Necrotizing Vasculitis: Disease-Characteristics Research Report

Target concept: Necrotizing vasculitis
MONDO: MONDO:0800113
Category: Immune-mediated/autoimmune vasculitis
Evidence cutoff: Literature prioritized through December 2024

Executive interpretation

“Necrotizing vasculitis” is best represented in a knowledge base as a histopathologic disease-pattern/umbrella concept, not as one etiologically uniform syndrome. It denotes inflammatory destruction and necrosis of vessel walls. The strongest modern evidence concerns ANCA-associated vasculitis (AAV)—granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and renal-limited pauci-immune necrotizing crescentic glomerulonephritis—but necrotizing lesions also occur in polyarteritis nodosa, immune-complex vasculitis, infection-associated vasculitis, drug-associated disease, and monogenic disorders such as DADA2. Consequently, epidemiology, genetics, phenotype frequencies, prognosis, and treatment should be stored on the specific child diagnosis whenever possible, with MONDO:0800113 retained as a parent/pathology node. (OpenTargets Search: necrotizing vasculitis, xiao2016overviewofthe pages 1-1, kitching2020ancaassociatedvasculitis pages 51-55)

Table: This table provides compact, ontology-ready annotations for necrotizing vasculitis while emphasizing that the term is best treated as a histopathologic umbrella or pattern rather than a single etiologically uniform disease. It is useful for structuring knowledge-base entries with explicit caveats about when evidence is AAV-specific versus broadly applicable.

1. Disease information

Definition and nomenclature

The 2012 Chapel Hill framework defines AAV as necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels. GPA adds necrotizing granulomatous respiratory inflammation; MPA lacks granulomatous inflammation; EGPA adds asthma, eosinophilia, and eosinophil-rich granulomatous inflammation. AAV also includes renal-limited pauci-immune necrotizing crescentic glomerulonephritis. The direct abstract wording from Xiao et al. is: “Antineutrophil cytoplasmic autoantibodies (ANCA) are associated with a spectrum of necrotizing vasculitis including granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited necrotizing and crescentic glomerulonephritis.” (Review; published December 2016; DOI 10.1159/000442323). (xiao2016overviewofthe pages 1-1)

Synonyms/descriptors: necrotising vasculitis; necrotizing angiitis; fibrinoid necrotizing vasculitis; pauci-immune necrotizing vasculitis; ANCA-associated necrotizing vasculitis. These are not fully interchangeable: “pauci-immune” and “ANCA-associated” identify a mechanistic/pathologic subset.

Identifiers: MONDO:0800113 is supported. A single OMIM or Orphanet identifier is not appropriate because this is not one Mendelian or uniformly defined rare disease. ICD-10 commonly codes the specific syndrome—e.g., M30–M31 systemic necrotizing vasculopathies—rather than this histologic umbrella. ICD-11, MeSH, SNOMED CT, and Orphanet mappings should therefore be assigned at subtype level and verified against the release used by the knowledge base.

Data provenance: This report uses aggregated disease-level literature, guidelines, trial registries, and ontology resources—not individual EHR records. Recent real-world studies may use aggregated registry or administrative data, but no patient-level record was accessed.

2. Etiology

Necrotizing vasculitis has no single cause. Upstream categories include primary autoimmunity, immune complexes, infection, drugs/toxins, malignancy, and rare monogenic autoinflammation. In AAV, causation is multifactorial: genetic susceptibility and environmental or infectious priming lead to loss of tolerance to neutrophil proteins, predominantly MPO and PR3, followed by ANCA-mediated effector injury. (xiao2016overviewofthe pages 1-1)

Risk factors

Genetic susceptibility—not deterministic causation. PR3-AAV is associated most strongly with the HLA-DP region, SERPINA1, and PRTN3; MPO-AAV has a different HLA architecture. These associations support classification by ANCA specificity rather than phenotype alone. Additional phenotype-dependent loci include IL12B and IRF1. No common pathogenic sequence variant, chromosomal abnormality, carrier frequency, or Mendelian penetrance can be assigned to MONDO:0800113. (yeo2024childhoodonsetancaassociatedvasculitis pages 14-16)

Rare monogenic mimics are clinically important. ADA2/CECR1 loss-of-function variants cause autosomal-recessive DADA2, which may present in childhood with PAN-like necrotizing arteritis, livedo, strokes, cytopenias, and immunodeficiency. Such cases warrant subtype-specific genetic testing rather than “necrotizing vasculitis” testing.

