Pyoderma Gangrenosum

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Classifications

Harrison's Part

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Definitions

3

Delphi consensus diagnostic criteria for ulcerative pyoderma gangrenosum

An international Delphi consensus (RAND/UCLA Appropriateness Method) yielding one major criterion — biopsy of the ulcer edge demonstrating a neutrophilic infiltrate — plus eight minor criteria: exclusion of infection; pathergy; history of inflammatory bowel disease or inflammatory arthritis; history of a papule, pustule, or vesicle ulcerating within 4 days of appearing; peripheral erythema, undermining border, and tenderness at the ulceration site; multiple ulcerations with at least one on an anterior lower leg; cribriform or "wrinkled paper" scars at healed ulcer sites; and decreased ulcer size within 1 month of starting immunosuppressive therapy. The major criterion plus at least 4 minor criteria supports the diagnosis. Scope is explicitly the ULCERATIVE variant; it is not validated for bullous, pustular, or vegetative PG.

DIAGNOSTIC_CRITERIA Ulcerative pyoderma gangrenosum

Major criterion

Biopsy of the ulcer edge demonstrating a neutrophilic infiltrate.

Minimum required: 1

Minor criteria

Four or more of the eight minor criteria are required alongside the major criterion.

Minimum required: 4

Show evidence (2 references)

PMID:29450466 SUPPORT Human Clinical

"8 minor criteria: (1) exclusion of infection; (2) pathergy; (3) history of inflammatory bowel disease or inflammatory arthritis"

Enumerates the leading minor criteria of the validated Delphi definition.

PMID:29450466 SUPPORT Human Clinical

"This Delphi exercise produced 1 major criterion and 8 minor criteria for the diagnosis of ulcerative pyoderma gangrenosum."

Establishes the overall structure of the criteria set.

Su criteria (2004)

The Su et al. (2004) clinicopathologic criteria, the historical predecessor of the Delphi and PARACELSUS instruments and still one of the three rating tools in contemporary use. Curated for completeness alongside the other two. Note the cited abstract is unusually thin — it announces that criteria are proposed without enumerating them — so this entry deliberately does not reproduce a criteria list that cannot be verified from the cached record; the criteria themselves are in the full text.

DIAGNOSTIC_CRITERIA

Show evidence (2 references)

PMID:15533059 SUPPORT Human Clinical

"Herein, we suggest diagnostic criteria and some historical perspectives on the diagnosis of pyoderma gangrenosum."

Establishes this publication as the source of the proposed Su diagnostic criteria set.

PMID:41923959 SUPPORT Human Clinical

"Three scoring tools are available for the diagnosis of pyoderma gangrenosum: PARACELSUS, Su and Delphi."

Confirms Su remains one of the three diagnostic rating tools in current use alongside the two curated above.

PARACELSUS score

A 10-criterion diagnostic score whose criteria initials form the acronym PARACELSUS. Three major criteria: rapidly progressing disease, assessment of relevant differential diagnoses, and a reddish-violaceous wound border (present in 98% of PG patients). Four minor criteria (evident in 61-95% of patients): amelioration by immunosuppressant drugs, characteristically irregular ulcer shape, extreme pain above 4/10 on a visual analogue scale, and localization of the lesion at the site of trauma (pathergy). Three additional criteria (up to 60% of patients): suppurative inflammation on histopathology, undermined wound borders, and an associated systemic disease. Unlike the Delphi criteria it does not require a biopsy, which is useful when biopsy itself risks pathergy.

DIAGNOSTIC_CRITERIA

Major criteria

Rapidly progressing disease; assessment of relevant differential diagnoses; reddish-violaceous wound border.

Minor criteria

Amelioration by immunosuppressant drugs; irregular ulcer shape; extreme pain > 4/10 on a visual analogue scale; localization at a site of trauma.

Additional criteria

Suppurative inflammation on histopathology; undermined wound borders; associated systemic disease.

Show evidence (2 references)

PMID:29388188 SUPPORT Human Clinical

"The three major diagnostic criteria are rapidly progressing disease, assessment of relevant differential diagnoses and a reddish-violaceous wound border (prevalent in 98% of patients with PG)."

Enumerates the three major criteria of the score.

PMID:29388188 SUPPORT Human Clinical

"Minor criteria (evident in 61-95% of patients with PG) include amelioration by immunosuppressant drugs, characteristically irregular shape of ulceration"

Enumerates the minor criteria tier and its prevalence range in PG patients.

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Subtypes

5

Classic ulcerative pyoderma gangrenosum MONDO:0035235

Predominant variant: 62 of 67 patients (93%) in a Japanese multicentre adalimumab cohort had ulcerative PG.

The classic and by far most common variant: a deep, rapidly enlarging, exquisitely painful ulcer with an undermined, irregular, erythematous-violaceous border, most often on the lower leg, healing with a cribriform ("wrinkled paper") scar. This is the variant for which the Delphi consensus diagnostic criteria and the PARACELSUS score were developed and validated. MONDO:0035235 carries "Ulcerative pyoderma gangrenosum" as an exact synonym, which is why this subtype is named Ulcerative here.

Show evidence (1 reference)

PMID:42107018 SUPPORT Human Clinical

"The PG subtypes among the enrolled patients were ulcerative (n = 62), pustular (n = 2), vegetative (n = 2), and bullous (n = 1)."

Quantifies the ulcerative variant as overwhelmingly predominant (62 of 67) in a prospective multicentre PG cohort.

Bullous (atypical) pyoderma gangrenosum MONDO:0035237

An atypical, more superficial variant presenting with rapidly extending hemorrhagic bullae, and characteristically associated with myeloproliferative and other hematologic disorders — so its recognition should prompt hematologic evaluation.

Pustular pyoderma gangrenosum MONDO:0035236

A variant in which discrete painful sterile pustules arise and may remain pustular without progressing to frank ulceration; classically described in the setting of active inflammatory bowel disease.

Vegetative (superficial granulomatous) pyoderma gangrenosum MONDO:0035238

Uncommon: 2 of 67 patients (3%) in a Japanese multicentre adalimumab cohort.

A localized, superficial and more indolent variant, recognized both by MONDO as a distinct child concept and in clinical cohorts alongside the ulcerative, bullous and pustular forms, where it is uncommon (2 of 67 patients in a prospective multicentre series). Its milder course has a measured mechanistic correlate: myeloperoxidase, IL-8 and MMP-9 are expressed significantly less in vegetative PG than in the ulcerative and bullous variants, i.e. less neutrophil-effector and MMP-mediated matrix destruction.

Show evidence (1 reference)

PMID:42107018 SUPPORT Human Clinical

"The PG subtypes among the enrolled patients were ulcerative (n = 62), pustular (n = 2), vegetative (n = 2), and bullous (n = 1)."

Documents and quantifies the vegetative variant as a recognized but uncommon clinical form in a prospective PG cohort.

Peristomal pyoderma gangrenosum

PG arising in the skin immediately surrounding an abdominal stoma, predominantly in patients with inflammatory bowel disease who have had an ostomy. Chronic mechanical irritation from the appliance is a plausible pathergic trigger, and appliance-related risk factors (pouch belt use, higher BMI) are associated with its development.

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Mechanistic Hypotheses

3

Autoinflammatory inflammasome/IL-1-driven neutrophil recruitment

autoinflammatory_neutrophil_model CANONICAL

Evidence balance 5 support

Pyoderma gangrenosum is modeled as an autoinflammatory disease of the innate immune system rather than an infection or a classical autoantibody-mediated autoimmune disease. Exaggerated inflammasome activation in genetically predisposed individuals drives interleukin-1 overproduction, which — amplified by a T helper 17/T helper 1-skewed adaptive layer supplying TNF, IL-8, IL-17, IL-23 and IL-36 — recruits and activates neutrophils into the dermis, producing the sterile neutrophil-dominant infiltrate that destroys tissue and yields the characteristic ulcer. Direct protein-array measurement in PG lesional skin supports the framework, but the primary literature is explicit that the exact pathogenesis is not yet fully understood.

Pathograph links

Inflammasome Activation and IL-1 Overproduction -> Th17/Th1-Skewed Cytokine Amplification IL-1 overproduction drives the exaggerated secondary cytokine and chemokine output that amplifies the inflammatory response.

Th17/Th1-Skewed Cytokine Amplification -> Neutrophil Recruitment to the Dermis The amplified cytokine/chemokine milieu (notably IL-8/CXCL8 and TNF) recruits neutrophils into the dermis.

Neutrophil Recruitment to the Dermis -> GSDMD-Dependent NETosis Recruited, activated neutrophils undergo gasdermin D-dependent formation of neutrophil extracellular traps.

Neutrophil Recruitment to the Dermis -> Sterile Neutrophilic Dermal Inflammation and Tissue Destruction Recruited, activated neutrophils accumulate as a dense sterile dermal infiltrate that destroys tissue.

JAK-STAT Pathway Overactivation -> GSDMD-Dependent NETosis DIRECT JAK/STAT overactivation in myeloid cells is associated with enhanced neutrophil extracellular trap formation.

JAK-STAT Pathway Overactivation -> Th17/Th1-Skewed Cytokine Amplification DIRECT JAK/STAT overactivation drives aberrant Th17 and Th17.1 differentiation and IL-17A production.

Complement C5a Generation and C5aR1 Signalling -> GSDMD-Dependent NETosis DIRECT C5a signalling through C5aR1 and ERK induces neutrophil extracellular trap formation, making it the proximal driver of the NETosis effector node.

GSDMD-Dependent NETosis -> Sterile Neutrophilic Dermal Inflammation and Tissue Destruction DIRECT NET release amplifies inflammatory cytokine output and contributes to the sterile neutrophilic tissue destruction that produces the ulcer.

Sterile Neutrophilic Dermal Inflammation and Tissue Destruction -> MMP-Mediated Extracellular Matrix Destruction The neutrophil-rich infiltrate releases matrix metalloproteinases that degrade dermal extracellular matrix.

Sterile Neutrophilic Dermal Inflammation and Tissue Destruction -> Progressive Cutaneous Ulceration with Undermined Violaceous Border Neutrophil-mediated dermal destruction manifests as the rapidly enlarging painful ulcer with an undermined violaceous border.

MMP-Mediated Extracellular Matrix Destruction -> Progressive Cutaneous Ulceration with Undermined Violaceous Border DIRECT MMP-mediated matrix degradation produces the tissue loss that constitutes the ulcer.

Pathergy - Trauma-Induced Lesion Initiation -> Sterile Neutrophilic Dermal Inflammation and Tissue Destruction DIRECT Minor cutaneous trauma locally triggers the neutrophilic inflammatory cascade, initiating or enlarging a lesion at the injured site.

PSTPIP1 Dysfunction (Monogenic PAPA Arm) -> Inflammasome Activation and IL-1 Overproduction DIRECT Hyper-phosphorylated PSTPIP1 alters inflammasome participation, producing IL-1beta overproduction.

Show evidence (5 references)

PMID:24903614 SUPPORT Human Clinical

"Over-expression of cytokines/chemokines and molecules amplifying the inflammatory network supports the view that PG and SS are autoinflammatory diseases."

Direct measurement in PG lesional skin supporting the autoinflammatory classification that this hypothesis group models.

PMID:33033263 SUPPORT Human Clinical

"The cause of PG is not well understood, but PG is generally considered an autoinflammatory disorder."

The authoritative Nature Reviews Disease Primers overview endorses the autoinflammatory framing while stating the cause is not well understood — supporting the model and its hedging simultaneously.

PMID:33033263 SUPPORT Human Clinical

"Studies have focused on the role of T cells, especially at the wound margin; these cells may support the destructive autoinflammatory response by the innate immune system."

Records the adaptive (wound-margin T cell) contribution to an innate-driven process, the interface this hypothesis group models; PARTIAL because the source hedges with "may support".

+ 2 more references

Follicular unit as the putative initiating target

follicular_unit_initiation EMERGING

Evidence balance 1 support

An emerging refinement holds that the pilosebaceous (follicular) unit is the initial target of the inflammatory process in pyoderma gangrenosum, which would explain the frequent follicular-based onset of lesions as papules or pustules that then ulcerate, and the overlap of PG with other follicular neutrophilic diseases (acne, hidradenitis suppurativa) in the PASH/PAPASH spectrum. This is presented in the literature as increasingly recognized rather than established.

Show evidence (1 reference)

PMID:35606650 SUPPORT Human Clinical

"involves a profound dysregulation of components of both innate and adaptive immunity in genetically predisposed individuals, with the follicular unit increasingly recognized as the putative initial target"

Directly states the follicular unit as the putative initial target, with the hedging ("increasingly recognized as the putative") that justifies an EMERGING rather than CANONICAL status.

Infectious etiology (historical, refuted)

infectious_etiology ⚠ DEPRECATED

⚠ Overturned model — shown for reference, not as current mechanism

DisMech records superseded hypotheses explicitly rather than deleting them, so that claims still circulating in reviews, textbooks and older diagnostic criteria can be checked against an assessment. This model is not part of the disease mechanism DisMech asserts.

Citation volume does not decide standing here. A hypothesis may retain more supporting than refuting citations simply because the supporting literature accumulated for decades before the refutation landed; where the two conflict, DisMech follows the more recent and more direct evidence. Supporting citations below are retained for the historical record.

Evidence balance 3 refute

The name "pyoderma gangrenosum" encodes a historical hypothesis that the disease is a pyogenic infection producing gangrene. Both halves are wrong. PG was initially thought to be an infectious disease and was subsequently reclassified as an inflammatory one; the lesion is sterile, culture is negative, exclusion of infection is a formal minor criterion of the validated Delphi definition, and the disease responds to immunosuppression rather than to antibiotics. This hypothesis is curated explicitly, rather than silently omitted, because the misnomer actively misleads — it is why PG ulcers are debrided as though infected, which triggers pathergy.

Show evidence (3 references)

PMID:40034857 REFUTE Human Clinical

"Initially, PG was thought to be an infectious disease and was later corrected to be an inflammatory skin disease."

Directly records that the infectious hypothesis was held historically and has been corrected, refuting it as the current model.

PMID:40034857 REFUTE Human Clinical

"Pyoderma gangrenosum (PG) is characterized by the agonizing necrotizing ulcers with non-infectious neutrophil infiltration."

States the infiltrate is non-infectious, contradicting an infectious etiology.

PMID:29450466 REFUTE Human Clinical

"8 minor criteria: (1) exclusion of infection; (2) pathergy"

Exclusion of infection being a formal diagnostic criterion is incompatible with an infectious etiology.

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Discussions and Knowledge Gaps

5

Should the pyoderma gangrenosum-inflammatory bowel disease association be promoted to a structured comorbidity entry linking this entry to the existing Crohn_Disease and Ulcerative_Colitis entries?

INTERPRETATION OPEN pg_ibd_comorbidity_edge

Inflammatory bowel disease is the single commonest systemic association of pyoderma gangrenosum (20.2% of patients in a UK population-based cohort), and PG appears reciprocally as an extraintestinal manifestation of IBD (1.2% of Crohn disease patients in a population-based study). PG is already curated as a phenotype inside Crohn_Disease.yaml. The Disease class has no comorbidities slot, so the relationship is recorded here rather than inline; a dedicated kb/comorbidities/ entry carrying the directional association and its EHR/cohort statistics is the natural follow-up, and is deliberately left out of scope of this entry's creation PR. The mechanistic content of that future edge is now partly specified. A multi-omics study reports Mendelian-randomization evidence that IBD is a causal risk factor for PG (not merely correlated), identifies six shared genetic loci, and finds a cross-tissue conserved inflammatory module centred on JAK-STAT with JAK2 and STAT3 as hubs — giving the gut-skin axis a candidate molecular substrate and a shared druggable target. That study is entirely computational and says so, so the causal direction is curated here as a computational finding rather than as settled fact; it is the strongest available specification of what a PG-IBD comorbidity entry should assert, and the reason the `JAK-STAT Pathway Overactivation` node exists in this entry.

Show evidence (3 references)

PMID:42123319 SUPPORT Computational

"The results revealed that genetic analysis confirmed IBD as a causal risk factor for PG, precisely identifying six shared genetic loci."

Provides a directional (IBD to PG) causal claim from Mendelian randomization plus shared loci — the substance of the proposed comorbidity edge. PARTIAL/COMPUTATIONAL because the study is in silico throughout.

PMID:22534879 SUPPORT Human Clinical

"Disease associations were present in 110 (33%) participants: IBD, n=67 (20.2%); RA, n=39 (11.8%); and hematological disorders, n=13 (3.9%)."

Quantifies IBD as the commonest systemic association of PG in a population-based cohort.

PMID:11316157 SUPPORT Human Clinical

"Pyoderma gangrenosum was more common in Crohn's (1.2%) with no gender predilection."

Quantifies the reciprocal direction — PG prevalence among IBD patients — supporting a bidirectional comorbidity edge.

How should the boundary between sporadic pyoderma gangrenosum and the monogenic PAPA/PASH/PAPASH spectrum be modeled?

INTERPRETATION OPEN pg_papa_entity_boundary

Attached to

pathophysiology#PSTPIP1 Dysfunction (Monogenic PAPA Arm)

PSTPIP1-driven PAPA syndrome (MONDO:0011462) provides the clean Mendelian demonstration that inflammasome-dependent IL-1beta overproduction can cause pyoderma gangrenosum, and PG is PAPA's cutaneous hallmark. But common sporadic PG is not a Mendelian disease and no causal gene is asserted for it here. This entry therefore curates PSTPIP1 as a mechanism-anchoring MODIFIER-typed gene rather than a causal gene of sporadic PG, and models the monogenic arm as an upstream pathophysiology node feeding the shared IL-1 node. PAPA syndrome itself remains an open curation stub and should be curated as its own Disease entry rather than folded in here; the PASH (PG, acne, suppurative hidradenitis) and PAPASH extensions overlap the existing Hidradenitis_Suppurativa entry and are likewise out of scope.

Show evidence (1 reference)

PMID:21532836 SUPPORT Human Clinical

"is a clear molecular feature of PAPA syndrome"

Supports treating the monogenic arm as a demonstration of the IL-1 mechanism while keeping PAPA a distinct entity.

Why has every late-phase targeted trial in pyoderma gangrenosum failed or been terminated, and what does that imply for how this entry's mechanism nodes should be read?

INTERPRETATION OPEN pg_trial_attrition

Attached to

pathophysiology#Complement C5a Generation and C5aR1 Signalling pathophysiology#Inflammasome Activation and IL-1 Overproduction

The curated trial record is dominated by attrition, and that negative pattern is itself the curated fact rather than an absence of data. Of the nine trials in this entry, five are terminated: all three gevokizumab (anti-IL-1beta) registrations (NCT02315417, NCT02326740, NCT02318914), the vilobelimab (anti-C5a) Phase III NCT05964413 — explicitly stopped for futility — and the spesolimab Phase II NCT06092216, which is the one non-futility termination (the sponsor redirected to a multicentre trial). Only infliximab (placebo-controlled, positive) and STOP GAP (prednisolone versus ciclosporin, no difference) reached informative completion, and adalimumab is approved on an open-label single-arm Phase 3. Three non-exclusive readings are worth holding open. (1) Mechanistic redundancy: the pathograph has multiple parallel neutrophil-recruiting inputs (C5a, IL-8/CXCL8, CXCL1/2/3, IL-36), so blocking any single one may be insufficient — the C5a primary paper anticipates exactly this. (2) Trial-design difficulty: PG had no validated diagnostic criteria until 2018 and still has no validated response criteria, so cohorts may be heterogeneous and endpoints insensitive; the Delphi authors give patient selection for trials as an explicit motivation for their criteria. (3) The mechanism nodes may be correct as descriptions of the inflammatory state while being wrong as rate-limiting therapeutic targets — a node can be genuinely active in disease and still not be the lever. Curation consequence: no targeted agent in this entry may be presented as established therapy on mechanistic grounds alone. The IL-1 blockade and C5a blockade treatments both carry explicit negative qualifiers for this reason.

Show evidence (3 references)

PMID:37516310 SUPPORT In Vitro

"However, C5a blockade alone may not be sufficient to block neutrophil infiltration in PG because other neutrophil chemokines such as IL-8 and CXCL2 are also overexpressed in PG lesional skin."

Supports the mechanistic-redundancy reading of the trial failures, stated by the authors of the C5a mechanism paper itself.

PMID:29450466 SUPPORT Human Clinical

"it is a "diagnosis of exclusion," a definition not compatible with clinical decision making or inclusion for clinical trials"

Supports the trial-design reading: the absence of usable diagnostic criteria was itself recognized as an obstacle to trial recruitment.

PMID:35606650 SUPPORT Human Clinical

"Low-evidence studies and a lack of validated diagnostic and response criteria have hindered the discovery and validation of new effective treatments for pyoderma gangrenosum."

Directly attributes the failure to discover effective PG treatments to low-evidence studies and missing validated criteria.

Is biopsy of the ulcer edge genuinely required for the diagnosis of pyoderma gangrenosum, given that it is the sole major Delphi criterion yet is nonspecific, insensitive, and itself risks pathergy?

KNOWLEDGE GAP OPEN pg_biopsy_diagnostic_utility

Attached to

pathophysiology#Pathergy - Trauma-Induced Lesion Initiation

This entry curates the ulcer-edge neutrophilic infiltrate as `diagnostic: true` histopathology because it is the single MAJOR criterion of the validated Delphi definition. That position is genuinely contested and the tension is recorded here rather than silently resolved in favour of either side. Against it: histological findings in PG are nonspecific, a retrospective cohort found that of 58 patients only 26 (45%) were biopsied and only 10 of those (38%) had a biopsy that contributed to the diagnosis, and the biopsy procedure itself can trigger pathergy — the mechanism this entry models as a causal edge. The PARACELSUS score was deliberately designed not to require biopsy, which is part of its practical appeal. For it: exclusion of infection and of the many mimickers is essential, and 10% of patients treated for PG in a consecutive series turned out to have something else. The open question is not whether tissue is ever useful but whether a mandatory biopsy criterion improves or degrades net diagnostic accuracy once pathergy risk is priced in.

Show evidence (3 references)

PMID:41923959 SUPPORT Human Clinical

"Among 58 patients, 26 (45%) underwent biopsies, with only 10 (38%) contributing to a PG diagnosis."

Quantifies the low diagnostic yield of biopsy in a consecutive PG cohort.

PMID:41923959 SUPPORT Human Clinical

"Given risk of pathergy, nonspecific histopathological findings and low sensitivity, in our opinion, based on this small sample size, biopsies have limited diagnostic value for PG."

States the contrary position directly, including the pathergy risk that makes this a mechanistically loaded question rather than a purely operational one.

PMID:12409543 SUPPORT Human Clinical

"These 64 included 15 of the 157 consecutive patients treated for pyoderma gangrenosum at our institution (10 percent)."

Quantifies the misdiagnosis rate that argues for rigorous exclusion of mimickers, the consideration on the other side of this question.

What is the initiating trigger of sporadic pyoderma gangrenosum, and is there an animal model that reproduces the integrated disease rather than one effector arm?

KNOWLEDGE GAP OPEN pg_pathogenesis_knowledge_gap

Attached to

pathophysiology#Inflammasome Activation and IL-1 Overproduction

Contemporary reviews state explicitly that the exact pathogenesis of pyoderma gangrenosum is not yet fully understood. The upstream trigger of sporadic disease is unknown and the follicular unit is only "increasingly recognized" as a putative initial target. An animal model now exists and is curated here (the PG-serum transfer mouse), but it reproduces the NETosis effector arm rather than the integrated syndrome: ulcers are induced by passive serum transfer, and the model shows neither pathergy, the undermined violaceous border, cribriform scarring, the associated systemic diseases, nor corticosteroid/ciclosporin responsiveness. So the gap is narrower than it was but not closed. Mechanistic understanding otherwise rests on human cohort, tissue and cytokine studies plus extrapolation from the monogenic PAPA arm. The low-evidence base is itself called out in the literature as having hindered discovery and validation of new treatments. The complement C5a/C5aR1 and MMP-2/MMP-9 effector arms previously tracked here as uncurated enrichment targets have since been curated as full nodes from primary sources, so they are no longer gaps. What remains genuinely open is upstream and therapeutic rather than descriptive: what initiates complement activation and inflammasome priming in sporadic PG in the first place, and why a pathograph this well characterized has yielded no successful targeted therapy — see `pg_trial_attrition`.

Show evidence (1 reference)

PMID:35606650 SUPPORT Human Clinical

"Low-evidence studies and a lack of validated diagnostic and response criteria have hindered the discovery and validation of new effective treatments for pyoderma gangrenosum."

Documents the weak evidence base that constitutes this knowledge gap.

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Pathophysiology

11

Inflammasome Activation and IL-1 Overproduction

The proximal molecular lesion in pyoderma gangrenosum is exaggerated, inappropriately triggered activation of the inflammasome in innate immune cells of genetically predisposed individuals, leading to overproduction of interleukin-1 (IL-1beta and IL-1alpha). Protein-array profiling of PG lesional skin shows significantly higher expression of IL-1 beta and its receptor I than in normal skin, and IL-1beta is the pivotal cytokine driving the downstream exaggerated production of cytokines and chemokines that recruit neutrophils. This node is the point at which the monogenic PAPA/PSTPIP1 arm and the far commoner sporadic disease converge, and it is the rationale for IL-1 blockade as therapy.

Autoinflammatory inflammasome/IL-1-driven neutrophil recruitment

Macrophage CL:0000235

Inflammasome-mediated signaling pathway GO:0141084 ↑ INCREASED Interleukin-1 beta production GO:0032611 ↑ INCREASED

Downstream

Th17/Th1-Skewed Cytokine Amplification IL-1 overproduction drives the exaggerated secondary cytokine and chemokine output that amplifies the inflammatory response.

Show evidence (3 references)

PMID:24903614 SUPPORT Human Clinical

"The expressions of interleukin (IL)-1 beta and its receptor I were significantly higher in PG"

Direct measurement of IL-1 beta and IL-1 receptor I overexpression in PG lesional skin versus controls, grounding this node in PG-specific data rather than extrapolation.

PMID:29742056 SUPPORT Human Clinical

"These mutations cause an uncontrolled activation of the inflammasome"

Establishes uncontrolled inflammasome activation as the proximal mechanism in the IL-1-mediated autoinflammatory diseases of which PAPA syndrome (whose cutaneous hallmark is PG) is one.

PMID:29742056 SUPPORT Human Clinical

"is the pivotal cytokine which is responsible for the exaggerated production of cytokines and chemokines that induce the recruitment of neutrophils, key cells in autoinflammation"

Identifies IL-1beta as the pivotal cytokine linking inflammasome activation to the downstream chemokine output and neutrophil recruitment modeled by the next nodes.

Th17/Th1-Skewed Cytokine Amplification

Downstream of IL-1, a T helper 17/T helper 1-skewed adaptive layer amplifies the innate signal, producing high levels of tumor necrosis factor-alpha, IL-1beta, IL-1alpha, IL-8/CXCL8, IL-12, IL-15, IL-17, IL-23 and IL-36. In PG lesional skin specifically, the chemokines IL-8, CXCL1/2/3, CXCL16 and RANTES are over-expressed, and this chemokine signal is stronger than in Sweet syndrome. This profile is the direct rationale for the biologic therapies used in PG — TNF, IL-1, IL-17, IL-23 and complement C5a inhibitors — and it is why pyoderma gangrenosum sits at the interface of innate autoinflammation and adaptive immunity rather than being purely innate.

Autoinflammatory inflammasome/IL-1-driven neutrophil recruitment

T-helper 17 cell CL:0000899 T-helper 1 cell CL:0000545

Positive regulation of inflammatory response GO:0050729 ↑ INCREASED

Downstream

Neutrophil Recruitment to the Dermis The amplified cytokine/chemokine milieu (notably IL-8/CXCL8 and TNF) recruits neutrophils into the dermis.

Show evidence (3 references)

PMID:24903614 SUPPORT Human Clinical

"In PG, chemokines such as IL-8"

Reports over-expression of the neutrophil-recruiting chemokine IL-8 (and CXCL1/2/3, CXCL16, RANTES) in PG lesional skin, the amplification output this node models.

