Generalized pustular psoriasis

Summary

Generalized pustular psoriasis (MONDO:0100491) is a disease with 2 cohort genes and 25 clinical trials. Top therapeutic interventions include spesolimab, adalimumab, and ixekizumab.

At a glance

• Prevalence: 1-9 / 1 000 000 (France) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 188
• Phenotypes (HPO): 27
• Clinical trials: 25

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.18	France	Validated
Point prevalence	1-9 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0002829	Arthralgia	Obligate (100%)
HP:0003565	Elevated erythrocyte sedimentation rate	Obligate (100%)
HP:0025474	Erythematous plaque	Obligate (100%)
HP:0200039	Pustule	Obligate (100%)
HP:0001019	Erythroderma	Very frequent (80-99%)
HP:0001597	Abnormality of the nail	Very frequent (80-99%)
HP:0012531	Pain	Very frequent (80-99%)
HP:0001369	Arthritis	Frequent (30-79%)
HP:0001945	Fever	Frequent (30-79%)
HP:0001974	Leukocytosis	Frequent (30-79%)
HP:0011227	Elevated circulating C-reactive protein concentration	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0025252	Geographic tongue	Frequent (30-79%)
HP:0025502	Overweight	Frequent (30-79%)
HP:0100825	Cheilitis	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0001513	Obesity	Occasional (5-29%)
HP:0001888	Lymphopenia	Occasional (5-29%)
HP:0002901	Hypocalcemia	Occasional (5-29%)
HP:0002902	Hyponatremia	Occasional (5-29%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Occasional (5-29%)
HP:0003073	Hypoalbuminemia	Occasional (5-29%)
HP:0010741	Pedal edema	Occasional (5-29%)
HP:0100847	Palmoplantar pustulosis	Occasional (5-29%)
HP:0000554	Uveitis	Very rare (<1-4%)
HP:0001635	Congestive heart failure	Very rare (<1-4%)
HP:0100806	Sepsis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	generalized pustular psoriasis
Mondo ID	MONDO:0100491
Orphanet	247353
ICD-10-CM	L40.1
SNOMED CT	238612002
UMLS	C0343055
MedGen	473074
GARD	0026245
Is cancer (heuristic)	no

Data availability: 188 ClinVar variants · 6 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › dermatitis › psoriasis › pustular psoriasis › generalized pustular psoriasis

Related subtypes (1): palmoplantar pustulosis

Subtypes (1): psoriasis 14, pustular

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

188 retrieved; paginated sample, class counts are floors:

82 uncertain significance, 59 likely benign, 20 conflicting classifications of pathogenicity, 12 benign, 8 pathogenic, 4 likely pathogenic, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071715	NC_000002.11:g.(?113816996)(113820274_?)del	IL36RN	Pathogenic	criteria provided, single submitter
1459348	NC_000002.11:g.(?113817016)(113890448_?)del	IL36RN	Pathogenic	criteria provided, single submitter
2183544	NM_012275.3(IL36RN):c.420_426del (p.Gly141fs)	IL36RN	Pathogenic	criteria provided, single submitter
2779032	NM_012275.3(IL36RN):c.184C>T (p.Gln62Ter)	IL36RN	Pathogenic	criteria provided, single submitter
30489	NM_012275.3(IL36RN):c.80T>C (p.Leu27Pro)	IL36RN	Pathogenic	criteria provided, multiple submitters, no conflicts
3640207	NM_012275.3(IL36RN):c.16del (p.Ala6fs)	IL36RN	Pathogenic	criteria provided, single submitter
3725838	NM_012275.3(IL36RN):c.273del (p.Ala92fs)	IL36RN	Pathogenic	criteria provided, single submitter
40005	NM_012275.3(IL36RN):c.115+6T>C	IL36RN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4747025	NM_012275.3(IL36RN):c.41C>A (p.Ser14Ter)	IL36RN	Pathogenic	criteria provided, single submitter
832164	NC_000002.12:g.(?113060832)(113116890_?)del	IL1F10	Likely pathogenic	criteria provided, single submitter
1066220	NM_012275.3(IL36RN):c.29+1G>A	IL36RN	Likely pathogenic	criteria provided, single submitter
2000447	NM_012275.3(IL36RN):c.30-2A>G	IL36RN	Likely pathogenic	criteria provided, single submitter
2712028	NM_012275.3(IL36RN):c.30-1G>T	IL36RN	Likely pathogenic	criteria provided, single submitter
1592833	NM_012275.3(IL36RN):c.381C>T (p.Ala127=)	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30490	NM_012275.3(IL36RN):c.338C>T (p.Ser113Leu)	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330780	NM_012275.3(IL36RN):c.363G>A (p.Leu121=)	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330783	NM_012275.3(IL36RN):c.*222T>C	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330784	NM_012275.3(IL36RN):c.*276A>G	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330787	NM_012275.3(IL36RN):c.*326C>A	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330789	NM_012275.3(IL36RN):c.*401A>T	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330790	NM_012275.3(IL36RN):c.*418A>G	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330792	NM_012275.3(IL36RN):c.*560C>G	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
40007	NM_012275.3(IL36RN):c.28C>T (p.Arg10Ter)	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
493284	NM_012275.3(IL36RN):c.169G>A (p.Val57Ile)	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
529886	NM_012275.3(IL36RN):c.436A>G (p.Ile146Val)	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
529889	NM_012275.3(IL36RN):c.6C>T (p.Val2=)	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
575254	NM_012275.3(IL36RN):c.227C>T (p.Pro76Leu)	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
662407	NM_012275.3(IL36RN):c.368C>T (p.Thr123Met)	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
728172	NM_012275.3(IL36RN):c.244-6C>T	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
732231	NM_012275.3(IL36RN):c.245C>T (p.Pro82Leu)	IL36RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IL36RN	Orphanet:163927	Pustulosis palmaris et plantaris
IL36RN	Orphanet:163931	Acrodermatitis continua of Hallopeau
IL36RN	Orphanet:247353	Generalized pustular psoriasis
IL36RN	Orphanet:404546	DITRA