Environmental/drug factors: silica exposure is an epidemiologic risk for AAV. Well-established secondary triggers include hydralazine, propylthiouracil, minocycline, and levamisole-adulterated cocaine. Drug-associated cases may have unusually broad autoantibody profiles; withdrawal of the exposure is essential. PTU can alter NET formation and MPO immunogenicity. (kitching2020ancaassociatedvasculitis pages 51-55)

Infectious factors: infections can supply TNF and complement-mediated neutrophil-priming signals and may trigger or mimic AAV. Endocarditis, hepatitis B or C, HIV, and other infections must be excluded according to phenotype. Infection is not equivalent to transmissible AAV.

Age/sex/geography: AAV is predominantly adult-onset and rises with age; childhood disease is rare. GPA/PR3-AAV is relatively more common in populations of European ancestry and northern Europe, whereas MPA/MPO-AAV is relatively more common in East Asia. Sex effects are modest and subtype/cohort dependent.

Protective factors and gene–environment interaction

No genetic allele, diet, supplement, exercise program, or environmental exposure is validated as specifically protective against the umbrella disease. Avoiding silica and culprit drugs is prudent for exposure reduction but has not been shown to prevent all primary disease. The plausible gene–environment chain is susceptibility genotype → infection/toxin-associated neutrophil priming or aberrant NET clearance → MPO/PR3 presentation → loss of B/T-cell tolerance → ANCA production. This remains probabilistic rather than a clinically validated individual-risk model. (xiao2016overviewofthe pages 1-1)

3. Phenotypes

Phenotypes are heterogeneous and often acute or subacute at onset, followed by relapsing-remitting or chronically damaging disease. Suggested HPO terms should be verified against the current HPO release.

• Constitutional: fever, fatigue, malaise, weight loss, myalgia and arthralgia; variable frequency and severity. Suggested HPO: Fever, Fatigue, Weight loss, Myalgia, Arthralgia.
• Renal: microscopic hematuria, red-cell casts, proteinuria, declining eGFR, hypertension, and rapidly progressive glomerulonephritis. Renal AAV commonly produces non-nephrotic proteinuria of approximately 1–3 g/day. Severity ranges from urinary abnormalities to dialysis-requiring kidney failure. Suggested HPO: Hematuria, Proteinuria, Hypertension, Rapidly progressive glomerulonephritis, Renal insufficiency. (draibe2024diagnosisandtreatment pages 2-3)
• Pulmonary: nodules, masses, cavitation, infiltrates, interstitial lung disease, dyspnea, cough, and diffuse alveolar hemorrhage/hemoptysis. Suggested HPO: Pulmonary hemorrhage, Hemoptysis, Dyspnea, Pulmonary nodule, Interstitial pulmonary disease.
• ENT/ocular: chronic sinusitis, nasal crusting or bloody discharge, otitis/hearing loss, subglottic disease, orbital inflammation, scleritis. Especially characteristic of GPA. Suggested HPO: Chronic sinusitis, Epistaxis, Hearing impairment, Subglottic stenosis, Scleritis.
• Skin: palpable purpura, petechiae, ulcers, nodules, livedo and digital ischemia. Suggested HPO: Purpura, Skin ulcer, Livedo reticularis, Digital ischemia.
• Neurologic: painful mononeuritis multiplex, asymmetric sensorimotor neuropathy, and less commonly CNS ischemia/hemorrhage. Suggested HPO: Mononeuritis multiplex, Peripheral neuropathy, Neuropathic pain.
• EGPA-specific: adult-onset asthma, chronic rhinosinusitis/nasal polyps, eosinophilia, pulmonary infiltrates, neuropathy, and sometimes eosinophilic cardiac disease. Suggested HPO: Asthma, Eosinophilia, Nasal polyposis, Cardiomyopathy.
• GI/cardiovascular: abdominal pain, ischemia or bleeding; myocarditis/pericarditis and accelerated cardiovascular disease in selected phenotypes.