PMID:35606650 SUPPORT Human Clinical

"T helper 17/T helper 1-skewed inflammation and exaggerated inflammasome activation lead to a dysregulated neutrophil-dominant milieu"

Documents the Th17/Th1-skewed amplification layer sitting between inflammasome activation and the neutrophil-dominant effector state.

PMID:37610614 SUPPORT Human Clinical

"an increasing number of studies on the positive effects of biologic therapies such as inhibitors of tumour necrosis factor"

The therapeutic responsiveness to cytokine-directed biologics supports these cytokines being mechanistically operative in the disease.

Neutrophil Recruitment to the Dermis

Driven by the amplified chemokine milieu, neutrophils undergo chemotaxis and migration into the dermis and become activated. Increased neutrophil granulocyte activity is the demonstrated cellular hallmark of the disease and the feature that places pyoderma gangrenosum within the neutrophilic dermatoses.

Autoinflammatory inflammasome/IL-1-driven neutrophil recruitment

Neutrophil CL:0000775

Neutrophil chemotaxis GO:0030593 ↑ INCREASED Neutrophil migration GO:1990266 ↑ INCREASED Neutrophil activation GO:0042119 ↑ INCREASED

Downstream

GSDMD-Dependent NETosis Recruited, activated neutrophils undergo gasdermin D-dependent formation of neutrophil extracellular traps.

Sterile Neutrophilic Dermal Inflammation and Tissue Destruction Recruited, activated neutrophils accumulate as a dense sterile dermal infiltrate that destroys tissue.

Show evidence (1 reference)

PMID:37610614 SUPPORT Human Clinical

"various auto-inflammatory phenomena with increased neutrophil granulocyte activity have been demonstrated"

Documents increased neutrophil granulocyte activity as the demonstrated cellular mechanism.

JAK-STAT Pathway Overactivation

The JAK/STAT pathway is the common downstream transducer for most of the cytokines this entry already models (IL-6, IL-12, IL-23, interferons), and single-cell RNA sequencing with multiplex immunohistochemistry shows it significantly overactivated in PG lesions — particularly in advanced-stage lesions — driven chiefly by myeloid cells and T cells. The activation is associated with enhanced NET formation in myeloid cells and with aberrant Th17 / Th17.1 differentiation and plasticity, so it converges on two nodes already in this pathograph. Independent multi-omics work identifies JAK2 and STAT3 as the network hubs of an inflammatory module conserved between PG skin and IBD gut, which is the molecular candidate for the gut-skin axis behind PG's commonest systemic association. This node is the rationale for JAK inhibition (tofacitinib, baricitinib), which remains investigational.

Autoinflammatory inflammasome/IL-1-driven neutrophil recruitment

Myeloid cell CL:0000763 T-helper 17 cell CL:0000899

JAK-STAT cascade GO:0007259 ↑ INCREASED

Downstream

GSDMD-Dependent NETosis JAK/STAT overactivation in myeloid cells is associated with enhanced neutrophil extracellular trap formation.

Th17/Th1-Skewed Cytokine Amplification JAK/STAT overactivation drives aberrant Th17 and Th17.1 differentiation and IL-17A production.

Show evidence (2 references)

PMID:42603447 SUPPORT Human Clinical

"We identified significant overactivation of the JAK/STAT pathway in PG lesions-particularly in advanced stages-which, in terms of immune inflammation, is primarily driven by myeloid cells and T cells."

Single-cell and multiplex-IHC evidence of JAK/STAT overactivation in human PG lesional tissue, establishing this node in the disease itself.

PMID:42123319 SUPPORT Computational

"Transcriptomic analysis identified a cross-tissue conserved inflammatory module centered on the JAK-STAT pathway, with JAK2 and STAT3 identified as network hubs."

Independent multi-omics support for a JAK-STAT-centred module shared between PG and IBD; graded PARTIAL and COMPUTATIONAL because the study is entirely in silico and states it lacks experimental validation.

Complement C5a Generation and C5aR1 Signalling

Complement activation generates the anaphylatoxin C5a, which signals through its receptor C5aR1 on neutrophils. In pyoderma gangrenosum this is the named proximal driver of NET release: among the candidate inducers expressed in PG (IL-1 beta, IL-6, IL-8 and C5aR1), C5a is the most potent inducer of NETosis, acting dose-dependently within 30 minutes and specifically through C5aR1 and ERK — C5aR blockade with avacopan and ERK inhibition each abolish it. The axis is active in human disease, not only in culture: C5a in PG wound fluid is more than 6-fold higher than in traumatic wound fluid, at concentrations sufficient to induce NETosis, and correlates with neutrophil elastase levels. C5a is also a classical neutrophil chemoattractant, so it plausibly contributes to recruitment as well as to NET release; only the NETosis arm is modeled as a causal edge here.

Autoinflammatory inflammasome/IL-1-driven neutrophil recruitment

Neutrophil CL:0000775

Complement activation GO:0006956 ↑ INCREASED Complement component C5a signaling pathway GO:0038178 ↑ INCREASED

Downstream

GSDMD-Dependent NETosis C5a signalling through C5aR1 and ERK induces neutrophil extracellular trap formation, making it the proximal driver of the NETosis effector node.

Show evidence (2 references)

PMID:37516310 SUPPORT Human Clinical

"The average C5a level in PG wound fluid (8.5 ng/mg, n=32) was more than 6-fold higher (P=0.0001) than the average level of C5a in wound fluid from traumatic wounds (1.3 ng/mg, n=13)"

Human PG wound-fluid measurement showing C5a is markedly elevated in disease versus traumatic-wound controls — the evidence that grounds this node in human disease rather than only in vitro.

PMID:37516310 SUPPORT Human Clinical

"The elastase levels correlated significantly with the C5a levels in PG wound fluid (r=0.5861, P=0.0004)"

Correlation between C5a and neutrophil elastase in PG wound fluid indirectly supports C5a driving NET release in vivo.

GSDMD-Dependent NETosis

Activated neutrophils release neutrophil extracellular traps (NETs) — decondensed chromatin studded with granule proteins — by a process regulated by gasdermin D (GSDMD), whose pores release neutrophil elastase and myeloperoxidase during early NETosis. Serum NET levels (MPO-DNA complexes) are elevated in PG patients versus healthy controls and fall after effective treatment. This is the effector cell-death programme of the neutrophilic arm and the node the only available PG animal model addresses: GSDMD-knockout mice develop significantly less severe ulcers in the PG-serum transfer model. It amplifies the surrounding cytokine milieu, feeding back on the inflammatory response.

Autoinflammatory inflammasome/IL-1-driven neutrophil recruitment

Neutrophil CL:0000775

Neutrophil extracellular trap formation GO:0140645 ↑ INCREASED

Animal models

PG-serum transfer mouse (wild-type and GSDMD-knockout) Mouse perturbs GSDMD knockout removes the regulator of NET formation and attenuates ulceration, directly testing this node's causal contribution.

Downstream

Sterile Neutrophilic Dermal Inflammation and Tissue Destruction NET release amplifies inflammatory cytokine output and contributes to the sterile neutrophilic tissue destruction that produces the ulcer.

Show evidence (3 references)

PMID:40034857 SUPPORT Human Clinical

"we discovered that the serum levels of NETs were elevated in PG patients compared to healthy controls"

Demonstrates elevated NETs in PG patients versus controls, grounding this node in human data rather than only the mouse model.

PMID:40034857 SUPPORT In Vitro

"Neutrophil extracellular traps (NETs) represent one of the mechanisms of neutrophils activation, and gasdermin D (GSDMD) plays a regulatory role in NETs."

Establishes GSDMD as the regulator of NET formation, the molecular basis for naming this node GSDMD-dependent.

PMID:29742056 SUPPORT Human Clinical

"Pyoderma gangrenosum, which is the cutaneous hallmark of the PAPA syndrome, is a prototypic neutrophil-mediated skin disease"

Establishes PG as a prototypic neutrophil-mediated disease, supporting neutrophil recruitment as the central effector step.

Sterile Neutrophilic Dermal Inflammation and Tissue Destruction

A dense, sterile (culture-negative) neutrophilic infiltrate accumulates in the dermis, most conspicuously at the advancing ulcer edge, and destroys dermal tissue. Over-expressed Fas/Fas ligand and CD40/CD40 ligand systems contribute to that tissue damage in PG. The absence of a causative organism is central: the inflammation is aseptic, which is why antibiotics do not resolve the lesion and why exclusion of infection is a formal diagnostic criterion. Biopsy of the ulcer edge demonstrating a neutrophilic infiltrate is the single major criterion in the Delphi consensus definition.

Autoinflammatory inflammasome/IL-1-driven neutrophil recruitment

Neutrophil CL:0000775

Inflammatory response GO:0006954 ↑ INCREASED

Downstream

MMP-Mediated Extracellular Matrix Destruction The neutrophil-rich infiltrate releases matrix metalloproteinases that degrade dermal extracellular matrix.

Progressive Cutaneous Ulceration with Undermined Violaceous Border Neutrophil-mediated dermal destruction manifests as the rapidly enlarging painful ulcer with an undermined violaceous border.

Show evidence (2 references)

PMID:24903614 SUPPORT Human Clinical

"contributing to tissue damage and inflammation"

Attributes tissue damage in PG to the over-expressed Fas/Fas ligand and CD40/CD40 ligand effector systems measured in lesional skin.

PMID:29450466 SUPPORT Human Clinical

"8 minor criteria: (1) exclusion of infection; (2) pathergy; (3) history of inflammatory bowel disease or inflammatory arthritis"

That exclusion of infection is a formal diagnostic criterion establishes the sterile (non-infectious) character of the neutrophilic infiltrate modeled by this node.

MMP-Mediated Extracellular Matrix Destruction

Matrix metalloproteinases released within the neutrophil-rich infiltrate — principally MMP-2 and MMP-9, alongside neutrophil elastase from NETs — degrade dermal extracellular matrix and are the proximate effectors of tissue loss. Immunohistochemistry of PG lesions shows MMP-2 and MMP-9 significantly elevated versus controls. Importantly this arm is subtype-graded rather than uniform: myeloperoxidase, IL-8 and MMP-9 are expressed more strongly in ulcerative and bullous PG than in vegetative PG, which is the mechanistic correlate of vegetative disease being the superficial, indolent, less destructive variant.

Autoinflammatory inflammasome/IL-1-driven neutrophil recruitment

Neutrophil CL:0000775

Extracellular matrix disassembly GO:0022617 ↑ INCREASED

Downstream

Progressive Cutaneous Ulceration with Undermined Violaceous Border MMP-mediated matrix degradation produces the tissue loss that constitutes the ulcer.

Show evidence (2 references)

PMID:20636397 SUPPORT Human Clinical

"Myeloperoxidase (neutrophil marker), IL-8 (cytokine chemotactic for neutrophils) and MMP-9 (proteinase-mediating tissue damage) were expressed more significantly in both ulcerative and bullous PG than in vegetative PG as well as in Sweet's syndrome"

Quantifies the subtype gradient in MMP-9 (and MPO/IL-8) expression — stronger in ulcerative and bullous than vegetative PG — grounding both this node and the vegetative subtype's milder course.

PMID:20636397 SUPPORT Human Clinical

"In ulcerative PG, the wound bed is the site of neutrophil-recruitment, whereas in the wound edge activated T lymphocytes and macrophages pave the way to ulcer formation."

Localizes the effector compartments — neutrophils in the wound bed, T cells and macrophages at the advancing edge — supporting the wound-margin adaptive contribution noted in the canonical hypothesis.

Progressive Cutaneous Ulceration with Undermined Violaceous Border

The converging neutrophilic process manifests clinically as the defining lesion: a painful, rapidly evolving cutaneous ulcer with undermined, irregular, erythematous-violaceous edges and a mucopurulent or hemorrhagic exudate. Rapid progression and a reddish-violaceous wound border are two of the three major criteria of the PARACELSUS diagnostic score, the border being present in 98% of patients. Healing characteristically leaves a cribriform scar, and the disease carries substantially increased mortality.

Animal models

PG-serum transfer mouse (wild-type and GSDMD-knockout) Mouse partially recapitulates Serum transfer produces localized cutaneous ulceration, but only the bare fact of ulcer formation — none of the features that make a PG ulcer diagnostically recognizable.

Show evidence (2 references)

PMID:35606650 SUPPORT Human Clinical

"clinically characterized by painful, rapidly evolving cutaneous ulcers with undermined, irregular, erythematous-violaceous edges"

Documents the clinical output of the pathophysiologic cascade — the painful, rapidly evolving undermined violaceous ulcer.

PMID:29388188 SUPPORT Human Clinical

"The three major diagnostic criteria are rapidly progressing disease, assessment of relevant differential diagnoses and a reddish-violaceous wound border (prevalent in 98% of patients with PG)."

Quantifies the violaceous wound border at 98% of patients and confirms rapid progression as a defining feature of the lesion.

Pathergy - Trauma-Induced Lesion Initiation

Pathergy is the induction of new lesions, or the marked enlargement of existing ones, at sites of minor cutaneous trauma — needle sticks, biopsies, surgical incisions, or chronic mechanical irritation such as an ostomy appliance. Mechanistically it represents a lowered threshold for triggering the neutrophilic inflammatory cascade in already primed skin, so trauma locally initiates the same pathway rather than causing a distinct process. This node is clinically load-bearing rather than merely descriptive: it is why surgical debridement and defect closure can exacerbate the injury, and why postsurgical pyoderma gangrenosum is a recognized entity. Pathergy is a minor criterion in the Delphi consensus definition and appears in the PARACELSUS score as localization of the lesion at a site of trauma.

Autoinflammatory inflammasome/IL-1-driven neutrophil recruitment

Downstream

Sterile Neutrophilic Dermal Inflammation and Tissue Destruction Minor cutaneous trauma locally triggers the neutrophilic inflammatory cascade, initiating or enlarging a lesion at the injured site.

Show evidence (2 references)

PMID:29388188 SUPPORT Human Clinical

"extreme pain > 4/10 on a visual analogue scale and localization of lesion at the site of the trauma"

Records localization of the lesion at the site of trauma (pathergy) as a scored minor diagnostic criterion for PG.

PMID:38250211 SUPPORT Human Clinical

"Thus, it is frequently seen in patients with underlying systemic illnesses or postoperatively."

Supports trauma/surgery as a recognized setting in which PG lesions arise, the clinical expression of pathergy.

PSTPIP1 Dysfunction (Monogenic PAPA Arm)

In PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum, and acne), an autosomal dominant autoinflammatory disease, missense variants in PSTPIP1/CD2BP1 (E250Q, A230T) severely reduce binding of the PSTPIP1 adaptor to PEST-type protein tyrosine phosphatase. The resulting hyper-phosphorylated PSTPIP1 protein alters its participation in inflammasome activation, and overproduction of IL-1beta is a clear molecular feature of the syndrome. This is the clean Mendelian arm that links a defined molecular lesion to the same IL-1/inflammasome node that drives sporadic pyoderma gangrenosum, of which PG is the cutaneous hallmark. Note this node models the mechanistic arm only: PAPA syndrome itself (MONDO:0011462) is a distinct disease entity and is not curated here.

Autoinflammatory inflammasome/IL-1-driven neutrophil recruitment

PSTPIP1 binding to PEST-type protein tyrosine phosphatase GO:0001784 ↓ DECREASED

Downstream

Inflammasome Activation and IL-1 Overproduction Hyper-phosphorylated PSTPIP1 alters inflammasome participation, producing IL-1beta overproduction.

Show evidence (2 references)

PMID:11971877 SUPPORT In Vitro

"Yeast two-hybrid assays demonstrate severely reduced binding between PTP PEST and both the E250Q and A230T mutant proteins."

Documents the molecular consequence of the PAPA-causing PSTPIP1/CD2BP1 variants — loss of PTP PEST binding — in a yeast two-hybrid assay.

PMID:21532836 SUPPORT Human Clinical

"is a clear molecular feature of PAPA syndrome"

Confirms IL-1 overproduction as the established molecular outcome of the monogenic arm, connecting it to the shared IL-1 node.

✶

Histopathology

1

Neutrophilic Infiltrate at the Ulcer Edge

Biopsy of the ulcer edge demonstrating a neutrophilic infiltrate is the single MAJOR criterion in the Delphi consensus diagnostic definition of ulcerative pyoderma gangrenosum. The infiltrate is sterile — cultures are negative and exclusion of infection is a separate minor criterion — which is what distinguishes it histologically and microbiologically from an infective ulcer. Suppurative inflammation on histopathology also features among the PARACELSUS criteria.

Show evidence (2 references)

PMID:29450466 SUPPORT Human Clinical

"This Delphi exercise produced 1 major criterion and 8 minor criteria for the diagnosis of ulcerative pyoderma gangrenosum."

Confirms the single-major-criterion structure whose major criterion is the ulcer-edge neutrophilic infiltrate.

PMID:29388188 SUPPORT Human Clinical

"Three additional criteria (observed in up to 60% of patients with PG) encompass suppurative inflammation in histopathology, undermined wound borders and systemic disease associated."

Documents suppurative (neutrophilic) inflammation on histopathology as a scored diagnostic feature, observed in up to 60% of PG patients.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

9

Immune 1

Sterile pustules HP:0200039

Show evidence (2 references)

PMID:25374597 SUPPORT Human Clinical

"The variants of PG noted were ulcerative (18), bullous (2), vegetative (2), and pustular (1)."

Documents the pustular variant as a recognized clinical form of PG in a consecutive inpatient cohort.

PMID:29450466 SUPPORT Human Clinical

"(4) history of papule, pustule, or vesicle ulcerating within 4 days of appearing"

Supports the pustular precursor lesion as a validated diagnostic feature, though this criterion describes onset in ulcerative PG rather than the pustular variant specifically.

Integument 4

Hemorrhagic bullae Abnormal blistering of the skin HP:0008066

Show evidence (1 reference)

PMID:10773715 SUPPORT Human Clinical

"Bullous pyoderma gangrenosum is an atypical, more superficial variety of the classical pyoderma and is often associated with myeloproliferative disorders."

Characterizes the bullous variant as an atypical, more superficial form associated with myeloproliferative disorders.

Superficial less-destructive vegetative lesion Skin ulcer HP:0200042

Show evidence (2 references)

PMID:20636397 SUPPORT Human Clinical

"Myeloperoxidase (neutrophil marker), IL-8 (cytokine chemotactic for neutrophils) and MMP-9 (proteinase-mediating tissue damage) were expressed more significantly in both ulcerative and bullous PG than in vegetative PG as well as in Sweet's syndrome"

Quantifies reduced neutrophil-effector and MMP-9 expression in vegetative versus ulcerative/bullous PG, the distinguishing feature of this subtype.

PMID:20636397 SUPPORT Human Clinical

"Less commonly, bullous and vegetative variants exist."

Confirms the vegetative variant as a recognized but less common form of PG.

Peristomal ulceration Skin ulcer HP:0200042

Show evidence (2 references)

PMID:32383278 SUPPORT Human Clinical

"Insufficient data exist for peristomal pyoderma gangrenosum (PPG), which primarily affects patients with inflammatory bowel disease (IBD)."

Establishes peristomal PG as a distinct clinical form arising in IBD patients with an ostomy.

PMID:25374597 SUPPORT Human Clinical

"Lesions were localised to lower limb in 13 patients, peristomal region in four, breast in three, and upper limb in one"

Quantifies peristomal localization (4 of 23) alongside the predominant lower-limb site in an inpatient PG cohort.

Lower limb predilection Skin ulcer HP:0200042

Show evidence (2 references)

PMID:25374597 SUPPORT Human Clinical

"Lesions were localised to lower limb in 13 patients, peristomal region in four, breast in three, and upper limb in one"

Documents the lower limb as the commonest site (13 of 23 patients).

PMID:29450466 SUPPORT Human Clinical

"(6) multiple ulcerations, at least 1 on an anterior lower leg"

Confirms anterior lower leg localization as a validated diagnostic criterion.

Musculoskeletal 1

Cribriform scarring HP:0100699

Show evidence (1 reference)

PMID:29450466 SUPPORT Human Clinical

"cribriform or "wrinkled paper" scar(s) at healed ulcer sites"

Documents cribriform scarring at healed ulcer sites as a validated diagnostic criterion.

Constitutional 1

Severe ulcer pain HP:0012531

Severity: SEVERE

Show evidence (1 reference)

PMID:29388188 SUPPORT Human Clinical

"extreme pain > 4/10 on a visual analogue scale"

Documents extreme pain as a scored diagnostic criterion for PG.

Other 2

Painful cutaneous ulcer with undermined violaceous border VERY_FREQUENT Pyoderma gangrenosum HP:0025452

Course: PROGRESSIVE

Show evidence (2 references)

PMID:29388188 SUPPORT Human Clinical

"The three major diagnostic criteria are rapidly progressing disease, assessment of relevant differential diagnoses and a reddish-violaceous wound border (prevalent in 98% of patients with PG)."

Quantifies the reddish-violaceous wound border at 98% of PG patients, supporting both the phenotype and the VERY_FREQUENT band (80-100%).

PMID:35606650 SUPPORT Human Clinical

"clinically characterized by painful, rapidly evolving cutaneous ulcers with undermined, irregular, erythematous-violaceous edges"

Documents the undermined violaceous ulcer as the defining lesion.

Pathergy OCCASIONAL

Deliberately NOT bound to an ontology term. Pathergy is trauma-induced lesion INITIATION, not a lesion morphology; HPO has no term for it, and the nearest candidates are all misleading. This phenotype previously carried HP:0200042 (Skin ulcer), which discarded the semantic content and made it indistinguishable from the three other Skin ulcer annotations in this file. Per the dismech-terms rule that no term beats a misleading or too-general one, the free-text `preferred_term` stands alone. NEEDS TERM / candidate HPO new-term request (NTR): pathergy is a formal scored criterion in both the Delphi consensus definition and the PARACELSUS score, and also occurs in Behcet disease, so a dedicated HP term would be reused. Raised in the PR #9115 review.

Show evidence (2 references)

PMID:29450466 SUPPORT Human Clinical

"8 minor criteria: (1) exclusion of infection; (2) pathergy; (3) history of inflammatory bowel disease or inflammatory arthritis"

Lists pathergy explicitly among the validated minor diagnostic criteria for ulcerative pyoderma gangrenosum.

PMID:29721816 SUPPORT Human Clinical

"In 16.3% (95% confidence interval 7.7-27.1) of cases, the onset of pyoderma gangrenosum was attributed to the pathergy phenomenon."

Quantifies pathergy-attributed onset at 16.3% across 21 studies, supporting the OCCASIONAL frequency band (5-29%).

🧬

Genetic Associations

5

PSTPIP1

Gene: PSTPIP1 hgnc:9580 relationship_type: MODIFIER

Show evidence (2 references)

PMID:11971877 SUPPORT Human Clinical

"We have now established this by the identification of co-segregating disease-causing mutations in the CD2-binding protein 1"

Establishes co-segregating disease-causing CD2BP1/PSTPIP1 mutations as the cause of PAPA syndrome.

PMID:21532836 SUPPORT Human Clinical

"is an autosomal dominant, hereditary auto-inflammatory disease arising from mutations in the PSTPIP1/CD2BP1 gene on chromosome 15q"

Confirms PSTPIP1/CD2BP1 as the gene of the autosomal dominant PAPA syndrome in which PG is a defining feature.

Variants (2)

PSTPIP1 p.Ala230Thr (A230T) Pathogenic

Gene: PSTPIP1 hgnc:9580 missense variant

Missense substitution in the CDC15-homologous domain, co-segregating with PAPA syndrome and severely reducing PSTPIP1 binding to PEST-type protein tyrosine phosphatase. Pathogenic for PAPA syndrome, not for sporadic PG.

Show evidence (1 reference)

PMID:11971877 SUPPORT In Vitro

"E250Q or A230T amino acid substitutions occur within a domain highly homologous to yeast cleavage furrow-associated protein CDC15."

Identifies A230T as one of the two originally reported PAPA-causing substitutions and localizes it to the CDC15-homologous domain.

PSTPIP1 p.Glu250Gln (E250Q) Pathogenic

Gene: PSTPIP1 hgnc:9580 missense variant

Missense substitution in the CDC15-homologous domain, co-segregating with PAPA syndrome and severely reducing PSTPIP1 binding to PEST-type protein tyrosine phosphatase. Pathogenic for PAPA syndrome, not for sporadic PG.

Show evidence (1 reference)

PMID:11971877 SUPPORT In Vitro

"Yeast two-hybrid assays demonstrate severely reduced binding between PTP PEST and both the E250Q and A230T mutant proteins."

Demonstrates the functional consequence of E250Q — loss of PTP PEST binding — in a yeast two-hybrid assay.

MEFV

Gene: MEFV hgnc:6998 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:40034857 SUPPORT Human Clinical

"This disease has genetic susceptibility, and genes related to the onset of PG reported in the literature include PTPN6, PSTPIP1, MEFV, NLRP3, NLRP12, LPIN2, and NOD2"

Lists MEFV among the reported genetic-susceptibility genes for pyoderma gangrenosum onset.

NLRP3

Gene: NLRP3 hgnc:16400 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:40034857 SUPPORT Human Clinical

"This disease has genetic susceptibility, and genes related to the onset of PG reported in the literature include PTPN6, PSTPIP1, MEFV, NLRP3, NLRP12, LPIN2, and NOD2"

Lists NLRP3 among the reported genetic-susceptibility genes for pyoderma gangrenosum onset.

JAK2

Gene: JAK2 hgnc:6192 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:25350484 SUPPORT Human Clinical

"Two patients had mutations in MTHFR and two had mutations in JAK2."

Documents JAK2 mutations in PG, in 2 of 823 reviewed cases — supporting a rare association and nothing stronger.

PMID:42123319 SUPPORT Computational

"with JAK2 and STAT3 identified as network hubs"

Identifies JAK2 as a hub of the PG-IBD shared inflammatory module; COMPUTATIONAL because the study is entirely in silico.

NOD2

Gene: NOD2 hgnc:5331 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:40034857 SUPPORT Human Clinical

"This disease has genetic susceptibility, and genes related to the onset of PG reported in the literature include PTPN6, PSTPIP1, MEFV, NLRP3, NLRP12, LPIN2, and NOD2"

Lists NOD2 among the reported genetic-susceptibility genes for pyoderma gangrenosum onset.

💊

Medical Actions

10

Systemic corticosteroids

Action: Pharmacotherapy NCIT:C15986

Agent: prednisolone CHEBI:8378

Systemic corticosteroids (prednisolone, typically 0.75 mg/kg/day) are one of the two first-line systemic therapies. In the STOP GAP randomised trial they did not differ from ciclosporin on speed of healing or any other objective or patient-reported outcome, with 47% of ulcers healed by six months in each arm; however serious adverse reactions, especially infections, were more common with prednisolone, so the choice between the two is driven by side effect profile and patient preference rather than efficacy.

Mechanism Target:

INHIBITS Sterile Neutrophilic Dermal Inflammation and Tissue Destruction — Broad immunosuppression suppresses the neutrophilic dermal inflammatory process driving ulceration.

Show evidence (2 references)

PMID:26071094 SUPPORT Human Clinical

"By six months, ulcers had healed in 28/59 (47%) participants in the ciclosporin group compared with 25/53 (47%) in the prednisolone group."

Quantifies six-month healing under prednisolone in the largest randomised trial in PG.

PMID:26071094 SUPPORT Human Clinical

"serious adverse reactions, especially infections, were more common in the prednisolone group"

Documents the safety signal that differentiates prednisolone from ciclosporin despite equivalent efficacy.

Ciclosporin

Action: Pharmacotherapy NCIT:C15986

Agent: ciclosporin CHEBI:4031

Ciclosporin (4 mg/kg/day, maximum 400 mg/day) is the other first-line systemic therapy and, together with corticosteroids, remains the systemic treatment of choice for most patients. The STOP GAP randomised controlled trial found no difference from prednisolone across objective and patient-reported outcomes.

