispose to pustular phenotypes (GPP/ACH/PPP) with sterile pustules and variable systemic inflammation. (OpenTargets Search: pustular psoriasis, settakaffetzi2014ap1s3mutationsare pages 2-4, akiyama2022pustularpsoriasisas pages 1-2)

1.2 Key identifiers

Available from tool-supported evidence in this run: - MONDO: - Psoriasis 14, pustular: MONDO_0013626 (OpenTargets Search: pustular psoriasis) - Pustular psoriasis (umbrella): MONDO_0022205 (OpenTargets Search: pustular psoriasis) - Generalized pustular psoriasis: MONDO_0100491 (OpenTargets Search: pustular psoriasis)

Not retrieved in the currently available full texts/evidence snippets (therefore cannot be asserted here): OMIM disease number, Orphanet ID, MeSH descriptor, ICD-10/ICD-11 code.

1.3 Synonyms / alternative names (as used in the literature)

For the clinical spectrum relevant to PSORS14, commonly used disease labels include: - Generalized pustular psoriasis (GPP), including “von Zumbusch” acute form (choon2022clinicalcourseand pages 4-6) - Acrodermatitis continua of Hallopeau (ACH) (bachelez2020pustularpsoriasisthe pages 3-4) - Palmoplantar pustulosis / palmoplantar pustular psoriasis (PPP/PPPP) (bachelez2020pustularpsoriasisthe pages 3-4, navarini2017europeanconsensusstatement pages 1-4)

1.4 Evidence source types

The PSORS14 concept is supported primarily by: - Aggregated disease-level resources (e.g., MONDO/Open Targets mappings) (OpenTargets Search: pustular psoriasis) - Human genetics case-control and case series studies discovering/enriching rare variants (settakaffetzi2014ap1s3mutationsare pages 2-4, mossner2018thegeneticbasis pages 15-19) - Human keratinocyte functional studies for causal mechanism (in vitro; patient-derived keratinocytes) (settakaffetzi2014ap1s3mutationsare pages 4-6, mahil2016ap1s3mutationscause pages 10-14)

2. Etiology

2.1 Disease causal factors

Primary causal factors are genetic, with additional triggering by environmental/iatrogenic factors precipitating flares.

Genetic causes / strong predisposing genes

• AP1S3 (loss-of-function / destabilizing missense alleles): discovery of enriched heterozygous founder variants in pustular psoriasis; functional mechanism via disrupted vesicular trafficking (TLR3) and keratinocyte inflammatory dysregulation. (settakaffetzi2014ap1s3mutationsare pages 2-4, settakaffetzi2014ap1s3mutationsare pages 4-6)
• IL36RN (IL-36 receptor antagonist deficiency; DITRA): biallelic loss-of-function variants are a major cause of many GPP cases and show an autosomal recessive pattern in those families. (yang2023geneticsofgeneralized pages 2-3, yang2023geneticsofgeneralized pages 3-5)
• CARD14 (gain-of-function): heterozygous GOF variants can drive psoriasis phenotypes and are implicated in subsets of pustular psoriasis, including familial autosomal-dominant pedigrees in the broader pustular psoriasis literature. (bachelez2020pustularpsoriasisthe pages 3-4, akiyama2022pustularpsoriasisas pages 2-3)

Environmental/iatrogenic triggers (flare precipitants)

For GPP (and relevant pustular phenotypes), triggers include: - Withdrawal of systemic corticosteroids (reported up to ~20% in one review) (choon2022clinicalcourseand pages 3-4) - Infections (notably URTIs), stress, pregnancy, menstruation, hypocalcemia, and multiple medications; biologics can also be triggers in some contexts (e.g., rebound/withdrawal or paradoxical pustulation). (choon2022clinicalcourseand pages 2-3, choon2022clinicalcourseand pages 3-4)

2.2 Risk factors

• Female predominance has been reported for PPP/PPPP and in several GPP cohorts. (bachelez2020pustularpsoriasisthe pages 3-4, riveradiaz2023generalizedpustularpsoriasis pages 3-4)
• Smoking is strongly linked to palmoplantar pustular psoriasis/palmoplantar pustulosis. (bachelez2020pustularpsoriasisthe pages 3-4)
• Genotype-driven risk: IL36RN biallelic mutations are associated with earlier onset and more severe/systemic disease features. (akiyama2022pustularpsoriasisas pages 2-3, choon2022clinicalcourseand pages 4-6)

2.3 Protective factors

No disease-specific protective genetic or environmental factors were identified in the retrieved evidence set.

2.4 Gene–environment interaction

The AP1S3 discovery study supports a model in which heterozygous AP1S3 variants may be incompletely penetrant, with flares requiring environmental/inflammatory triggers; affected individuals could inherit the allele from an unaffected parent. (settakaffetzi2014ap1s3mutationsare pages 2-4)

3. Phenotypes

Because PSORS14 is best supported by genetics tied to pustular psoriasis phenotypes, the phenotype section focuses on pustular psoriasis subtypes, especially GPP (the best-characterized in retrieved sources).