Frequency estimates must be attached to GPA, MPA, EGPA or the serotype, not to MONDO:0800113. In renal disease, biopsy-confirmed pauci-immune glomerulonephritis is a major disease-defining phenotype. In AAV generally, kidneys, lungs, ENT tract, skin, and peripheral nerves are the principal sites. (kitching2020ancaassociatedvasculitis pages 51-55)

Quality of life: Fatigue, pain, anxiety about relapse, treatment toxicity, work disability, and irreversible organ damage persist even during physician-rated remission. German registry data from 2007–2021 showed employment among patients younger than 65 rising from 47% to 57%, but remaining below the general population; patient-reported outcomes largely did not improve despite lower physician-rated activity. This supports collecting SF-36, EQ-5D, PROMIS, fatigue, pain, work participation, and the AAV-PRO rather than disease activity alone.

4. Genetic and molecular information

Causal genes and variants

There is no universal causal gene, no recurrent pathogenic variant, and no characteristic chromosome abnormality for necrotizing vasculitis. Primary AAV is polygenic/multifactorial. Therefore, ClinVar-style pathogenic/likely pathogenic/VUS classification, allele frequency, germline mosaicism, anticipation, carrier frequency, and karyotype findings are not applicable at umbrella level.

Relevant molecular categories are:

• Autoantigens/effector proteins: MPO, PRTN3.
• Susceptibility/modifier loci: HLA-DP-region alleles, SERPINA1, PRTN3, and phenotype-associated IL12B/IRF1 signals.
• Therapeutically validated targets: MS4A1/CD20 for rituximab, C5AR1 for avacopan, and IL5 for mepolizumab in EGPA. Open Targets links MONDO:0800113 most strongly to MS4A1 and C5AR1 and also to NR3C1, IL5 and purine-synthesis targets; these associations reflect drug evidence and must not be mislabeled as causal genes. (OpenTargets Search: necrotizing vasculitis)
• Rare differential diagnoses: ADA2/CECR1 in DADA2; subtype-directed panels can also include genes responsible for autoinflammation, immunodeficiency, complement dysregulation, and interferonopathies when onset is very early or atypical.

Epigenetics

Aberrant control of neutrophil MPO/PRTN3 expression, DNA methylation and histone states has been reported in AAV, but no epigenetic mark is sufficiently validated for routine diagnosis or prognosis. Large chromosomal changes, repeat expansions, mitochondrial variants, and somatic cancer-type driver mutations are not established defining features.

5. Environmental information

Relevant non-genetic factors include respirable crystalline silica, selected drugs, levamisole-contaminated cocaine, and infection-associated immune activation. Smoking has inconsistent subtype-specific associations and should not be presented as a universal cause. Lifestyle management should address conventional cardiovascular risk, bone health, physical deconditioning, smoking cessation, and infection prevention, mainly to reduce morbidity rather than proven primary disease incidence.

Because infections can both trigger inflammation and mimic vasculitis, cultures, echocardiography, viral serology, and targeted microbiology should precede or accompany immunosuppression when clinically indicated. There is no zoonotic transmission.

6. Mechanism and pathophysiology

Causal chain in pauci-immune AAV

1. Upstream susceptibility and priming: genetic susceptibility plus infectious/environmental inflammatory signals induce cytokines and alternative-complement activation.
2. Antigen display: primed neutrophils externalize MPO/PR3 from granules.
3. ANCA ligation: ANCA binds MPO/PR3, with Fcγ-receptor and Fab-dependent neutrophil activation.
4. Amplification: activated neutrophils generate complement fragments; C5a–C5aR1 recruits and primes more neutrophils.
5. Vascular injury: adhesion to activated endothelium, respiratory burst, protease release, degranulation and NETosis injure endothelial cells and extracellular matrix.
6. Morphology: fibrinoid necrosis and leukocytoclasia develop; in glomeruli, capillary rupture drives crescent formation.
7. Downstream outcome: individual lesions evolve over approximately 1–2 weeks toward resolution or fibrosis; continued waves of new lesions produce active systemic disease. Remission-induction stops new waves but cannot reverse all scar. (massicotteazarniouch2022mechanismsofvascular pages 9-11, xiao2016overviewofthe pages 1-1)