Mechanism Target:

INHIBITS Th17/Th1-Skewed Cytokine Amplification — Calcineurin inhibition suppresses T-cell cytokine production, damping the Th17/Th1 amplification layer.

Show evidence (2 references)

PMID:26071094 SUPPORT Human Clinical

"Prednisolone and ciclosporin did not differ across a range of objective and patient reported outcomes."

Establishes therapeutic equivalence of ciclosporin and prednisolone in a randomised controlled trial.

PMID:37610614 SUPPORT Human Clinical

"Corticosteroids and/or cyclosporine remain the systemic therapeutics of choice for most patients."

Confirms corticosteroids and ciclosporin as the systemic therapies of choice.

Infliximab (anti-TNF biologic therapy)

Action: Pharmacotherapy NCIT:C15986

Agent: infliximab NCIT:C1789

Infliximab, a monoclonal antibody against tumour necrosis factor alpha, is the only agent with randomised placebo-controlled evidence in pyoderma gangrenosum. In the Brooklyn trial — the first randomised placebo-controlled trial of any drug for PG — a single 5 mg/kg infusion produced clinical improvement at week 2 in 46% versus 6% on placebo. Anti-TNF therapy is particularly relevant where PG coexists with inflammatory bowel disease, and achieved the highest medical complete-resolution rate (63%) in a peristomal PG cohort.

Mechanism Target:

INHIBITS Th17/Th1-Skewed Cytokine Amplification — TNF neutralization removes a principal cytokine of the amplification layer driving neutrophil recruitment.

Show evidence (1 reference)

PMID:16188920 SUPPORT Human Clinical

"This study has demonstrated that infliximab at a dose of 5 mg/kg is superior to placebo in the treatment of PG."

Randomised placebo-controlled demonstration that TNF blockade therapeutically modifies the disease, supporting TNF as mechanistically operative.

Show evidence (2 references)

PMID:16188920 SUPPORT Human Clinical

"At week 2, significantly more patients in the infliximab group had improved (46% (6/13)) compared with the placebo group (6% (1/17); p = 0.025)."

Reports the primary endpoint of the only placebo-controlled randomised trial in PG.

PMID:32383278 SUPPORT Human Clinical

"Higher rates of complete resolution were reported with anti-tumour necrosis factor (TNF) agents (63%) and surgical interventions (80%)."

Quantifies anti-TNF response in peristomal PG, the highest medical complete-resolution rate in that cohort.

Interleukin-1 blockade

Action: Pharmacotherapy NCIT:C15986

Agent: anakinra CHEBI:231683

IL-1 inhibition (anakinra, an IL-1 receptor antagonist; canakinumab and gevokizumab, anti-IL-1beta antibodies) is a mechanism-directed therapy targeting the inflammasome/IL-1 node that is the proximal lesion in PG — IL-1 beta and its receptor I are directly over-expressed in PG lesional skin — and the proven molecular defect in PSTPIP1-driven PAPA syndrome. IMPORTANT NEGATIVE QUALIFIER: mechanistic rationale has not translated into demonstrated efficacy. All three registered gevokizumab (anti-IL-1beta) trials in PG were terminated (NCT02315417, NCT02326740 and the open-label safety extension NCT02318914, all Phase 3), and the canakinumab study (NCT01302795) was an open-label Phase 2 pilot with no control arm. No randomised controlled trial has shown IL-1 blockade to be effective in PG. This treatment is therefore curated as a mechanistically motivated but unproven option, NOT as established therapy — see the `pg_trial_attrition` discussion.

Mechanism Target:

INHIBITS Inflammasome Activation and IL-1 Overproduction — IL-1 receptor antagonism blocks signaling from the overproduced IL-1 that initiates the neutrophil-recruiting cascade. Note the cited evidence establishes that the drug target is over-expressed in PG lesional skin, which is the mechanistic rationale; it is not itself evidence of clinical efficacy.

Show evidence (1 reference)

PMID:24903614 SUPPORT Human Clinical

"The expressions of interleukin (IL)-1 beta and its receptor I were significantly higher in PG"

Establishes the drug target (IL-1 beta and its receptor I) as over-expressed in PG lesional skin, the mechanistic rationale for targeting this node.

Show evidence (1 reference)

PMID:37610614 SUPPORT Human Clinical

"an increasing number of studies on the positive effects of biologic therapies such as inhibitors of tumour necrosis factor"

Supports the biologic class including IL-1 inhibitors as having reported positive effects; graded PARTIAL because this sentence groups IL-1 blockade with other biologics rather than reporting a trial of it.

Adalimumab (anti-TNF biologic therapy)

Action: Pharmacotherapy NCIT:C15986

Agent: adalimumab NCIT:C65216

Adalimumab is a TNF-alpha inhibitor approved for pyoderma gangrenosum in Japan on the basis of the Phase 3 open-label trial NCT03311464. A 52-week multicentre prospective postmarketing observational study of 67 patients reported Physician Global Assessment (total lesions) scores of 0/1 in 36.0% at week 12, 46.2% at week 26 and 57.7% at week 52, with infections reported as adverse drug reactions in 14.9% and serious ADRs in 9.0%. Effectiveness was seen across PG subtypes and in patients on concomitant systemic steroids.

Mechanism Target:

INHIBITS Th17/Th1-Skewed Cytokine Amplification — TNF neutralization removes a principal cytokine of the amplification layer driving neutrophil recruitment.

Show evidence (2 references)

PMID:42107018 SUPPORT Human Clinical

"The proportions of patients with a PGA score (total lesions) of 0/1 at weeks 12, 26, and 52 were 36.0%, 46.2%, and 57.7%, respectively"

Quantifies adalimumab effectiveness over 52 weeks in a prospective multicentre PG cohort.

PMID:42107018 SUPPORT Human Clinical

"These findings support its use as a standard treatment for PG, including in patients receiving concomitant systemic steroid therapy."

The authors' conclusion supporting adalimumab as a standard PG treatment.

Topical corticosteroid therapy (clobetasol propionate)

Action: Pharmacotherapy NCIT:C15986

Agent: clobetasol propionate CHEBI:31414

Topical therapy — most commonly clobetasol propionate 0.05%, sometimes topical tacrolimus — is a genuine first-line option for limited disease, not merely an adjunct. In a prospective cohort of 66 UK patients whose PG was judged suitable for topical treatment, 43.8% of ulcers healed by 6 months with a median time to healing of 145 days. It avoids the adverse effects of systemic immunosuppression, though whether more severe disease responds adequately to topical therapy alone remains unclear, and the study had no randomized comparator.

Mechanism Target:

INHIBITS Sterile Neutrophilic Dermal Inflammation and Tissue Destruction — Locally delivered high-potency corticosteroid suppresses the neutrophilic dermal inflammatory process at the lesion itself.

Show evidence (2 references)

PMID:27502313 SUPPORT Human Clinical

"Overall, 28 of 66 (43.8%) ulcers healed by 6 months."

Quantifies healing under topical therapy in a prospective PG cohort.

PMID:27502313 SUPPORT Human Clinical

"Topical therapy is potentially an effective first-line treatment for PG that avoids the possible side effects associated with systemic therapy."

Supports topical therapy as a first-line option; graded PARTIAL because the study was a single-arm cohort without a randomized comparator.

Complement C5a blockade (vilobelimab)

Action: Pharmacotherapy NCIT:C15986

Agent: vilobelimab NCIT:C172643

Vilobelimab is a C5a-neutralizing monoclonal antibody targeting the complement node this entry models as the proximal driver of NETosis, and is the most direct test of that mechanism to date. IMPORTANT NEGATIVE QUALIFIER: the exploratory open-label Phase IIa trial (NCT03971643, OPTIMA) completed, but the subsequent randomised, double-blind, placebo-controlled Phase III trial in ulcerative PG (NCT05964413) was TERMINATED and the registry records the reason as futility. This treatment is curated because the target is mechanistically well evidenced in human PG wound fluid, NOT because efficacy is established — on current evidence it is a failed Phase III. Note the primary mechanistic paper itself anticipated a reason this might happen: C5a blockade alone may not suffice, because other neutrophil chemokines (IL-8, CXCL2) are independently over-expressed in PG lesional skin.

Mechanism Target:

INHIBITS Complement C5a Generation and C5aR1 Signalling — C5a neutralization removes the ligand for C5aR1, the proximal driver of NET release in PG.

Show evidence (2 references)

PMID:37516310 SUPPORT In Vitro

"NETosis induction by C5a provides a molecular basis for targeting C5a in PG therapy."

States the mechanistic rationale for C5a-directed therapy in PG, which is why this treatment is curated despite the negative trial result.

PMID:37516310 SUPPORT In Vitro

"However, C5a blockade alone may not be sufficient to block neutrophil infiltration in PG because other neutrophil chemokines such as IL-8 and CXCL2 are also overexpressed in PG lesional skin."

The primary mechanistic paper's own caveat, which anticipates the redundancy that may underlie the Phase III futility result.

JAK inhibition (tofacitinib, baricitinib)

Action: Pharmacotherapy NCIT:C15986

Agent: tofacitinib CHEBI:71200

JAK inhibitors target the JAK/STAT node overactivated in PG lesions. In vitro, tofacitinib suppresses STAT phosphorylation in myeloid and T cells, myeloid NETosis, and IL-17A production — hitting three processes this pathograph models. Computational multi-omics work nominates baricitinib for the PG-IBD comorbid setting via the shared JAK2/STAT3 hub. EVIDENCE LEVEL: investigational only. Support is in vitro plus case reports and small series; the authors of the tofacitinib work describe their own evidence as preliminary, and the baricitinib nomination is a docking and systems-modelling prediction with no experimental validation. No controlled trial is curated, and no JAK inhibitor is approved for PG.

Mechanism Target:

INHIBITS JAK-STAT Pathway Overactivation — JAK inhibition suppresses STAT phosphorylation, damping the myeloid NETosis and Th17 arms downstream of this node.

Show evidence (1 reference)

PMID:42603447 SUPPORT In Vitro

"In vitro cell experiments further demonstrated that the JAK inhibitor tofacitinib suppresses STAT phosphorylation in myeloid and T cells, myeloid NETosis, and IL-17A production."

Directly demonstrates the drug acting on this node and its two downstream arms, in vitro.

Show evidence (2 references)

PMID:42603447 SUPPORT In Vitro

"provide preliminary in vitro evidence supporting potential inhibitory effects of tofacitinib on key pathological processes of PG"

The authors' own characterization of the evidence as preliminary and in vitro, which is why this is curated as investigational.

PMID:42123319 SUPPORT Computational

"Although this study provides multiscale computational simulation evidence, the lack of direct experimental validation of these predicted results necessitates further confirmation through in vitro and in vivo experiments."

The computational study's own statement that its JAK-inhibitor predictions lack experimental validation.

Wound care, pain control and avoidance of debridement

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Concomitant topical therapy, wound management and pain control should always be addressed alongside systemic treatment. Critically, because of pathergy, surgical debridement and defect closure may exacerbate the injury, so aggressive debridement of an active PG ulcer is generally avoided and surgery — where required for reconstruction — is undertaken only under adequate immunosuppression. Note that the peristomal cohort reported high resolution rates with surgical intervention (80%), so the caution is against reflexive debridement of misdiagnosed active disease rather than an absolute prohibition on surgery. A retrospective inpatient series makes the same point from the other direction: all three patients who underwent split skin grafting under immunosuppressive cover had no postoperative graft failure or pathergy, and the authors conclude surgery should be considered alongside immunosuppressive (and hyperbaric) therapy once disease is quiescent. The operative principle is therefore "not on active disease without cover", not "never".

Show evidence (4 references)

PMID:37610614 SUPPORT Human Clinical

"In addition, concomitant topical pharmacologic therapy, wound management and pain control should always be addressed."

Establishes wound management and pain control as standard adjunctive care.

PMID:38250211 SUPPORT Human Clinical

"Accurate diagnosis of PSPG, prevention of further surgical injury, and timely medical management are vital for improving patient outcomes."

Supports prevention of further surgical injury as a management principle driven by pathergy.

PMID:23903083 SUPPORT Human Clinical

"All 3 patients who underwent split skin grafting under immunosuppressive cover (with 2 having hyperbaric oxygen therapy) had no postoperative graft failure or pathergy."

Counterweight to blanket surgical avoidance: grafting under immunosuppressive cover did not trigger pathergy. PARTIAL because n=3.

+ 1 more reference

Treatment of associated systemic disease

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Because a third to nearly half of patients have an associated systemic disease — most often inflammatory bowel disease, inflammatory arthritis, or a hematologic disorder — identification and treatment of that disease is part of managing the dermatosis, and in some settings determines the choice of systemic agent (for example anti-TNF therapy where PG coexists with IBD).

Show evidence (1 reference)

PMID:25374597 SUPPORT Human Clinical

"This study also highlights the importance of early and aggressive treatment of patients admitted with PG as well as treating associated systemic diseases and wound infections."

Directly recommends treating associated systemic disease as part of PG management.

🔬

Diagnosis

3

Positive diagnosis using validated scoring systems

Pyoderma gangrenosum was historically a diagnosis of exclusion, a status explicitly criticized as incompatible with clinical decision making and trial recruitment. Two validated instruments now permit a positive diagnosis: the Delphi consensus criteria for ulcerative PG (one major criterion plus at least 4 of 8 minor criteria) and the PARACELSUS score (a 10-criterion score, with 10 or more points indicating high likelihood). Exclusion of infection and consideration of relevant differential diagnoses remain formal components of both instruments rather than being superseded by them.

Show evidence (2 references)

PMID:37610614 SUPPORT Human Clinical

"Despite the limited understanding of the pathogenesis, it is no longer a diagnosis of exclusion, as it can now be made on the basis of validated scoring systems."

States directly that validated scoring systems have replaced diagnosis by exclusion.

PMID:19470075 SUPPORT Human Clinical

"The diagnosis, mainly based on the clinical presentation and course, is confirmed through a process of elimination of other causes of cutaneous ulcers."

Documents the historical diagnosis-of-exclusion approach that the validated scores were developed to replace.

Exclusion of mimickers and the misdiagnosis rate

Rigorous exclusion of alternative causes of severe cutaneous ulceration is the substance of the diagnosis, and the cost of getting it wrong is measurable: in a consecutive series, 15 of 157 patients (10%) treated for presumed PG had another diagnosis — vascular occlusive or venous disease, vasculitis, cancer, primary infection, drug-induced or exogenous tissue injury, or another inflammatory disorder. Among misdiagnosed patients whose course was documented, 12% had ulcers actively exacerbated by PG-directed treatment, which is the clinical harm this exclusion step exists to prevent.

Show evidence (3 references)

PMID:12409543 SUPPORT Human Clinical

"These 64 included 15 of the 157 consecutive patients treated for pyoderma gangrenosum at our institution (10 percent)."

Quantifies the misdiagnosis rate in a consecutive series of patients treated for presumed PG.

PMID:12409543 SUPPORT Human Clinical

"The final diagnoses were vascular occlusive or venous disease, vasculitis, cancer, primary infection, drug-induced or exogenous tissue injury, and other inflammatory disorders."

Enumerates the mimicker categories that the exclusion work-up must cover.

PMID:12409543 SUPPORT Human Clinical

"those in 8 (12 percent) were exacerbated by such treatment"

Documents active harm from PG-directed treatment given on a mistaken diagnosis.

Evaluation for associated systemic disease

Because a substantial proportion of patients have an associated systemic disease, evaluation should include assessment for inflammatory bowel disease, inflammatory/rheumatologic arthritis, paraproteinemia, and hematologic malignancy. A bullous (atypical) presentation in particular should prompt hematologic evaluation including blood and bone marrow examination.

Show evidence (2 references)

PMID:19470075 SUPPORT Human Clinical

"Pyoderma gangrenosum often occurs in association with a systemic disease such as inflammatory bowel disease, rheumatologic disease, paraproteinaemia, or haematological malignancy."

Enumerates the associated systemic diseases that the work-up should address.

PMID:10773715 SUPPORT Human Clinical

"the importance of regular blood and bone marrow examinations in patients with atypical bullous pyoderma gangrenosum"

Supports hematologic work-up specifically in the bullous variant.

📊

Prevalence

1

United Kingdom

Annual Incidence 0.63 per 100,000 (0.57–0.71) 1–9 per 1,000,000

Age-standardized (European standard population) incidence from the General Practice Research Database, the first population-based epidemiological study of PG.

Show evidence (1 reference)

PMID:22534879 SUPPORT Human Clinical

"The adjusted incidence rate standardized to European standard population was 0.63 (95% confidence interval (CI) 0.57-0.71) per 100,000 person-years."

Directly reports the population-based standardized incidence rate.

🌍

Epidemiology

5

Associated systemic disease

Associated systemic disease is frequent in pyoderma gangrenosum, but the reported proportion depends strongly on the setting. A UK population-based primary-care cohort found associations in 33% of patients (IBD 20.2%, rheumatoid arthritis 11.8%, hematological disorders 3.9%), whereas a hospital inpatient series found 47.8%. Both figures are curated with their populations rather than collapsed into the commonly quoted single "~50%" claim, because they are not measuring the same thing.

Show evidence (2 references)

PMID:22534879 SUPPORT Human Clinical

"Disease associations were present in 110 (33%) participants: IBD, n=67 (20.2%); RA, n=39 (11.8%); and hematological disorders, n=13 (3.9%)."

Provides the population-based breakdown of associated systemic disease.

PMID:25374597 SUPPORT Human Clinical

"Associated systemic diseases were observed in 11 patients (47.8%)."

Provides the higher hospital-inpatient estimate, contrasted with the population-based figure.

Pooled prevalence of underlying systemic disease (meta-analysis)

The strongest single estimate comes from a systematic review and meta-analysis of 21 studies comprising 2611 patients: pooled prevalence of an associated systemic disease 56.8% (95% CI 45.5-67.4), led by inflammatory bowel disease (17.6%), arthritis (12.8%), hematological malignancies (8.9%) and solid malignancies (7.4%). This reconciles the range seen between the population-based (33%) and inpatient (47.8%) figures above, and is the number closest to the frequently quoted "about half of patients". Heterogeneity between the pooled studies was high, so the authors advise interpreting with caution.

Show evidence (2 references)

PMID:29721816 SUPPORT Human Clinical

"The overall random-effects pooled prevalence of associated systemic diseases was 56.8% (95% confidence interval 45.5-67.4)."

Provides the pooled meta-analytic estimate across 21 studies and 2611 patients.

PMID:29721816 SUPPORT Human Clinical

"The leading underlying disease was inflammatory bowel disease (17.6%; 95% confidence interval 13.0-22.7), followed by arthritis (12.8%; 95% confidence interval 9.2-16.9), hematological malignancies (8.9%; 95% confidence interval 6.5-11.6), and solid malignancies (7.4%; 95% confidence interval 5.8-9.1)."

Breaks the pooled prevalence down by associated disease category.

Solid malignancy is not an associated risk

Despite solid malignancies appearing at 7.4% in the meta-analytic breakdown, a dedicated population-based cohort and case-control study found no association in either direction: the prevalence of preexisting solid malignancy was comparable in PG patients and matched controls, the odds of PG after a solid malignancy diagnosis were not increased, and PG patients were not more likely to develop one. The authors conclude that routine solid-malignancy screening in new-onset PG is unnecessary. This is curated as an explicit negative because the hematologic association is real and is easily over-generalized to malignancy as a whole.

Show evidence (2 references)

PMID:34076886 REFUTE Human Clinical

"SM is not associated with provoking PG, and patients with PG are not at an increased risk of developing SM."

Directly refutes a bidirectional association between solid malignancy and pyoderma gangrenosum.

PMID:34076886 REFUTE Human Clinical

"The prevalence of a preexisting SM was comparable in patients with PG and controls (7.5% vs. 8.8%, respectively; P = 0.490)."

Quantifies the absence of excess preexisting solid malignancy in PG versus matched controls.

Mortality

Pyoderma gangrenosum carries substantially increased mortality — three times that of matched general population controls, and still 72% higher than that of matched inflammatory-bowel-disease controls, indicating the excess is not merely attributable to the associated systemic disease.

Show evidence (2 references)

PMID:22534879 SUPPORT Human Clinical

"The risk of death was three times higher than that for general controls (adjusted hazard ratio=3.03, 95% CI 1.84-4.73, P<0.001)"

Quantifies the substantially increased mortality of PG.

PMID:22534879 SUPPORT Human Clinical

"72% higher than that for IBD controls (adjusted hazard ratio=1.72, 95% CI 1.17-2.59, P=0.013)"

Shows the mortality excess persists against IBD-matched controls, so it is not solely explained by the associated systemic disease.

Age and sex distribution

In the UK population-based cohort of 313 patients the median age was 59 years (interquartile range 41-72) and 59% were female.

Show evidence (1 reference)

PMID:22534879 SUPPORT Human Clinical

"In all there were 313 people with the median age of 59 (interquartile range 41-72) years, and of them 185 (59%) were female."

Reports the age and sex distribution of PG in a population cohort.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Pyoderma Gangrenosum:

Sweet syndrome MONDO:0011959

Overlapping Features Sweet syndrome is the other prototypic neutrophilic dermatosis and shares the sterile dermal neutrophilic infiltrate, pathergy, and paraneoplastic potential, but produces abrupt tender edematous erythematous plaques and nodules that heal without scarring, rather than the deep, undermined, violaceous, cribriform-scarring ulcers of pyoderma gangrenosum. The two are kept as distinct dismech entities. Comparative protein-array profiling of the two diseases found chemokine-mediated signals lower in Sweet syndrome than in PG, which the authors propose explains PG's stronger local aggressiveness.

Distinguishing Features

Pyoderma gangrenosum: painful ulcers with undermined violaceous borders, cribriform scarring, strong pathergy
Sweet syndrome: abrupt tender edematous plaques/nodules with fever and neutrophilia, heal without scarring

Show evidence (1 reference)

PMID:24903614 SUPPORT Human Clinical

"The differences in expression profile of inflammatory effectors between these two disorders may explain the stronger local aggressiveness in PG than SS."

Provides a mechanistic basis for the clinical distinction between PG and its closest differential, Sweet syndrome.

Venous leg ulcer

Overlapping Features Venous leg ulceration is the single most important clinical mimic, because both favor the lower leg and are chronic. It was the explicit control cohort against which the PARACELSUS score was validated. Venous ulcers lack the rapidly progressing course, the reddish-violaceous undermined border, and the extreme disproportionate pain of PG.

Distinguishing Features

Pyoderma gangrenosum: rapidly progressing, reddish-violaceous undermined border, extreme pain, improves on immunosuppression
Venous leg ulcer: chronic indolent course, sloping non-undermined margin, venous insufficiency signs, improves with compression

Show evidence (1 reference)

PMID:29388188 SUPPORT Human Clinical

"a control cohort of 50 patients with venous leg ulcers"

Confirms venous leg ulcer as the principal comparator mimic in the score's validation study.

Cutaneous infection and necrotizing soft tissue infection

Overlapping Features Infective ulceration is the critical exclusion, and misdiagnosis runs in both directions: an infected ulcer treated as PG with immunosuppression, or PG debrided as though it were necrotizing infection, which triggers pathergy. Exclusion of infection is a formal minor criterion in the Delphi definition; PG lesions are culture-negative and do not respond to antibiotics.

Distinguishing Features

Pyoderma gangrenosum: sterile/culture-negative, no response to antibiotics, worsens with debridement (pathergy), responds to immunosuppression
Cutaneous/necrotizing infection: positive cultures, responds to antibiotics, requires surgical debridement

Show evidence (1 reference)

PMID:29450466 SUPPORT Human Clinical

"8 minor criteria: (1) exclusion of infection; (2) pathergy"

Establishes exclusion of infection as a formal diagnostic criterion, making infective ulceration the key differential.

Behcet disease MONDO:0007191

Overlapping Features Behcet disease is a variable-vessel vasculitis on the neutrophilic/ autoinflammatory spectrum that also displays pathergy and can produce cutaneous ulceration, but is defined by recurrent oral and genital ulceration with ocular inflammation in a chronic relapsing multisystem course.

Distinguishing Features

Pyoderma gangrenosum: cutaneous ulcers with undermined violaceous borders, no obligate oral/genital ulceration
Behcet disease: recurrent oral and genital ulcers, uveitis, multisystem variable-vessel vasculitis

🔬

Clinical Trials

10

NCT03311464 PHASE_III COMPLETED

A Phase 3 multicentre, open-label, single-arm study of the efficacy and safety of adalimumab in active ulcer(s) of pyoderma gangrenosum in subjects in Japan. This trial underpins the Japanese approval of adalimumab for PG.

Target Phenotypes: Cutaneous ulcer with undermined violaceous border HP:0025452

Show evidence (1 reference)

clinicaltrials:NCT03311464 SUPPORT Other

"This study is designed to investigate the efficacy, safety and pharmacokinetics of adalimumab in subjects in Japan with active ulcer(s) due to Pyoderma Gangrenosum (PG)."

ClinicalTrials.gov record establishing the trial's design and its PG indication.

NCT03971643 PHASE_II COMPLETED

OPTIMA: open-label exploratory Phase IIa trial of vilobelimab (IFX-1), a C5a-neutralizing antibody, in pyoderma gangrenosum. The Phase II step of the C5a-directed programme whose Phase III was subsequently terminated.

Target Phenotypes: Cutaneous ulcer with undermined violaceous border HP:0025452

Show evidence (1 reference)

clinicaltrials:NCT03971643 SUPPORT Other

"The purpose of this study is to determine whether vilobelimab (development name: IFX-1) is safe and effective in the treatment of pyoderma gangrenosum."

ClinicalTrials.gov record establishing the trial's drug and PG indication.

NCT05964413 PHASE_III TERMINATED

Randomised, double-blind, placebo-controlled, multicentre adaptive Phase III trial of vilobelimab in ulcerative pyoderma gangrenosum. TERMINATED; the ClinicalTrials.gov record gives the reason as "Study stopped for futility". This is the single most important negative result for the complement arm of this entry's pathograph and is why the C5a-blockade treatment is curated as a failed Phase III rather than as effective therapy.

Target Phenotypes: Cutaneous ulcer with undermined violaceous border HP:0025452

NCT02315417 PHASE_III TERMINATED

Randomised, double-blind, placebo-controlled Phase III study of gevokizumab (anti-IL-1beta) in active ulcers of pyoderma gangrenosum. TERMINATED. One of three terminated gevokizumab registrations in PG.

Target Phenotypes: Cutaneous ulcer with undermined violaceous border HP:0025452

Show evidence (1 reference)

clinicaltrials:NCT02315417 SUPPORT Other

"The study will evaluate the efficacy and safety of gevokizumab in treating active ulcers of pyoderma gangrenosum (PG)."

ClinicalTrials.gov record establishing the trial's drug and PG indication.

NCT02326740 PHASE_III TERMINATED

The second randomised, double-blind, placebo-controlled Phase III study of gevokizumab in active ulcers of pyoderma gangrenosum. TERMINATED.

Target Phenotypes: Cutaneous ulcer with undermined violaceous border HP:0025452

Show evidence (1 reference)

clinicaltrials:NCT02326740 SUPPORT Other

"The study will evaluate the efficacy and safety of gevokizumab in treating active ulcers of pyoderma gangrenosum (PG)."

ClinicalTrials.gov record establishing the trial's drug and PG indication.

NCT02318914 PHASE_III TERMINATED

Two-year open-label safety extension study of gevokizumab in pyoderma gangrenosum, registered as Phase 3 and TERMINATED. Note this is the extension arm of the gevokizumab programme rather than a third independent randomised efficacy trial — it is curated separately because it is a distinct registration with its own terminated status.

Target Phenotypes: Cutaneous ulcer with undermined violaceous border HP:0025452

Show evidence (1 reference)

clinicaltrials:NCT02318914 SUPPORT Other

"The study will evaluate the long-term safety of gevokizumab in treating active PG ulcers"

ClinicalTrials.gov record establishing this as the long-term safety extension of the gevokizumab PG programme.

