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Primary Polyarteritis Nodosa

Primary Polyarteritis Nodosa (Primary PAN): Comprehensive Disease Characteristics Report

2026-05-05
Falcon MONDO:0018593 Model: Edison Scientific Literature 39 citations

Primary Polyarteritis Nodosa (Primary PAN): Comprehensive Disease Characteristics Report

Executive summary (current understanding)

Primary polyarteritis nodosa (PAN) is a rare, systemic necrotizing vasculitis that predominantly targets medium-sized arteries and is classically distinguished from ANCA-associated vasculitis by absence of glomerulonephritis and typical ANCA negativity, with pathology showing segmental, transmural necrotizing arteritis with fibrinoid necrosis and without granulomas. (wolff2023polyarteritisnodosaold pages 1-2, chung20212021americancollegea pages 1-2, puechal2022polyarteritisnodosastate pages 1-2)

A major 2023–2024 development is the ongoing “re-framing” of what was historically called idiopathic PAN into (i) truly primary/idiopathic disease and (ii) PAN phenotypes driven by identifiable causes or mimics (e.g., HBV-associated PAN, monogenic ADA2 deficiency/DADA2, VEXAS), with important treatment implications (etiology-directed therapy rather than uniform immunosuppression). (wolff2023polyarteritisnodosaold pages 2-3, wolff2023polyarteritisnodosareviewed pages 8-9)

Evidence map table

The following table consolidates key evidence items and quantitative data for rapid curation.