The strongest direct abstract statement is: “Activated neutrophils adhere to and penetrate vessel walls, and they release toxic oxygen radicals and destructive enzymes that cause apoptosis and necrosis of the neutrophils as well as of the adjacent vessel wall cells and matrix.” (Xiao et al., December 2016; DOI 10.1159/000442323). (xiao2016overviewofthe pages 1-1)

Human samples show higher C3a, C5a and C5b-9 during active MPO- and PR3-AAV than in controls, with reductions in remission. Mouse C5aR blockade prevents or attenuates anti-MPO glomerulonephritis, and clinical C5aR1 inhibition validates this pathway therapeutically. (massicotteazarniouch2022mechanismsofvascular pages 9-11)

Suggested GO biological processes: neutrophil activation; neutrophil degranulation; respiratory burst; reactive oxygen species metabolic process; Fc receptor signaling; alternative complement activation; leukocyte adhesion to vascular endothelial cell; neutrophil extracellular-trap formation; endothelial-cell apoptotic process; extracellular-matrix disassembly; inflammatory response; wound healing/fibrosis.

Suggested CL terms: neutrophil; B cell; plasmablast/plasma cell; CD4-positive T cell; CD8-positive T cell; monocyte; macrophage; eosinophil (EGPA); endothelial cell; glomerular parietal epithelial cell; mesangial cell; podocyte.

Molecular profiling and 2024 advances

A 2024 Nature Communications study applied spatial and single-cell transcriptomics to kidneys from 34 patients with ANCA glomerulonephritis, identifying pro-inflammatory cytokine-producing CD4 and CD8 T-cell niches. Digital pharmacology nominated ustekinumab (IL-12/23 blockade); four patients with relapsing ANCA-GN subsequently received ustekinumab plus low-dose cyclophosphamide and glucocorticoids, and all showed clinical responses over 26 weeks. This is hypothesis-generating, uncontrolled precision-therapy evidence—not a treatment standard. Direct abstract quote: “Here, using spatial and single-cell transcriptome analysis, we characterize inflammatory niches in kidney samples from 34 patients with ANCA-GN and identify proinflammatory, cytokine-producing CD4+ and CD8+ T cells as a pathogenic signature.” Published September 2024; DOI 10.1038/s41467-024-52525-w.

A 2024 spatial-transcriptomic preprint analyzed 32 ANCA, 19 lupus-nephritis, six anti-GBM, and six control kidneys, mapping more than 3.2 million cells. It proposed early PDGF signaling to parietal epithelial cells followed by macrophage/T-cell/renal-cell TGF-β signaling and sclerosis. As a preprint, it requires peer-reviewed validation.

7. Anatomical structures affected

Primary: small arteries, arterioles, capillaries, and venules; medium arteries in PAN-like disease. Major organs: kidney/glomerulus, lung/alveolar capillary bed, upper and lower respiratory tract, skin, peripheral nerve/vasa nervorum, eye/orbit, GI tract, and heart. Secondary damage includes chronic kidney disease, pulmonary fibrosis, hearing loss, neuropathic disability, and cardiovascular disease.

Suggested UBERON labels: blood vessel; arteriole; capillary; venule; kidney; renal glomerulus; lung; pulmonary alveolus; nasal cavity; paranasal sinus; trachea; skin; peripheral nerve; eye; gastrointestinal tract; heart.

Subcellular compartments: neutrophil azurophilic granule containing MPO/PR3, plasma membrane after priming, phagosome, cytosol, nucleus/chromatin during NETosis, and extracellular region/NET. Suggested GO-CC labels: azurophil granule, secretory granule, plasma membrane, extracellular region, chromatin, phagosome.

Disease is usually systemic, multifocal, patchy and asymmetric rather than consistently lateralized. Mononeuritis multiplex and ENT destruction may be particularly asymmetric.

8. Temporal development

Onset is usually adult and acute-to-subacute, although indolent ENT/pulmonary GPA and childhood AAV occur. Untreated organ-threatening disease can progress over days to weeks. Active AAV contains asynchronously initiated lesions, each evolving through stereotyped stages over about 1–2 weeks. (xiao2016overviewofthe pages 1-1)

A practical course model is: susceptibility/preclinical autoimmunity → symptomatic active disease → remission induction → treatment-induced remission → relapse or sustained remission → cumulative damage/organ failure. Disease is commonly relapsing-remitting; PR3-AAV generally relapses more often than MPO-AAV, whereas MPO-AAV more often leaves severe renal or fibrotic lung damage. Remission is usually treatment-induced, and spontaneous durable remission is unreliable. The critical intervention window is before irreversible crescentic renal scarring, alveolar hemorrhage, nerve infarction, or airway destruction.