NCT06624670 PHASE_III RECRUITING

Multicentre, randomised, placebo-controlled, double-blind, parallel-group Phase III trial of spesolimab (anti-IL-36 receptor) in adults with ulcerative pyoderma gangrenosum requiring systemic therapy. RECRUITING at the time of curation — the main active late-phase trial in PG, and the test of the IL-36 arm of the cytokine profile this entry models.

Target Phenotypes: Cutaneous ulcer with undermined violaceous border HP:0025452

NCT06092216 PHASE_II TERMINATED

Phase II study characterizing PG lesion regression and remission by IL-36 receptor targeting with spesolimab. TERMINATED; the registry records that the funding sponsor terminated the study in favour of a multicentre trial, so unlike the vilobelimab Phase III this termination is NOT a futility signal.

Target Phenotypes: Cutaneous ulcer with undermined violaceous border HP:0025452

Show evidence (1 reference)

clinicaltrials:NCT06092216 SUPPORT Other

"The purpose of this research study is to assess the feasibility of using spesolimab in participants with moderate to severe pyoderma gangrenosum."

ClinicalTrials.gov record establishing the trial's drug and PG indication.

NCT01302795 PHASE_II COMPLETED

Phase II multicentre open-label pilot study of canakinumab, an anti-IL-1beta antibody, in pyoderma gangrenosum. Open-label with no control arm, so it supports the IL-1 rationale without establishing efficacy.

Target Phenotypes: Cutaneous ulcer with undermined violaceous border HP:0025452

Show evidence (1 reference)

clinicaltrials:NCT01302795 SUPPORT Other

"This study is a prospective open label evaluation of Canakinumab (Ilaris) for treatment of subjects with pyoderma gangrenosum."

Establishes the trial as an open-label evaluation — the design limitation that prevents it supporting efficacy.

ISRCTN35898459 PHASE_IV COMPLETED

STOP GAP: a multicentre, parallel group, observer blind randomised controlled trial across 39 UK hospitals comparing oral prednisolone 0.75 mg/kg/day with ciclosporin 4 mg/kg/day in 121 patients with pyoderma gangrenosum, with speed of healing over six weeks as the primary outcome. Registered on ISRCTN rather than ClinicalTrials.gov, so keyed on its WHO ICTRP identifier.

Target Phenotypes: Cutaneous ulcer with undermined violaceous border HP:0200042

Show evidence (2 references)

ICTRP:ISRCTN35898459 SUPPORT Other

"| Main ID | ISRCTN35898459 |"

WHO ICTRP registration record establishing the trial's identity and registry of origin.

PMID:26071094 SUPPORT Human Clinical

"Multicentre, parallel group, observer blind, randomised controlled trial."

Documents the trial design reported in the primary publication.

🐁

Animal Models

1

PG-serum transfer mouse (wild-type and GSDMD-knockout)

The only animal model of pyoderma gangrenosum curated here. Serum from PG patients is injected into the dorsal skin of wild-type mice, producing localized cutaneous ulcers with increased NETs and GSDMD in lesional skin and serum. Repeating the model in GSDMD-knockout mice significantly reduces ulcer severity, which is what makes it a perturbation experiment on the NETosis node rather than only a descriptive lesion model.

Species

Mouse

Genotype

Wild-type C57BL/6 and GSDMD-/-

Publication

PMID:40034857

Pathograph links

GSDMD-Dependent NETosis perturbs fidelity: moderate GSDMD knockout removes the regulator of NET formation and attenuates ulceration, directly testing this node's causal contribution.

Limitations: Ulcers are induced by passive transfer of patient serum rather than arising spontaneously, so the model reproduces an effector arm rather than the upstream disease trigger. It does not recapitulate pathergy, the undermined violaceous border, cribriform scarring, the associated systemic diseases, or the corticosteroid/ciclosporin responsiveness that define human PG, and the knockout is constitutive rather than neutrophil-restricted.

Readouts

Skin ulcer severity in GSDMD-knockout versus wild-type mice

Direction: DECREASED

Interpretation: Loss of GSDMD attenuates ulceration, indicating GSDMD-dependent NETosis contributes causally to lesion severity in this model.

Show evidence (1 reference)

PMID:40034857 SUPPORT Model Organism

"In GSDMD -/- mice, the severity of skin ulcers after modeling was significantly diminished."

Reports the knockout-versus-wild-type ulcer severity result.

Show evidence (1 reference)

PMID:40034857 SUPPORT Model Organism

"Overall, our findings shed light on the role of GSDMD in regulating the production of NETs by neutrophils and the release of inflammatory factors in the pathogenesis of PG and establish an animal model for studying PG."

The authors' own framing of the system as an animal model informative for GSDMD-regulated NET production in PG.

Progressive Cutaneous Ulceration with Undermined Violaceous Border partially recapitulates fidelity: low Serum transfer produces localized cutaneous ulceration, but only the bare fact of ulcer formation — none of the features that make a PG ulcer diagnostically recognizable.

Limitations: The model yields localized ulcers without the undermined, erythematous-violaceous border, rapid centrifugal progression, disproportionate pain, or cribriform scarring that define the human lesion and constitute the major diagnostic criteria. Ulceration here is an induced endpoint, not a spontaneous relapsing disease course.

Readouts

Cutaneous ulcer formation after PG-serum injection

Direction: INCREASED

Interpretation: PG patient serum is sufficient to induce cutaneous ulceration in wild-type mouse skin.

Show evidence (1 reference)

PMID:40034857 SUPPORT Model Organism

"Injection of serum from PG patients into the dorsal skin of wild-type mice led to the formation of localized cutaneous ulcers."

Reports the induced ulceration endpoint of the model.

Show evidence (1 reference)

PMID:40034857 SUPPORT Model Organism

"Injection of serum from PG patients into the dorsal skin of wild-type mice led to the formation of localized cutaneous ulcers."

Supports treating the model as informative for the ulceration node, with the fidelity caveats recorded in `limitations`.

{ }

Source YAML

click to show

name: Pyoderma Gangrenosum
creation_date: "2026-08-20T00:00:00Z"
category: Complex
disease_term:
  preferred_term: Pyoderma gangrenosum
  term:
    id: MONDO:0018824
    label: pyoderma gangrenosum
parents:
- Neutrophilic dermatosis
- Autoinflammatory syndrome
description: >-
  Pyoderma gangrenosum (PG) is a rare, primarily sterile inflammatory
  neutrophilic dermatosis characterized by recurrent, rapidly progressive and
  exquisitely painful cutaneous ulceration with undermined, irregular
  violaceous borders and a mucopurulent or hemorrhagic exudate. Despite a name
  that implies infection and gangrene, PG is neither: it is an autoinflammatory
  disease of dysregulated innate immunity, and MONDO classifies it under both
  pyoderma and autoinflammatory syndrome. Pathogenesis centers on exaggerated
  inflammasome activation with interleukin-1 overproduction, amplified by a
  T helper 17/T helper 1-skewed cytokine milieu (TNF, IL-8, IL-17, IL-23,
  IL-36), producing a neutrophil-dominant sterile infiltrate that destroys
  dermal tissue. Pathergy — new or enlarging lesions at sites of minor trauma —
  is a defining and clinically load-bearing feature, because it is why surgical
  debridement can worsen the disease. Recognized clinical variants (classic
  ulcerative, bullous, pustular, vegetative, and peristomal) differ in
  morphology, site, course, and disease associations. A substantial minority to
  roughly half of patients have an associated systemic disease, most often
  inflammatory bowel disease, inflammatory arthritis, or a hematologic
  disorder/monoclonal gammopathy. The monogenic anchor for the mechanism is
  PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum, and acne), caused by
  PSTPIP1/CD2BP1 variants that drive inflammasome-dependent IL-1beta
  overproduction. Diagnosis was historically one of exclusion; validated
  instruments (the Delphi consensus criteria for ulcerative PG and the
  PARACELSUS score) now allow a positive diagnosis.

references:
- reference: PMID:16188920
  title: "Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial."
- reference: PMID:26071094
  title: "Comparison of the two most commonly used treatments for pyoderma gangrenosum: results of the STOP GAP randomised controlled trial."
- reference: PMID:29450466
  title: "Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum: A Delphi Consensus of International Experts."
- reference: PMID:29388188
  title: "The PARACELSUS score: a novel diagnostic tool for pyoderma gangrenosum."
- reference: PMID:24903614
  title: "Expression of cytokines, chemokines and other effector molecules in two prototypic autoinflammatory skin diseases, pyoderma gangrenosum and Sweet's syndrome."
- reference: PMID:35606650
  title: "Pyoderma Gangrenosum: An Updated Literature Review on Established and Emerging Pharmacological Treatments."
- reference: PMID:22534879
  title: "Incidence, mortality, and disease associations of pyoderma gangrenosum in the United Kingdom: a retrospective cohort study."
- reference: PMID:11971877
  title: "Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder."
- reference: PMID:33033263
  title: "Pyoderma gangrenosum."
- reference: PMID:29721816
  title: "Underlying Systemic Diseases in Pyoderma Gangrenosum: A Systematic Review and Meta-Analysis."
- reference: PMID:40034857
  title: "Gasdermin D-dependent neutrophil extracellular traps exacerbate cytokine storm contributing to pyoderma gangrenosum pathogenesis."
- reference: PMID:42107018
  title: "Safety and Effectiveness of Adalimumab for the Treatment of Pyoderma Gangrenosum: A 52-Week Real-World Prospective Observational Study."
- reference: PMID:37516310
  title: "NETosis Is Induced by Complement Component 5a: Implications in the Pathogenesis of Pyoderma Gangrenosum."
- reference: PMID:20636397
  title: "Role of inflammatory cells, cytokines and matrix metalloproteinases in neutrophil-mediated skin diseases."
- reference: PMID:42603447
  title: "Preliminary exploration of effects of the JAK inhibitor tofacitinib on pyoderma gangrenosum: In vitro inhibition of NETs and Th17 differentiation."

has_subtypes:
- name: Ulcerative
  display_name: Classic ulcerative pyoderma gangrenosum
  subtype_term:
    preferred_term: Classic (ulcerative) pyoderma gangrenosum
    term:
      id: MONDO:0035235
      label: classic pyoderma gangrenosum
  description: >-
    The classic and by far most common variant: a deep, rapidly enlarging,
    exquisitely painful ulcer with an undermined, irregular,
    erythematous-violaceous border, most often on the lower leg, healing with a
    cribriform ("wrinkled paper") scar. This is the variant for which the
    Delphi consensus diagnostic criteria and the PARACELSUS score were
    developed and validated. MONDO:0035235 carries "Ulcerative pyoderma
    gangrenosum" as an exact synonym, which is why this subtype is named
    Ulcerative here.
  subtype_frequency: >-
    Predominant variant: 62 of 67 patients (93%) in a Japanese multicentre
    adalimumab cohort had ulcerative PG.
  evidence:
  - reference: PMID:42107018
    reference_title: "Safety and Effectiveness of Adalimumab for the Treatment of Pyoderma Gangrenosum: A 52-Week Real-World Prospective Observational Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The PG subtypes among the enrolled patients were ulcerative (n = 62),
      pustular (n = 2), vegetative (n = 2), and bullous (n = 1).
    explanation: >-
      Quantifies the ulcerative variant as overwhelmingly predominant (62 of
      67) in a prospective multicentre PG cohort.
- name: Bullous
  display_name: Bullous (atypical) pyoderma gangrenosum
  subtype_term:
    preferred_term: Bullous (atypical) pyoderma gangrenosum
    term:
      id: MONDO:0035237
      label: bullous pyoderma gangrenosum
  description: >-
    An atypical, more superficial variant presenting with rapidly extending
    hemorrhagic bullae, and characteristically associated with
    myeloproliferative and other hematologic disorders — so its recognition
    should prompt hematologic evaluation.
- name: Pustular
  display_name: Pustular pyoderma gangrenosum
  subtype_term:
    preferred_term: Pustular pyoderma gangrenosum
    term:
      id: MONDO:0035236
      label: pustular pyoderma gangrenosum
  description: >-
    A variant in which discrete painful sterile pustules arise and may remain
    pustular without progressing to frank ulceration; classically described in
    the setting of active inflammatory bowel disease.
- name: Vegetative
  display_name: Vegetative (superficial granulomatous) pyoderma gangrenosum
  subtype_term:
    preferred_term: Vegetative (superficial granulomatous) pyoderma gangrenosum
    term:
      id: MONDO:0035238
      label: vegetative pyoderma gangrenosum
  description: >-
    A localized, superficial and more indolent variant, recognized both by
    MONDO as a distinct child concept and in clinical cohorts alongside the
    ulcerative, bullous and pustular forms, where it is uncommon (2 of 67
    patients in a prospective multicentre series). Its milder course has a
    measured mechanistic correlate: myeloperoxidase, IL-8 and MMP-9 are
    expressed significantly less in vegetative PG than in the ulcerative and
    bullous variants, i.e. less neutrophil-effector and MMP-mediated matrix
    destruction.
  subtype_frequency: >-
    Uncommon: 2 of 67 patients (3%) in a Japanese multicentre adalimumab
    cohort.
  evidence:
  - reference: PMID:42107018
    reference_title: "Safety and Effectiveness of Adalimumab for the Treatment of Pyoderma Gangrenosum: A 52-Week Real-World Prospective Observational Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The PG subtypes among the enrolled patients were ulcerative (n = 62),
      pustular (n = 2), vegetative (n = 2), and bullous (n = 1).
    explanation: >-
      Documents and quantifies the vegetative variant as a recognized but
      uncommon clinical form in a prospective PG cohort.
- name: Peristomal
  display_name: Peristomal pyoderma gangrenosum
  description: >-
    PG arising in the skin immediately surrounding an abdominal stoma,
    predominantly in patients with inflammatory bowel disease who have had an
    ostomy. Chronic mechanical irritation from the appliance is a plausible
    pathergic trigger, and appliance-related risk factors (pouch belt use,
    higher BMI) are associated with its development.

mechanistic_hypotheses:
- hypothesis_group_id: autoinflammatory_neutrophil_model
  hypothesis_label: Autoinflammatory inflammasome/IL-1-driven neutrophil recruitment
  status: CANONICAL
  description: >-
    Pyoderma gangrenosum is modeled as an autoinflammatory disease of the
    innate immune system rather than an infection or a classical
    autoantibody-mediated autoimmune disease. Exaggerated inflammasome activation in
    genetically predisposed individuals drives interleukin-1 overproduction,
    which — amplified by a T helper 17/T helper 1-skewed adaptive layer
    supplying TNF, IL-8, IL-17, IL-23 and IL-36 — recruits and activates
    neutrophils into the dermis, producing the sterile neutrophil-dominant
    infiltrate that destroys tissue and yields the characteristic ulcer.
    Direct protein-array measurement in PG lesional skin supports the
    framework, but the primary literature is explicit that the exact
    pathogenesis is not yet fully understood.
  evidence:
  - reference: PMID:24903614
    reference_title: "Expression of cytokines, chemokines and other effector molecules in two prototypic autoinflammatory skin diseases, pyoderma gangrenosum and Sweet's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Over-expression of cytokines/chemokines and molecules amplifying the
      inflammatory network supports the view that PG and SS are
      autoinflammatory diseases.
    explanation: >-
      Direct measurement in PG lesional skin supporting the autoinflammatory
      classification that this hypothesis group models.
  - reference: PMID:33033263
    reference_title: "Pyoderma gangrenosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cause of PG is not well understood, but PG is generally considered an
      autoinflammatory disorder.
    explanation: >-
      The authoritative Nature Reviews Disease Primers overview endorses the
      autoinflammatory framing while stating the cause is not well understood —
      supporting the model and its hedging simultaneously.
  - reference: PMID:33033263
    reference_title: "Pyoderma gangrenosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Studies have focused on the role of T cells, especially at the wound
      margin; these cells may support the destructive autoinflammatory response
      by the innate immune system.
    explanation: >-
      Records the adaptive (wound-margin T cell) contribution to an
      innate-driven process, the interface this hypothesis group models;
      PARTIAL because the source hedges with "may support".
  - reference: PMID:35606650
    reference_title: "Pyoderma Gangrenosum: An Updated Literature Review on Established and Emerging Pharmacological Treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      T helper 17/T helper 1-skewed inflammation and exaggerated inflammasome
      activation lead to a dysregulated neutrophil-dominant milieu
    explanation: >-
      States the inflammasome-driven, Th17/Th1-amplified neutrophil-dominant
      mechanism that this hypothesis group models.
  - reference: PMID:37610614
    reference_title: "Pyoderma Gangrenosum: Treatment Options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the exact pathogenesis is not yet fully understood, various
      auto-inflammatory phenomena with increased neutrophil granulocyte
      activity have been demonstrated.
    explanation: >-
      Supports the autoinflammatory framing while recording explicitly that the
      pathogenesis remains incompletely established — the reason this is
      curated as a hypothesis rather than a settled chain.
- hypothesis_group_id: follicular_unit_initiation
  hypothesis_label: Follicular unit as the putative initiating target
  status: EMERGING
  description: >-
    An emerging refinement holds that the pilosebaceous (follicular) unit is
    the initial target of the inflammatory process in pyoderma gangrenosum,
    which would explain the frequent follicular-based onset of lesions as
    papules or pustules that then ulcerate, and the overlap of PG with other
    follicular neutrophilic diseases (acne, hidradenitis suppurativa) in the
    PASH/PAPASH spectrum. This is presented in the literature as increasingly
    recognized rather than established.
  evidence:
  - reference: PMID:35606650
    reference_title: "Pyoderma Gangrenosum: An Updated Literature Review on Established and Emerging Pharmacological Treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      involves a profound dysregulation of components of both innate and
      adaptive immunity in genetically predisposed individuals, with the
      follicular unit increasingly recognized as the putative initial target
    explanation: >-
      Directly states the follicular unit as the putative initial target, with
      the hedging ("increasingly recognized as the putative") that justifies an
      EMERGING rather than CANONICAL status.

- hypothesis_group_id: infectious_etiology
  hypothesis_label: Infectious etiology (historical, refuted)
  status: DEPRECATED
  description: >-
    The name "pyoderma gangrenosum" encodes a historical hypothesis that the
    disease is a pyogenic infection producing gangrene. Both halves are wrong.
    PG was initially thought to be an infectious disease and was subsequently
    reclassified as an inflammatory one; the lesion is sterile, culture is
    negative, exclusion of infection is a formal minor criterion of the
    validated Delphi definition, and the disease responds to immunosuppression
    rather than to antibiotics. This hypothesis is curated explicitly, rather
    than silently omitted, because the misnomer actively misleads — it is why
    PG ulcers are debrided as though infected, which triggers pathergy.
  evidence:
  - reference: PMID:40034857
    reference_title: "Gasdermin D-dependent neutrophil extracellular traps exacerbate cytokine storm contributing to pyoderma gangrenosum pathogenesis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Initially, PG was thought to be an infectious disease and was later
      corrected to be an inflammatory skin disease.
    explanation: >-
      Directly records that the infectious hypothesis was held historically and
      has been corrected, refuting it as the current model.
  - reference: PMID:40034857
    reference_title: "Gasdermin D-dependent neutrophil extracellular traps exacerbate cytokine storm contributing to pyoderma gangrenosum pathogenesis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pyoderma gangrenosum (PG) is characterized by the agonizing necrotizing
      ulcers with non-infectious neutrophil infiltration.
    explanation: >-
      States the infiltrate is non-infectious, contradicting an infectious
      etiology.
  - reference: PMID:29450466
    reference_title: "Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum: A Delphi Consensus of International Experts."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      8 minor criteria: (1) exclusion of infection; (2) pathergy
    explanation: >-
      Exclusion of infection being a formal diagnostic criterion is
      incompatible with an infectious etiology.