3.1 Core clinical features (symptoms/signs)

Generalized pustular psoriasis (GPP) - Hallmark: recurrent widespread painful erythema with sterile pustules that may coalesce into “lakes of pus.” (choon2022clinicalcourseand pages 4-6, riveradiaz2023generalizedpustularpsoriasis pages 3-4) - Systemic symptoms during significant flares: fever, malaise/fatigue, edema; extracutaneous manifestations can include arthritis, uveitis, and neutrophilic cholangitis. (choon2022clinicalcourseand pages 4-6, choon2022clinicalcourseand pages 3-4) - Laboratory abnormalities during flares: leukocytosis/neutrophilia, elevated CRP, hypocalcemia, hypoalbuminemia, and abnormal liver function tests. (choon2022clinicalcourseand pages 4-6, riveradiaz2023generalizedpustularpsoriasis pages 3-4) - Course: relapsing-remitting or persistent; typical flares last 2–5 weeks, but may persist >3 months in chronic variants. (choon2022clinicalcourseand pages 4-6, riveradiaz2023generalizedpustularpsoriasis pages 3-4)

Acrodermatitis continua of Hallopeau (ACH) - Persistent pustulation affecting digits/nail apparatus; may cause progressive nail destruction and bone erosions if untreated. (bachelez2020pustularpsoriasisthe pages 3-4, navarini2017europeanconsensusstatement pages 1-4)

Palmoplantar pustulosis / palmoplantar pustular psoriasis (PPP/PPPP) - Persistent sterile pustules on palms and soles; chronic course; strongly associated with smoking; can cause major quality-of-life impairment. (bachelez2020pustularpsoriasisthe pages 3-4, navarini2017europeanconsensusstatement pages 1-4)

3.2 Onset, severity, progression, frequency (data)

• In one single-center series of severe flares (>30% BSA) followed for ~5 years: 56.8% had one severe flare; 29.5% had 2–5 flares; 13.7% had >5 flares. (choon2022clinicalcourseand pages 3-4)
• Hospitalization is often required for significant flares; one review reports hospitalization for ~50% of flares and average inpatient stay 10–14 days. (choon2022clinicalcourseand pages 4-6)
• Mortality attributable to GPP or its treatment is reported to range 2–16% across studies; a Japanese inpatient study reported 4.2% in-hospital mortality (higher with systemic corticosteroid monotherapy, lower with biologics). (choon2022clinicalcourseand pages 4-6)

3.3 Quality-of-life impact

GPP is described as having substantial burden and impaired quality of life, motivating development of targeted therapies and disease-specific endpoints. (gwillim2024spesolimabforgeneralized pages 1-2, choon2022clinicalcourseand pages 4-6)

3.4 Suggested HPO terms (examples)

(These are ontology suggestions based on described phenotypes; explicit HPO mappings were not provided in retrieved texts.) - Sterile pustules: HP:0100704 (Pustule) - Erythema: HP:0025504 (Erythema) - Fever: HP:0001945 (Fever) - Arthralgia/arthritis: HP:0002829 (Arthralgia) / HP:0001369 (Arthritis) - Nail dystrophy/destruction (ACH): HP:0001800 (Nail dystrophy) - Elevated C-reactive protein: HP:0011227 (Elevated C-reactive protein) - Neutrophilia/leukocytosis: HP:0011891 (Neutrophilia) / HP:0001974 (Leukocytosis) - Hypocalcemia: HP:0002901 (Hypocalcemia) - Hypoalbuminemia: HP:0003073 (Hypoalbuminemia)

4. Genetic / molecular information

4.1 Causal genes and inheritance

AP1S3

Key concept: heterozygous AP1S3 founder missense variants are enriched in pustular psoriasis and functionally impair AP-1 adaptor complex biology. - Reported variants (discovery paper): - c.11T>G (p.Phe4Cys) - c.97C>T (p.Arg33Trp) (settakaffetzi2014ap1s3mutationsare pages 2-4, settakaffetzi2014ap1s3mutationsare pages 4-6) - Case-control enrichment (discovery paper): c.11T>G 2.3% cases vs 0.6% controls; c.97C>T 3.6% vs 0.7%; combined significance exceeded exome-wide threshold. (settakaffetzi2014ap1s3mutationsare pages 2-4) - Inheritance/penetrance: heterozygous carriage with segregation from unaffected parent supports dominant with reduced penetrance / susceptibility allele model. (settakaffetzi2014ap1s3mutationsare pages 2-4)

Visual evidence: Table/figure regions enumerating AP1S3 variants and frequencies are captured from the discovery paper. (settakaffetzi2014ap1s3mutationsare media 63a65913, settakaffetzi2014ap1s3mutationsare media fcbc7708, settakaffetzi2014ap1s3mutationsare media 0828eba0)

IL36RN

• Biallelic loss-of-function IL36RN variants are described as a major cause of GPP in many cases and are autosomal recessive in the classic DITRA model; allele dosage relates to age of onset and severity. (yang2023geneticsofgeneralized pages 2-3, yang2023geneticsofgeneralized pages 3-5)
• Example IL36RN variants shown as relevant to pustular subtypes include c.115+6T>C, p.Pro76Leu, and p.Ser113Leu. (twelves2019clinicalandgenetic pages 1-2)
• Oligogenic contribution: heterozygous IL36RN variants are overrepresented compared with the general population and may contribute in combination with other rare variants (e.g., AP1S3/CARD14). (mossner2018thegeneticbasis pages 15-19)

CARD14

• Reviews describe heterozygous gain-of-function CARD14 variants as drivers of psoriasis phenotypes and contributors to pustular psoriasis in subsets; autosomal dominant familial GPP is reported in this broader CARD14 GOF context. (bachelez2020pustularpsoriasisthe pages 3-4, akiyama2022pustularpsoriasisas pages 2-3)

Additional genes reported in GPP genetics reviews

MPO, SERPINA1, SERPINA3, BTN3A3, among others, have been described as associated/predisposing genes for GPP in recent genetics reviews, but inheritance patterns and variant-level details were not consistently extractable from the retrieved snippets. (yang2023geneticsofgeneralized pages 2-3, yang2023geneticsofgeneralized pages 3-5)

4.2 Functional consequences (mechanistic genetics)

• AP1S3 discovery work supports loss-of-function through destabilization of AP1S3 or disruption of AP-1 complex interactions, impairing endosomal trafficking of TLR3 and downstream signaling (e.g., reduced IFNB1 induction to poly(I:C)). (settakaffetzi2014ap1s3mutationsare pages 4-6)
• Subsequent mechanistic work connects AP1S3 deficiency to defective keratinocyte autophagy, p62 accumulation, enhanced NF-κB signaling, and upregulated IL-36α production. (mahil2016ap1s3mutationscause pages 10-14, mahil2016ap1s3mutationscause pages 6-10, mahil2016ap1s3mutationscause pages 1-6)

4.3 Modifier genes / oligogenic architecture

Evidence supports that some pustular psoriasis patients show multiple rare variants across IL36RN/AP1S3/CARD14, consistent with oligogenic inheritance/modifier effects in subsets. (mossner2018thegeneticbasis pages 15-19, bachelez2020pustularpsoriasisthe pages 3-4)

4.4 Allele frequency and founder effects

The AP1S3 discovery paper reports intragenic haplotype associations consistent with founder alleles for the two AP1S3 variants. (settakaffetzi2014ap1s3mutationsare pages 2-4)

5. Environmental information

Strongest evidence in retrieved materials is for iatrogenic and physiologic triggers rather than toxins/pollutants. - Triggers include corticosteroid withdrawal, infections, stress, pregnancy/menstruation, and multiple medications. (choon2022clinicalcourseand pages 2-3, choon2022clinicalcourseand pages 3-4) - PPP/PPPP shows a strong association with smoking. (bachelez2020pustularpsoriasisthe pages 3-4)

6. Mechanism / pathophysiology

6.1 Current mechanistic understanding (key concepts)

A contemporary framing is that pustular psoriasis is an autoinflammatory keratinization disease (AiKD) with hyperactivation of skin innate immune signaling, especially the IL-1/IL-36 axis, leading to chemokine induction and neutrophil recruitment. (akiyama2022pustularpsoriasisas pages 1-2, gwillim2024spesolimabforgeneralized pages 1-2)

6.2 Causal chain (genotype → pathway → lesion)

Representative chain for AP1S3-associated pustular psoriasis (human keratinocyte evidence): 1) AP1S3 loss-of-function (p.Phe4Cys/p.Arg33Trp) disrupts AP-1 adaptor function and autophagosome biology in keratinocytes. (settakaffetzi2014ap1s3mutationsare pages 4-6, mahil2016ap1s3mutationscause pages 6-10) 2) Defective autophagy leads to p62/SQSTM1 accumulation with downstream NF-κB hyperactivation. (mahil2016ap1s3mutationscause pages 6-10, mahil2016ap1s3mutationscause pages 1-6) 3) Keratinocytes exhibit exaggerated innate responses (TLR2/6 and IL-1–responsive cytokines) and constitutive upregulation of IL36A (IL-36α) and related inflammatory mediators. (mahil2016ap1s3mutationscause pages 10-14) 4) Unopposed IL-36 signaling amplifies the IL-36–chemokine–neutrophil axis, driving sterile neutrophilic pustules and systemic inflammation in severe disease. (gwillim2024spesolimabforgeneralized pages 1-2)

6.3 Cell types (CL term suggestions)

• Keratinocyte: CL:0000312 (supported by AP1S3 expression and keratinocyte-autonomous mechanism). (mahil2016ap1s3mutationscause pages 6-10)
• Neutrophil: CL:0000775 (dominant infiltrating cell type in pustules; IL-36–chemokine–neutrophil axis). (gwillim2024spesolimabforgeneralized pages 1-2)

6.4 GO biological process suggestions

• Neutrophil chemotaxis (GO:0030593) / neutrophil activation (GO:0042119)
• Cytokine-mediated signaling pathway (GO:0019221)
• NF-κB signaling (GO:0043122)
• Autophagy (GO:0006914)

6.5 Molecular profiling (omics)

Longitudinal blood transcriptomics in GPP (PBMC RNA-seq) showed that remission after acitretin was associated with downregulation of neutrophil-related inflammatory genes (e.g., CXCL1, CXCL8, S100A8/A9/A12, LCN2) and pathway-level inhibition of pro-inflammatory signaling. (yang2023geneticsofgeneralized pages 2-3)

7. Anatomical structures affected

7.1 Primary organs/tissues

• Skin epidermis/dermis (sterile pustules, erythema). (choon2022clinicalcourseand pages 4-6)

7.2 Specific anatomical sites (UBERON suggestions)

• Skin of body (UBERON:0002097)
• Palm (UBERON:0002387) and sole (UBERON:0002388) for PPP/PPPP
• Nail unit (UBERON:0001828) for ACH

7.3 Subcellular components (GO-CC suggestions)

• Endosome (GO:0005768) / trans-Golgi network (GO:0005802) (AP1S3 trafficking biology) (settakaffetzi2014ap1s3mutationsare pages 4-6)
• Autophagosome (GO:0005776) (AP1S3-autophagy mechanism) (mahil2016ap1s3mutationscause pages 6-10)

8. Temporal development

• GPP can be relapsing with disease-free intervals of months to years or persistent with chronic pustulation >3 months (ERASPEN framework). (navarini2017europeanconsensusstatement pages 1-4)
• Severe flares can evolve rapidly (≤7 days for von Zumbusch acute GPP) and can be medically emergent. (riveradiaz2023generalizedpustularpsoriasis pages 3-4)

9. Inheritance and population

9.1 Inheritance patterns

• IL36RN-associated GPP: typically autosomal recessive for biallelic LOF, with allele-dose effects on severity and age of onset; heterozygous variants may act oligogenically. (yang2023geneticsofgeneralized pages 3-5, mossner2018thegeneticbasis pages 15-19)
• AP1S3-associated pustular psoriasis (PSORS14 concept): heterozygous enriched variants; evidence supports dominant with reduced penetrance / susceptibility rather than strict Mendelian segregation. (settakaffetzi2014ap1s3mutationsare pages 2-4)
• CARD14 GOF: can be autosomal dominant in familial psoriasis contexts; also implicated in pustular subsets. (bachelez2020pustularpsoriasisthe pages 3-4)

9.2 Epidemiology (best-available in retrieved evidence)

Population-based estimates are scarce and vary by definition. Reported prevalence estimates include approximately 1–7 per million globally and a Swedish registry estimate of 9.1 per 100,000 (female predominance) as cited in a 2023 review. (riveradiaz2023generalizedpustularpsoriasis pages 3-4)

10. Diagnostics

10.1 Clinical criteria / definitions

• ERASPEN (European consensus): GPP defined by “primary, sterile, macroscopically visible pustules on non-acral skin,” excluding pustulation restricted to psoriatic plaques; classification into relapsing (>1 episode) vs persistent (>3 months) and by coexisting psoriasis vulgaris. (navarini2017europeanconsensusstatement pages 1-4, fujita2022diagnosisofgeneralized pages 1-2)
• Japanese Dermatological Association (JDA) diagnostic criteria: require systemic symptoms (e.g., fever/fatigue), extensive erythema with multiple sterile pustules (may form lakes of pus), histopathology showing neutrophilic subcorneal pustules (Kogoj spongiform pustules), and recurrence. (puig2023generalizedpustularpsoriasis pages 6-6)

10.2 Laboratory and pathology findings

• Suggested evaluation includes CBC with differential (leukocytosis/neutrophilia), CRP/ESR, albumin, electrolytes (including calcium), and organ function tests to evaluate systemic inflammation and complications. (puig2023generalizedpustularpsoriasis pages 6-6, ly2019diagnosisandscreening pages 2-3)
• Histopathology often shows Kogoj spongiform pustules and psoriasis features including Munro microabscesses. (ly2019diagnosisandscreening pages 2-3)

10.3 Differential diagnosis

Key differential includes acute generalized exanthematous pustulosis (AGEP), which can mimic GPP; differentiation relies on clinical course (shorter, nonrecurrent), drug exposure history, lack of psoriasis history, and histopathologic clues (e.g., eosinophilia/necrotic keratinocytes in AGEP). (ly2019diagnosisandscreening pages 2-3, bachelez2020pustularpsoriasisthe pages 3-4)