Table (click to expand)
Domain Key points Quantitative data Key sources (with year, DOI/URL if known)
Identifiers / definitions Primary polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis of predominantly medium-sized arteries; diagnosis/classification emphasizes absence of glomerulonephritis, granulomas, and usually ANCA. CHCC 2012/overview definitions separate PAN from microscopic polyangiitis and other small-vessel vasculitides. ACR/VF 2021 guideline focuses on systemic, non-HBV PAN. CHCC wording summarized as necrotizing inflammation of medium/small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, venules; ACR/VF guideline issued 16 recommendations + 1 ungraded statement. Wolff et al., 2023, https://doi.org/10.3390/ijms242316668; Jennette, 2013, https://doi.org/10.1007/s10157-013-0869-6; Chung et al., 2021, https://doi.org/10.1002/acr.24633 (wolff2023polyarteritisnodosaold pages 1-2, chung20212021americancollegea pages 1-2, hocevar2021clinicalapproachto pages 1-2)
Key distinguishing features Distinguished from AAV/MPA by lack of pauci-immune glomerulonephritis and usual ANCA negativity; histology shows segmental, transmural necrotizing arteritis with fibrinoid necrosis and no granulomas; angiography may show aneurysms/stenoses of mesenteric, hepatic, and renal arteries. ACR 1990 criteria require >=3/10 items for classification. Wolff et al., 2023, https://doi.org/10.3390/ijms242316668; Hočevar et al., 2021, https://doi.org/10.1007/s11926-021-00983-2; Puéchal, 2022, https://doi.org/10.1016/j.jbspin.2021.105320 (wolff2023polyarteritisnodosaold pages 2-3, chung20212021americancollegea pages 1-2, hocevar2021clinicalapproachto pages 5-6, puechal2022polyarteritisnodosastate pages 1-2)
Epidemiology PAN is rare in Europe and has become less common since reduction of HBV-related disease; contemporary idiopathic PAN is considered uncommon. Adult cohorts show middle age at onset and male predominance. Prevalence in Europe about 2-31 per million; mean age ~51-54 years (one cohort 53.6 ± 18 years); male:female ratio ~1.5-1.7. Wolff et al., 2023, https://doi.org/10.3390/ijms242316668; Walter et al., 2024, https://doi.org/10.1186/s12872-024-03841-y (wolff2023polyarteritisnodosaold pages 1-2, wolff2023polyarteritisnodosaold pages 2-3, walter2024shiftingperspectivesin pages 7-9)
Etiologies / associations: HBV Historically a major cause; pathogenesis linked to HBsAg-containing immune complexes. Modern vaccination/public-health measures markedly reduced HBV-PAN frequency. HBV-associated PAN is treated differently from primary PAN. Historical importance high; no current pooled rate given in extracted evidence. Wolff et al., 2023, https://doi.org/10.3390/ijms242316668; Hočevar et al., 2021, https://doi.org/10.1007/s11926-021-00983-2; Puéchal, 2022, https://doi.org/10.1016/j.jbspin.2021.105320 (wolff2023polyarteritisnodosaold pages 2-3, wolff2023polyarteritisnodosareviewed pages 8-9, hocevar2021clinicalapproachto pages 1-2, puechal2022polyarteritisnodosastate pages 1-2)
Etiologies / associations: HCV, HIV, parvovirus B19 HCV has been reported but is uncommon in PAN; HIV has occasional associations; parvovirus B19 has been investigated without convincing enrichment versus controls in one PCR-based study. HCV association estimated at ~5% of PAN patients in reviewed evidence. Wolff et al., 2023, https://doi.org/10.3390/ijms242316668 (wolff2023polyarteritisnodosaold pages 2-3)
Etiologies / associations: drugs / vaccines Drug-induced PAN-like disease reported, including minocycline; post-COVID-19 vaccination PAN/cPAN-like cases have been reported, but causal inference remains limited. No robust incidence estimate available in extracted evidence. Wolff et al., 2023, https://doi.org/10.3390/ijms242316668 (wolff2023polyarteritisnodosaold pages 2-3)
Etiologies / associations: malignancy PAN can occur as a paraneoplastic/associated vasculitis, especially with hematologic disease including myelodysplastic syndrome (MDS); this is important in “secondary” PAN differential diagnosis. In one series of 70 patients with MDS and vasculitis, 9% had PAN. Wolff et al., 2023, https://doi.org/10.3390/ijms242316668 (wolff2023polyarteritisnodosaold pages 2-3)
Etiologies / associations: DADA2 / ADA2 Deficiency of ADA2 (CECR1/ADA2) is a key monogenic PAN mimic/cause, especially in early-onset disease; testing is important in childhood and young-adult PAN or unusual phenotypes. Anti-TNF therapy is favored in DADA2. >300 cases reported since 2014; 4.3% of 118 adults with idiopathic PAN had biallelic ADA2 pathogenic variants; in DADA2, ~85% manifest before age 12, mucocutaneous involvement ~75%, livedo reticularis ~50%, neurologic involvement ~51%, ischemic stroke ~27%. Wolff et al., 2023, https://doi.org/10.3390/ijms242316668; Hočevar et al., 2021, https://doi.org/10.1007/s11926-021-00983-2 (wolff2023polyarteritisnodosaold pages 1-2, wolff2023polyarteritisnodosaold pages 2-3, wolff2023polyarteritisnodosaold pages 7-8, hocevar2021clinicalapproachto pages 5-6, hocevar2021clinicalapproachto pages 1-2)
Etiologies / associations: VEXAS, FMF, SAVI VEXAS (UBA1 somatic mutations), FMF-associated PAN, and SAVI/interferonopathy-related PAN-like disease broaden PAN nosology and are key differentials in “primary” PAN workup. VEXAS inaugural cohort: 3/12 met PAN criteria; FMF-associated PAN prevalence ~0.9%. Wolff et al., 2023, https://doi.org/10.3390/ijms242316668 (wolff2023polyarteritisnodosaold pages 2-3)
Clinical phenotypes Heterogeneous multisystem disease with constitutional symptoms plus skin, peripheral nerve, GI, renal vascular, musculoskeletal, cardiac, CNS, and gonadal involvement. Orchitis/testicular pain is uncommon but relatively specific; coronary involvement may occur. >90% systemic symptoms in meta-analysis; fever ~52%, myalgia ~53%, cutaneous involvement ~56%; muscle biopsy diagnostic in up to 50%; cutaneous and myalgia common among relapsers. Wolff et al., 2023, https://doi.org/10.3390/ijms242316668; Taprantzis et al., 2026, https://doi.org/10.1007/s00296-026-06082-8; Walter et al., 2024, https://doi.org/10.1186/s12872-024-03841-y (wolff2023polyarteritisnodosaold pages 1-2, wolff2023polyarteritisnodosareviewed pages 7-8, taprantzis2026clinicalmanifestationsprognostic pages 1-2, walter2024shiftingperspectivesin pages 7-9)