pathophysiology:
- name: Inflammasome Activation and IL-1 Overproduction
  biological_scale: MOLECULAR
  description: >-
    The proximal molecular lesion in pyoderma gangrenosum is exaggerated,
    inappropriately triggered activation of the inflammasome in innate immune
    cells of genetically predisposed individuals, leading to overproduction of
    interleukin-1 (IL-1beta and IL-1alpha). Protein-array profiling of PG
    lesional skin shows significantly higher expression of IL-1 beta and its
    receptor I than in normal skin, and IL-1beta is the pivotal cytokine
    driving the downstream exaggerated production of cytokines and chemokines
    that recruit neutrophils. This node is the point at which the monogenic
    PAPA/PSTPIP1 arm and the far commoner sporadic disease converge, and it is
    the rationale for IL-1 blockade as therapy.
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: Inflammasome-mediated signaling pathway
    term:
      id: GO:0141084
      label: inflammasome-mediated signaling pathway
    modifier: INCREASED
  - preferred_term: Interleukin-1 beta production
    term:
      id: GO:0032611
      label: interleukin-1 beta production
    modifier: INCREASED
  downstream:
  - target: Th17/Th1-Skewed Cytokine Amplification
    description: >-
      IL-1 overproduction drives the exaggerated secondary cytokine and
      chemokine output that amplifies the inflammatory response.
    hypothesis_groups:
    - autoinflammatory_neutrophil_model
  evidence:
  - reference: PMID:24903614
    reference_title: "Expression of cytokines, chemokines and other effector molecules in two prototypic autoinflammatory skin diseases, pyoderma gangrenosum and Sweet's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The expressions of interleukin (IL)-1 beta and its receptor I were
      significantly higher in PG
    explanation: >-
      Direct measurement of IL-1 beta and IL-1 receptor I overexpression in PG
      lesional skin versus controls, grounding this node in PG-specific data
      rather than extrapolation.
  - reference: PMID:29742056
    reference_title: "A dermatologic perspective on autoinflammatory diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These mutations cause an uncontrolled activation of the inflammasome
    explanation: >-
      Establishes uncontrolled inflammasome activation as the proximal
      mechanism in the IL-1-mediated autoinflammatory diseases of which PAPA
      syndrome (whose cutaneous hallmark is PG) is one.
  - reference: PMID:29742056
    reference_title: "A dermatologic perspective on autoinflammatory diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      is the pivotal cytokine which is responsible for the exaggerated
      production of cytokines and chemokines that induce the recruitment of
      neutrophils, key cells in autoinflammation
    explanation: >-
      Identifies IL-1beta as the pivotal cytokine linking inflammasome
      activation to the downstream chemokine output and neutrophil recruitment
      modeled by the next nodes.
- name: Th17/Th1-Skewed Cytokine Amplification
  biological_scale: CELLULAR
  description: >-
    Downstream of IL-1, a T helper 17/T helper 1-skewed adaptive layer amplifies
    the innate signal, producing high levels of tumor necrosis factor-alpha,
    IL-1beta, IL-1alpha, IL-8/CXCL8, IL-12, IL-15, IL-17, IL-23 and IL-36. In PG
    lesional skin specifically, the chemokines IL-8, CXCL1/2/3, CXCL16 and
    RANTES are over-expressed, and this chemokine signal is stronger than in
    Sweet syndrome. This profile is the direct rationale for the biologic
    therapies used in PG — TNF, IL-1, IL-17, IL-23 and complement C5a
    inhibitors — and it is why pyoderma gangrenosum sits at the interface of
    innate autoinflammation and adaptive immunity rather than being purely
    innate.
  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: Positive regulation of inflammatory response
    term:
      id: GO:0050729
      label: positive regulation of inflammatory response
    modifier: INCREASED
  downstream:
  - target: Neutrophil Recruitment to the Dermis
    description: >-
      The amplified cytokine/chemokine milieu (notably IL-8/CXCL8 and TNF)
      recruits neutrophils into the dermis.
    hypothesis_groups:
    - autoinflammatory_neutrophil_model
  evidence:
  - reference: PMID:24903614
    reference_title: "Expression of cytokines, chemokines and other effector molecules in two prototypic autoinflammatory skin diseases, pyoderma gangrenosum and Sweet's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In PG, chemokines such as IL-8
    explanation: >-
      Reports over-expression of the neutrophil-recruiting chemokine IL-8 (and
      CXCL1/2/3, CXCL16, RANTES) in PG lesional skin, the amplification output
      this node models.
  - reference: PMID:35606650
    reference_title: "Pyoderma Gangrenosum: An Updated Literature Review on Established and Emerging Pharmacological Treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      T helper 17/T helper 1-skewed inflammation and exaggerated inflammasome
      activation lead to a dysregulated neutrophil-dominant milieu
    explanation: >-
      Documents the Th17/Th1-skewed amplification layer sitting between
      inflammasome activation and the neutrophil-dominant effector state.
  - reference: PMID:37610614
    reference_title: "Pyoderma Gangrenosum: Treatment Options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an increasing number of studies on the positive effects of biologic
      therapies such as inhibitors of tumour necrosis factor
    explanation: >-
      The therapeutic responsiveness to cytokine-directed biologics supports
      these cytokines being mechanistically operative in the disease.
- name: Neutrophil Recruitment to the Dermis
  biological_scale: CELLULAR
  description: >-
    Driven by the amplified chemokine milieu, neutrophils undergo chemotaxis
    and migration into the dermis and become activated. Increased neutrophil
    granulocyte activity is the demonstrated cellular hallmark of the disease
    and the feature that places pyoderma gangrenosum within the neutrophilic
    dermatoses.
  cell_types:
  - preferred_term: Neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: Neutrophil chemotaxis
    term:
      id: GO:0030593
      label: neutrophil chemotaxis
    modifier: INCREASED
  - preferred_term: Neutrophil migration
    term:
      id: GO:1990266
      label: neutrophil migration
    modifier: INCREASED
  - preferred_term: Neutrophil activation
    term:
      id: GO:0042119
      label: neutrophil activation
    modifier: INCREASED
  downstream:
  - target: GSDMD-Dependent NETosis
    description: >-
      Recruited, activated neutrophils undergo gasdermin D-dependent formation
      of neutrophil extracellular traps.
    hypothesis_groups:
    - autoinflammatory_neutrophil_model
  - target: Sterile Neutrophilic Dermal Inflammation and Tissue Destruction
    description: >-
      Recruited, activated neutrophils accumulate as a dense sterile dermal
      infiltrate that destroys tissue.
    hypothesis_groups:
    - autoinflammatory_neutrophil_model
  evidence:
  - reference: PMID:37610614
    reference_title: "Pyoderma Gangrenosum: Treatment Options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      various auto-inflammatory phenomena with increased neutrophil granulocyte
      activity have been demonstrated
    explanation: >-
      Documents increased neutrophil granulocyte activity as the demonstrated
      cellular mechanism.
- name: JAK-STAT Pathway Overactivation
  biological_scale: MOLECULAR
  description: >-
    The JAK/STAT pathway is the common downstream transducer for most of the
    cytokines this entry already models (IL-6, IL-12, IL-23, interferons), and
    single-cell RNA sequencing with multiplex immunohistochemistry shows it
    significantly overactivated in PG lesions — particularly in advanced-stage
    lesions — driven chiefly by myeloid cells and T cells. The activation is
    associated with enhanced NET formation in myeloid cells and with aberrant
    Th17 / Th17.1 differentiation and plasticity, so it converges on two nodes
    already in this pathograph. Independent multi-omics work identifies JAK2 and
    STAT3 as the network hubs of an inflammatory module conserved between PG
    skin and IBD gut, which is the molecular candidate for the gut-skin axis
    behind PG's commonest systemic association. This node is the rationale for
    JAK inhibition (tofacitinib, baricitinib), which remains investigational.
  cell_types:
  - preferred_term: Myeloid cell
    term:
      id: CL:0000763
      label: myeloid cell
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  biological_processes:
  - preferred_term: JAK-STAT cascade
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    modifier: INCREASED
  downstream:
  - target: GSDMD-Dependent NETosis
    description: >-
      JAK/STAT overactivation in myeloid cells is associated with enhanced
      neutrophil extracellular trap formation.
    causal_link_type: DIRECT
    hypothesis_groups:
    - autoinflammatory_neutrophil_model
    evidence:
    - reference: PMID:42603447
      reference_title: "Preliminary exploration of effects of the JAK inhibitor tofacitinib on pyoderma gangrenosum: In vitro inhibition of NETs and Th17 differentiation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In vitro cell experiments further demonstrated that the JAK inhibitor
        tofacitinib suppresses STAT phosphorylation in myeloid and T cells,
        myeloid NETosis, and IL-17A production.
      explanation: >-
        Pharmacological JAK inhibition suppresses myeloid NETosis, supporting a
        causal JAK/STAT to NETosis edge.
  - target: Th17/Th1-Skewed Cytokine Amplification
    description: >-
      JAK/STAT overactivation drives aberrant Th17 and Th17.1 differentiation
      and IL-17A production.
    causal_link_type: DIRECT
    hypothesis_groups:
    - autoinflammatory_neutrophil_model
  evidence:
  - reference: PMID:42603447
    reference_title: "Preliminary exploration of effects of the JAK inhibitor tofacitinib on pyoderma gangrenosum: In vitro inhibition of NETs and Th17 differentiation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified significant overactivation of the JAK/STAT pathway in PG
      lesions-particularly in advanced stages-which, in terms of immune
      inflammation, is primarily driven by myeloid cells and T cells.
    explanation: >-
      Single-cell and multiplex-IHC evidence of JAK/STAT overactivation in human
      PG lesional tissue, establishing this node in the disease itself.
  - reference: PMID:42123319
    reference_title: "Integrative Multi-Omics Analysis and Computational Modeling Identifying Shared Inflammatory Pathways and JAK Inhibitor Targets in PG and IBD."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Transcriptomic analysis identified a cross-tissue conserved inflammatory
      module centered on the JAK-STAT pathway, with JAK2 and STAT3 identified as
      network hubs.
    explanation: >-
      Independent multi-omics support for a JAK-STAT-centred module shared
      between PG and IBD; graded PARTIAL and COMPUTATIONAL because the study is
      entirely in silico and states it lacks experimental validation.
- name: Complement C5a Generation and C5aR1 Signalling
  biological_scale: MOLECULAR
  description: >-
    Complement activation generates the anaphylatoxin C5a, which signals through
    its receptor C5aR1 on neutrophils. In pyoderma gangrenosum this is the named
    proximal driver of NET release: among the candidate inducers expressed in PG
    (IL-1 beta, IL-6, IL-8 and C5aR1), C5a is the most potent inducer of NETosis,
    acting dose-dependently within 30 minutes and specifically through C5aR1 and
    ERK — C5aR blockade with avacopan and ERK inhibition each abolish it. The
    axis is active in human disease, not only in culture: C5a in PG wound fluid
    is more than 6-fold higher than in traumatic wound fluid, at concentrations
    sufficient to induce NETosis, and correlates with neutrophil elastase levels.
    C5a is also a classical neutrophil chemoattractant, so it plausibly
    contributes to recruitment as well as to NET release; only the NETosis arm is
    modeled as a causal edge here.
  cell_types:
  - preferred_term: Neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: Complement activation
    term:
      id: GO:0006956
      label: complement activation
    modifier: INCREASED
  - preferred_term: Complement component C5a signaling pathway
    term:
      id: GO:0038178
      label: complement component C5a signaling pathway
    modifier: INCREASED
  downstream:
  - target: GSDMD-Dependent NETosis
    description: >-
      C5a signalling through C5aR1 and ERK induces neutrophil extracellular trap
      formation, making it the proximal driver of the NETosis effector node.
    causal_link_type: DIRECT
    hypothesis_groups:
    - autoinflammatory_neutrophil_model
    evidence:
    - reference: PMID:37516310
      reference_title: "NETosis Is Induced by Complement Component 5a: Implications in the Pathogenesis of Pyoderma Gangrenosum."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        These data demonstrate that C5a is the most potent inducer of NETosis
        among the candidates identified in our database.
      explanation: >-
        Establishes C5a as the most potent NETosis inducer among the candidates
        expressed in PG, which is the causal edge this link asserts.
    - reference: PMID:37516310
      reference_title: "NETosis Is Induced by Complement Component 5a: Implications in the Pathogenesis of Pyoderma Gangrenosum."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This indicates that C5a induced NETosis is specifically mediated through
        C5aR and ERK.
      explanation: >-
        Pharmacological dissection (avacopan, U0126) establishes the receptor and
        kinase route from C5a to NET formation.
  evidence:
  - reference: PMID:37516310
    reference_title: "NETosis Is Induced by Complement Component 5a: Implications in the Pathogenesis of Pyoderma Gangrenosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The average C5a level in PG wound fluid (8.5 ng/mg, n=32) was more than
      6-fold higher (P=0.0001) than the average level of C5a in wound fluid from
      traumatic wounds (1.3 ng/mg, n=13)
    explanation: >-
      Human PG wound-fluid measurement showing C5a is markedly elevated in
      disease versus traumatic-wound controls — the evidence that grounds this
      node in human disease rather than only in vitro.
  - reference: PMID:37516310
    reference_title: "NETosis Is Induced by Complement Component 5a: Implications in the Pathogenesis of Pyoderma Gangrenosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The elastase levels correlated significantly with the C5a levels in PG
      wound fluid (r=0.5861, P=0.0004)
    explanation: >-
      Correlation between C5a and neutrophil elastase in PG wound fluid
      indirectly supports C5a driving NET release in vivo.
- name: GSDMD-Dependent NETosis
  biological_scale: CELLULAR
  description: >-
    Activated neutrophils release neutrophil extracellular traps (NETs) —
    decondensed chromatin studded with granule proteins — by a process
    regulated by gasdermin D (GSDMD), whose pores release neutrophil elastase
    and myeloperoxidase during early NETosis. Serum NET levels (MPO-DNA
    complexes) are elevated in PG patients versus healthy controls and fall
    after effective treatment. This is the effector cell-death programme of the
    neutrophilic arm and the node the only available PG animal model addresses:
    GSDMD-knockout mice develop significantly less severe ulcers in the
    PG-serum transfer model. It amplifies the surrounding cytokine milieu,
    feeding back on the inflammatory response.
  cell_types:
  - preferred_term: Neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: Neutrophil extracellular trap formation
    term:
      id: GO:0140645
      label: neutrophil extracellular trap formation
    modifier: INCREASED
  downstream:
  - target: Sterile Neutrophilic Dermal Inflammation and Tissue Destruction
    description: >-
      NET release amplifies inflammatory cytokine output and contributes to the
      sterile neutrophilic tissue destruction that produces the ulcer.
    causal_link_type: DIRECT
    hypothesis_groups:
    - autoinflammatory_neutrophil_model
    evidence:
    - reference: PMID:40034857
      reference_title: "Gasdermin D-dependent neutrophil extracellular traps exacerbate cytokine storm contributing to pyoderma gangrenosum pathogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In GSDMD -/- mice, the severity of skin ulcers after modeling was
        significantly diminished.
      explanation: >-
        Genetic ablation of GSDMD reduces ulcer severity, establishing the
        causal contribution of GSDMD-dependent NETosis to ulceration.
  evidence:
  - reference: PMID:40034857
    reference_title: "Gasdermin D-dependent neutrophil extracellular traps exacerbate cytokine storm contributing to pyoderma gangrenosum pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we discovered that the serum levels of NETs were elevated in PG patients
      compared to healthy controls
    explanation: >-
      Demonstrates elevated NETs in PG patients versus controls, grounding this
      node in human data rather than only the mouse model.
  - reference: PMID:40034857
    reference_title: "Gasdermin D-dependent neutrophil extracellular traps exacerbate cytokine storm contributing to pyoderma gangrenosum pathogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Neutrophil extracellular traps (NETs) represent one of the mechanisms of
      neutrophils activation, and gasdermin D (GSDMD) plays a regulatory role
      in NETs.
    explanation: >-
      Establishes GSDMD as the regulator of NET formation, the molecular basis
      for naming this node GSDMD-dependent.
  - reference: PMID:29742056
    reference_title: "A dermatologic perspective on autoinflammatory diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pyoderma gangrenosum, which is the cutaneous hallmark of the PAPA
      syndrome, is a prototypic neutrophil-mediated skin disease
    explanation: >-
      Establishes PG as a prototypic neutrophil-mediated disease, supporting
      neutrophil recruitment as the central effector step.
- name: Sterile Neutrophilic Dermal Inflammation and Tissue Destruction
  biological_scale: TISSUE
  description: >-
    A dense, sterile (culture-negative) neutrophilic infiltrate accumulates in
    the dermis, most conspicuously at the advancing ulcer edge, and destroys
    dermal tissue. Over-expressed Fas/Fas ligand and CD40/CD40 ligand systems
    contribute to that tissue damage in PG. The absence of a causative organism
    is central: the inflammation is aseptic, which is why antibiotics do not
    resolve the lesion and why exclusion of infection is a formal diagnostic
    criterion. Biopsy of the ulcer edge demonstrating a neutrophilic infiltrate
    is the single major criterion in the Delphi consensus definition.
  cell_types:
  - preferred_term: Neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: Inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  downstream:
  - target: MMP-Mediated Extracellular Matrix Destruction
    description: >-
      The neutrophil-rich infiltrate releases matrix metalloproteinases that
      degrade dermal extracellular matrix.
    hypothesis_groups:
    - autoinflammatory_neutrophil_model
  - target: Progressive Cutaneous Ulceration with Undermined Violaceous Border
    description: >-
      Neutrophil-mediated dermal destruction manifests as the rapidly enlarging
      painful ulcer with an undermined violaceous border.
    hypothesis_groups:
    - autoinflammatory_neutrophil_model
  evidence:
  - reference: PMID:24903614
    reference_title: "Expression of cytokines, chemokines and other effector molecules in two prototypic autoinflammatory skin diseases, pyoderma gangrenosum and Sweet's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      contributing to tissue damage and inflammation
    explanation: >-
      Attributes tissue damage in PG to the over-expressed Fas/Fas ligand and
      CD40/CD40 ligand effector systems measured in lesional skin.
  - reference: PMID:29450466
    reference_title: "Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum: A Delphi Consensus of International Experts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      8 minor criteria: (1) exclusion of infection; (2) pathergy; (3) history
      of inflammatory bowel disease or inflammatory arthritis
    explanation: >-
      That exclusion of infection is a formal diagnostic criterion establishes
      the sterile (non-infectious) character of the neutrophilic infiltrate
      modeled by this node.
- name: MMP-Mediated Extracellular Matrix Destruction
  biological_scale: TISSUE
  description: >-
    Matrix metalloproteinases released within the neutrophil-rich infiltrate —
    principally MMP-2 and MMP-9, alongside neutrophil elastase from NETs —
    degrade dermal extracellular matrix and are the proximate effectors of
    tissue loss. Immunohistochemistry of PG lesions shows MMP-2 and MMP-9
    significantly elevated versus controls. Importantly this arm is
    subtype-graded rather than uniform: myeloperoxidase, IL-8 and MMP-9 are
    expressed more strongly in ulcerative and bullous PG than in vegetative PG,
    which is the mechanistic correlate of vegetative disease being the
    superficial, indolent, less destructive variant.
  cell_types:
  - preferred_term: Neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: Extracellular matrix disassembly
    term:
      id: GO:0022617
      label: extracellular matrix disassembly
    modifier: INCREASED
  downstream:
  - target: Progressive Cutaneous Ulceration with Undermined Violaceous Border
    description: >-
      MMP-mediated matrix degradation produces the tissue loss that constitutes
      the ulcer.
    causal_link_type: DIRECT
    hypothesis_groups:
    - autoinflammatory_neutrophil_model
    evidence:
    - reference: PMID:20636397
      reference_title: "Role of inflammatory cells, cytokines and matrix metalloproteinases in neutrophil-mediated skin diseases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our study identifies PG as a paradigm of neutrophil-mediated
        inflammation, with proinflammatory cytokines/chemokines and MMPs acting
        as important effectors for the tissue damage, particularly in ulcerative
        and bullous PG where damage is stronger.
      explanation: >-
        Identifies MMPs as important effectors of the tissue damage that
        produces the ulcer, which is the causal edge this link asserts.
  evidence:
  - reference: PMID:20636397
    reference_title: "Role of inflammatory cells, cytokines and matrix metalloproteinases in neutrophil-mediated skin diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myeloperoxidase (neutrophil marker), IL-8 (cytokine chemotactic for
      neutrophils) and MMP-9 (proteinase-mediating tissue damage) were expressed
      more significantly in both ulcerative and bullous PG than in vegetative PG
      as well as in Sweet's syndrome
    explanation: >-
      Quantifies the subtype gradient in MMP-9 (and MPO/IL-8) expression —
      stronger in ulcerative and bullous than vegetative PG — grounding both
      this node and the vegetative subtype's milder course.
  - reference: PMID:20636397
    reference_title: "Role of inflammatory cells, cytokines and matrix metalloproteinases in neutrophil-mediated skin diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In ulcerative PG, the wound bed is the site of neutrophil-recruitment,
      whereas in the wound edge activated T lymphocytes and macrophages pave the
      way to ulcer formation.
    explanation: >-
      Localizes the effector compartments — neutrophils in the wound bed, T
      cells and macrophages at the advancing edge — supporting the
      wound-margin adaptive contribution noted in the canonical hypothesis.
- name: Progressive Cutaneous Ulceration with Undermined Violaceous Border
  biological_scale: ORGANISM
  description: >-
    The converging neutrophilic process manifests clinically as the defining
    lesion: a painful, rapidly evolving cutaneous ulcer with undermined,
    irregular, erythematous-violaceous edges and a mucopurulent or hemorrhagic
    exudate. Rapid progression and a reddish-violaceous wound border are two of
    the three major criteria of the PARACELSUS diagnostic score, the border
    being present in 98% of patients. Healing characteristically leaves a
    cribriform scar, and the disease carries substantially increased mortality.
  evidence:
  - reference: PMID:35606650
    reference_title: "Pyoderma Gangrenosum: An Updated Literature Review on Established and Emerging Pharmacological Treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      clinically characterized by painful, rapidly evolving cutaneous ulcers
      with undermined, irregular, erythematous-violaceous edges
    explanation: >-
      Documents the clinical output of the pathophysiologic cascade — the
      painful, rapidly evolving undermined violaceous ulcer.
  - reference: PMID:29388188
    reference_title: "The PARACELSUS score: a novel diagnostic tool for pyoderma gangrenosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The three major diagnostic criteria are rapidly progressing disease,
      assessment of relevant differential diagnoses and a reddish-violaceous
      wound border (prevalent in 98% of patients with PG).
    explanation: >-
      Quantifies the violaceous wound border at 98% of patients and confirms
      rapid progression as a defining feature of the lesion.
- name: Pathergy - Trauma-Induced Lesion Initiation
  biological_scale: TISSUE
  description: >-
    Pathergy is the induction of new lesions, or the marked enlargement of
    existing ones, at sites of minor cutaneous trauma — needle sticks, biopsies,
    surgical incisions, or chronic mechanical irritation such as an ostomy
    appliance. Mechanistically it represents a lowered threshold for triggering
    the neutrophilic inflammatory cascade in already primed skin, so trauma
    locally initiates the same pathway rather than causing a distinct process.
    This node is clinically load-bearing rather than merely descriptive: it is
    why surgical debridement and defect closure can exacerbate the injury, and
    why postsurgical pyoderma gangrenosum is a recognized entity. Pathergy is a
    minor criterion in the Delphi consensus definition and appears in the
    PARACELSUS score as localization of the lesion at a site of trauma.
  downstream:
  - target: Sterile Neutrophilic Dermal Inflammation and Tissue Destruction
    description: >-
      Minor cutaneous trauma locally triggers the neutrophilic inflammatory
      cascade, initiating or enlarging a lesion at the injured site.
    causal_link_type: DIRECT
    hypothesis_groups:
    - autoinflammatory_neutrophil_model
    evidence:
    - reference: PMID:38250211
      reference_title: "Postsurgical Pyoderma Gangrenosum Requiring Plastic Surgical Intervention: A Practical Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Pyoderma gangrenosum is a neutrophilic dermatosis characterized by
        immune dysfunction and pathergy.
      explanation: >-
        Directly links pathergy to the neutrophilic dermatosis process, which
        is the causal edge this link asserts.
    - reference: PMID:38250211
      reference_title: "Postsurgical Pyoderma Gangrenosum Requiring Plastic Surgical Intervention: A Practical Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        However, both procedures may exacerbate the injury.
      explanation: >-
        Documents that surgical debridement and closure can worsen the lesion —
        the clinically load-bearing consequence of this pathergic edge.
  evidence:
  - reference: PMID:29388188
    reference_title: "The PARACELSUS score: a novel diagnostic tool for pyoderma gangrenosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      extreme pain > 4/10 on a visual analogue scale and localization of lesion
      at the site of the trauma
    explanation: >-
      Records localization of the lesion at the site of trauma (pathergy) as a
      scored minor diagnostic criterion for PG.
  - reference: PMID:38250211
    reference_title: "Postsurgical Pyoderma Gangrenosum Requiring Plastic Surgical Intervention: A Practical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, it is frequently seen in patients with underlying systemic
      illnesses or postoperatively.
    explanation: >-
      Supports trauma/surgery as a recognized setting in which PG lesions
      arise, the clinical expression of pathergy.
- name: PSTPIP1 Dysfunction (Monogenic PAPA Arm)
  biological_scale: MOLECULAR
  description: >-
    In PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum, and acne), an
    autosomal dominant autoinflammatory disease, missense variants in
    PSTPIP1/CD2BP1 (E250Q, A230T) severely reduce binding of the PSTPIP1
    adaptor to PEST-type protein tyrosine phosphatase. The resulting
    hyper-phosphorylated PSTPIP1 protein alters its participation in
    inflammasome activation, and overproduction of IL-1beta is a clear
    molecular feature of the syndrome. This is the clean Mendelian arm that
    links a defined molecular lesion to the same IL-1/inflammasome node that
    drives sporadic pyoderma gangrenosum, of which PG is the cutaneous
    hallmark. Note this node models the mechanistic arm only: PAPA syndrome
    itself (MONDO:0011462) is a distinct disease entity and is not curated
    here.
  molecular_functions:
  - preferred_term: PSTPIP1 binding to PEST-type protein tyrosine phosphatase
    term:
      id: GO:0001784
      label: phosphotyrosine residue binding
    modifier: DECREASED
  downstream:
  - target: Inflammasome Activation and IL-1 Overproduction
    description: >-
      Hyper-phosphorylated PSTPIP1 alters inflammasome participation, producing
      IL-1beta overproduction.
    causal_link_type: DIRECT
    hypothesis_groups:
    - autoinflammatory_neutrophil_model
    evidence:
    - reference: PMID:21532836
      reference_title: "Clinical, Molecular, and Genetic Characteristics of PAPA Syndrome: A Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These mutations produce a hyper-phosphorylated PSTPIP1 protein and
        alter its participation in activation of the
      explanation: >-
        States the causal edge directly: PSTPIP1 variants alter inflammasome
        activation, which the same sentence ties to interleukin-1 production.
  evidence:
  - reference: PMID:11971877
    reference_title: "Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Yeast two-hybrid assays demonstrate severely reduced binding between PTP
      PEST and both the E250Q and A230T mutant proteins.
    explanation: >-
      Documents the molecular consequence of the PAPA-causing PSTPIP1/CD2BP1
      variants — loss of PTP PEST binding — in a yeast two-hybrid assay.
  - reference: PMID:21532836
    reference_title: "Clinical, Molecular, and Genetic Characteristics of PAPA Syndrome: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      is a clear molecular feature of PAPA syndrome
    explanation: >-
      Confirms IL-1 overproduction as the established molecular outcome of the
      monogenic arm, connecting it to the shared IL-1 node.

phenotypes:
- category: Clinical
  name: Painful cutaneous ulcer with undermined violaceous border
  subtype: Ulcerative
  description: >-
    The defining lesion of classic ulcerative PG: a rapidly enlarging, deep,
    exquisitely painful ulcer with an undermined, irregular,
    erythematous-violaceous border. The violaceous border is present in 98% of
    patients and is one of the three PARACELSUS major criteria.
  phenotype_term:
    preferred_term: Cutaneous ulcer with undermined violaceous border
    term:
      id: HP:0025452
      label: Pyoderma gangrenosum
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:29388188
    reference_title: "The PARACELSUS score: a novel diagnostic tool for pyoderma gangrenosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The three major diagnostic criteria are rapidly progressing disease,
      assessment of relevant differential diagnoses and a reddish-violaceous
      wound border (prevalent in 98% of patients with PG).
    explanation: >-
      Quantifies the reddish-violaceous wound border at 98% of PG patients,
      supporting both the phenotype and the VERY_FREQUENT band (80-100%).
  - reference: PMID:35606650
    reference_title: "Pyoderma Gangrenosum: An Updated Literature Review on Established and Emerging Pharmacological Treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      clinically characterized by painful, rapidly evolving cutaneous ulcers
      with undermined, irregular, erythematous-violaceous edges
    explanation: Documents the undermined violaceous ulcer as the defining lesion.
- category: Clinical
  name: Severe ulcer pain
  description: >-
    Pain out of proportion to the size of the lesion is characteristic; extreme
    pain scored above 4/10 on a visual analogue scale is a minor criterion in
    the PARACELSUS score.
  phenotype_term:
    preferred_term: Severe pain at the ulceration site
    term:
      id: HP:0012531
      label: Pain
    severity: SEVERE
  evidence:
  - reference: PMID:29388188
    reference_title: "The PARACELSUS score: a novel diagnostic tool for pyoderma gangrenosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      extreme pain > 4/10 on a visual analogue scale
    explanation: >-
      Documents extreme pain as a scored diagnostic criterion for PG.
- category: Clinical
  name: Pathergy
  description: >-
    New lesions or marked enlargement of existing lesions at sites of minor
    trauma. Pathergy is a minor criterion in the Delphi consensus definition of
    ulcerative PG, is scored in the PARACELSUS instrument as localization of
    the lesion at a site of trauma, and underlies the clinical caution against
    debridement. A systematic review and meta-analysis of 21 studies (2611
    patients) attributed PG onset to the pathergy phenomenon in 16.3% of cases.
  phenotype_term:
    preferred_term: Pathergy (new or enlarging lesion induced at a site of minor trauma)
  frequency: OCCASIONAL
  notes: >-
    Deliberately NOT bound to an ontology term. Pathergy is trauma-induced
    lesion INITIATION, not a lesion morphology; HPO has no term for it, and the
    nearest candidates are all misleading. This phenotype previously carried
    HP:0200042 (Skin ulcer), which discarded the semantic content and made it
    indistinguishable from the three other Skin ulcer annotations in this file.
    Per the dismech-terms rule that no term beats a misleading or too-general
    one, the free-text `preferred_term` stands alone. NEEDS TERM / candidate
    HPO new-term request (NTR): pathergy is a formal scored criterion in both
    the Delphi consensus definition and the PARACELSUS score, and also occurs
    in Behcet disease, so a dedicated HP term would be reused. Raised in the
    PR #9115 review.
  evidence:
  - reference: PMID:29450466
    reference_title: "Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum: A Delphi Consensus of International Experts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      8 minor criteria: (1) exclusion of infection; (2) pathergy; (3) history
      of inflammatory bowel disease or inflammatory arthritis
    explanation: >-
      Lists pathergy explicitly among the validated minor diagnostic criteria
      for ulcerative pyoderma gangrenosum.
  - reference: PMID:29721816
    reference_title: "Underlying Systemic Diseases in Pyoderma Gangrenosum: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 16.3% (95% confidence interval 7.7-27.1) of cases, the onset of
      pyoderma gangrenosum was attributed to the pathergy phenomenon.
    explanation: >-
      Quantifies pathergy-attributed onset at 16.3% across 21 studies,
      supporting the OCCASIONAL frequency band (5-29%).
- category: Clinical
  name: Hemorrhagic bullae
  subtype: Bullous
  description: >-
    In the bullous (atypical) variant, rapidly extending superficial
    hemorrhagic bullae replace the deep ulcer of classic disease. This
    presentation is characteristically associated with myeloproliferative
    disease and should prompt hematologic evaluation.
  phenotype_term:
    preferred_term: Hemorrhagic bullae
    term:
      id: HP:0008066
      label: Abnormal blistering of the skin
  evidence:
  - reference: PMID:10773715
    reference_title: "Pyoderma gangrenosum as an early revelator of acute leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bullous pyoderma gangrenosum is an atypical, more superficial variety of
      the classical pyoderma and is often associated with myeloproliferative
      disorders.
    explanation: >-
      Characterizes the bullous variant as an atypical, more superficial form
      associated with myeloproliferative disorders.
- category: Clinical
  name: Sterile pustules
  subtype: Pustular
  description: >-
    Discrete painful sterile pustules characterize the pustular variant, which
    may remain pustular without progressing to frank ulceration. A history of a
    papule, pustule, or vesicle ulcerating within 4 days of appearing is a
    minor Delphi criterion, reflecting the pustular onset of many PG lesions.
  phenotype_term:
    preferred_term: Pustule
    term:
      id: HP:0200039
      label: Pustule
  evidence:
  - reference: PMID:25374597
    reference_title: "Pyoderma gangrenosum: a review of clinical features and outcomes of 23 cases requiring inpatient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The variants of PG noted were ulcerative (18), bullous (2), vegetative
      (2), and pustular (1).
    explanation: >-
      Documents the pustular variant as a recognized clinical form of PG in a
      consecutive inpatient cohort.
  - reference: PMID:29450466
    reference_title: "Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum: A Delphi Consensus of International Experts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      (4) history of papule, pustule, or vesicle ulcerating within 4 days of
      appearing
    explanation: >-
      Supports the pustular precursor lesion as a validated diagnostic feature,
      though this criterion describes onset in ulcerative PG rather than the
      pustular variant specifically.
- category: Clinical
  name: Superficial less-destructive vegetative lesion
  subtype: Vegetative
  description: >-
    The vegetative variant produces a more superficial, indolent and less
    destructive lesion than classic ulcerative or bullous PG. This is not only a
    clinical impression: immunohistochemistry shows myeloperoxidase, IL-8 and
    MMP-9 — the neutrophil marker, the neutrophil chemoattractant, and the
    tissue-damaging proteinase respectively — expressed significantly less in
    vegetative PG than in ulcerative and bullous PG, giving the milder
    phenotype a measured mechanistic correlate in reduced MMP-mediated matrix
    destruction.
  phenotype_term:
    preferred_term: Superficial vegetative cutaneous lesion
    term:
      id: HP:0200042
      label: Skin ulcer
  evidence:
  - reference: PMID:20636397
    reference_title: "Role of inflammatory cells, cytokines and matrix metalloproteinases in neutrophil-mediated skin diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myeloperoxidase (neutrophil marker), IL-8 (cytokine chemotactic for
      neutrophils) and MMP-9 (proteinase-mediating tissue damage) were expressed
      more significantly in both ulcerative and bullous PG than in vegetative PG
      as well as in Sweet's syndrome
    explanation: >-
      Quantifies reduced neutrophil-effector and MMP-9 expression in vegetative
      versus ulcerative/bullous PG, the distinguishing feature of this subtype.
  - reference: PMID:20636397
    reference_title: "Role of inflammatory cells, cytokines and matrix metalloproteinases in neutrophil-mediated skin diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Less commonly, bullous and vegetative variants exist.
    explanation: >-
      Confirms the vegetative variant as a recognized but less common form of
      PG.
- category: Clinical
  name: Peristomal ulceration
  subtype: Peristomal
  description: >-
    Ulceration in the skin immediately surrounding an abdominal stoma,
    occurring predominantly in patients with inflammatory bowel disease who
    have an ostomy.
  phenotype_term:
    preferred_term: Peristomal skin ulceration
    term:
      id: HP:0200042
      label: Skin ulcer
  evidence:
  - reference: PMID:32383278
    reference_title: "Risk factors and treatment outcomes of peristomal pyoderma gangrenosum in patients with inflammatory bowel disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Insufficient data exist for peristomal pyoderma gangrenosum (PPG), which
      primarily affects patients with inflammatory bowel disease (IBD).
    explanation: >-
      Establishes peristomal PG as a distinct clinical form arising in IBD
      patients with an ostomy.
  - reference: PMID:25374597
    reference_title: "Pyoderma gangrenosum: a review of clinical features and outcomes of 23 cases requiring inpatient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lesions were localised to lower limb in 13 patients, peristomal region in
      four, breast in three, and upper limb in one
    explanation: >-
      Quantifies peristomal localization (4 of 23) alongside the predominant
      lower-limb site in an inpatient PG cohort.
- category: Clinical
  name: Lower limb predilection
  subtype: Ulcerative
  description: >-
    Classic ulcerative PG shows a marked predilection for the lower legs;
    multiple ulcerations with at least one on an anterior lower leg is a minor
    Delphi criterion.
  phenotype_term:
    preferred_term: Skin ulcer of the lower limb
    term:
      id: HP:0200042
      label: Skin ulcer
  evidence:
  - reference: PMID:25374597
    reference_title: "Pyoderma gangrenosum: a review of clinical features and outcomes of 23 cases requiring inpatient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lesions were localised to lower limb in 13 patients, peristomal region in
      four, breast in three, and upper limb in one
    explanation: >-
      Documents the lower limb as the commonest site (13 of 23 patients).
  - reference: PMID:29450466
    reference_title: "Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum: A Delphi Consensus of International Experts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      (6) multiple ulcerations, at least 1 on an anterior lower leg
    explanation: >-
      Confirms anterior lower leg localization as a validated diagnostic
      criterion.
- category: Clinical
  name: Cribriform scarring
  subtype: Ulcerative
  description: >-
    Healed ulcers characteristically leave cribriform or "wrinkled paper"
    scars, a minor Delphi diagnostic criterion.
  phenotype_term:
    preferred_term: Cribriform ("wrinkled paper") scar
    term:
      id: HP:0100699
      label: Scarring
  evidence:
  - reference: PMID:29450466
    reference_title: "Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum: A Delphi Consensus of International Experts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cribriform or "wrinkled paper" scar(s) at healed ulcer sites
    explanation: >-
      Documents cribriform scarring at healed ulcer sites as a validated
      diagnostic criterion.