9. Inheritance and population

Primary AAV and the umbrella necrotizing-vasculitis concept have multifactorial/polygenic inheritance, low familial recurrence, incomplete age-dependent susceptibility, and variable expression. Mendelian inheritance, anticipation, germline mosaicism, founder variants, carrier frequency and consanguinity are not generally applicable. These become relevant only for a defined monogenic mimic such as autosomal-recessive DADA2.

No defensible incidence or prevalence can be assigned to MONDO:0800113 because registry definitions and included diseases differ. AAV itself is rare, with strong geographic, ancestry and age variation; most published estimates are in the low tens per million person-years for incidence and tens to several hundred per million for prevalence. Those values should be stored with jurisdiction, calendar period and subtype rather than generalized to necrotizing vasculitis.

A 2024 Swedish population cohort of 374 AAV cases was 47% female; under the EMA algorithm, 192 had GPA, 159 MPA, and 23 EGPA. Under 2022 ACR/EULAR criteria, 199 were GPA, 136 MPA and 22 EGPA; 1.1% met two categories and 3.5% were unclassifiable. This illustrates classification-dependent population statistics.

10. Diagnostics

Clinical and laboratory approach

Diagnosis is integrative; no single test excludes or confirms every case.

1. Confirm compatible organ injury and urgency: CBC with differential/eosinophils, creatinine/eGFR, urinalysis with microscopy, urine protein quantification, CRP/ESR, liver tests.
2. Test high-quality antigen-specific PR3-ANCA and MPO-ANCA immunoassays. ANCA-negative disease exists, especially localized GPA and many EGPA cases.
3. Exclude mimics: blood cultures/endocarditis, hepatitis B/C and HIV where appropriate, anti-GBM antibodies, ANA/complement/cryoglobulins, infection, embolic disease, malignancy, thrombotic vasculopathy, and drug exposure.
4. Image the affected organ: chest radiograph/CT for nodules, cavitation, hemorrhage or ILD; sinus CT/MRI; echocardiography or vascular imaging as indicated.
5. Obtain tissue where feasible: kidney, skin, lung, ENT or nerve/muscle. Kidney biopsy typically shows focal/segmental necrotizing crescentic glomerulonephritis with few immune deposits by immunofluorescence. Biopsy also provides chronicity and prognostic information. (draibe2024diagnosisandtreatment pages 2-3, kitching2020ancaassociatedvasculitis pages 67-70)
6. Assess activity and damage using BVAS and Vasculitis Damage Index; monitor renal function, urine sediment/protein, blood count, immunoglobulins, infection and treatment toxicity. ANCA titers alone should not dictate treatment.

Biomarkers: MPO-/PR3-ANCA are clinically established. Complement fragments and urinary soluble CD163 are promising activity markers but not universal standalone diagnostics. ANCA, pathology and clinical phenotype can disagree.

Classification criteria

The 2022 ACR/EULAR criteria are research-classification criteria applied after a small-/medium-vessel vasculitis diagnosis and exclusion of mimics—not screening or diagnostic criteria. GPA classification at a score ≥5 achieved 93% sensitivity and 94% specificity in validation. A 2024 Japanese cohort, using EMA as reference, found sensitivity/specificity of 100%/96% for EGPA, 40%/97% for GPA and 90%/49% for MPA, demonstrating population and reference-standard limitations.

Genetic/omics testing

Routine WES, WGS, CMA, karyotyping, FISH, mtDNA or repeat-expansion testing is not indicated for typical adult AAV. Use a vasculitis/autoinflammation/immunodeficiency panel or WES/WGS for childhood onset, family history, strokes, cytopenias, immunodeficiency, recurrent fever, or treatment-refractory atypical disease. RNA-seq, proteomics, metabolomics and epigenomics remain research tools. There is no population, newborn or asymptomatic genetic screening program.