Diagnostics: biopsy Tissue biopsy is the diagnostic gold standard when feasible. Recommended targets are symptomatic tissues (deep skin/subcutis, muscle, sural nerve; combined nerve+muscle biopsy if neuropathy). Deep skin biopsy is preferred over superficial punch because medium-sized vessels lie deeper. Histology: segmental necrotizing transmural inflammation with fibrinoid necrosis; muscle biopsy positive in up to 50% of cases. Chung et al., 2021, https://doi.org/10.1002/acr.24633; Hočevar et al., 2021, https://doi.org/10.1007/s11926-021-00983-2; Wolff et al., 2023, https://doi.org/10.3390/ijms242316668 (chung20212021americancollegea pages 5-6, chung20212021americancollegea pages 1-2, hocevar2021clinicalapproachto pages 5-6, wolff2023polyarteritisnodosareviewed pages 7-8)
Diagnostics: angiography / imaging Angiography is used when biopsy is not available or unsafe. Conventional angiography remains highest-resolution standard; CTA may better visualize distal mesenteric branches; MRA is an alternative when iodinated contrast is undesirable. Angiography can also define disease extent and detect aneurysms. Typical findings: saccular/fusiform aneurysms and stenotic lesions in mesenteric, hepatic, renal arteries. Chung et al., 2021, https://doi.org/10.1002/acr.24633; Hočevar et al., 2021, https://doi.org/10.1007/s11926-021-00983-2; Puéchal, 2022, https://doi.org/10.1016/j.jbspin.2021.105320 (chung20212021americancollegea pages 5-6, chung20212021americancollegea pages 1-2, hocevar2021clinicalapproachto pages 5-6, puechal2022polyarteritisnodosastate pages 1-2)
Diagnostics: labs / classification criteria No specific serologic biomarker exists for primary PAN. ANCA is typically absent and its presence should prompt reconsideration of AAV/MPA. ACR 1990 criteria remain widely cited but were developed before MPA separation; EMA algorithm plus CHCC definition improves classification. ACR 1990 sensitivity 82.2%, specificity 86.6%; later performance lower after MPA separation (sensitivity reportedly fell to 40.6% in re-evaluation). Lin et al., 2021, https://doi.org/10.1002/acr2.11189; Hočevar et al., 2021, https://doi.org/10.1007/s11926-021-00983-2; Puéchal, 2022, https://doi.org/10.1016/j.jbspin.2021.105320; Walter et al., 2024, https://doi.org/10.1186/s12872-024-03841-y (lin2021polyarteritisnodosaa pages 1-2, hocevar2021clinicalapproachto pages 5-6, puechal2022polyarteritisnodosastate pages 2-3, walter2024shiftingperspectivesin pages 7-9)
Prognosis / Five-Factor Score Prognosis is commonly stratified using the Five-Factor Score (FFS), which informs intensity of induction therapy. Poor-prognosis organ involvement drives morbidity and mortality. FFS items: proteinuria >1 g/day, creatinine >140 µmol/L, cardiomyopathy, severe GI involvement, CNS involvement (1 point each). Meta-analysis: relapse ~27%, mortality ~13%, remission ~65%. Wolff et al., 2023, https://doi.org/10.3390/ijms242316668; Taprantzis et al., 2026, https://doi.org/10.1007/s00296-026-06082-8 (wolff2023polyarteritisnodosareviewed pages 7-8, wolff2023polyarteritisnodosaold pages 7-8, taprantzis2026clinicalmanifestationsprognostic pages 1-2)
Treatment by severity: mild / FFS 0 For newly diagnosed nonsevere PAN, glucocorticoids are often effective, but guidelines and reviews increasingly favor adding a nonglucocorticoid immunosuppressant (AZA or MTX) to reduce relapse/steroid exposure. GC monotherapy associated with relapse concern; review cites ~40% relapse rate for mild PAN treated with GC alone. ACR/VF suggests AZA 2-3 mg/kg/day or MTX 0.3 mg/kg/week as options. Chung et al., 2021, https://doi.org/10.1002/acr.24633; Wolff et al., 2023, https://doi.org/10.3390/ijms242316668 (chung20212021americancollegea pages 5-6, wolff2023polyarteritisnodosareviewed pages 7-8, wolff2023polyarteritisnodosaold pages 7-8)
Treatment by severity: severe / FFS >0 Severe or organ-/life-threatening PAN is treated with pulse IV glucocorticoids or high-dose oral glucocorticoids plus cyclophosphamide; rituximab is not preferred first-line because evidence is sparse. If cyclophosphamide cannot be used, AZA/MTX may be combined with glucocorticoids rather than GC alone. Induction typically 3-6 months; prednisone about 1 mg/kg/day (max 60 mg/day); cyclophosphamide usually limited to <=6 months. One cited comparison found 12 monthly cyclophosphamide doses superior to a shorter 6-dose strategy for survival (HR 0.44) and sustained remission (HR 0.34) at 32 months. Chung et al., 2021, https://doi.org/10.1002/acr.24633; Walter et al., 2024, https://doi.org/10.1186/s12872-024-03841-y; Wolff et al., 2023, https://doi.org/10.3390/ijms242316668 (chung20212021americancollegea pages 5-6, walter2024shiftingperspectivesin pages 7-9, wolff2023polyarteritisnodosareviewed pages 7-8, wolff2023polyarteritisnodosaold pages 7-8)
Maintenance therapy After remission induction, cyclophosphamide should be transitioned to a less toxic maintenance agent such as azathioprine or methotrexate; maintenance generally continues 12-18 months, with some guidance allowing discontinuation after ~18 months of sustained remission. Maintenance duration commonly 12-18 months; French recommendations for systemic necrotizing vasculitides describe maintenance 12-48 months depending on context. Chung et al., 2021, https://doi.org/10.1002/acr.24633; Terrier et al., 2020, https://doi.org/10.1186/s13023-020-01621-3; Wolff et al., 2023, https://doi.org/10.3390/ijms242316668 (chung20212021americancollegea pages 5-6, wolff2023polyarteritisnodosareviewed pages 8-9, wolff2023polyarteritisnodosaold pages 7-8)
Refractory / relapsing disease Biologics are reserved for refractory/relapsing PAN or specific molecular subtypes. Evidence is limited to retrospective cohorts and case reports; etiology-directed therapy is increasingly emphasized (anti-TNF for DADA2; JAK inhibition/tocilizumab in selected VEXAS; disease-specific therapy for malignancy-associated PAN). European retrospective series complete remission: tocilizumab 50%, TNF inhibitors 40%, rituximab 33%. Wolff et al., 2023, https://doi.org/10.3390/ijms242316668 (wolff2023polyarteritisnodosareviewed pages 7-8, wolff2023polyarteritisnodosareviewed pages 8-9, wolff2023polyarteritisnodosaold pages 7-8)
HBV-PAN treatment HBV-associated PAN is managed differently from primary PAN: antiviral therapy is central, with short-course glucocorticoids and plasma exchange used in severe disease. Classic older trial data did not show benefit of plasma exchange added to steroids alone in non-HBV PAN/CSS, underscoring etiology-specific use. Older randomized trial in PAN/CSS: no superiority of steroids + plasma exchange over steroids alone; HBV-PAN recommendations are based largely on uncontrolled studies/guidelines rather than modern RCTs. Guillevin et al., 1992, https://doi.org/10.1002/art.1780350214; Hočevar et al., 2021, https://doi.org/10.1007/s11926-021-00983-2; Puéchal, 2022, https://doi.org/10.1016/j.jbspin.2021.105320 (hocevar2021clinicalapproachto pages 1-2, puechal2022polyarteritisnodosastate pages 1-2)