histopathology:
- name: Neutrophilic Infiltrate at the Ulcer Edge
  finding_term:
    preferred_term: Neutrophilic infiltrate on biopsy of the ulcer edge
    term:
      id: NCIT:C35978
      label: Inflammatory Infiltrate
  diagnostic: true
  description: >-
    Biopsy of the ulcer edge demonstrating a neutrophilic infiltrate is the
    single MAJOR criterion in the Delphi consensus diagnostic definition of
    ulcerative pyoderma gangrenosum. The infiltrate is sterile — cultures are
    negative and exclusion of infection is a separate minor criterion — which
    is what distinguishes it histologically and microbiologically from an
    infective ulcer. Suppurative inflammation on histopathology also features
    among the PARACELSUS criteria.
  evidence:
  - reference: PMID:29450466
    reference_title: "Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum: A Delphi Consensus of International Experts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This Delphi exercise produced 1 major criterion and 8 minor criteria for
      the diagnosis of ulcerative pyoderma gangrenosum.
    explanation: >-
      Confirms the single-major-criterion structure whose major criterion is
      the ulcer-edge neutrophilic infiltrate.
  - reference: PMID:29388188
    reference_title: "The PARACELSUS score: a novel diagnostic tool for pyoderma gangrenosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three additional criteria (observed in up to 60% of patients with PG)
      encompass suppurative inflammation in histopathology, undermined wound
      borders and systemic disease associated.
    explanation: >-
      Documents suppurative (neutrophilic) inflammation on histopathology as a
      scored diagnostic feature, observed in up to 60% of PG patients.

genetic:
- name: PSTPIP1
  notes: >-
    PSTPIP1 (also CD2BP1) encodes a proline-serine-threonine phosphatase
    interacting adaptor protein. Autosomal dominant missense variants (E250Q,
    A230T) cause PAPA syndrome, in which pyoderma gangrenosum is the cutaneous
    hallmark, by disrupting binding to PEST-type protein tyrosine phosphatase
    and dysregulating inflammasome-dependent IL-1beta production. PSTPIP1 is
    the causal gene of the monogenic PAPA/PASH/PAPASH spectrum rather than of
    common sporadic pyoderma gangrenosum, which is not a Mendelian disease; it
    is curated here because it anchors the IL-1 mechanism, not as a cause of
    sporadic PG. Typed MODIFIER for that reason.
  gene_term:
    preferred_term: PSTPIP1
    term:
      id: hgnc:9580
      label: PSTPIP1
  relationship_type: MODIFIER
  variants:
  - name: PSTPIP1 p.Ala230Thr (A230T)
    description: >-
      Missense substitution in the CDC15-homologous domain, co-segregating with
      PAPA syndrome and severely reducing PSTPIP1 binding to PEST-type protein
      tyrosine phosphatase. Pathogenic for PAPA syndrome, not for sporadic PG.
    type: missense variant
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: PSTPIP1
      term:
        id: hgnc:9580
        label: PSTPIP1
    evidence:
    - reference: PMID:11971877
      reference_title: "Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        E250Q or A230T amino acid substitutions occur within a domain highly
        homologous to yeast cleavage furrow-associated protein CDC15.
      explanation: >-
        Identifies A230T as one of the two originally reported PAPA-causing
        substitutions and localizes it to the CDC15-homologous domain.
  - name: PSTPIP1 p.Glu250Gln (E250Q)
    description: >-
      Missense substitution in the CDC15-homologous domain, co-segregating with
      PAPA syndrome and severely reducing PSTPIP1 binding to PEST-type protein
      tyrosine phosphatase. Pathogenic for PAPA syndrome, not for sporadic PG.
    type: missense variant
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: PSTPIP1
      term:
        id: hgnc:9580
        label: PSTPIP1
    evidence:
    - reference: PMID:11971877
      reference_title: "Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Yeast two-hybrid assays demonstrate severely reduced binding between
        PTP PEST and both the E250Q and A230T mutant proteins.
      explanation: >-
        Demonstrates the functional consequence of E250Q — loss of PTP PEST
        binding — in a yeast two-hybrid assay.
  evidence:
  - reference: PMID:11971877
    reference_title: "Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have now established this by the identification of co-segregating
      disease-causing mutations in the CD2-binding protein 1
    explanation: >-
      Establishes co-segregating disease-causing CD2BP1/PSTPIP1 mutations as
      the cause of PAPA syndrome.
  - reference: PMID:21532836
    reference_title: "Clinical, Molecular, and Genetic Characteristics of PAPA Syndrome: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      is an autosomal dominant, hereditary auto-inflammatory disease arising
      from mutations in the PSTPIP1/CD2BP1 gene on chromosome 15q
    explanation: >-
      Confirms PSTPIP1/CD2BP1 as the gene of the autosomal dominant PAPA
      syndrome in which PG is a defining feature.
- name: MEFV
  notes: >-
    MEFV encodes pyrin, an inflammasome component that PSTPIP1 binds, so MEFV
    sits on the same IL-1/inflammasome axis this entry's pathograph models.
    Typed SUSCEPTIBILITY rather than causal: sporadic PG is not Mendelian, and
    the cited source reports these as reported susceptibility genes, not as
    proven monogenic causes of common PG.
  gene_term:
    preferred_term: MEFV
    term:
      id: hgnc:6998
      label: MEFV
  relationship_type: SUSCEPTIBILITY
  evidence:
  - reference: PMID:40034857
    reference_title: "Gasdermin D-dependent neutrophil extracellular traps exacerbate cytokine storm contributing to pyoderma gangrenosum pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This disease has genetic susceptibility, and genes related to the onset
      of PG reported in the literature include PTPN6, PSTPIP1, MEFV, NLRP3,
      NLRP12, LPIN2, and NOD2
    explanation: >-
      Lists MEFV among the reported genetic-susceptibility genes for pyoderma
      gangrenosum onset.
- name: NLRP3
  notes: >-
    NLRP3 encodes the sensor of the canonical NLRP3 inflammasome, the assembly
    that licenses IL-1beta maturation — the proximal node of this entry's
    pathograph. Typed SUSCEPTIBILITY for the same reason as MEFV.
  gene_term:
    preferred_term: NLRP3
    term:
      id: hgnc:16400
      label: NLRP3
  relationship_type: SUSCEPTIBILITY
  evidence:
  - reference: PMID:40034857
    reference_title: "Gasdermin D-dependent neutrophil extracellular traps exacerbate cytokine storm contributing to pyoderma gangrenosum pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This disease has genetic susceptibility, and genes related to the onset
      of PG reported in the literature include PTPN6, PSTPIP1, MEFV, NLRP3,
      NLRP12, LPIN2, and NOD2
    explanation: >-
      Lists NLRP3 among the reported genetic-susceptibility genes for pyoderma
      gangrenosum onset.
- name: JAK2
  notes: >-
    JAK2 appears in the PG genetic literature from two independent directions.
    A systematic review of 208 articles describing 823 PG cases found two
    patients with JAK2 mutations (and two with MTHFR) — a very small share, so
    this is curated as a rare reported association, not a common determinant.
    Separately, computational multi-omics analysis identifies JAK2 (with STAT3)
    as a network hub of the inflammatory module shared between PG and IBD, and
    JAK2 is the target of the JAK inhibitors curated as investigational
    treatment. SCOPE CAUTION: the systematic review reports "mutations in JAK2"
    without specifying the allele or its somatic/germline origin, so this entry
    deliberately does NOT assert JAK2 V617F or a SOMATIC `variant_origin`,
    despite V617F being the canonical JAK2 allele in the myeloproliferative
    neoplasms that constitute part of PG's hematologic association. Asserting
    it would go beyond the cited sources.
  gene_term:
    preferred_term: JAK2
    term:
      id: hgnc:6192
      label: JAK2
  relationship_type: SUSCEPTIBILITY
  evidence:
  - reference: PMID:25350484
    reference_title: "The genetics of pyoderma gangrenosum and implications for treatment: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two patients had mutations in MTHFR and two had mutations in JAK2.
    explanation: >-
      Documents JAK2 mutations in PG, in 2 of 823 reviewed cases — supporting a
      rare association and nothing stronger.
  - reference: PMID:42123319
    reference_title: "Integrative Multi-Omics Analysis and Computational Modeling Identifying Shared Inflammatory Pathways and JAK Inhibitor Targets in PG and IBD."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      with JAK2 and STAT3 identified as network hubs
    explanation: >-
      Identifies JAK2 as a hub of the PG-IBD shared inflammatory module;
      COMPUTATIONAL because the study is entirely in silico.
- name: NOD2
  notes: >-
    NOD2 is the strongest Crohn disease susceptibility gene and is also
    reported among PG susceptibility genes — mechanistically interesting given
    that inflammatory bowel disease is PG's commonest systemic association.
    Typed SUSCEPTIBILITY.
  gene_term:
    preferred_term: NOD2
    term:
      id: hgnc:5331
      label: NOD2
  relationship_type: SUSCEPTIBILITY
  evidence:
  - reference: PMID:40034857
    reference_title: "Gasdermin D-dependent neutrophil extracellular traps exacerbate cytokine storm contributing to pyoderma gangrenosum pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This disease has genetic susceptibility, and genes related to the onset
      of PG reported in the literature include PTPN6, PSTPIP1, MEFV, NLRP3,
      NLRP12, LPIN2, and NOD2
    explanation: >-
      Lists NOD2 among the reported genetic-susceptibility genes for pyoderma
      gangrenosum onset.

prevalence:
- population: United Kingdom
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.63
  rate_low: 0.57
  rate_high: 0.71
  notes: >-
    Age-standardized (European standard population) incidence from the General
    Practice Research Database, the first population-based epidemiological
    study of PG.
  evidence:
  - reference: PMID:22534879
    reference_title: "Incidence, mortality, and disease associations of pyoderma gangrenosum in the United Kingdom: a retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The adjusted incidence rate standardized to European standard population
      was 0.63 (95% confidence interval (CI) 0.57-0.71) per 100,000
      person-years.
    explanation: >-
      Directly reports the population-based standardized incidence rate.

epidemiology:
- name: Associated systemic disease
  description: >-
    Associated systemic disease is frequent in pyoderma gangrenosum, but the
    reported proportion depends strongly on the setting. A UK population-based
    primary-care cohort found associations in 33% of patients (IBD 20.2%,
    rheumatoid arthritis 11.8%, hematological disorders 3.9%), whereas a
    hospital inpatient series found 47.8%. Both figures are curated with their
    populations rather than collapsed into the commonly quoted single "~50%"
    claim, because they are not measuring the same thing.
  evidence:
  - reference: PMID:22534879
    reference_title: "Incidence, mortality, and disease associations of pyoderma gangrenosum in the United Kingdom: a retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Disease associations were present in 110 (33%) participants: IBD, n=67
      (20.2%); RA, n=39 (11.8%); and hematological disorders, n=13 (3.9%).
    explanation: >-
      Provides the population-based breakdown of associated systemic disease.
  - reference: PMID:25374597
    reference_title: "Pyoderma gangrenosum: a review of clinical features and outcomes of 23 cases requiring inpatient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Associated systemic diseases were observed in 11 patients (47.8%).
    explanation: >-
      Provides the higher hospital-inpatient estimate, contrasted with the
      population-based figure.
- name: Pooled prevalence of underlying systemic disease (meta-analysis)
  description: >-
    The strongest single estimate comes from a systematic review and
    meta-analysis of 21 studies comprising 2611 patients: pooled prevalence of
    an associated systemic disease 56.8% (95% CI 45.5-67.4), led by
    inflammatory bowel disease (17.6%), arthritis (12.8%), hematological
    malignancies (8.9%) and solid malignancies (7.4%). This reconciles the
    range seen between the population-based (33%) and inpatient (47.8%)
    figures above, and is the number closest to the frequently quoted
    "about half of patients". Heterogeneity between the pooled studies was
    high, so the authors advise interpreting with caution.
  evidence:
  - reference: PMID:29721816
    reference_title: "Underlying Systemic Diseases in Pyoderma Gangrenosum: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The overall random-effects pooled prevalence of associated systemic
      diseases was 56.8% (95% confidence interval 45.5-67.4).
    explanation: >-
      Provides the pooled meta-analytic estimate across 21 studies and 2611
      patients.
  - reference: PMID:29721816
    reference_title: "Underlying Systemic Diseases in Pyoderma Gangrenosum: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The leading underlying disease was inflammatory bowel disease (17.6%;
      95% confidence interval 13.0-22.7), followed by arthritis (12.8%; 95%
      confidence interval 9.2-16.9), hematological malignancies (8.9%; 95%
      confidence interval 6.5-11.6), and solid malignancies (7.4%; 95%
      confidence interval 5.8-9.1).
    explanation: >-
      Breaks the pooled prevalence down by associated disease category.
- name: Solid malignancy is not an associated risk
  description: >-
    Despite solid malignancies appearing at 7.4% in the meta-analytic
    breakdown, a dedicated population-based cohort and case-control study found
    no association in either direction: the prevalence of preexisting solid
    malignancy was comparable in PG patients and matched controls, the odds of
    PG after a solid malignancy diagnosis were not increased, and PG patients
    were not more likely to develop one. The authors conclude that routine
    solid-malignancy screening in new-onset PG is unnecessary. This is curated
    as an explicit negative because the hematologic association is real and is
    easily over-generalized to malignancy as a whole.
  evidence:
  - reference: PMID:34076886
    reference_title: "Is pyoderma gangrenosum associated with solid malignancies? Insights from a population-based cohort study."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SM is not associated with provoking PG, and patients with PG are not at
      an increased risk of developing SM.
    explanation: >-
      Directly refutes a bidirectional association between solid malignancy and
      pyoderma gangrenosum.
  - reference: PMID:34076886
    reference_title: "Is pyoderma gangrenosum associated with solid malignancies? Insights from a population-based cohort study."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of a preexisting SM was comparable in patients with PG and
      controls (7.5% vs. 8.8%, respectively; P = 0.490).
    explanation: >-
      Quantifies the absence of excess preexisting solid malignancy in PG
      versus matched controls.
- name: Mortality
  description: >-
    Pyoderma gangrenosum carries substantially increased mortality — three
    times that of matched general population controls, and still 72% higher
    than that of matched inflammatory-bowel-disease controls, indicating the
    excess is not merely attributable to the associated systemic disease.
  evidence:
  - reference: PMID:22534879
    reference_title: "Incidence, mortality, and disease associations of pyoderma gangrenosum in the United Kingdom: a retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The risk of death was three times higher than that for general controls
      (adjusted hazard ratio=3.03, 95% CI 1.84-4.73, P<0.001)
    explanation: Quantifies the substantially increased mortality of PG.
  - reference: PMID:22534879
    reference_title: "Incidence, mortality, and disease associations of pyoderma gangrenosum in the United Kingdom: a retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      72% higher than that for IBD controls (adjusted hazard ratio=1.72, 95% CI
      1.17-2.59, P=0.013)
    explanation: >-
      Shows the mortality excess persists against IBD-matched controls, so it
      is not solely explained by the associated systemic disease.
- name: Age and sex distribution
  description: >-
    In the UK population-based cohort of 313 patients the median age was 59
    years (interquartile range 41-72) and 59% were female.
  evidence:
  - reference: PMID:22534879
    reference_title: "Incidence, mortality, and disease associations of pyoderma gangrenosum in the United Kingdom: a retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all there were 313 people with the median age of 59 (interquartile
      range 41-72) years, and of them 185 (59%) were female.
    explanation: Reports the age and sex distribution of PG in a population cohort.

diagnosis:
- name: Positive diagnosis using validated scoring systems
  description: >-
    Pyoderma gangrenosum was historically a diagnosis of exclusion, a status
    explicitly criticized as incompatible with clinical decision making and
    trial recruitment. Two validated instruments now permit a positive
    diagnosis: the Delphi consensus criteria for ulcerative PG (one major
    criterion plus at least 4 of 8 minor criteria) and the PARACELSUS score
    (a 10-criterion score, with 10 or more points indicating high likelihood).
    Exclusion of infection and consideration of relevant differential diagnoses
    remain formal components of both instruments rather than being superseded
    by them.
  evidence:
  - reference: PMID:37610614
    reference_title: "Pyoderma Gangrenosum: Treatment Options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite the limited understanding of the pathogenesis, it is no longer a
      diagnosis of exclusion, as it can now be made on the basis of validated
      scoring systems.
    explanation: >-
      States directly that validated scoring systems have replaced diagnosis by
      exclusion.
  - reference: PMID:19470075
    reference_title: "Pyoderma gangrenosum: an updated review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis, mainly based on the clinical presentation and course, is
      confirmed through a process of elimination of other causes of cutaneous
      ulcers.
    explanation: >-
      Documents the historical diagnosis-of-exclusion approach that the
      validated scores were developed to replace.
- name: Exclusion of mimickers and the misdiagnosis rate
  description: >-
    Rigorous exclusion of alternative causes of severe cutaneous ulceration is
    the substance of the diagnosis, and the cost of getting it wrong is
    measurable: in a consecutive series, 15 of 157 patients (10%) treated for
    presumed PG had another diagnosis — vascular occlusive or venous disease,
    vasculitis, cancer, primary infection, drug-induced or exogenous tissue
    injury, or another inflammatory disorder. Among misdiagnosed patients whose
    course was documented, 12% had ulcers actively exacerbated by PG-directed
    treatment, which is the clinical harm this exclusion step exists to
    prevent.
  evidence:
  - reference: PMID:12409543
    reference_title: "Skin ulcers misdiagnosed as pyoderma gangrenosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These 64 included 15 of the 157 consecutive patients treated for pyoderma
      gangrenosum at our institution (10 percent).
    explanation: >-
      Quantifies the misdiagnosis rate in a consecutive series of patients
      treated for presumed PG.
  - reference: PMID:12409543
    reference_title: "Skin ulcers misdiagnosed as pyoderma gangrenosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The final diagnoses were vascular occlusive or venous disease,
      vasculitis, cancer, primary infection, drug-induced or exogenous tissue
      injury, and other inflammatory disorders.
    explanation: >-
      Enumerates the mimicker categories that the exclusion work-up must cover.
  - reference: PMID:12409543
    reference_title: "Skin ulcers misdiagnosed as pyoderma gangrenosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      those in 8 (12 percent) were exacerbated by such treatment
    explanation: >-
      Documents active harm from PG-directed treatment given on a mistaken
      diagnosis.
- name: Evaluation for associated systemic disease
  description: >-
    Because a substantial proportion of patients have an associated systemic
    disease, evaluation should include assessment for inflammatory bowel
    disease, inflammatory/rheumatologic arthritis, paraproteinemia, and
    hematologic malignancy. A bullous (atypical) presentation in particular
    should prompt hematologic evaluation including blood and bone marrow
    examination.
  evidence:
  - reference: PMID:19470075
    reference_title: "Pyoderma gangrenosum: an updated review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pyoderma gangrenosum often occurs in association with a systemic disease
      such as inflammatory bowel disease, rheumatologic disease,
      paraproteinaemia, or haematological malignancy.
    explanation: >-
      Enumerates the associated systemic diseases that the work-up should
      address.
  - reference: PMID:10773715
    reference_title: "Pyoderma gangrenosum as an early revelator of acute leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the importance of regular blood and bone marrow examinations in patients
      with atypical bullous pyoderma gangrenosum
    explanation: >-
      Supports hematologic work-up specifically in the bullous variant.

definitions:
- name: Delphi consensus diagnostic criteria for ulcerative pyoderma gangrenosum
  definition_type: DIAGNOSTIC_CRITERIA
  derivation_basis: ESTABLISHED_CRITERIA
  validation_status:
    status: VALIDATED_AGAINST_GOLD_STANDARD
    rationale: >-
      Criteria were validated against peer-reviewed established cases of
      pyoderma gangrenosum and mimickers using k-fold cross-validation with
      multiple imputation. Receiver operating characteristic analysis showed
      that requiring 4 of 8 minor criteria maximized discrimination, giving
      sensitivity 86% and specificity 90%.
    evidence:
    - reference: PMID:29450466
      reference_title: "Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum: A Delphi Consensus of International Experts."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Receiver operating characteristic analysis revealed that 4 of 8 minor
        criteria maximized discrimination, yielding sensitivity and specificity
        of 86% and 90%, respectively.
      explanation: >-
        Reports the operating characteristics establishing the criteria as
        validated against a reference case/mimicker set.
  description: >-
    An international Delphi consensus (RAND/UCLA Appropriateness Method)
    yielding one major criterion — biopsy of the ulcer edge demonstrating a
    neutrophilic infiltrate — plus eight minor criteria: exclusion of
    infection; pathergy; history of inflammatory bowel disease or inflammatory
    arthritis; history of a papule, pustule, or vesicle ulcerating within 4 days
    of appearing; peripheral erythema, undermining border, and tenderness at the
    ulceration site; multiple ulcerations with at least one on an anterior lower
    leg; cribriform or "wrinkled paper" scars at healed ulcer sites; and
    decreased ulcer size within 1 month of starting immunosuppressive therapy.
    The major criterion plus at least 4 minor criteria supports the diagnosis.
    Scope is explicitly the ULCERATIVE variant; it is not validated for bullous,
    pustular, or vegetative PG.
  scope: Ulcerative pyoderma gangrenosum
  criteria_sets:
  - name: Major criterion
    minimum_required: 1
    description: >-
      Biopsy of the ulcer edge demonstrating a neutrophilic infiltrate.
  - name: Minor criteria
    minimum_required: 4
    description: >-
      Four or more of the eight minor criteria are required alongside the major
      criterion.
  evidence:
  - reference: PMID:29450466
    reference_title: "Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum: A Delphi Consensus of International Experts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      8 minor criteria: (1) exclusion of infection; (2) pathergy; (3) history
      of inflammatory bowel disease or inflammatory arthritis
    explanation: >-
      Enumerates the leading minor criteria of the validated Delphi definition.
  - reference: PMID:29450466
    reference_title: "Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum: A Delphi Consensus of International Experts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This Delphi exercise produced 1 major criterion and 8 minor criteria for
      the diagnosis of ulcerative pyoderma gangrenosum.
    explanation: Establishes the overall structure of the criteria set.
- name: Su criteria (2004)
  definition_type: DIAGNOSTIC_CRITERIA
  derivation_basis: ESTABLISHED_CRITERIA
  validation_status:
    status: UNVALIDATED
    rationale: >-
      The Su criteria are the historical two-major-plus-two-minor criteria set
      and remain one of the three diagnostic rating tools in current use, but
      unlike Delphi and PARACELSUS their sensitivity and specificity have not
      been reported in the literature. Curated as UNVALIDATED on that basis.
    evidence:
    - reference: PMID:41923959
      reference_title: "The utility of biopsy in pyoderma gangrenosum: a retrospective cohort study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the Su method (specific sensitivity and specificity data remain
        unreported in the existing literature)
      explanation: >-
        States directly that operating characteristics for the Su criteria are
        unreported, which is why this definition is UNVALIDATED while the other
        two are VALIDATED_AGAINST_GOLD_STANDARD.
  description: >-
    The Su et al. (2004) clinicopathologic criteria, the historical
    predecessor of the Delphi and PARACELSUS instruments and still one of the
    three rating tools in contemporary use. Curated for completeness alongside
    the other two. Note the cited abstract is unusually thin — it announces
    that criteria are proposed without enumerating them — so this entry
    deliberately does not reproduce a criteria list that cannot be verified
    from the cached record; the criteria themselves are in the full text.
  evidence:
  - reference: PMID:15533059
    reference_title: "Pyoderma gangrenosum: clinicopathologic correlation and proposed diagnostic criteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Herein, we suggest diagnostic criteria and some historical perspectives
      on the diagnosis of pyoderma gangrenosum.
    explanation: >-
      Establishes this publication as the source of the proposed Su diagnostic
      criteria set.
  - reference: PMID:41923959
    reference_title: "The utility of biopsy in pyoderma gangrenosum: a retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three scoring tools are available for the diagnosis of pyoderma
      gangrenosum: PARACELSUS, Su and Delphi.
    explanation: >-
      Confirms Su remains one of the three diagnostic rating tools in current
      use alongside the two curated above.
- name: PARACELSUS score
  definition_type: DIAGNOSTIC_CRITERIA
  derivation_basis: ESTABLISHED_CRITERIA
  validation_status:
    status: VALIDATED_AGAINST_GOLD_STANDARD
    rationale: >-
      Developed and assessed retrospectively against 60 participants with
      previously confirmed PG of the lower extremity and a control cohort of 50
      patients with venous leg ulcers, evaluated by expert teams at two tertiary
      wound-care centres. A total score of 10 or more points indicates high
      likelihood of PG and discriminates PG from venous leg ulcers. The control
      group was venous leg ulcers specifically, so discrimination against other
      mimickers is not established by this study.
    evidence:
    - reference: PMID:29388188
      reference_title: "The PARACELSUS score: a novel diagnostic tool for pyoderma gangrenosum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A total score value of 10 points or higher indicates a high likelihood
        of PG and differentiates PG from venous leg ulcers.
      explanation: >-
        States the validated threshold and the comparator against which the
        score was assessed.
  description: >-
    A 10-criterion diagnostic score whose criteria initials form the acronym
    PARACELSUS. Three major criteria: rapidly progressing disease, assessment
    of relevant differential diagnoses, and a reddish-violaceous wound border
    (present in 98% of PG patients). Four minor criteria (evident in 61-95% of
    patients): amelioration by immunosuppressant drugs, characteristically
    irregular ulcer shape, extreme pain above 4/10 on a visual analogue scale,
    and localization of the lesion at the site of trauma (pathergy). Three
    additional criteria (up to 60% of patients): suppurative inflammation on
    histopathology, undermined wound borders, and an associated systemic
    disease. Unlike the Delphi criteria it does not require a biopsy, which is
    useful when biopsy itself risks pathergy.
  criteria_sets:
  - name: Major criteria
    description: >-
      Rapidly progressing disease; assessment of relevant differential
      diagnoses; reddish-violaceous wound border.
  - name: Minor criteria
    description: >-
      Amelioration by immunosuppressant drugs; irregular ulcer shape; extreme
      pain > 4/10 on a visual analogue scale; localization at a site of trauma.
  - name: Additional criteria
    description: >-
      Suppurative inflammation on histopathology; undermined wound borders;
      associated systemic disease.
  evidence:
  - reference: PMID:29388188
    reference_title: "The PARACELSUS score: a novel diagnostic tool for pyoderma gangrenosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The three major diagnostic criteria are rapidly progressing disease,
      assessment of relevant differential diagnoses and a reddish-violaceous
      wound border (prevalent in 98% of patients with PG).
    explanation: Enumerates the three major criteria of the score.
  - reference: PMID:29388188
    reference_title: "The PARACELSUS score: a novel diagnostic tool for pyoderma gangrenosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Minor criteria (evident in 61-95% of patients with PG) include
      amelioration by immunosuppressant drugs, characteristically irregular
      shape of ulceration
    explanation: >-
      Enumerates the minor criteria tier and its prevalence range in PG
      patients.