11. Outcomes and prognosis

Modern immunosuppression transformed AAV from frequently fatal disease into a chronic relapsing-remitting condition, but mortality, kidney failure, infection, cardiovascular disease, malignancy and treatment toxicity remain substantial. (kitching2020ancaassociatedvasculitis pages 51-55)

Renal function is a dominant prognostic variable. The 2024 GLOMCAT consensus reports that patients with eGFR <50 mL/min/1.73 m² face approximately a 50% risk of death or kidney failure within five years. (draibe2024diagnosisandtreatment pages 2-3) Adverse factors include older age, severe renal impairment/dialysis, diffuse alveolar hemorrhage, cardiac disease, infection, high cumulative glucocorticoid/cyclophosphamide exposure and chronic scarring on biopsy. PR3-ANCA, prior relapse and persistent upper-airway disease predict relapse more than mortality.

Complications include ESRD, chronic pulmonary/ENT damage, subglottic stenosis, hearing loss, neuropathy, venous thromboembolism, cardiovascular events, osteoporosis, diabetes, infertility/cancer after cyclophosphamide, hypogammaglobulinemia after B-cell depletion, and opportunistic infection. Recovery is greatest when treatment precedes irreversible fibrosis; nerve, hearing, airway and advanced renal damage may be permanent.

12. Treatment

Treatment must follow the specific syndrome, organ severity, ANCA phenotype, comorbidity and fertility preferences.

GPA/MPA and renal-limited AAV

Organ-/life-threatening induction: rituximab or cyclophosphamide plus a rapidly tapered glucocorticoid regimen. Rituximab is often preferred in relapsing PR3-AAV, younger patients needing fertility preservation, or prior cyclophosphamide exposure. Cyclophosphamide remains useful in fulminant disease. Avacopan, an oral C5aR1 antagonist, can reduce glucocorticoid exposure in eligible GPA/MPA patients. Suggested NCIT intervention labels: Rituximab Therapy, Cyclophosphamide Therapy, Corticosteroid Therapy, Avacopan, Immunosuppressive Therapy. (OpenTargets Search: necrotizing vasculitis, nakazawa2019pathogenesisandtherapeutic pages 9-9)

ADVOCATE quantitative evidence: among 214 rituximab-treated participants, week-26 remission occurred in 77.6% with avacopan versus 75.7% with prednisone taper; sustained week-52 remission was 71.0% versus 56.1%. Serious adverse events occurred in 34.6% versus 39.3%. Renal recovery, albuminuria reduction and glucocorticoid toxicity favored avacopan. Direct abstract conclusion: “efficacy of treatment with avacopan compared with a prednisone taper was similar at week 26 and greater at week 52.” Published February 2024; trial NCT02994927; DOI 10.1136/ard-2023-224816.

Non-organ-threatening disease: glucocorticoids plus rituximab or, in selected patients, methotrexate/mycophenolate according to renal function and guideline context.

Maintenance: rituximab is generally preferred after severe GPA/MPA; azathioprine or methotrexate are alternatives. Duration is individualized, commonly at least 18–24 months and longer for high-relapse-risk PR3-AAV. Monitor IgG, infections, blood counts and renal/liver toxicity.

Plasma exchange: not routine for all severe AAV after PEXIVAS; consider selectively for anti-GBM overlap, exceptional life-threatening pulmonary hemorrhage, or very severe rapidly deteriorating renal disease after individualized risk assessment.

EGPA

Glucocorticoids are foundational. Add cyclophosphamide or rituximab for organ-threatening vasculitic disease. Mepolizumab, targeting IL-5, is established for relapsing/refractory non-life-threatening eosinophilic/asthmatic disease and steroid sparing. Suggested NCIT terms: Mepolizumab, Anti-IL-5 Monoclonal Antibody Therapy.

Supportive and real-world care

Provide Pneumocystis prophylaxis when immunosuppression warrants it, vaccination, osteoporosis and gastric-risk management, cardiovascular-risk treatment, fertility preservation before cyclophosphamide, rehabilitation, pain/neuropathy management, smoking cessation, psychosocial support, and nephrology/pulmonary/ENT/neurology collaboration. Surgery is reserved for damage—airway stenosis, reconstructive ENT disease, ischemic bowel, aneurysm, dialysis access or transplantation—not primary immune control.

Experimental treatments and trials

• Ustekinumab: four-patient, immune-profile-guided pilot in relapsing ANCA-GN; investigational.
• Obinutuzumab versus rituximab: ObiVas phase II, ISRCTN13069630, planned n=26.
• Rituximab plus telitacicept: NCT05962840, phase IV, planned n=40.
• BDB-001 complement-directed programs: NCT05197842 completed phase I/II, n=93; later phase III programs are ongoing.
• CD19 CAR-T: preclinical MPO-AAV proof of principle; not standard clinical therapy.

No validated pharmacogenomic genotype currently selects induction therapy. Precision treatment is instead phenotype-, serotype-, organ-, relapse- and toxicity-guided.

13. Prevention

There is no validated primary prevention for idiopathic AAV. Avoid silica where occupationally feasible, avoid levamisole-contaminated cocaine, and discontinue culprit drugs. Genetic counseling is appropriate only for a suspected monogenic syndrome.

Secondary prevention consists of rapid recognition of hematuria, pulmonary hemorrhage, neuropathy or ENT destruction in symptomatic/high-risk patients; there is no population screening program. Tertiary prevention includes relapse monitoring, medication adherence, minimized glucocorticoid exposure, cardiovascular and renal protection, vaccination, infection prophylaxis, bone protection, malignancy surveillance after cyclophosphamide, and rehabilitation.

Administer indicated non-live vaccines—seasonal influenza, COVID-19, pneumococcal, recombinant zoster, hepatitis B where relevant—preferably before rituximab when disease urgency permits. Live vaccines are generally avoided during substantial immunosuppression. Screen for latent infection according to the planned therapy and local guidance.

14. Other species and natural disease

Necrotizing vasculitis occurs naturally in dogs, cats, horses and other species as heterogeneous immune-mediated, infectious, drug-associated or breed-associated syndromes. It is not one veterinary counterpart of MONDO:0800113. Therefore, no single breed ontology term, orthologous causal gene, prevalence, or inheritance pattern should be assigned.

Human AAV is not zoonotic and is not transmitted between species. Comparative value lies in conserved neutrophil, Fc-receptor, complement, endothelial-injury and repair pathways. Relevant taxa for experimental work include Mus musculus (NCBI Taxon 10090) and Rattus norvegicus (10116).

15. Model organisms

The canonical induced model is the anti-MPO passive-transfer mouse model: MPO-deficient mice are immunized with murine MPO; anti-MPO IgG or anti-MPO-producing splenocytes are transferred into wild-type recipients, producing pauci-immune necrotizing crescentic glomerulonephritis and sometimes pulmonary capillaritis. It directly demonstrates MPO-ANCA pathogenicity and is useful for complement, Fc receptor, neutrophil and treatment studies. C5/C5aR disruption protects mice, supporting complement amplification. (massicotteazarniouch2022mechanismsofvascular pages 9-11, xiao2016overviewofthe pages 1-1)

A 2024 preclinical study used CD19-targeted CAR-T cells in an MPO-AAV mouse model. CAR-T cells depleted B cells/plasmablasts, accelerated MPO-ANCA decline and protected against necrotizing crescentic GN. Direct abstract conclusion: “Our proof-of-principle study may encourage further exploration of CAR T cells as a treatment for ANCA-vasculitis patients with the goal of drug-free remission.” Published April 2024; DOI 10.1136/ard-2023-224875.

Limitations include stronger recapitulation of MPO-AAV than PR3-AAV, short experimental time courses, induced rather than spontaneous autoimmunity, and incomplete modeling of human granulomatous ENT disease, relapse, age, infection and treatment toxicity. Additional systems include human neutrophil/endothelial coculture, organ-on-chip vascular assays, ex-vivo kidney tissue, and patient-derived single-cell/spatial atlases. No model fully reproduces the umbrella condition.

Knowledge-base curation recommendations

1. Treat MONDO:0800113 as an umbrella/pathology node and attach incidence, phenotype frequencies, variants, prognosis and therapy to GPA, MPA, EGPA, PAN, DADA2 or another defined child diagnosis.
2. Qualify mechanistic assertions as AAV-specific unless evidence covers other necrotizing vasculitides.
3. Separate susceptibility genes from causal Mendelian genes and therapeutic targets. MS4A1/C5AR1/IL5 are clinically actionable targets, not universal causes. (OpenTargets Search: necrotizing vasculitis)
4. Record evidence type: human clinical/biopsy, guideline, registry, in vitro, mouse, computational or preprint.
5. Do not infer a pathogenic variant, inheritance mode, protective factor, population prevalence, or screening program where none is established.

References

1. (OpenTargets Search: necrotizing vasculitis): Open Targets Query (necrotizing vasculitis, 35 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

2. (xiao2016overviewofthe pages 1-1): Hong Xiao, Peiqi Hu, Ronald J. Falk, and J. Charles Jennette. Overview of the pathogenesis of anca-associated vasculitis. Kidney Diseases, 1:205-215, Dec 2016. URL: https://doi.org/10.1159/000442323, doi:10.1159/000442323. This article has 164 citations and is from a peer-reviewed journal.

3. (kitching2020ancaassociatedvasculitis pages 51-55): A. Richard Kitching, Hans-Joachim Anders, Neil Basu, Elisabeth Brouwer, Jennifer Gordon, David R. Jayne, Joyce Kullman, Paul A. Lyons, Peter A. Merkel, Caroline O. S. Savage, Ulrich Specks, and Renate Kain. Anca-associated vasculitis. Nature Reviews Disease Primers, 6:1-27, Aug 2020. URL: https://doi.org/10.1038/s41572-020-0204-y, doi:10.1038/s41572-020-0204-y. This article has 1157 citations.

4. (nakazawa2019pathogenesisandtherapeutic pages 9-9): Daigo Nakazawa, Sakiko Masuda, Utano Tomaru, and Akihiro Ishizu. Pathogenesis and therapeutic interventions for anca-associated vasculitis. Nature Reviews Rheumatology, 15:91-101, Dec 2019. URL: https://doi.org/10.1038/s41584-018-0145-y, doi:10.1038/s41584-018-0145-y. This article has 571 citations and is from a domain leading peer-reviewed journal.

5. (massicotteazarniouch2022mechanismsofvascular pages 9-11): David Massicotte-Azarniouch, Carolina A. Herrera, J. Charles Jennette, Ronald J. Falk, and Meghan E. Free. Mechanisms of vascular damage in anca vasculitis. Seminars in Immunopathology, 44:325-345, Mar 2022. URL: https://doi.org/10.1007/s00281-022-00920-0, doi:10.1007/s00281-022-00920-0. This article has 58 citations and is from a domain leading peer-reviewed journal.

6. (draibe2024diagnosisandtreatment pages 2-3): Juliana Bordignon Draibe, Helena Marco, Meritxell Ibernon, Irene Agraz, Carola Arcal, Xoana Barros, Victoria Cabrera, Iara Da Silva, Montserrat Díaz, Xavier Fulladosa, Elena Guillén, Patricia Lescano, Laura Martínez Valenzuela, Eva Márquez, Nadia Martín, Ana Merino, Maru Navarro, Eva Rodríguez, Mª José Soler, Joan Torras, and Luís F. Quintana. Diagnosis and treatment of renal anca vasculitis: a summary of the consensus document of the catalan group for the study of glomerular diseases (glomcat). Journal of Clinical Medicine, 13:6793, Nov 2024. URL: https://doi.org/10.3390/jcm13226793, doi:10.3390/jcm13226793. This article has 3 citations.

7. (yeo2024childhoodonsetancaassociatedvasculitis pages 14-16): Liching Yeo, Asma Naheed, Chantelle Richards, and Coziana Ciurtin. Childhood-onset anca-associated vasculitis: from genetic studies to advances in pathogenesis, classification and novel therapeutic approaches. International Journal of Molecular Sciences, 25:13704, Dec 2024. URL: https://doi.org/10.3390/ijms252413704, doi:10.3390/ijms252413704. This article has 10 citations.

8. (kitching2020ancaassociatedvasculitis pages 67-70): A. Richard Kitching, Hans-Joachim Anders, Neil Basu, Elisabeth Brouwer, Jennifer Gordon, David R. Jayne, Joyce Kullman, Paul A. Lyons, Peter A. Merkel, Caroline O. S. Savage, Ulrich Specks, and Renate Kain. Anca-associated vasculitis. Nature Reviews Disease Primers, 6:1-27, Aug 2020. URL: https://doi.org/10.1038/s41572-020-0204-y, doi:10.1038/s41572-020-0204-y. This article has 1157 citations.

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