10.4 Clinical outcome measures

GPP-specific measures developed to address limitations of PASI/PGA include: - GPPGA (Generalized Pustular Psoriasis Physician Global Assessment) - GPPASI (Generalized Pustular Psoriasis Area and Severity Index) (burden2022clinicaldiseasemeasures pages 1-3)

10.5 Genetic testing strategy (knowledge-base oriented)

For pustular psoriasis phenotypes consistent with PSORS14/GPP/ACH, consider targeted sequencing/panels including IL36RN, AP1S3, CARD14 (and expanded panels as clinically appropriate) to support subtype definition and potential targeted therapy decisions. (ly2019diagnosisandscreening pages 2-3, akiyama2022pustularpsoriasisas pages 1-2)

11. Outcomes / prognosis

• Severe GPP flares can lead to sepsis and organ failure; reported mortality attributable to GPP/treatment ranges 2–16% across studies summarized in a 2022 review, with substantial hospitalization rates. (choon2022clinicalcourseand pages 4-6)

12. Treatment

12.1 Current applications and real-world implementation (2023–2024 priority)

IL-36 receptor inhibitors (targeted therapy; major 2022–2024 advance)

Spesolimab (anti–IL-36R) - Regulatory status: US FDA approval September 2022 for adult GPP flares (reviewed in 2024). (gwillim2024spesolimabforgeneralized pages 1-2) - Acute flare RCT (Effisayil 1; NCT03782792): at week 1, pustulation clearance (GPPGA pustulation subscore 0) in 19/35 (54%) spesolimab vs 1/18 (6%) placebo (P<0.001); GPPGA total 0/1 in 15/35 (43%) vs 2/18 (11%) (P=0.02). (gwillim2024spesolimabforgeneralized pages 1-2) - Safety signal (acute): week-1 infections 6/35 (17%) spesolimab vs 1/18 (6%) placebo. (gwillim2024spesolimabforgeneralized pages 1-2) - Flare prevention trial (Effisayil 2; NCT04399837): a 2024 systematic review summary reports by week 48 flare rates of 10% (high-dose) vs 52% placebo, with HR 0.16 (time to first flare) in high-dose vs placebo. (puig2024currenttreatmentsfor pages 19-21)

Imsidolimab (ANB019; anti–IL-36R) - Phase 2 open-label regimen (NCT03619902): 750 mg IV day 1 followed by 100 mg SC on days 29/57/85; primary endpoints included CGI response at weeks 4 and 16 and percent change in pustular erythema BSA. (NCT03619902 chunk 1) - Phase 3 RCT record (NCT05352893): randomized, double-blind, placebo-controlled with IV 750 mg and 300 mg arms; primary endpoint is GPPPGA clear/almost clear at week 4. (NCT05352893 chunk 1)

Expert interpretation (authoritative synthesis) A 2024 review emphasizes that abnormal IL-36 signaling has a central role in GPP and that spesolimab provides “rapid and sustained clinical improvement,” reflecting a shift from off-label plaque-psoriasis paradigms toward disease-specific targeted therapy. (gwillim2024spesolimabforgeneralized pages 1-2)

12.2 Conventional systemic options (context)

Before IL-36R inhibitors, commonly used systemic therapies for GPP included retinoids, cyclosporine, and methotrexate, largely supported by case reports/small studies rather than robust RCT evidence. (bernardo2024spesolimabforthe pages 2-3)

12.3 MAXO term suggestions

• Anti–IL-36 receptor monoclonal antibody therapy: MAXO:0000000 (placeholder; requires ontology lookup outside current tool context)
• Systemic retinoid therapy; calcineurin inhibitor therapy; antimetabolite therapy (methotrexate) (MAXO terms not resolvable from provided tool context).

13. Prevention

Primary prevention is not established for Mendelian pustular psoriasis phenotypes; practical prevention focuses on avoiding known triggers (e.g., systemic corticosteroid withdrawal, implicated medications) and flare prevention using maintenance strategies such as subcutaneous spesolimab protocols studied in Effisayil 2. (choon2022clinicalcourseand pages 2-3, puig2024currenttreatmentsfor pages 19-21)

14. Other species / natural disease

No other-species naturally occurring PSORS14/AP1S3-driven pustular psoriasis evidence was retrieved in this run.

15. Model organisms and experimental models

15.1 In vitro / cellular models (direct evidence)

• Human keratinocyte models (HaCaT/HEK293; patient-derived keratinocytes) demonstrate AP1S3-dependent defects in TLR3 trafficking and autophagy, supporting a keratinocyte-autonomous disease mechanism. (settakaffetzi2014ap1s3mutationsare pages 4-6, mahil2016ap1s3mutationscause pages 6-10)

15.2 Suggested in vivo model directions (not directly retrieved)

No mouse genetic model for AP1S3-driven pustular psoriasis was identified in retrieved evidence. Mechanistic plausibility suggests keratinocyte-specific autophagy pathway perturbation models may recapitulate aspects of inflammation, but explicit AP1S3 animal models require additional retrieval.

Recent developments (2023–2024 highlights)

1) Genetics consolidation and therapeutic implications: 2023 genetics review emphasizes IL36RN’s causal role (autosomal recessive biallelic disease) and the expanding gene list (including AP1S3, MPO, SERPIN genes), framing IL-36 axis targeting as mechanism-driven therapy. (yang2023geneticsofgeneralized pages 2-3) 2) Targeted IL-36R blockade becomes standard of care for flares: 2024 review summarizes that spesolimab was FDA-approved in Sept 2022 and provides RCT-level efficacy with rapid pustule clearance; flare-prevention studies (Effisayil 2) extend the paradigm toward chronic disease control. (gwillim2024spesolimabforgeneralized pages 1-2, puig2024currenttreatmentsfor pages 19-21) 3) Clinical practice evolution: newer trials and systematic reviews note improved standardization using GPP-specific endpoints (GPPGA/GPPASI), addressing prior limitations of psoriasis-vulgaris instruments. (burden2022clinicaldiseasemeasures pages 1-3, gwillim2024spesolimabforgeneralized pages 1-2)

Evidence table (quick reference)

The following table consolidates identifiers, key genes/variants, and IL-36R inhibitor trial outcomes.

Table: This table condenses the main identifiers, gene-level evidence, and IL-36 receptor inhibitor trial results relevant to psoriasis 14, pustular and the broader pustular psoriasis/GPP spectrum. It is useful as a quick-reference scaffold for nomenclature, genetics, mechanism, and therapy evidence.

Key abstract-supported quotes (for knowledge-base evidence items)

• IL-36 axis therapeutic concept: “Abnormal signaling of the interleukin-36 (IL-36) pathway appears to have a central role in GPP immunopathology, and provides a rational therapeutic target.” (Frontiers in Immunology review; 2024-07; https://doi.org/10.3389/fimmu.2024.1359481) (gwillim2024spesolimabforgeneralized pages 1-2)
• GPP flare prevention trial intent: “The aim of the Effisayil™ 2 study is to see whether long-term treatment with the antibody spesolimab helps prevent skin flares…” (Dermatology and Therapy; 2023-11; https://doi.org/10.1007/s13555-022-00835-6) (vilaca2024newandemerging pages 11-12)
• AP1S3 pathogenic mechanism (study title as mechanistic claim anchor): “AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36 Production” (J Invest Dermatol; 2016-11; https://doi.org/10.1016/j.jid.2016.06.618) (mahil2016ap1s3mutationscause pages 1-6)

Limitations of the current report (due to retrieval constraints)

• OMIM/Orphanet/ICD/MeSH identifiers for “Psoriasis 14, pustular” were not present in the retrieved full-text excerpts, so they are not provided.
• MAXO/HPO/GO/CL/UBERON codes were suggested where appropriate but not validated via ontology lookup tools in this run.
• Some trial outcomes for imsidolimab Phase 3 are summarized via secondary review sources; full primary publication text for Br J Dermatol 2023 was not available in the retrieved corpus for direct quotation.

References

1. (akiyama2022pustularpsoriasisas pages 1-2): Masashi Akiyama. Pustular psoriasis as an autoinflammatory keratinization disease (aikd): genetic predisposing factors and promising therapeutic targets. Journal of Dermatological Science, 105:11-17, Jan 2022. URL: https://doi.org/10.1016/j.jdermsci.2021.11.009, doi:10.1016/j.jdermsci.2021.11.009. This article has 38 citations and is from a peer-reviewed journal.

2. (gwillim2024spesolimabforgeneralized pages 1-2): Eran C. Gwillim and Anna J. Nichols. Spesolimab for generalized pustular psoriasis: a review of two key clinical trials supporting initial us regulatory approval. Frontiers in Immunology, Jul 2024. URL: https://doi.org/10.3389/fimmu.2024.1359481, doi:10.3389/fimmu.2024.1359481. This article has 15 citations and is from a peer-reviewed journal.

3. (OpenTargets Search: pustular psoriasis): Open Targets Query (pustular psoriasis, 31 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

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5. (choon2022clinicalcourseand pages 4-6): Siew Eng Choon, Alexander A. Navarini, and Andreas Pinter. Clinical course and characteristics of generalized pustular psoriasis. American Journal of Clinical Dermatology, 23:21-29, Jan 2022. URL: https://doi.org/10.1007/s40257-021-00654-z, doi:10.1007/s40257-021-00654-z. This article has 183 citations and is from a peer-reviewed journal.

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13. (akiyama2022pustularpsoriasisas pages 2-3): Masashi Akiyama. Pustular psoriasis as an autoinflammatory keratinization disease (aikd): genetic predisposing factors and promising therapeutic targets. Journal of Dermatological Science, 105:11-17, Jan 2022. URL: https://doi.org/10.1016/j.jdermsci.2021.11.009, doi:10.1016/j.jdermsci.2021.11.009. This article has 38 citations and is from a peer-reviewed journal.

14. (choon2022clinicalcourseand pages 3-4): Siew Eng Choon, Alexander A. Navarini, and Andreas Pinter. Clinical course and characteristics of generalized pustular psoriasis. American Journal of Clinical Dermatology, 23:21-29, Jan 2022. URL: https://doi.org/10.1007/s40257-021-00654-z, doi:10.1007/s40257-021-00654-z. This article has 183 citations and is from a peer-reviewed journal.

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19. (settakaffetzi2014ap1s3mutationsare media 0828eba0): Niovi Setta-Kaffetzi, Michael A. Simpson, Alexander A. Navarini, Varsha M. Patel, Hui-Chun Lu, Michael H. Allen, Michael Duckworth, Hervé Bachelez, A. David Burden, Siew-Eng Choon, Christopher E.M. Griffiths, Brian Kirby, Antonios Kolios, Marieke M.B. Seyger, Christa Prins, Asma Smahi, Richard C. Trembath, Franca Fraternali, Catherine H. Smith, Jonathan N. Barker, and Francesca Capon. Ap1s3 mutations are associated with pustular psoriasis and impaired toll-like receptor 3 trafficking. American journal of human genetics, 94 5:790-7, May 2014. URL: https://doi.org/10.1016/j.ajhg.2014.04.005, doi:10.1016/j.ajhg.2014.04.005. This article has 241 citations and is from a highest quality peer-reviewed journal.

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22. (mahil2016ap1s3mutationscause pages 1-6): Satveer K. Mahil, Sophie Twelves, Katalin Farkas, Niovi Setta-Kaffetzi, A. David Burden, Joanna E. Gach, Alan D. Irvine, László Képíró, Maja Mockenhaupt, Hazel H. Oon, Jason Pinner, Annamari Ranki, Marieke M.B. Seyger, Pere Soler-Palacin, Eoin R. Storan, Eugene S. Tan, Laurence Valeyrie-Allanore, Helen S. Young, Richard C. Trembath, Siew-Eng Choon, Marta Szell, Zsuzsanna Bata-Csorgo, Catherine H. Smith, Paola Di Meglio, Jonathan N. Barker, and Francesca Capon. Ap1s3 mutations cause skin autoinflammation by disrupting keratinocyte autophagy and up-regulating il-36 production. The Journal of Investigative Dermatology, 136:2251-2259, Nov 2016. URL: https://doi.org/10.1016/j.jid.2016.06.618, doi:10.1016/j.jid.2016.06.618. This article has 184 citations.

23. (fujita2022diagnosisofgeneralized pages 1-2): Hideki Fujita, Melinda Gooderham, and Ricardo Romiti. Diagnosis of generalized pustular psoriasis. American Journal of Clinical Dermatology, 23:31-38, Jan 2022. URL: https://doi.org/10.1007/s40257-021-00652-1, doi:10.1007/s40257-021-00652-1. This article has 89 citations and is from a peer-reviewed journal.

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26. (burden2022clinicaldiseasemeasures pages 1-3): A. David Burden, Siew Eng Choon, Alice B. Gottlieb, Alexander A. Navarini, and Richard B. Warren. Clinical disease measures in generalized pustular psoriasis. American Journal of Clinical Dermatology, 23:39-50, Jan 2022. URL: https://doi.org/10.1007/s40257-021-00653-0, doi:10.1007/s40257-021-00653-0. This article has 64 citations and is from a peer-reviewed journal.

27. (puig2024currenttreatmentsfor pages 19-21): Lluís Puig, Hideki Fujita, Diamant Thaçi, Min Zheng, Ana Cristina Hernandez Daly, Craig Leonardi, Mark G. Lebwohl, and Jonathan Barker. Current treatments for generalized pustular psoriasis: a narrative summary of a systematic literature search. Dermatology and Therapy, 14:2331-2378, Aug 2024. URL: https://doi.org/10.1007/s13555-024-01230-z, doi:10.1007/s13555-024-01230-z. This article has 14 citations.

28. (NCT03619902 chunk 1): A Study to Evaluate the Efficacy and Safety of Imsidolimab (ANB019) in Adults With Generalized Pustular Psoriasis. Vanda Pharmaceuticals. 2019. ClinicalTrials.gov Identifier: NCT03619902

29. (NCT05352893 chunk 1): Study to Evaluate the Efficacy and Safety of Imsidolimab (ANB019) in the Treatment of Subjects With GPP. Vanda Pharmaceuticals. 2022. ClinicalTrials.gov Identifier: NCT05352893

30. (bernardo2024spesolimabforthe pages 2-3): Diana Bernardo, Diamant Thaçi, and Tiago Torres. Spesolimab for the treatment of generalized pustular psoriasis. Drugs, 84:45-58, Dec 2023. URL: https://doi.org/10.1007/s40265-023-01988-0, doi:10.1007/s40265-023-01988-0. This article has 44 citations and is from a domain leading peer-reviewed journal.

31. (yang2023geneticsofgeneralized pages 1-2): Syuan-Fei Yang, Min-Huei Lin, Pei-Chen Chou, Sheng-Kai Hu, Sin-Yi Shih, Hsin-Su Yu, and Sebastian Yu. Genetics of generalized pustular psoriasis: current understanding and implications for future therapeutics. Genes, 14:1297, Jun 2023. URL: https://doi.org/10.3390/genes14061297, doi:10.3390/genes14061297. This article has 31 citations.

32. (settakaffetzi2014ap1s3mutationsare pages 1-2): Niovi Setta-Kaffetzi, Michael A. Simpson, Alexander A. Navarini, Varsha M. Patel, Hui-Chun Lu, Michael H. Allen, Michael Duckworth, Hervé Bachelez, A. David Burden, Siew-Eng Choon, Christopher E.M. Griffiths, Brian Kirby, Antonios Kolios, Marieke M.B. Seyger, Christa Prins, Asma Smahi, Richard C. Trembath, Franca Fraternali, Catherine H. Smith, Jonathan N. Barker, and Francesca Capon. Ap1s3 mutations are associated with pustular psoriasis and impaired toll-like receptor 3 trafficking. American journal of human genetics, 94 5:790-7, May 2014. URL: https://doi.org/10.1016/j.ajhg.2014.04.005, doi:10.1016/j.ajhg.2014.04.005. This article has 241 citations and is from a highest quality peer-reviewed journal.

33. (akiyama2022pustularpsoriasisas pages 3-4): Masashi Akiyama. Pustular psoriasis as an autoinflammatory keratinization disease (aikd): genetic predisposing factors and promising therapeutic targets. Journal of Dermatological Science, 105:11-17, Jan 2022. URL: https://doi.org/10.1016/j.jdermsci.2021.11.009, doi:10.1016/j.jdermsci.2021.11.009. This article has 38 citations and is from a peer-reviewed journal.

34. (vilaca2024newandemerging pages 5-6): João Vilaça, Orhan Yilmaz, and Tiago Torres. New and emerging treatments for generalized pustular psoriasis: focus on il-36 receptor inhibitors. Pharmaceutics, 16:908, Jul 2024. URL: https://doi.org/10.3390/pharmaceutics16070908, doi:10.3390/pharmaceutics16070908. This article has 12 citations.

35. (NCT04399837 chunk 1): A Study to Test Whether BI 655130 (Spesolimab) Prevents Flare-ups in Patients With Generalized Pustular Psoriasis. Boehringer Ingelheim. 2020. ClinicalTrials.gov Identifier: NCT04399837

36. (alzahrani2026theefficacyand pages 3-4): Dhaii Alzahrani, Afnan Hasanain, Renad Alharthy, Yara Aljefri, Yara Alghamdi, Renad Alshaikh, Almaha Alhijab, Faris Neazy, Abdulmajeed Alosaimi, Badr Felemban, Reshale Johar, and Roaa E. Morya. The efficacy and safety of spesolimab in patients with generalized pustular psoriasis flares: a systematic review and meta-analysis. Frontiers in Medicine, Jan 2026. URL: https://doi.org/10.3389/fmed.2025.1749320, doi:10.3389/fmed.2025.1749320. This article has 0 citations.

37. (bernardo2024spesolimabforthe pages 13-14): Diana Bernardo, Diamant Thaçi, and Tiago Torres. Spesolimab for the treatment of generalized pustular psoriasis. Drugs, 84:45-58, Dec 2023. URL: https://doi.org/10.1007/s40265-023-01988-0, doi:10.1007/s40265-023-01988-0. This article has 44 citations and is from a domain leading peer-reviewed journal.

38. (vilaca2024newandemerging pages 11-12): João Vilaça, Orhan Yilmaz, and Tiago Torres. New and emerging treatments for generalized pustular psoriasis: focus on il-36 receptor inhibitors. Pharmaceutics, 16:908, Jul 2024. URL: https://doi.org/10.3390/pharmaceutics16070908, doi:10.3390/pharmaceutics16070908. This article has 12 citations.

39. (vilaca2024newandemerging pages 8-9): João Vilaça, Orhan Yilmaz, and Tiago Torres. New and emerging treatments for generalized pustular psoriasis: focus on il-36 receptor inhibitors. Pharmaceutics, 16:908, Jul 2024. URL: https://doi.org/10.3390/pharmaceutics16070908, doi:10.3390/pharmaceutics16070908. This article has 12 citations.

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