differential_diagnoses:
- name: Sweet syndrome
  description: >-
    Sweet syndrome is the other prototypic neutrophilic dermatosis and shares
    the sterile dermal neutrophilic infiltrate, pathergy, and paraneoplastic
    potential, but produces abrupt tender edematous erythematous plaques and
    nodules that heal without scarring, rather than the deep, undermined,
    violaceous, cribriform-scarring ulcers of pyoderma gangrenosum. The two are
    kept as distinct dismech entities. Comparative protein-array profiling of
    the two diseases found chemokine-mediated signals lower in Sweet syndrome
    than in PG, which the authors propose explains PG's stronger local
    aggressiveness.
  distinguishing_features:
  - "Pyoderma gangrenosum: painful ulcers with undermined violaceous borders, cribriform scarring, strong pathergy"
  - "Sweet syndrome: abrupt tender edematous plaques/nodules with fever and neutrophilia, heal without scarring"
  disease_term:
    preferred_term: Sweet syndrome
    term:
      id: MONDO:0011959
      label: sweet syndrome
  evidence:
  - reference: PMID:24903614
    reference_title: "Expression of cytokines, chemokines and other effector molecules in two prototypic autoinflammatory skin diseases, pyoderma gangrenosum and Sweet's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The differences in expression profile of inflammatory effectors between
      these two disorders may explain the stronger local aggressiveness in PG
      than SS.
    explanation: >-
      Provides a mechanistic basis for the clinical distinction between PG and
      its closest differential, Sweet syndrome.
- name: Venous leg ulcer
  description: >-
    Venous leg ulceration is the single most important clinical mimic, because
    both favor the lower leg and are chronic. It was the explicit control
    cohort against which the PARACELSUS score was validated. Venous ulcers lack
    the rapidly progressing course, the reddish-violaceous undermined border,
    and the extreme disproportionate pain of PG.
  distinguishing_features:
  - "Pyoderma gangrenosum: rapidly progressing, reddish-violaceous undermined border, extreme pain, improves on immunosuppression"
  - "Venous leg ulcer: chronic indolent course, sloping non-undermined margin, venous insufficiency signs, improves with compression"
  evidence:
  - reference: PMID:29388188
    reference_title: "The PARACELSUS score: a novel diagnostic tool for pyoderma gangrenosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a control cohort of 50 patients with venous leg ulcers
    explanation: >-
      Confirms venous leg ulcer as the principal comparator mimic in the
      score's validation study.
- name: Cutaneous infection and necrotizing soft tissue infection
  description: >-
    Infective ulceration is the critical exclusion, and misdiagnosis runs in
    both directions: an infected ulcer treated as PG with immunosuppression, or
    PG debrided as though it were necrotizing infection, which triggers
    pathergy. Exclusion of infection is a formal minor criterion in the Delphi
    definition; PG lesions are culture-negative and do not respond to
    antibiotics.
  distinguishing_features:
  - "Pyoderma gangrenosum: sterile/culture-negative, no response to antibiotics, worsens with debridement (pathergy), responds to immunosuppression"
  - "Cutaneous/necrotizing infection: positive cultures, responds to antibiotics, requires surgical debridement"
  evidence:
  - reference: PMID:29450466
    reference_title: "Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum: A Delphi Consensus of International Experts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      8 minor criteria: (1) exclusion of infection; (2) pathergy
    explanation: >-
      Establishes exclusion of infection as a formal diagnostic criterion,
      making infective ulceration the key differential.
- name: Behcet disease
  description: >-
    Behcet disease is a variable-vessel vasculitis on the neutrophilic/
    autoinflammatory spectrum that also displays pathergy and can produce
    cutaneous ulceration, but is defined by recurrent oral and genital
    ulceration with ocular inflammation in a chronic relapsing multisystem
    course.
  distinguishing_features:
  - "Pyoderma gangrenosum: cutaneous ulcers with undermined violaceous borders, no obligate oral/genital ulceration"
  - "Behcet disease: recurrent oral and genital ulcers, uveitis, multisystem variable-vessel vasculitis"
  disease_term:
    preferred_term: Behcet disease
    term:
      id: MONDO:0007191
      label: Behcet disease

treatments:
- name: Systemic corticosteroids
  description: >-
    Systemic corticosteroids (prednisolone, typically 0.75 mg/kg/day) are one of
    the two first-line systemic therapies. In the STOP GAP randomised trial they
    did not differ from ciclosporin on speed of healing or any other objective
    or patient-reported outcome, with 47% of ulcers healed by six months in each
    arm; however serious adverse reactions, especially infections, were more
    common with prednisolone, so the choice between the two is driven by side
    effect profile and patient preference rather than efficacy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisolone
      term:
        id: CHEBI:8378
        label: prednisolone
  target_mechanisms:
  - target: Sterile Neutrophilic Dermal Inflammation and Tissue Destruction
    treatment_effect: INHIBITS
    description: >-
      Broad immunosuppression suppresses the neutrophilic dermal inflammatory
      process driving ulceration.
  evidence:
  - reference: PMID:26071094
    reference_title: "Comparison of the two most commonly used treatments for pyoderma gangrenosum: results of the STOP GAP randomised controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By six months, ulcers had healed in 28/59 (47%) participants in the
      ciclosporin group compared with 25/53 (47%) in the prednisolone group.
    explanation: >-
      Quantifies six-month healing under prednisolone in the largest randomised
      trial in PG.
  - reference: PMID:26071094
    reference_title: "Comparison of the two most commonly used treatments for pyoderma gangrenosum: results of the STOP GAP randomised controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      serious adverse reactions, especially infections, were more common in the
      prednisolone group
    explanation: >-
      Documents the safety signal that differentiates prednisolone from
      ciclosporin despite equivalent efficacy.
- name: Ciclosporin
  description: >-
    Ciclosporin (4 mg/kg/day, maximum 400 mg/day) is the other first-line
    systemic therapy and, together with corticosteroids, remains the systemic
    treatment of choice for most patients. The STOP GAP randomised controlled
    trial found no difference from prednisolone across objective and
    patient-reported outcomes.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ciclosporin
      term:
        id: CHEBI:4031
        label: cyclosporin A
  target_mechanisms:
  - target: Th17/Th1-Skewed Cytokine Amplification
    treatment_effect: INHIBITS
    description: >-
      Calcineurin inhibition suppresses T-cell cytokine production, damping the
      Th17/Th1 amplification layer.
  evidence:
  - reference: PMID:26071094
    reference_title: "Comparison of the two most commonly used treatments for pyoderma gangrenosum: results of the STOP GAP randomised controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prednisolone and ciclosporin did not differ across a range of objective
      and patient reported outcomes.
    explanation: >-
      Establishes therapeutic equivalence of ciclosporin and prednisolone in a
      randomised controlled trial.
  - reference: PMID:37610614
    reference_title: "Pyoderma Gangrenosum: Treatment Options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Corticosteroids and/or cyclosporine remain the systemic therapeutics of
      choice for most patients.
    explanation: >-
      Confirms corticosteroids and ciclosporin as the systemic therapies of
      choice.
- name: Infliximab (anti-TNF biologic therapy)
  description: >-
    Infliximab, a monoclonal antibody against tumour necrosis factor alpha, is
    the only agent with randomised placebo-controlled evidence in pyoderma
    gangrenosum. In the Brooklyn trial — the first randomised placebo-controlled
    trial of any drug for PG — a single 5 mg/kg infusion produced clinical
    improvement at week 2 in 46% versus 6% on placebo. Anti-TNF therapy is
    particularly relevant where PG coexists with inflammatory bowel disease, and
    achieved the highest medical complete-resolution rate (63%) in a peristomal
    PG cohort.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: infliximab
      term:
        id: NCIT:C1789
        label: Infliximab
  target_mechanisms:
  - target: Th17/Th1-Skewed Cytokine Amplification
    treatment_effect: INHIBITS
    description: >-
      TNF neutralization removes a principal cytokine of the amplification
      layer driving neutrophil recruitment.
    evidence:
    - reference: PMID:16188920
      reference_title: "Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This study has demonstrated that infliximab at a dose of 5 mg/kg is
        superior to placebo in the treatment of PG.
      explanation: >-
        Randomised placebo-controlled demonstration that TNF blockade
        therapeutically modifies the disease, supporting TNF as mechanistically
        operative.
  evidence:
  - reference: PMID:16188920
    reference_title: "Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At week 2, significantly more patients in the infliximab group had
      improved (46% (6/13)) compared with the placebo group (6% (1/17); p =
      0.025).
    explanation: >-
      Reports the primary endpoint of the only placebo-controlled randomised
      trial in PG.
  - reference: PMID:32383278
    reference_title: "Risk factors and treatment outcomes of peristomal pyoderma gangrenosum in patients with inflammatory bowel disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Higher rates of complete resolution were reported with anti-tumour
      necrosis factor (TNF) agents (63%) and surgical interventions (80%).
    explanation: >-
      Quantifies anti-TNF response in peristomal PG, the highest medical
      complete-resolution rate in that cohort.
- name: Interleukin-1 blockade
  description: >-
    IL-1 inhibition (anakinra, an IL-1 receptor antagonist; canakinumab and
    gevokizumab, anti-IL-1beta antibodies) is a mechanism-directed therapy
    targeting the inflammasome/IL-1 node that is the proximal lesion in PG —
    IL-1 beta and its receptor I are directly over-expressed in PG lesional
    skin — and the proven molecular defect in PSTPIP1-driven PAPA syndrome.
    IMPORTANT NEGATIVE QUALIFIER: mechanistic rationale has not translated into
    demonstrated efficacy. All three registered gevokizumab (anti-IL-1beta)
    trials in PG were terminated (NCT02315417, NCT02326740 and the open-label
    safety extension NCT02318914, all Phase 3), and the canakinumab study
    (NCT01302795) was an open-label Phase 2 pilot with no control arm. No
    randomised controlled trial has shown IL-1 blockade to be effective in PG.
    This treatment is therefore curated as a mechanistically motivated but
    unproven option, NOT as established therapy — see the
    `pg_trial_attrition` discussion.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anakinra
      term:
        id: CHEBI:231683
        label: Anakinra
  target_mechanisms:
  - target: Inflammasome Activation and IL-1 Overproduction
    treatment_effect: INHIBITS
    description: >-
      IL-1 receptor antagonism blocks signaling from the overproduced IL-1 that
      initiates the neutrophil-recruiting cascade. Note the cited evidence
      establishes that the drug target is over-expressed in PG lesional skin,
      which is the mechanistic rationale; it is not itself evidence of clinical
      efficacy.
    evidence:
    - reference: PMID:24903614
      reference_title: "Expression of cytokines, chemokines and other effector molecules in two prototypic autoinflammatory skin diseases, pyoderma gangrenosum and Sweet's syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The expressions of interleukin (IL)-1 beta and its receptor I were
        significantly higher in PG
      explanation: >-
        Establishes the drug target (IL-1 beta and its receptor I) as
        over-expressed in PG lesional skin, the mechanistic rationale for
        targeting this node.
  evidence:
  - reference: PMID:37610614
    reference_title: "Pyoderma Gangrenosum: Treatment Options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an increasing number of studies on the positive effects of biologic
      therapies such as inhibitors of tumour necrosis factor
    explanation: >-
      Supports the biologic class including IL-1 inhibitors as having reported
      positive effects; graded PARTIAL because this sentence groups IL-1
      blockade with other biologics rather than reporting a trial of it.
- name: Adalimumab (anti-TNF biologic therapy)
  description: >-
    Adalimumab is a TNF-alpha inhibitor approved for pyoderma gangrenosum in
    Japan on the basis of the Phase 3 open-label trial NCT03311464. A 52-week
    multicentre prospective postmarketing observational study of 67 patients
    reported Physician Global Assessment (total lesions) scores of 0/1 in 36.0%
    at week 12, 46.2% at week 26 and 57.7% at week 52, with infections reported
    as adverse drug reactions in 14.9% and serious ADRs in 9.0%. Effectiveness
    was seen across PG subtypes and in patients on concomitant systemic
    steroids.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: adalimumab
      term:
        id: NCIT:C65216
        label: Adalimumab
  target_mechanisms:
  - target: Th17/Th1-Skewed Cytokine Amplification
    treatment_effect: INHIBITS
    description: >-
      TNF neutralization removes a principal cytokine of the amplification
      layer driving neutrophil recruitment.
  evidence:
  - reference: PMID:42107018
    reference_title: "Safety and Effectiveness of Adalimumab for the Treatment of Pyoderma Gangrenosum: A 52-Week Real-World Prospective Observational Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proportions of patients with a PGA score (total lesions) of 0/1 at
      weeks 12, 26, and 52 were 36.0%, 46.2%, and 57.7%, respectively
    explanation: >-
      Quantifies adalimumab effectiveness over 52 weeks in a prospective
      multicentre PG cohort.
  - reference: PMID:42107018
    reference_title: "Safety and Effectiveness of Adalimumab for the Treatment of Pyoderma Gangrenosum: A 52-Week Real-World Prospective Observational Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings support its use as a standard treatment for PG, including
      in patients receiving concomitant systemic steroid therapy.
    explanation: >-
      The authors' conclusion supporting adalimumab as a standard PG treatment.
- name: Topical corticosteroid therapy (clobetasol propionate)
  description: >-
    Topical therapy — most commonly clobetasol propionate 0.05%, sometimes
    topical tacrolimus — is a genuine first-line option for limited disease,
    not merely an adjunct. In a prospective cohort of 66 UK patients whose PG
    was judged suitable for topical treatment, 43.8% of ulcers healed by 6
    months with a median time to healing of 145 days. It avoids the adverse
    effects of systemic immunosuppression, though whether more severe disease
    responds adequately to topical therapy alone remains unclear, and the study
    had no randomized comparator.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: clobetasol propionate
      term:
        id: CHEBI:31414
        label: clobetasol propionate
  target_mechanisms:
  - target: Sterile Neutrophilic Dermal Inflammation and Tissue Destruction
    treatment_effect: INHIBITS
    description: >-
      Locally delivered high-potency corticosteroid suppresses the neutrophilic
      dermal inflammatory process at the lesion itself.
  evidence:
  - reference: PMID:27502313
    reference_title: "Clinical outcomes and response of patients applying topical therapy for pyoderma gangrenosum: A prospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, 28 of 66 (43.8%) ulcers healed by 6 months.
    explanation: >-
      Quantifies healing under topical therapy in a prospective PG cohort.
  - reference: PMID:27502313
    reference_title: "Clinical outcomes and response of patients applying topical therapy for pyoderma gangrenosum: A prospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Topical therapy is potentially an effective first-line treatment for PG
      that avoids the possible side effects associated with systemic therapy.
    explanation: >-
      Supports topical therapy as a first-line option; graded PARTIAL because
      the study was a single-arm cohort without a randomized comparator.
- name: Complement C5a blockade (vilobelimab)
  description: >-
    Vilobelimab is a C5a-neutralizing monoclonal antibody targeting the
    complement node this entry models as the proximal driver of NETosis, and is
    the most direct test of that mechanism to date. IMPORTANT NEGATIVE
    QUALIFIER: the exploratory open-label Phase IIa trial (NCT03971643, OPTIMA)
    completed, but the subsequent randomised, double-blind, placebo-controlled
    Phase III trial in ulcerative PG (NCT05964413) was TERMINATED and the
    registry records the reason as futility. This treatment is curated because
    the target is mechanistically well evidenced in human PG wound fluid, NOT
    because efficacy is established — on current evidence it is a failed Phase
    III. Note the primary mechanistic paper itself anticipated a reason this
    might happen: C5a blockade alone may not suffice, because other neutrophil
    chemokines (IL-8, CXCL2) are independently over-expressed in PG lesional
    skin.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: vilobelimab
      term:
        id: NCIT:C172643
        label: Vilobelimab
  target_mechanisms:
  - target: Complement C5a Generation and C5aR1 Signalling
    treatment_effect: INHIBITS
    description: >-
      C5a neutralization removes the ligand for C5aR1, the proximal driver of
      NET release in PG.
  evidence:
  - reference: PMID:37516310
    reference_title: "NETosis Is Induced by Complement Component 5a: Implications in the Pathogenesis of Pyoderma Gangrenosum."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      NETosis induction by C5a provides a molecular basis for targeting C5a in
      PG therapy.
    explanation: >-
      States the mechanistic rationale for C5a-directed therapy in PG, which is
      why this treatment is curated despite the negative trial result.
  - reference: PMID:37516310
    reference_title: "NETosis Is Induced by Complement Component 5a: Implications in the Pathogenesis of Pyoderma Gangrenosum."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      However, C5a blockade alone may not be sufficient to block neutrophil
      infiltration in PG because other neutrophil chemokines such as IL-8 and
      CXCL2 are also overexpressed in PG lesional skin.
    explanation: >-
      The primary mechanistic paper's own caveat, which anticipates the
      redundancy that may underlie the Phase III futility result.
- name: JAK inhibition (tofacitinib, baricitinib)
  description: >-
    JAK inhibitors target the JAK/STAT node overactivated in PG lesions. In
    vitro, tofacitinib suppresses STAT phosphorylation in myeloid and T cells,
    myeloid NETosis, and IL-17A production — hitting three processes this
    pathograph models. Computational multi-omics work nominates baricitinib for
    the PG-IBD comorbid setting via the shared JAK2/STAT3 hub. EVIDENCE LEVEL:
    investigational only. Support is in vitro plus case reports and small
    series; the authors of the tofacitinib work describe their own evidence as
    preliminary, and the baricitinib nomination is a docking and
    systems-modelling prediction with no experimental validation. No controlled
    trial is curated, and no JAK inhibitor is approved for PG.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tofacitinib
      term:
        id: CHEBI:71200
        label: tofacitinib
  target_mechanisms:
  - target: JAK-STAT Pathway Overactivation
    treatment_effect: INHIBITS
    description: >-
      JAK inhibition suppresses STAT phosphorylation, damping the myeloid
      NETosis and Th17 arms downstream of this node.
    evidence:
    - reference: PMID:42603447
      reference_title: "Preliminary exploration of effects of the JAK inhibitor tofacitinib on pyoderma gangrenosum: In vitro inhibition of NETs and Th17 differentiation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In vitro cell experiments further demonstrated that the JAK inhibitor
        tofacitinib suppresses STAT phosphorylation in myeloid and T cells,
        myeloid NETosis, and IL-17A production.
      explanation: >-
        Directly demonstrates the drug acting on this node and its two
        downstream arms, in vitro.
  evidence:
  - reference: PMID:42603447
    reference_title: "Preliminary exploration of effects of the JAK inhibitor tofacitinib on pyoderma gangrenosum: In vitro inhibition of NETs and Th17 differentiation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      provide preliminary in vitro evidence supporting potential inhibitory
      effects of tofacitinib on key pathological processes of PG
    explanation: >-
      The authors' own characterization of the evidence as preliminary and in
      vitro, which is why this is curated as investigational.
  - reference: PMID:42123319
    reference_title: "Integrative Multi-Omics Analysis and Computational Modeling Identifying Shared Inflammatory Pathways and JAK Inhibitor Targets in PG and IBD."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Although this study provides multiscale computational simulation
      evidence, the lack of direct experimental validation of these predicted
      results necessitates further confirmation through in vitro and in vivo
      experiments.
    explanation: >-
      The computational study's own statement that its JAK-inhibitor
      predictions lack experimental validation.
- name: Wound care, pain control and avoidance of debridement
  description: >-
    Concomitant topical therapy, wound management and pain control should
    always be addressed alongside systemic treatment. Critically, because of
    pathergy, surgical debridement and defect closure may exacerbate the injury,
    so aggressive debridement of an active PG ulcer is generally avoided and
    surgery — where required for reconstruction — is undertaken only under
    adequate immunosuppression. Note that the peristomal cohort reported high
    resolution rates with surgical intervention (80%), so the caution is
    against reflexive debridement of misdiagnosed active disease rather than an
    absolute prohibition on surgery. A retrospective inpatient series makes the
    same point from the other direction: all three patients who underwent split
    skin grafting under immunosuppressive cover had no postoperative graft
    failure or pathergy, and the authors conclude surgery should be considered
    alongside immunosuppressive (and hyperbaric) therapy once disease is
    quiescent. The operative principle is therefore "not on active disease
    without cover", not "never".
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:37610614
    reference_title: "Pyoderma Gangrenosum: Treatment Options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, concomitant topical pharmacologic therapy, wound management
      and pain control should always be addressed.
    explanation: >-
      Establishes wound management and pain control as standard adjunctive
      care.
  - reference: PMID:38250211
    reference_title: "Postsurgical Pyoderma Gangrenosum Requiring Plastic Surgical Intervention: A Practical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Accurate diagnosis of PSPG, prevention of further surgical injury, and
      timely medical management are vital for improving patient outcomes.
    explanation: >-
      Supports prevention of further surgical injury as a management principle
      driven by pathergy.
  - reference: PMID:23903083
    reference_title: "Inpatient management of pyoderma gangrenosum: treatments, outcomes, and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 3 patients who underwent split skin grafting under immunosuppressive
      cover (with 2 having hyperbaric oxygen therapy) had no postoperative graft
      failure or pathergy.
    explanation: >-
      Counterweight to blanket surgical avoidance: grafting under
      immunosuppressive cover did not trigger pathergy. PARTIAL because n=3.
  - reference: PMID:23903083
    reference_title: "Inpatient management of pyoderma gangrenosum: treatments, outcomes, and clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgery should be considered in conjunction with combined hyperbaric and
      immunosuppressive therapy once the disease is quiescent
    explanation: >-
      States the conditional-surgery principle curated in this treatment's
      description.
- name: Treatment of associated systemic disease
  description: >-
    Because a third to nearly half of patients have an associated systemic
    disease — most often inflammatory bowel disease, inflammatory arthritis, or
    a hematologic disorder — identification and treatment of that disease is
    part of managing the dermatosis, and in some settings determines the choice
    of systemic agent (for example anti-TNF therapy where PG coexists with
    IBD).
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:25374597
    reference_title: "Pyoderma gangrenosum: a review of clinical features and outcomes of 23 cases requiring inpatient management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study also highlights the importance of early and aggressive
      treatment of patients admitted with PG as well as treating associated
      systemic diseases and wound infections.
    explanation: >-
      Directly recommends treating associated systemic disease as part of PG
      management.

animal_models:
- name: PG-serum transfer mouse (wild-type and GSDMD-knockout)
  species: Mouse
  genotype: Wild-type C57BL/6 and GSDMD-/-
  publication: PMID:40034857
  description: >-
    The only animal model of pyoderma gangrenosum curated here. Serum from PG
    patients is injected into the dorsal skin of wild-type mice, producing
    localized cutaneous ulcers with increased NETs and GSDMD in lesional skin
    and serum. Repeating the model in GSDMD-knockout mice significantly reduces
    ulcer severity, which is what makes it a perturbation experiment on the
    NETosis node rather than only a descriptive lesion model.
  modeled_mechanisms:
  - target: GSDMD-Dependent NETosis
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      GSDMD knockout removes the regulator of NET formation and attenuates
      ulceration, directly testing this node's causal contribution.
    limitations: >-
      Ulcers are induced by passive transfer of patient serum rather than
      arising spontaneously, so the model reproduces an effector arm rather
      than the upstream disease trigger. It does not recapitulate pathergy,
      the undermined violaceous border, cribriform scarring, the associated
      systemic diseases, or the corticosteroid/ciclosporin responsiveness that
      define human PG, and the knockout is constitutive rather than
      neutrophil-restricted.
    readouts:
    - name: Skin ulcer severity in GSDMD-knockout versus wild-type mice
      target: GSDMD-Dependent NETosis
      direction: DECREASED
      interpretation: >-
        Loss of GSDMD attenuates ulceration, indicating GSDMD-dependent NETosis
        contributes causally to lesion severity in this model.
      evidence:
      - reference: PMID:40034857
        reference_title: "Gasdermin D-dependent neutrophil extracellular traps exacerbate cytokine storm contributing to pyoderma gangrenosum pathogenesis."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In GSDMD -/- mice, the severity of skin ulcers after modeling was
          significantly diminished.
        explanation: Reports the knockout-versus-wild-type ulcer severity result.
    evidence:
    - reference: PMID:40034857
      reference_title: "Gasdermin D-dependent neutrophil extracellular traps exacerbate cytokine storm contributing to pyoderma gangrenosum pathogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Overall, our findings shed light on the role of GSDMD in regulating the
        production of NETs by neutrophils and the release of inflammatory
        factors in the pathogenesis of PG and establish an animal model for
        studying PG.
      explanation: >-
        The authors' own framing of the system as an animal model informative
        for GSDMD-regulated NET production in PG.
  - target: Progressive Cutaneous Ulceration with Undermined Violaceous Border
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Serum transfer produces localized cutaneous ulceration, but only the
      bare fact of ulcer formation — none of the features that make a PG ulcer
      diagnostically recognizable.
    limitations: >-
      The model yields localized ulcers without the undermined,
      erythematous-violaceous border, rapid centrifugal progression,
      disproportionate pain, or cribriform scarring that define the human
      lesion and constitute the major diagnostic criteria. Ulceration here is
      an induced endpoint, not a spontaneous relapsing disease course.
    readouts:
    - name: Cutaneous ulcer formation after PG-serum injection
      target: Progressive Cutaneous Ulceration with Undermined Violaceous Border
      direction: INCREASED
      interpretation: >-
        PG patient serum is sufficient to induce cutaneous ulceration in
        wild-type mouse skin.
      evidence:
      - reference: PMID:40034857
        reference_title: "Gasdermin D-dependent neutrophil extracellular traps exacerbate cytokine storm contributing to pyoderma gangrenosum pathogenesis."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Injection of serum from PG patients into the dorsal skin of wild-type
          mice led to the formation of localized cutaneous ulcers.
        explanation: Reports the induced ulceration endpoint of the model.
    evidence:
    - reference: PMID:40034857
      reference_title: "Gasdermin D-dependent neutrophil extracellular traps exacerbate cytokine storm contributing to pyoderma gangrenosum pathogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Injection of serum from PG patients into the dorsal skin of wild-type
        mice led to the formation of localized cutaneous ulcers.
      explanation: >-
        Supports treating the model as informative for the ulceration node,
        with the fidelity caveats recorded in `limitations`.