Table: This table consolidates core disease-characteristic evidence for primary polyarteritis nodosa, including definition, epidemiology, etiologic associations, phenotypes, diagnostic criteria, prognosis, and treatment. It is designed as a compact evidence map for knowledge-base curation and report drafting.

1. Disease information

1.1 What is the disease?

Definition (CHCC concept and modern reviews): PAN is defined as necrotizing inflammation of medium-sized (and sometimes small muscular) arteries, without glomerulonephritis and without vasculitis of arterioles/capillaries/venules. (puechal2022polyarteritisnodosastate pages 1-2)

Guideline clinical framing (ACR/Vasculitis Foundation 2021): PAN is a systemic necrotizing vasculitis of medium-sized vessels; typical clinical patterns include constitutional symptoms plus cutaneous, neurologic (peripheral neuropathy/mononeuritis multiplex), gastrointestinal, and renovascular manifestations; diagnosis is generally confirmed by biopsy of an affected organ or by angiography when biopsy cannot be obtained. (chung20212021americancollegea pages 1-2)

1.2 Key identifiers (ontology/coding)

ICD-10: Polyarteritis nodosa is commonly coded as M30.0 (standard clinical coding; not directly extracted from retrieved texts).

MeSH / MONDO / Orphanet: A specific MONDO ID and ORPHAcode for “primary/idiopathic systemic PAN” were not retrievable from the tool-accessible corpus in this run; knowledge base ingestion should pull these directly from MONDO and Orphanet inventories. (Evidence gap; see “Limitations”.)

1.3 Common synonyms / alternative names

1.4 Source types (patient-level vs aggregated)

Current understanding is derived from a mixture of (i) cohort/registry experience and guideline syntheses (ACR/VF 2021; French recommendations), (ii) older randomized trials in systemic necrotizing vasculitides, (iii) observational studies and case series in refractory disease, and (iv) increasingly, genotype-first studies that identify monogenic causes/mimics in “idiopathic” cohorts. (chung20212021americancollegea pages 5-6, wolff2023polyarteritisnodosaold pages 2-3)

2. Etiology

2.1 Disease causal factors (primary vs secondary)

Primary (idiopathic) PAN is diagnosed after excluding secondary causes (notably HBV) and important mimics/phenocopies (e.g., DADA2/ADA2 deficiency; VEXAS). Modern reviews emphasize that PAN is now better viewed as a spectrum where identifying an underlying driver changes management. (wolff2023polyarteritisnodosaold pages 2-3, wolff2023polyarteritisnodosareviewed pages 8-9)

2.2 Risk factors and associated conditions

Infectious associations

Drug-/vaccine-associated reports

Drug-induced PAN-like cases (e.g., minocycline) and post–COVID-19 vaccination temporal associations have been reported, but population-level causality is not established in the extracted evidence. (wolff2023polyarteritisnodosaold pages 2-3)

Malignancy associations

PAN may occur in association with hematologic malignancy, including myelodysplastic syndrome (MDS); in one referenced series, among 70 patients with MDS and vasculitis, 9% presented with PAN. (wolff2023polyarteritisnodosaold pages 2-3)

Genetic/monogenic causes and mimics (high priority in “primary PAN” workup)

2.3 Protective factors

No robust protective genetic or environmental factors were identified in the tool-accessible evidence.

2.4 Gene–environment interactions

Not specifically established in the retrieved evidence; a plausible interaction is genetic predisposition (e.g., ADA2 deficiency) plus infectious triggers, but this remains incompletely defined here. (wolff2023polyarteritisnodosaold pages 2-3)

3. Phenotypes (clinical features)

3.1 Core phenotype domains (with suggested HPO terms)

PAN can involve virtually any organ, with preferential involvement of skin, peripheral nervous system, and GI tract in many series/reviews. (wolff2023polyarteritisnodosaold pages 1-2)

Constitutional/systemic - Fever, asthenia/fatigue, weight loss (e.g., HP:0001945 Fever; HP:0001254 Lethargy/fatigue; HP:0001824 Weight loss). (wolff2023polyarteritisnodosaold pages 1-2, taprantzis2026clinicalmanifestationsprognostic pages 1-2)

Cutaneous - Livedo reticularis/racemosa (HP:0000973), subcutaneous nodules (HP:0001480), skin ulcers (HP:0001053), palpable purpura (HP:0000964). (chung20212021americancollegea pages 1-2, taprantzis2026clinicalmanifestationsprognostic pages 1-2)

Peripheral nervous system - Peripheral neuropathy and mononeuritis multiplex (HP:0009830 Peripheral neuropathy; HP:0001305 Mononeuritis multiplex). (chung20212021americancollegea pages 1-2, taprantzis2026clinicalmanifestationsprognostic pages 1-2)

Gastrointestinal/mesenteric ischemia - Abdominal pain (HP:0002027), bowel ischemia/perforation/bleeding (HP:0031944 Intestinal ischemia; HP:0004395 Gastrointestinal hemorrhage). (taprantzis2026clinicalmanifestationsprognostic pages 1-2)

Renovascular - Hypertension (HP:0000822), renal artery stenosis/aneurysm with hematuria/proteinuria (HP:0000790 Hematuria; HP:0000093 Proteinuria). (taprantzis2026clinicalmanifestationsprognostic pages 1-2)

Musculoskeletal - Myalgia (HP:0003326), arthralgia (HP:0002829). (taprantzis2026clinicalmanifestationsprognostic pages 1-2)

Cardiac - Coronary arteritis/stenosis/aneurysm leading to myocardial ischemia or heart failure (e.g., HP:0001658 Myocardial infarction; HP:0001635 Congestive heart failure). (wolff2023polyarteritisnodosaold pages 1-2, walter2024shiftingperspectivesin pages 7-9)

Genitourinary - Orchitis/testicular pain (HP:0000035 Orchitis; HP:0030547 Testicular pain). Orchitis is described as rare but relatively specific for PAN. (wolff2023polyarteritisnodosaold pages 1-2, wolff2023polyarteritisnodosareviewed pages 7-8)

3.2 Frequency/statistics from recent syntheses

A 2026 systematic review/meta-analysis (not within 2023–2024 but recent and quantitative) reported: fever ~52%, myalgia ~53%, cutaneous involvement ~56%, relapse ~27%, mortality ~13%, remission ~65%, and >90% with systemic manifestations. (taprantzis2026clinicalmanifestationsprognostic pages 1-2)

3.3 Quality-of-life impact

Direct validated QoL instruments (SF-36/EQ-5D) were not extractable from the retrieved texts; however, PAN is consistently framed as potentially disabling due to neuropathy, ischemic complications, and treatment toxicity. (chung20212021americancollegea pages 1-2)

4. Genetic/molecular information

4.1 Causal genes

Primary/idiopathic PAN is generally not monogenic, but a major modern development is recognition that a subset of cases labeled “idiopathic PAN” actually reflect monogenic vasculitis/vasculopathy, especially ADA2 (CECR1/ADA2) deficiency. (wolff2023polyarteritisnodosaold pages 2-3)

4.2 Pathogenic variants and molecular testing implications

  • ADA2 (CECR1/ADA2) biallelic pathogenic variants: detected in 4.3% of a 118-patient idiopathic adult PAN cohort; this supports routine consideration of ADA2 testing in early-onset/atypical or familial PAN-like disease. (wolff2023polyarteritisnodosaold pages 2-3)

Suggested molecular diagnostic actions (MAXO-style actions, illustrative): - ADA2 enzyme activity assay (MAXO:0000115 “enzyme activity measurement”) - CECR1/ADA2 sequencing (MAXO:0000127 “gene sequencing”) (hocevar2021clinicalapproachto pages 5-6)

4.3 Epigenetics / omics

No PAN-specific epigenetic or multi-omics profiling signatures were identified in the retrieved evidence.

5. Environmental information

No robust toxin/pollution/occupational exposures were identified. The dominant “environmental” component supported here is infectious association (HBV; occasional HCV/HIV reports). (wolff2023polyarteritisnodosaold pages 2-3)

6. Mechanism / pathophysiology

6.1 Core vascular lesion and inflammatory biology

Histopathology features emphasized in modern reviews include segmental, necrotizing, transmural arteritis with fibrinoid necrosis, microaneurysms, and mixed inflammatory infiltrates, typically without granulomas. (wolff2023polyarteritisnodosaold pages 2-3, chung20212021americancollegea pages 1-2)

Cytokine elevations and immune cell infiltrates reported in a 2023 review include IFN-α, IL-2, TNFα, and IL-1β, with macrophage and T-cell involvement in lesions. (wolff2023polyarteritisnodosaold pages 2-3)

6.2 Causal chain (generalized)

Upstream trigger (often unknown in primary PAN; or immune complexes in HBV-PAN; or intrinsic immune dysregulation in monogenic phenocopies) → medium-artery wall inflammation and fibrinoid necrosis → stenosis, thrombosis, aneurysm formation → tissue ischemia/hemorrhage in affected vascular territories → organ-specific manifestations (neuropathy, GI ischemia, renal ischemia/hypertension, skin ulcers/nodules, coronary events). (chung20212021americancollegea pages 1-2, wolff2023polyarteritisnodosaold pages 1-2)

6.3 Ontology suggestions

GO biological process (suggested): - GO:0006954 inflammatory response - GO:0002682 regulation of immune system process - GO:0001525 angiogenesis (aneurysm/repair context) - GO:0007596 blood coagulation (thrombosis complications)

Cell Ontology (CL) (suggested): - Macrophage (CL:0000235) - T cell (CL:0000084) - Endothelial cell (CL:0000115) - Vascular smooth muscle cell (CL:0000192)

UBERON anatomy (suggested): - Medium-sized artery / muscular artery (e.g., UBERON:0001637 artery; more specific vessel terms should be selected per organ) - Mesenteric artery, renal artery, hepatic artery

(These ontology mappings are proposed based on described biology; no ontology IDs were explicitly enumerated in the retrieved texts.)

7. Anatomical structures affected

Primary: medium-sized arteries, especially visceral arterial branches (mesenteric, hepatic, renal) with aneurysms/stenoses; skin and peripheral nerve involvement are common. (chung20212021americancollegea pages 1-2, wolff2023polyarteritisnodosaold pages 1-2)

Secondary/complications: mesenteric infarction/hemorrhage, cardiac ischemia, cerebrovascular events, renal ischemia/hypertension. (wolff2023polyarteritisnodosaold pages 1-2, walter2024shiftingperspectivesin pages 7-9)

8. Temporal development

Typical presentation is adult-onset in many cohorts (mean ~early 50s) with male predominance, though monogenic mimics (DADA2) often present in childhood. (wolff2023polyarteritisnodosaold pages 1-2, wolff2023polyarteritisnodosaold pages 7-8)

Disease course may be relapsing, with relapse estimates around ~27% in pooled data. (taprantzis2026clinicalmanifestationsprognostic pages 1-2)

9. Inheritance and population

9.1 Epidemiology

Reported European prevalence range in modern reviews is ~2–31 per million. (wolff2023polyarteritisnodosaold pages 1-2)

Demographics in a contemporary cohort cited in a 2023 review: mean age 53.6 ± 18 years, male predominance with sex ratio ~1.5. (wolff2023polyarteritisnodosaold pages 2-3)

9.2 Genetic etiologies and inheritance (for mimics)

10. Diagnostics

10.1 Clinical criteria/classification

ACR 1990 PAN classification criteria: ≥3 of 10 items yields sensitivity 82.2% and specificity 86.6% for classification; limitations recognized because criteria predate separation of microscopic polyangiitis. (walter2024shiftingperspectivesin pages 7-9, puechal2022polyarteritisnodosastate pages 2-3)

CHCC definition (quoted in a 2022 state-of-the-art review): “Necrotising inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules.” (puechal2022polyarteritisnodosastate pages 1-2)

10.2 Laboratory testing

There is no specific serologic biomarker for primary PAN; ANCA negativity supports PAN classification, and ANCA positivity should raise suspicion for AAV/MPA rather than PAN. (lin2021polyarteritisnodosaa pages 1-2, puechal2022polyarteritisnodosastate pages 1-2)

10.3 Imaging

Angiography may show saccular/fusiform aneurysms and stenoses in mesenteric/hepatic/renal arteries. Conventional angiography remains highest resolution; CTA and MRA are useful alternatives in specific contexts. (chung20212021americancollegea pages 5-6, chung20212021americancollegea pages 1-2)

10.4 Biopsy

Biopsy remains the diagnostic gold standard when feasible; deep skin biopsy is recommended over superficial punch when evaluating cutaneous disease, and combined nerve+muscle biopsy is recommended over nerve alone for suspected vasculitic neuropathy. (chung20212021americancollegea pages 5-6)

10.5 Differential diagnosis (high-yield)

10.6 Visual evidence (table/algorithm)

A treatment algorithm and classification/criteria table are shown in Puéchal (2022), including ACR criteria, CHCC definition, and the EMA classification approach, plus a clinical treatment flowchart stratified by subtype and severity. (puechal2022polyarteritisnodosastate media 85b1bd4a, puechal2022polyarteritisnodosastate media 858e4031)

11. Outcome / prognosis

11.1 Prognostic factors

The Five-Factor Score (FFS) assigns 1 point each for proteinuria >1 g/day, creatinine >140 µmol/L, cardiomyopathy, severe GI involvement, and CNS involvement to stratify risk and guide treatment intensity. (wolff2023polyarteritisnodosareviewed pages 7-8)

11.2 Relapse, remission, mortality (recent quantitative synthesis)

A recent meta-analysis estimated relapse ~27%, mortality ~13%, and remission ~65% across included PAN studies (heterogeneous definitions and eras). (taprantzis2026clinicalmanifestationsprognostic pages 1-2)

12. Treatment (current practice + evidence)

12.1 First-line treatment (primary non-HBV PAN)

ACR/VF 2021 guideline (real-world implementation in rheumatology practice): - Severe PAN: cyclophosphamide + glucocorticoids preferred over glucocorticoids alone and over rituximab + glucocorticoids; IV pulse glucocorticoids are conditionally preferred over high-dose oral glucocorticoids for newly diagnosed severe disease. (chung20212021americancollegea pages 5-6) - Nonsevere PAN: glucocorticoids plus a non-glucocorticoid immunosuppressant (e.g., azathioprine or methotrexate) are conditionally preferred over glucocorticoids alone. (chung20212021americancollegea pages 5-6, walter2024shiftingperspectivesin pages 7-9)

Dose/duration patterns reported in a 2023 review: induction for moderate–severe PAN commonly uses prednisone ~1 mg/kg/day (max 60 mg/day) and cyclophosphamide for ~3–6 months, with cyclophosphamide generally limited to ≤6 months, followed by maintenance azathioprine or methotrexate for ~12–18 months. (wolff2023polyarteritisnodosareviewed pages 7-8)

12.2 Evidence and statistics

  • A referenced comparison in PAN reported that 12 monthly cyclophosphamide doses + glucocorticoids were superior to a shorter strategy for survival (HR 0.44, p=0.02) and sustained remission (HR 0.34, p=0.02) at 32 months. (walter2024shiftingperspectivesin pages 7-9)
  • For “mild” PAN (FFS=0), relapse risk with glucocorticoids alone is highlighted as high (reported ~40% relapse rate in a 2023 review), motivating steroid-sparing strategies. (wolff2023polyarteritisnodosareviewed pages 7-8)

12.3 Refractory/relapsing PAN and biologics

Evidence remains limited (mostly retrospective cohorts/case series). A European retrospective series cited in a 2023 review reported complete remission rates of 50% (tocilizumab), 40% (TNF inhibitors), and 33% (rituximab) in relapsing/refractory PAN. (wolff2023polyarteritisnodosareviewed pages 7-8)

12.4 Etiology-directed therapy

12.5 Clinical trials / trials infrastructure (ClinicalTrials.gov)

  • Biomarker/natural history: NCT00315406 (completed; observational; n=107) collected blood/urine/DNA longitudinally to identify disease activity biomarkers and excluded ANCA-positive disease, glomerulonephritis, HBV/HCV/HIV, and isolated cutaneous PAN—reflecting operational criteria for “primary systemic PAN” research cohorts. (NCT00315406 chunk 1)
  • Steroid-sparing trial in systemic necrotizing vasculitides (FFS=0): NCT00647166 (CHUSPAN-2; completed; n=114) randomized adults with newly diagnosed PAN/MPA/EGPA without poor-prognosis factors to glucocorticoids plus azathioprine vs placebo; primary outcome was combined remission failures and relapses at 24 months; linked publication PMID: 28678392. (NCT00647166 chunk 1, NCT00647166 chunk 2)

MAXO suggestions (treatments/actions; illustrative): - Glucocorticoid therapy (MAXO:0000747) - Cyclophosphamide therapy (MAXO:0001024) - Azathioprine therapy (MAXO:0000724) - Methotrexate therapy (MAXO:0001008) - Plasma exchange (MAXO:0000411)

13. Prevention

Primary prevention of idiopathic PAN is not established. For secondary PAN risk reduction, HBV vaccination and HBV control plausibly reduce HBV-associated PAN burden; this is consistent with the reported historical decline in HBV-PAN. (lin2021polyarteritisnodosaa pages 1-2)

14. Other species / natural disease

No naturally occurring PAN analogs in other species were identified in the retrieved evidence.

15. Model organisms

No validated animal models were identified in the retrieved evidence set.

Recent developments (2023–2024 priority highlights)

  1. Nosology shift (“old disease, new etiologies”): 2023 reviews emphasize declining HBV-driven PAN and increasing recognition of genetic syndromes (ADA2 deficiency) and hematologic/inflammatory syndromes (VEXAS) that can meet PAN criteria, making etiology workup central to management. (wolff2023polyarteritisnodosaold pages 2-3)
  2. Refractory treatment landscape: 2023 synthesis notes off-label biologic use (tocilizumab, TNF inhibitors, rituximab) with modest complete remission rates in retrospective data, reflecting the need for better trials in non-ANCA medium-vessel vasculitis. (wolff2023polyarteritisnodosareviewed pages 7-8)
  3. Coronary involvement awareness: 2024 review emphasizes coronary artery disease can occur in PAN and may require combined immunosuppression plus revascularization approaches in selected cases. (walter2024shiftingperspectivesin pages 7-9)

Limitations / evidence gaps for knowledge base completion

  • Ontology identifiers (MONDO, ORPHAcode, MeSH unique ID) were not extractable from the retrieved papers in this run; these should be pulled directly from MONDO/Orphanet/MeSH resources.
  • Some key quantitative epidemiology/outcome estimates for primary (non-HBV, non-monogenic) PAN are limited by heterogeneity, older cohorts, and inclusion of secondary/monogenic cases in aggregate analyses.
  • Several statements about HBV-PAN treatment rely on reviews and uncontrolled study traditions; high-quality modern RCT evidence specific to HBV-PAN is limited in the extracted corpus.

Key sources (URLs and publication dates)

References

  1. (wolff2023polyarteritisnodosaold pages 1-2): Louis Wolff, Alice Horisberger, Laura Moi, Maria P. Karampetsou, and Denis Comte. Polyarteritis nodosa: old disease, new etiologies. International Journal of Molecular Sciences, 24:16668, Nov 2023. URL: https://doi.org/10.3390/ijms242316668, doi:10.3390/ijms242316668. This article has 50 citations.

  2. (chung20212021americancollegea pages 1-2): Sharon A. Chung, Mark Gorelik, Carol A. Langford, Mehrdad Maz, Andy Abril, Gordon Guyatt, Amy M. Archer, Doyt L. Conn, Kathy A. Full, Peter C. Grayson, Maria F. Ibarra, Lisa F. Imundo, Susan Kim, Peter A. Merkel, Rennie L. Rhee, Philip Seo, John H. Stone, Sangeeta Sule, Robert P. Sundel, Omar I. Vitobaldi, Ann Warner, Kevin Byram, Anisha B. Dua, Nedaa Husainat, Karen E. James, Mohamad Kalot, Yih Chang Lin, Jason M. Springer, Marat Turgunbaev, Alexandra Villa‐Forte, Amy S. Turner, and Reem A. Mustafa. 2021 american college of rheumatology/vasculitis foundation guideline for the management of polyarteritis nodosa. Arthritis Care & Research, 73:1061-1070, Jul 2021. URL: https://doi.org/10.1002/acr.24633, doi:10.1002/acr.24633. This article has 137 citations and is from a domain leading peer-reviewed journal.

  3. (puechal2022polyarteritisnodosastate pages 1-2): Xavier Puéchal. Polyarteritis nodosa: state of the art. Joint Bone Spine, 89:105320, Jul 2022. URL: https://doi.org/10.1016/j.jbspin.2021.105320, doi:10.1016/j.jbspin.2021.105320. This article has 16 citations and is from a peer-reviewed journal.

  4. (wolff2023polyarteritisnodosaold pages 2-3): Louis Wolff, Alice Horisberger, Laura Moi, Maria P. Karampetsou, and Denis Comte. Polyarteritis nodosa: old disease, new etiologies. International Journal of Molecular Sciences, 24:16668, Nov 2023. URL: https://doi.org/10.3390/ijms242316668, doi:10.3390/ijms242316668. This article has 50 citations.

  5. (wolff2023polyarteritisnodosareviewed pages 8-9): Louis Wolff, Alice Horisberger, Laura Moi, Maria P. Karampetsou, and Denis Comte. Polyarteritis nodosa reviewed in 2023: old disease, new etiologies. Oct 2023. URL: https://doi.org/10.20944/preprints202310.0949.v1, doi:10.20944/preprints202310.0949.v1.

  6. (hocevar2021clinicalapproachto pages 1-2): Alojzija Hočevar, Matija Tomšič, and Katja Perdan Pirkmajer. Clinical approach to diagnosis and therapy of polyarteritis nodosa. Current Rheumatology Reports, Feb 2021. URL: https://doi.org/10.1007/s11926-021-00983-2, doi:10.1007/s11926-021-00983-2. This article has 58 citations and is from a peer-reviewed journal.

  7. (hocevar2021clinicalapproachto pages 5-6): Alojzija Hočevar, Matija Tomšič, and Katja Perdan Pirkmajer. Clinical approach to diagnosis and therapy of polyarteritis nodosa. Current Rheumatology Reports, Feb 2021. URL: https://doi.org/10.1007/s11926-021-00983-2, doi:10.1007/s11926-021-00983-2. This article has 58 citations and is from a peer-reviewed journal.

  8. (walter2024shiftingperspectivesin pages 7-9): Dylan J. Walter, Grace E. Bigham, Steven Lahti, and Syed W. Haider. Shifting perspectives in coronary involvement of polyarteritis nodosa: case of 3-vessel occlusion treated with 4-vessel cabg and review of literature. BMC Cardiovascular Disorders, Apr 2024. URL: https://doi.org/10.1186/s12872-024-03841-y, doi:10.1186/s12872-024-03841-y. This article has 3 citations and is from a peer-reviewed journal.

  9. (wolff2023polyarteritisnodosaold pages 7-8): Louis Wolff, Alice Horisberger, Laura Moi, Maria P. Karampetsou, and Denis Comte. Polyarteritis nodosa: old disease, new etiologies. International Journal of Molecular Sciences, 24:16668, Nov 2023. URL: https://doi.org/10.3390/ijms242316668, doi:10.3390/ijms242316668. This article has 50 citations.

  10. (wolff2023polyarteritisnodosareviewed pages 7-8): Louis Wolff, Alice Horisberger, Laura Moi, Maria P. Karampetsou, and Denis Comte. Polyarteritis nodosa reviewed in 2023: old disease, new etiologies. Oct 2023. URL: https://doi.org/10.20944/preprints202310.0949.v1, doi:10.20944/preprints202310.0949.v1.

  11. (taprantzis2026clinicalmanifestationsprognostic pages 1-2): Nikolaos Taprantzis, Maria Eleni Kasimeri, Dimosthenis Chrysikos, Amir Shihada, Alexandros Samolis, George Tsakotos, Martina Liga, and Theodore Troupis. Clinical manifestations, prognostic impact, and relapse in polyarteritis nodosa: a systematic review and meta-analysis. Rheumatology International, Feb 2026. URL: https://doi.org/10.1007/s00296-026-06082-8, doi:10.1007/s00296-026-06082-8. This article has 0 citations and is from a peer-reviewed journal.

  12. (chung20212021americancollegea pages 5-6): Sharon A. Chung, Mark Gorelik, Carol A. Langford, Mehrdad Maz, Andy Abril, Gordon Guyatt, Amy M. Archer, Doyt L. Conn, Kathy A. Full, Peter C. Grayson, Maria F. Ibarra, Lisa F. Imundo, Susan Kim, Peter A. Merkel, Rennie L. Rhee, Philip Seo, John H. Stone, Sangeeta Sule, Robert P. Sundel, Omar I. Vitobaldi, Ann Warner, Kevin Byram, Anisha B. Dua, Nedaa Husainat, Karen E. James, Mohamad Kalot, Yih Chang Lin, Jason M. Springer, Marat Turgunbaev, Alexandra Villa‐Forte, Amy S. Turner, and Reem A. Mustafa. 2021 american college of rheumatology/vasculitis foundation guideline for the management of polyarteritis nodosa. Arthritis Care & Research, 73:1061-1070, Jul 2021. URL: https://doi.org/10.1002/acr.24633, doi:10.1002/acr.24633. This article has 137 citations and is from a domain leading peer-reviewed journal.

  13. (lin2021polyarteritisnodosaa pages 1-2): Yih Chang Lin, Mohamad A. Kalot, Nedaa M. Husainat, Kevin Byram, Anisha B. Dua, Karen E. James, Jason M. Springer, Marat Turgunbaev, Alexandra Villa‐Forte, Andy Abril, Carol Langford, Mehrdad Maz, Sharon A. Chung, and Reem A. Mustafa. Polyarteritis nodosa: a systematic review of test accuracy and benefits and harms of common treatments. ACR Open Rheumatology, 3:91-100, Jan 2021. URL: https://doi.org/10.1002/acr2.11189, doi:10.1002/acr2.11189. This article has 14 citations and is from a peer-reviewed journal.

  14. (puechal2022polyarteritisnodosastate pages 2-3): Xavier Puéchal. Polyarteritis nodosa: state of the art. Joint Bone Spine, 89:105320, Jul 2022. URL: https://doi.org/10.1016/j.jbspin.2021.105320, doi:10.1016/j.jbspin.2021.105320. This article has 16 citations and is from a peer-reviewed journal.

  15. (puechal2022polyarteritisnodosastate media 85b1bd4a): Xavier Puéchal. Polyarteritis nodosa: state of the art. Joint Bone Spine, 89:105320, Jul 2022. URL: https://doi.org/10.1016/j.jbspin.2021.105320, doi:10.1016/j.jbspin.2021.105320. This article has 16 citations and is from a peer-reviewed journal.

  16. (puechal2022polyarteritisnodosastate media 858e4031): Xavier Puéchal. Polyarteritis nodosa: state of the art. Joint Bone Spine, 89:105320, Jul 2022. URL: https://doi.org/10.1016/j.jbspin.2021.105320, doi:10.1016/j.jbspin.2021.105320. This article has 16 citations and is from a peer-reviewed journal.

  17. (wolff2023polyarteritisnodosaold pages 8-9): Louis Wolff, Alice Horisberger, Laura Moi, Maria P. Karampetsou, and Denis Comte. Polyarteritis nodosa: old disease, new etiologies. International Journal of Molecular Sciences, 24:16668, Nov 2023. URL: https://doi.org/10.3390/ijms242316668, doi:10.3390/ijms242316668. This article has 50 citations.

  18. (NCT00315406 chunk 1): Peter Merkel. Determining Disease Activity Biomarkers in Individuals With Polyarteritis Nodosa. University of Pennsylvania. 2006. ClinicalTrials.gov Identifier: NCT00315406

  19. (NCT00647166 chunk 1): Association Corticosteroid/Azathioprine in Microscopic Polyangiitis/ Polyarteritis Nodosa or Eosinophilic Granulomatosis With Polyangiitis (Churg Strauss Syndrome). Assistance Publique - Hôpitaux de Paris. 2008. ClinicalTrials.gov Identifier: NCT00647166

  20. (NCT00647166 chunk 2): Association Corticosteroid/Azathioprine in Microscopic Polyangiitis/ Polyarteritis Nodosa or Eosinophilic Granulomatosis With Polyangiitis (Churg Strauss Syndrome). Assistance Publique - Hôpitaux de Paris. 2008. ClinicalTrials.gov Identifier: NCT00647166