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IL1F10	HGNC:15552	ENSG00000136697	Q8WWZ1	Interleukin-1 family member 10	clinvar
IL36RN	HGNC:15561	ENSG00000136695	Q9UBH0	Interleukin-36 receptor antagonist protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IL1F10	Interleukin-1 family member 10	Cytokine with immunomodulatory activity.
IL36RN	Interleukin-36 receptor antagonist protein	Inhibits the activity of interleukin-36 (IL36A,IL36B and IL36G) by binding to receptor IL1RL2 and preventing its association with the coreceptor IL1RAP for signaling.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IL1F10	Other/Unknown	no		IL-1_fam, IL-1RA/IL-36, IL1/FGF
IL36RN	Other/Unknown	no		IL-1_fam, IL-1RA/IL-36, IL1/FGF

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skin of abdomen	1
skin of leg	1
zone of skin	1
amniotic fluid	1
gingiva	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IL1F10	32		yes	skin of leg, zone of skin, skin of abdomen
IL36RN	106	tissue_specific	yes	amniotic fluid, upper arm skin, gingiva

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IL36RN	1,137
IL1F10	777

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IL36RN	Q9UBH0	3
IL1F10	Q8WWZ1	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interleukin-36 pathway	2	1631.4×	6e-07	IL1F10, IL36RN
Interleukin-38 signaling	1	1427.5×	7e-04	IL1F10

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cellular response to lipopolysaccharide	2	98.0×	0.001	IL1F10, IL36RN
antifungal humoral response	1	1685.2×	0.002	IL36RN
immune response	2	47.1×	0.002	IL1F10, IL36RN
inflammatory response	2	37.7×	0.002	IL1F10, IL36RN
negative regulation of cytokine-mediated signaling pathway	1	936.2×	0.002	IL36RN
negative regulation of interleukin-17 production	1	526.6×	0.003	IL36RN
negative regulation of type II interferon production	1	191.5×	0.007	IL36RN
negative regulation of interleukin-6 production	1	175.5×	0.007	IL36RN
cytokine-mediated signaling pathway	1	65.3×	0.017	IL1F10
innate immune response	1	16.8×	0.059	IL36RN

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IL1F10	0	0
IL36RN	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	IL1F10, IL36RN

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
IL1F10	0	—
IL36RN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 25.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	7
Not specified	7
PHASE2	6
PHASE4	2
PHASE1	2
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06013969	PHASE4	ACTIVE_NOT_RECRUITING	A Study to Test Whether Spesolimab Helps People With Generalized Pustular Psoriasis (GPP) Who Need Treatment for Repeated Flares
NCT03942042	PHASE4	COMPLETED	A Study of Ixekizumab (LY2439821) in Participants in Japan With Generalized Pustular Psoriasis and Erythrodermic Psoriasis
NCT06295692	PHASE3	ACTIVE_NOT_RECRUITING	A Study of JNJ-77242113 for the Treatment of Participants With Generalized Pustular Psoriasis or Erythrodermic Psoriasis
NCT06323356	PHASE3	ACTIVE_NOT_RECRUITING	A Study of TAK-279 in Adult Participants With Generalized Pustular Psoriasis or Erythrodermic Psoriasis
NCT06477536	PHASE2/PHASE3	RECRUITING	Long-Term Safety and Efficacy of HB0034 in Subjects With Generalized Pustular Psoriasis
NCT02533375	PHASE3	COMPLETED	Study to Investigate Efficacy and Safety of Adalimumab in Japanese Subjects With Generalized Pustular Psoriasis (GPP)
NCT05200247	PHASE3	COMPLETED	An Expanded Access Trial in Japan to Provide Spesolimab to People With a Flare-up in Generalized Pustular Psoriasis Who Have no Other Treatment Options
NCT05239039	PHASE3	COMPLETED	An Expanded Access Program in China to Provide Spesolimab to People With a Flare-up in Generalized Pustular Psoriasis Who Have no Other Treatment Options
NCT05352893	PHASE3	COMPLETED	Study to Evaluate the Efficacy and Safety of Imsidolimab (ANB019) in the Treatment of Subjects With GPP
NCT05366855	PHASE3	TERMINATED	Study to Evaluate the Long-Term Safety and Efficacy of Imsidolimab (ANB019) in the Treatment of Subjects With GPP
NCT03886246	PHASE2	ACTIVE_NOT_RECRUITING	Effisayil™ ON: A Study to Test Long-term Treatment With Spesolimab in People With Generalized Pustular Psoriasis Who Took Part in a Previous Study
NCT06231381	PHASE2	RECRUITING	Efficacy and Safety of HB0034 in Patients with Generalized Pustular Psoriasis (GPP)
NCT07314060	PHASE2	RECRUITING	A Clinical Trial of TQH2929 Injection in Patients With Acute Flare-up of Generalized Pustular Psoriasis
NCT03619902	PHASE2	COMPLETED	A Study to Evaluate the Efficacy and Safety of Imsidolimab (ANB019) in Adults With Generalized Pustular Psoriasis
NCT03782792	PHASE2	COMPLETED	Effisayil™ 1: A Study to Test Spesolimab (BI 655130) in Patients With a Flare-up of a Skin Disease Called Generalized Pustular Psoriasis
NCT04399837	PHASE2	COMPLETED	A Study to Test Whether BI 655130 (Spesolimab) Prevents Flare-ups in Patients With Generalized Pustular Psoriasis
NCT06433531	PHASE1	ACTIVE_NOT_RECRUITING	A Clinical Study of TQH2929 Injection in Treatment With Generalized Pustular Psoriasis (GPP)
NCT05512598	PHASE1	COMPLETED	HB0034 in Patients With Generalized Pustular Psoriasis (GPP)
NCT06100991	Not specified	RECRUITING	CorEvitas Generalized Pustular Psoriasis (GPP) Drug Safety and Effectiveness Registry
NCT07448428	Not specified	NOT_YET_RECRUITING	Generalized Pustular Psoriasis Registry in Costa Rica
NCT04566471	Not specified	UNKNOWN	Palmoplantar Pustulosis and Generalized Pustular Psoriasis: A National Population-based Analysis of Prevalence
NCT05670821	Not specified	COMPLETED	PMS of Spesolimab I.V. in GPP Patients With Acute Symptoms
NCT06391996	Not specified	COMPLETED	Biologic Therapy for Generalized Pustular Psoriasis
NCT06886009	Not specified	WITHDRAWN	Spesolimab Post-marketing Surveillance in Korean Patients With Flares With Generalized Pustular Psoriasis
NCT07428915	Not specified	COMPLETED	Evaluating Legit.Health Plus Support for Improving Diagnosis of Generalized Pustular Psoriasis and Other Skin Conditions Among Primary Care Physicians and Dermatologists

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SPESOLIMAB	4	7
ADALIMUMAB	4	1
IXEKIZUMAB	4	1
IMSIDOLIMAB	3	3
ZASOCITINIB	3	1