clinical_trials:
- name: NCT03311464
  phase: PHASE_III
  status: COMPLETED
  description: >-
    A Phase 3 multicentre, open-label, single-arm study of the efficacy and
    safety of adalimumab in active ulcer(s) of pyoderma gangrenosum in subjects
    in Japan. This trial underpins the Japanese approval of adalimumab for PG.
  target_phenotypes:
  - preferred_term: Cutaneous ulcer with undermined violaceous border
    term:
      id: HP:0025452
      label: Pyoderma gangrenosum
  evidence:
  - reference: clinicaltrials:NCT03311464
    reference_title: "A Phase 3 Multicenter, Open-Label, Single Arm Study of the Efficacy and Safety of Adalimumab in Active Ulcer(s) of Pyoderma Gangrenosum in Subjects in Japan"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This study is designed to investigate the efficacy, safety and
      pharmacokinetics of adalimumab in subjects in Japan with active ulcer(s)
      due to Pyoderma Gangrenosum (PG).
    explanation: >-
      ClinicalTrials.gov record establishing the trial's design and its PG
      indication.
- name: NCT03971643
  phase: PHASE_II
  status: COMPLETED
  description: >-
    OPTIMA: open-label exploratory Phase IIa trial of vilobelimab (IFX-1), a
    C5a-neutralizing antibody, in pyoderma gangrenosum. The Phase II step of the
    C5a-directed programme whose Phase III was subsequently terminated.
  target_phenotypes:
  - preferred_term: Cutaneous ulcer with undermined violaceous border
    term:
      id: HP:0025452
      label: Pyoderma gangrenosum
  evidence:
  - reference: clinicaltrials:NCT03971643
    reference_title: "Open Label Exploratory Phase IIa Trial to Investigate the Safety and Efficacy of IFX-1 in Treating Patients With Pyoderma Gangrenosum (OPTIMA)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The purpose of this study is to determine whether vilobelimab
      (development name: IFX-1) is safe and effective in the treatment of
      pyoderma gangrenosum.
    explanation: >-
      ClinicalTrials.gov record establishing the trial's drug and PG
      indication.
- name: NCT05964413
  phase: PHASE_III
  status: TERMINATED
  description: >-
    Randomised, double-blind, placebo-controlled, multicentre adaptive Phase III
    trial of vilobelimab in ulcerative pyoderma gangrenosum. TERMINATED; the
    ClinicalTrials.gov record gives the reason as "Study stopped for futility".
    This is the single most important negative result for the complement arm of
    this entry's pathograph and is why the C5a-blockade treatment is curated as
    a failed Phase III rather than as effective therapy.
  target_phenotypes:
  - preferred_term: Cutaneous ulcer with undermined violaceous border
    term:
      id: HP:0025452
      label: Pyoderma gangrenosum
  notes: >-
    Phase and status were taken from the ClinicalTrials.gov API record
    (overallStatus TERMINATED, phase PHASE3, whyStopped "Study stopped for
    futility"), not from the cached brief summary, which restates the trial
    title only.
- name: NCT02315417
  phase: PHASE_III
  status: TERMINATED
  description: >-
    Randomised, double-blind, placebo-controlled Phase III study of gevokizumab
    (anti-IL-1beta) in active ulcers of pyoderma gangrenosum. TERMINATED. One of
    three terminated gevokizumab registrations in PG.
  target_phenotypes:
  - preferred_term: Cutaneous ulcer with undermined violaceous border
    term:
      id: HP:0025452
      label: Pyoderma gangrenosum
  evidence:
  - reference: clinicaltrials:NCT02315417
    reference_title: "A Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of Gevokizumab in Treating Active Ulcers of Pyoderma Gangrenosum"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The study will evaluate the efficacy and safety of gevokizumab in treating
      active ulcers of pyoderma gangrenosum (PG).
    explanation: >-
      ClinicalTrials.gov record establishing the trial's drug and PG
      indication.
- name: NCT02326740
  phase: PHASE_III
  status: TERMINATED
  description: >-
    The second randomised, double-blind, placebo-controlled Phase III study of
    gevokizumab in active ulcers of pyoderma gangrenosum. TERMINATED.
  target_phenotypes:
  - preferred_term: Cutaneous ulcer with undermined violaceous border
    term:
      id: HP:0025452
      label: Pyoderma gangrenosum
  evidence:
  - reference: clinicaltrials:NCT02326740
    reference_title: "A Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of Gevokizumab in Treating Active Ulcers of Pyoderma Gangrenosum"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The study will evaluate the efficacy and safety of gevokizumab in treating
      active ulcers of pyoderma gangrenosum (PG).
    explanation: >-
      ClinicalTrials.gov record establishing the trial's drug and PG
      indication.
- name: NCT02318914
  phase: PHASE_III
  status: TERMINATED
  description: >-
    Two-year open-label safety extension study of gevokizumab in pyoderma
    gangrenosum, registered as Phase 3 and TERMINATED. Note this is the
    extension arm of the gevokizumab programme rather than a third independent
    randomised efficacy trial — it is curated separately because it is a
    distinct registration with its own terminated status.
  target_phenotypes:
  - preferred_term: Cutaneous ulcer with undermined violaceous border
    term:
      id: HP:0025452
      label: Pyoderma gangrenosum
  evidence:
  - reference: clinicaltrials:NCT02318914
    reference_title: "A 2-Year, Open-Label, Safety Extension Study of Gevokizumab in Patients With Pyoderma Gangrenosum"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The study will evaluate the long-term safety of gevokizumab in treating
      active PG ulcers
    explanation: >-
      ClinicalTrials.gov record establishing this as the long-term safety
      extension of the gevokizumab PG programme.
- name: NCT06624670
  phase: PHASE_III
  status: RECRUITING
  description: >-
    Multicentre, randomised, placebo-controlled, double-blind, parallel-group
    Phase III trial of spesolimab (anti-IL-36 receptor) in adults with
    ulcerative pyoderma gangrenosum requiring systemic therapy. RECRUITING at
    the time of curation — the main active late-phase trial in PG, and the test
    of the IL-36 arm of the cytokine profile this entry models.
  target_phenotypes:
  - preferred_term: Cutaneous ulcer with undermined violaceous border
    term:
      id: HP:0025452
      label: Pyoderma gangrenosum
  notes: >-
    Phase and status taken from the ClinicalTrials.gov API record
    (overallStatus RECRUITING, phase PHASE3). Status is time-sensitive and
    should be re-checked on future edits.
- name: NCT06092216
  phase: PHASE_II
  status: TERMINATED
  description: >-
    Phase II study characterizing PG lesion regression and remission by IL-36
    receptor targeting with spesolimab. TERMINATED; the registry records that
    the funding sponsor terminated the study in favour of a multicentre trial,
    so unlike the vilobelimab Phase III this termination is NOT a futility
    signal.
  target_phenotypes:
  - preferred_term: Cutaneous ulcer with undermined violaceous border
    term:
      id: HP:0025452
      label: Pyoderma gangrenosum
  evidence:
  - reference: clinicaltrials:NCT06092216
    reference_title: "Characterizing Pyoderma Gangrenosum Lesion Regression and Remission by IL-36 Receptor Targeting With Spesolimab"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The purpose of this research study is to assess the feasibility of using
      spesolimab in participants with moderate to severe pyoderma gangrenosum.
    explanation: >-
      ClinicalTrials.gov record establishing the trial's drug and PG
      indication.
- name: NCT01302795
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Phase II multicentre open-label pilot study of canakinumab, an anti-IL-1beta
    antibody, in pyoderma gangrenosum. Open-label with no control arm, so it
    supports the IL-1 rationale without establishing efficacy.
  target_phenotypes:
  - preferred_term: Cutaneous ulcer with undermined violaceous border
    term:
      id: HP:0025452
      label: Pyoderma gangrenosum
  evidence:
  - reference: clinicaltrials:NCT01302795
    reference_title: "A Phase II Multi Center Open Label Pilot Study To Assess a Potential Effect of an Anti-Il-1-Beta Antagonist in the Treatment of Pyoderma Gangrenosum"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This study is a prospective open label evaluation of Canakinumab (Ilaris)
      for treatment of subjects with pyoderma gangrenosum.
    explanation: >-
      Establishes the trial as an open-label evaluation — the design limitation
      that prevents it supporting efficacy.
- name: ISRCTN35898459
  phase: PHASE_IV
  status: COMPLETED
  description: >-
    STOP GAP: a multicentre, parallel group, observer blind randomised
    controlled trial across 39 UK hospitals comparing oral prednisolone
    0.75 mg/kg/day with ciclosporin 4 mg/kg/day in 121 patients with pyoderma
    gangrenosum, with speed of healing over six weeks as the primary outcome.
    Registered on ISRCTN rather than ClinicalTrials.gov, so keyed on its WHO
    ICTRP identifier.
  target_phenotypes:
  - preferred_term: Cutaneous ulcer with undermined violaceous border
    term:
      id: HP:0200042
      label: Skin ulcer
  evidence:
  - reference: ICTRP:ISRCTN35898459
    reference_title: "Study of treatments for pyoderma gangrenosum"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "| Main ID | ISRCTN35898459 |"
    explanation: >-
      WHO ICTRP registration record establishing the trial's identity and
      registry of origin.
  - reference: PMID:26071094
    reference_title: "Comparison of the two most commonly used treatments for pyoderma gangrenosum: results of the STOP GAP randomised controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Multicentre, parallel group, observer blind, randomised controlled trial.
    explanation: >-
      Documents the trial design reported in the primary publication.

discussions:
- discussion_id: pg_ibd_comorbidity_edge
  kind: INTERPRETATION
  status: OPEN
  prompt: >-
    Should the pyoderma gangrenosum-inflammatory bowel disease association be
    promoted to a structured comorbidity entry linking this entry to the
    existing Crohn_Disease and Ulcerative_Colitis entries?
  rationale: >-
    Inflammatory bowel disease is the single commonest systemic association of
    pyoderma gangrenosum (20.2% of patients in a UK population-based cohort),
    and PG appears reciprocally as an extraintestinal manifestation of IBD
    (1.2% of Crohn disease patients in a population-based study). PG is already
    curated as a phenotype inside Crohn_Disease.yaml. The Disease class has no
    comorbidities slot, so the relationship is recorded here rather than
    inline; a dedicated kb/comorbidities/ entry carrying the directional
    association and its EHR/cohort statistics is the natural follow-up, and is
    deliberately left out of scope of this entry's creation PR.

    The mechanistic content of that future edge is now partly specified. A
    multi-omics study reports Mendelian-randomization evidence that IBD is a
    causal risk factor for PG (not merely correlated), identifies six shared
    genetic loci, and finds a cross-tissue conserved inflammatory module
    centred on JAK-STAT with JAK2 and STAT3 as hubs — giving the gut-skin axis
    a candidate molecular substrate and a shared druggable target. That study
    is entirely computational and says so, so the causal direction is curated
    here as a computational finding rather than as settled fact; it is the
    strongest available specification of what a PG-IBD comorbidity entry should
    assert, and the reason the `JAK-STAT Pathway Overactivation` node exists in
    this entry.
  evidence:
  - reference: PMID:42123319
    reference_title: "Integrative Multi-Omics Analysis and Computational Modeling Identifying Shared Inflammatory Pathways and JAK Inhibitor Targets in PG and IBD."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      The results revealed that genetic analysis confirmed IBD as a causal risk
      factor for PG, precisely identifying six shared genetic loci.
    explanation: >-
      Provides a directional (IBD to PG) causal claim from Mendelian
      randomization plus shared loci — the substance of the proposed comorbidity
      edge. PARTIAL/COMPUTATIONAL because the study is in silico throughout.
  - reference: PMID:22534879
    reference_title: "Incidence, mortality, and disease associations of pyoderma gangrenosum in the United Kingdom: a retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Disease associations were present in 110 (33%) participants: IBD, n=67
      (20.2%); RA, n=39 (11.8%); and hematological disorders, n=13 (3.9%).
    explanation: >-
      Quantifies IBD as the commonest systemic association of PG in a
      population-based cohort.
  - reference: PMID:11316157
    reference_title: "The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pyoderma gangrenosum was more common in Crohn's (1.2%) with no gender
      predilection.
    explanation: >-
      Quantifies the reciprocal direction — PG prevalence among IBD patients —
      supporting a bidirectional comorbidity edge.
- discussion_id: pg_papa_entity_boundary
  kind: INTERPRETATION
  status: OPEN
  prompt: >-
    How should the boundary between sporadic pyoderma gangrenosum and the
    monogenic PAPA/PASH/PAPASH spectrum be modeled?
  rationale: >-
    PSTPIP1-driven PAPA syndrome (MONDO:0011462) provides the clean Mendelian
    demonstration that inflammasome-dependent IL-1beta overproduction can cause
    pyoderma gangrenosum, and PG is PAPA's cutaneous hallmark. But common
    sporadic PG is not a Mendelian disease and no causal gene is asserted for
    it here. This entry therefore curates PSTPIP1 as a mechanism-anchoring
    MODIFIER-typed gene rather than a causal gene of sporadic PG, and models
    the monogenic arm as an upstream pathophysiology node feeding the shared
    IL-1 node. PAPA syndrome itself remains an open curation stub and should be
    curated as its own Disease entry rather than folded in here; the PASH
    (PG, acne, suppurative hidradenitis) and PAPASH extensions overlap the
    existing Hidradenitis_Suppurativa entry and are likewise out of scope.
  attaches_to:
  - pathophysiology#PSTPIP1 Dysfunction (Monogenic PAPA Arm)
  evidence:
  - reference: PMID:21532836
    reference_title: "Clinical, Molecular, and Genetic Characteristics of PAPA Syndrome: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      is a clear molecular feature of PAPA syndrome
    explanation: >-
      Supports treating the monogenic arm as a demonstration of the IL-1
      mechanism while keeping PAPA a distinct entity.
- discussion_id: pg_trial_attrition
  kind: INTERPRETATION
  status: OPEN
  prompt: >-
    Why has every late-phase targeted trial in pyoderma gangrenosum failed or
    been terminated, and what does that imply for how this entry's mechanism
    nodes should be read?
  rationale: >-
    The curated trial record is dominated by attrition, and that negative
    pattern is itself the curated fact rather than an absence of data. Of the
    nine trials in this entry, five are terminated: all three gevokizumab
    (anti-IL-1beta) registrations (NCT02315417, NCT02326740, NCT02318914), the
    vilobelimab (anti-C5a) Phase III NCT05964413 — explicitly stopped for
    futility — and the spesolimab Phase II NCT06092216, which is the one
    non-futility termination (the sponsor redirected to a multicentre trial).
    Only infliximab (placebo-controlled, positive) and STOP GAP
    (prednisolone versus ciclosporin, no difference) reached informative
    completion, and adalimumab is approved on an open-label single-arm Phase 3.

    Three non-exclusive readings are worth holding open. (1) Mechanistic
    redundancy: the pathograph has multiple parallel neutrophil-recruiting
    inputs (C5a, IL-8/CXCL8, CXCL1/2/3, IL-36), so blocking any single one may
    be insufficient — the C5a primary paper anticipates exactly this. (2)
    Trial-design difficulty: PG had no validated diagnostic criteria until 2018
    and still has no validated response criteria, so cohorts may be
    heterogeneous and endpoints insensitive; the Delphi authors give patient
    selection for trials as an explicit motivation for their criteria. (3) The
    mechanism nodes may be correct as descriptions of the inflammatory state
    while being wrong as rate-limiting therapeutic targets — a node can be
    genuinely active in disease and still not be the lever.

    Curation consequence: no targeted agent in this entry may be presented as
    established therapy on mechanistic grounds alone. The IL-1 blockade and C5a
    blockade treatments both carry explicit negative qualifiers for this reason.
  attaches_to:
  - pathophysiology#Complement C5a Generation and C5aR1 Signalling
  - pathophysiology#Inflammasome Activation and IL-1 Overproduction
  evidence:
  - reference: PMID:37516310
    reference_title: "NETosis Is Induced by Complement Component 5a: Implications in the Pathogenesis of Pyoderma Gangrenosum."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      However, C5a blockade alone may not be sufficient to block neutrophil
      infiltration in PG because other neutrophil chemokines such as IL-8 and
      CXCL2 are also overexpressed in PG lesional skin.
    explanation: >-
      Supports the mechanistic-redundancy reading of the trial failures, stated
      by the authors of the C5a mechanism paper itself.
  - reference: PMID:29450466
    reference_title: "Diagnostic Criteria of Ulcerative Pyoderma Gangrenosum: A Delphi Consensus of International Experts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it is a "diagnosis of exclusion," a definition not compatible with
      clinical decision making or inclusion for clinical trials
    explanation: >-
      Supports the trial-design reading: the absence of usable diagnostic
      criteria was itself recognized as an obstacle to trial recruitment.
  - reference: PMID:35606650
    reference_title: "Pyoderma Gangrenosum: An Updated Literature Review on Established and Emerging Pharmacological Treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Low-evidence studies and a lack of validated diagnostic and response
      criteria have hindered the discovery and validation of new effective
      treatments for pyoderma gangrenosum.
    explanation: >-
      Directly attributes the failure to discover effective PG treatments to
      low-evidence studies and missing validated criteria.
- discussion_id: pg_biopsy_diagnostic_utility
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is biopsy of the ulcer edge genuinely required for the diagnosis of
    pyoderma gangrenosum, given that it is the sole major Delphi criterion yet
    is nonspecific, insensitive, and itself risks pathergy?
  rationale: >-
    This entry curates the ulcer-edge neutrophilic infiltrate as `diagnostic:
    true` histopathology because it is the single MAJOR criterion of the
    validated Delphi definition. That position is genuinely contested and the
    tension is recorded here rather than silently resolved in favour of either
    side. Against it: histological findings in PG are nonspecific, a
    retrospective cohort found that of 58 patients only 26 (45%) were biopsied
    and only 10 of those (38%) had a biopsy that contributed to the diagnosis,
    and the biopsy procedure itself can trigger pathergy — the mechanism this
    entry models as a causal edge. The PARACELSUS score was deliberately
    designed not to require biopsy, which is part of its practical appeal. For
    it: exclusion of infection and of the many mimickers is essential, and
    10% of patients treated for PG in a consecutive series turned out to have
    something else. The open question is not whether tissue is ever useful but
    whether a mandatory biopsy criterion improves or degrades net diagnostic
    accuracy once pathergy risk is priced in.
  attaches_to:
  - pathophysiology#Pathergy - Trauma-Induced Lesion Initiation
  evidence:
  - reference: PMID:41923959
    reference_title: "The utility of biopsy in pyoderma gangrenosum: a retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among 58 patients, 26 (45%) underwent biopsies, with only 10 (38%)
      contributing to a PG diagnosis.
    explanation: >-
      Quantifies the low diagnostic yield of biopsy in a consecutive PG cohort.
  - reference: PMID:41923959
    reference_title: "The utility of biopsy in pyoderma gangrenosum: a retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given risk of pathergy, nonspecific histopathological findings and low
      sensitivity, in our opinion, based on this small sample size, biopsies
      have limited diagnostic value for PG.
    explanation: >-
      States the contrary position directly, including the pathergy risk that
      makes this a mechanistically loaded question rather than a purely
      operational one.
  - reference: PMID:12409543
    reference_title: "Skin ulcers misdiagnosed as pyoderma gangrenosum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These 64 included 15 of the 157 consecutive patients treated for pyoderma
      gangrenosum at our institution (10 percent).
    explanation: >-
      Quantifies the misdiagnosis rate that argues for rigorous exclusion of
      mimickers, the consideration on the other side of this question.
- discussion_id: pg_pathogenesis_knowledge_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the initiating trigger of sporadic pyoderma gangrenosum, and is
    there an animal model that reproduces the integrated disease rather than
    one effector arm?
  rationale: >-
    Contemporary reviews state explicitly that the exact pathogenesis of
    pyoderma gangrenosum is not yet fully understood. The upstream trigger of
    sporadic disease is unknown and the follicular unit is only "increasingly
    recognized" as a putative initial target. An animal model now exists and is
    curated here (the PG-serum transfer mouse), but it reproduces the
    NETosis effector arm rather than the integrated syndrome: ulcers are
    induced by passive serum transfer, and the model shows neither pathergy,
    the undermined violaceous border, cribriform scarring, the associated
    systemic diseases, nor corticosteroid/ciclosporin responsiveness. So the
    gap is narrower than it was but not closed. Mechanistic understanding
    otherwise rests on human cohort, tissue and cytokine studies plus
    extrapolation from the monogenic PAPA arm. The low-evidence base is itself
    called out in the literature as having hindered discovery and validation of
    new treatments. The complement C5a/C5aR1 and MMP-2/MMP-9 effector arms
    previously tracked here as uncurated enrichment targets have since been
    curated as full nodes from primary sources, so they are no longer gaps. What
    remains genuinely open is upstream and therapeutic rather than descriptive:
    what initiates complement activation and inflammasome priming in sporadic PG
    in the first place, and why a pathograph this well characterized has yielded
    no successful targeted therapy — see `pg_trial_attrition`.
  attaches_to:
  - pathophysiology#Inflammasome Activation and IL-1 Overproduction
  evidence:
  - reference: PMID:35606650
    reference_title: "Pyoderma Gangrenosum: An Updated Literature Review on Established and Emerging Pharmacological Treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Low-evidence studies and a lack of validated diagnostic and response
      criteria have hindered the discovery and validation of new effective
      treatments for pyoderma gangrenosum.
    explanation: >-
      Documents the weak evidence base that constitutes this knowledge gap.

classifications:
  harrisons_chapter:
  - classification_value: DERMATOLOGY
    evidence:
    - reference: PMID:35606650
      reference_title: "Pyoderma Gangrenosum: An Updated Literature Review on Established and Emerging Pharmacological Treatments."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Pyoderma gangrenosum is a rare inflammatory skin disease classified
        within the group of neutrophilic dermatoses
      explanation: >-
        A rare inflammatory skin disease within the neutrophilic dermatoses
        supports a dermatology placement.
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:24903614
      reference_title: "Expression of cytokines, chemokines and other effector molecules in two prototypic autoinflammatory skin diseases, pyoderma gangrenosum and Sweet's syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Over-expression of cytokines/chemokines and molecules amplifying the
        inflammatory network supports the view that PG and SS are
        autoinflammatory diseases.
      explanation: >-
        The autoinflammatory, innate-immune-driven pathogenesis supports a
        secondary immune/rheumatologic placement, consistent with MONDO's
        autoinflammatory syndrome parent.

notes: >-
  Entry created for issue #9069. Curated from primary literature retrieved via
  the PubMed E-utilities API; every PMID was fetched with `just fetch-reference`
  and every snippet independently verified as an exact substring of the cached
  reference.

  DEEP RESEARCH. A `claude_code` deep-research run
  (research/Pyoderma_Gangrenosum-deep-research-claude_code.md) completed after
  the entry had already been drafted from primary literature, and was used only
  as a cross-check and lead source, not as the basis of the entry. Its own
  reference validation is clean (124/124 references resolved, 0 unresolved,
  2/2 quoted claims found in source, 0 off topic). `just preflight-dr` returns
  SKIP because MONDO records no causal gene (RO:0004003) for MONDO:0018824 —
  correct, since sporadic PG is not Mendelian — so the manual NEC preflight was
  run instead: `runoak -i sqlite:obo:mondo info MONDO:0018824 -O obo` confirms
  the label `pyoderma gangrenosum`, the Orphanet:48104 xref, and the two parents
  MONDO:0002922 (pyoderma) and MONDO:0019751 (autoinflammatory syndrome). The
  report's top gene is PSTPIP1 (19 mentions), which is the correct
  PG-associated gene, and the single OMIM it cites (604416) is PAPA syndrome,
  discussed correctly as the monogenic anchor rather than as PG itself — so no
  named entity confusion. The one substantive lead taken from the report was
  PMID:24903614 (Marzano 2014), which the report cited with a `[paraphrase]`
  marker; the real abstract was fetched and quoted verbatim instead.
  Following the PR #9115 review the report was consumed considerably more
  deeply: the GSDMD-dependent NETosis node, the PG-serum-transfer animal model,
  the susceptibility-gene set (MEFV/NLRP3/NOD2), adalimumab, topical
  clobetasol, the Su criteria, the biopsy-utility controversy, the
  systemic-disease meta-analysis, and the refuted infectious-etiology and
  solid-malignancy claims were all added — each from an independently fetched
  source quoted verbatim, never from the report's own paraphrases.

  A third review round closed the two effector arms that had been deferred. The
  earlier deferral reason recorded here — that no primary source had been
  "fetched and verified in this pass" — was an *effort* statement dressed as a
  scoping decision, and the reviewer was right to reject it: declining a claim
  because it is unsupported is legitimate, declining it because the work was not
  done is not. Both arms are now curated from disease-specific primary sources —
  `Complement C5a Generation and C5aR1 Signalling` (PMID:37516310: C5a is the
  most potent NETosis inducer among the candidates expressed in PG, acts through
  C5aR1 and ERK, and is more than 6-fold elevated in PG wound fluid) and
  `MMP-Mediated Extracellular Matrix Destruction` (PMID:20636397) — together
  with a `JAK-STAT Pathway Overactivation` node (PMID:42603447, PMID:42123319).
  The same round added the Phase II/III trial landscape. Nothing from the DR
  report is asserted on the report's own authority.

  TRIAL EVIDENCE DISCIPLINE. Five of the nine curated trials are terminated, and
  that negative record is curated as fact rather than omitted: the vilobelimab
  Phase III (NCT05964413) was stopped for futility and all three gevokizumab
  registrations were terminated. Consequently the C5a-blockade and IL-1-blockade
  treatments carry explicit negative qualifiers and must NOT be read as
  established therapy — a mechanism node can be genuinely active in disease and
  still not be the therapeutic lever, which is the point of the
  `pg_trial_attrition` discussion. Trial phase and status were taken from the
  ClinicalTrials.gov API rather than from the review or the DR report; that
  check found NCT02318914 is the open-label safety *extension* of the
  gevokizumab programme rather than a third independent randomised trial, and it
  is described as such.

  ENTITY SHAPE. MONDO:0018824 has four `is_a` children — MONDO:0035235 classic
  (exact synonym "Ulcerative pyoderma gangrenosum"), MONDO:0035236 pustular,
  MONDO:0035237 bullous, and MONDO:0035238 vegetative — and each of those four
  `has_subtypes` entries is bound to its MONDO term via `subtype_term`. The
  Peristomal subtype is correctly left unbound: MONDO has no term for it.
  (An earlier revision of this entry asserted that MONDO:0018824 had no
  children and rested the single-entry decision on that; the claim was false
  and has been removed rather than softened — see PR #9115 review and the
  correction on issue #9069.)

  The decision to model these as `has_subtypes` on one Disease entry rather
  than as four separate Disease entries does NOT rest on that ontology claim.
  It rests on the variants being differences of morphology, site and course
  within one disease process — the discriminator-expressible case — sharing a
  single pathograph, one set of diagnostic instruments, and one treatment
  ladder. Four of the five carry a real `subtype:` back-reference on a
  phenotype claim that actually differs by variant (issue #7082): Ulcerative
  (border/site/scarring), Bullous (hemorrhagic bullae, hematologic
  association), Pustular (sterile pustules), Peristomal (peristomal
  ulceration). Vegetative still has no phenotype back-reference — the sources
  available enumerate and quantify it without characterizing a distinguishing
  morphological feature in quotable form — but it is no longer bare: it now
  carries its MONDO binding, a quantified `subtype_frequency` (2 of 67), and
  its own evidence item.

  FRAMING. PG is curated as autoinflammatory, not infectious — MONDO's
  MONDO:0019751 parent is the mechanistically informative one and drives the
  pathograph. The name is a historical misnomer: the lesion is sterile, is not
  gangrene, and exclusion of infection is a formal diagnostic criterion.

  EVIDENCE DISCIPLINE. Greek letters and middle-dot decimal separators were
  avoided inside snippets where the cached rendering is ambiguous (PMID:29742056
  renders "(IL)- 1beta" with an interior space; PMID:24903614 uses "P = 0·0001"
  with a middle dot; PMID:21532836 uses a Unicode beta), so descriptions say
  "IL-1beta" while snippets quote only spans that are unambiguously present in
  the cached text. The ~50% associated-systemic-disease figure commonly quoted
  for PG is NOT asserted as a single number: the population-based cohort gives
  33% and a hospital inpatient series 47.8%, and both are curated with their
  populations because they are not measuring the same thing.

  SCOPE. PAPA syndrome (MONDO:0011462, PSTPIP1) is an open curation stub and is
  deliberately NOT curated here — it is cross-referenced as the monogenic arm
  only. A kb/comorbidities/ entry for the PG-IBD relationship is likewise left
  as tracked follow-up in `discussions`. No existing mechanism module was a
  clean fit: the closest conceptual neighbours (`granuloma_formation`,
  `fibrotic_response`) model different processes, and a neutrophilic-dermatosis
  or IL-1/inflammasome module does not exist, so no `conforms_to` is declared.
  Sweet_Syndrome already lists pyoderma gangrenosum as a differential diagnosis;
  this entry reciprocates, and the two are kept as distinct entities.

📚

References & Deep Research

References

15

PMID:16188920

Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial.