Microscopic Polyangiitis

Autoimmune MONDO:0019124 Pathograph 6 Show in embeddings browser Autoimmune Disease Vasculitis

A rare anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic necrotizing vasculitis predominantly affecting small vessels (arterioles, capillaries, venules) in multiple organs, especially the kidney, lung, skin, and peripheral nerves. Strongly associated with anti-myeloperoxidase (MPO-ANCA / perinuclear p-ANCA) antibodies. The clinical hallmark is the pulmonary-renal syndrome: pauci-immune necrotizing crescentic glomerulonephritis combined with pulmonary capillaritis and diffuse alveolar hemorrhage. One of the three ANCA-associated vasculitides (AAV). Distinguished from granulomatosis with polyangiitis (MPA lacks granulomatous inflammation and destructive upper-airway/sinonasal disease, and is usually MPO-ANCA rather than PR3-ANCA) and from eosinophilic granulomatosis with polyangiitis (MPA lacks asthma and eosinophilia). Formerly grouped with classic polyarteritis nodosa as "microscopic polyarteritis," but now separated as a small-vessel, ANCA-associated entity.

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4
Pathophys.
23
Phenotypes
6
Pathograph
3
Genes
6
Medical Actions
12
References
1
Deep Research
🏷

Classifications

Harrison's Chapter
IMMUNE_RHEUMATOLOGIC
⚙

Pathophysiology

4
Loss of Tolerance and MPO-ANCA Production
On a permissive HLA class II background (HLA-DQ for MPO-ANCA), with environmental priming (silica, culprit drugs, infection) and epigenetic de-repression of the MPO autoantigen gene, autoreactive B cells generate anti-myeloperoxidase IgG (MPO-ANCA). This break in tolerance to a neutrophil granule antigen is the defining upstream event. Genetics segregate by ANCA serotype rather than by clinical syndrome, and MPA is predominantly the MPO-ANCA arm of AAV.
B cell CL:0000236
B Cell Activation GO:0042113
Downstream
ANCA-Mediated Neutrophil Activation
Show evidence (2 references)
PMID:22808956 SUPPORT Human Clinical
"Anti-myeloperoxidase ANCA was associated with HLA-DQ"
The Lyons GWAS shows MPO-ANCA (the dominant serotype in MPA) is genetically associated with HLA-DQ, supporting an HLA class II-restricted loss of tolerance to MPO as the upstream susceptibility mechanism.
PMID:22808956 SUPPORT Human Clinical
"Microscopic polyangiitis is associated with myeloperoxidase ANCA in 58% of cases and with proteinase 3 ANCA in 26% of cases."
Confirms MPO-ANCA is the predominant autoantibody in MPA, distinguishing it from the PR3-ANCA-dominant GPA.
ANCA-Mediated Neutrophil Activation
Cytokine-primed neutrophils (primed by TNF-alpha, IL-1beta, and complement C5a) translocate MPO from azurophilic granules to the cell surface, where MPO-ANCA IgG engages it together with Fc-gamma receptors. This triggers the respiratory burst, degranulation, and release of reactive oxygen species and lytic enzymes. Passive transfer of anti-MPO IgG reproduces pauci-immune necrotizing crescentic glomerulonephritis in mice, and neutrophil depletion completely prevents it, establishing the neutrophil as the obligate effector.
Neutrophil CL:0000775 Monocyte-derived macrophage CL:0000235
Neutrophil Activation GO:0042119 ↑ INCREASED Neutrophil Degranulation GO:0043312 ↑ INCREASED Respiratory Burst GO:0045730 ↑ INCREASED
Downstream
Necrotizing Small-Vessel Capillaritis
NET Formation and Complement Amplification
Show evidence (2 references)
PMID:12370273 SUPPORT Model Organism
"anti-MPO IgG alone was able to cause pauci-immune glomerular necrosis and crescent formation in the absence of functional T or B lymphocytes in Rag2(-/-) mice and in the presence of an intact immune system in wild-type C57BL/6J mice."
The Xiao passive-transfer model proves anti-MPO IgG is directly pathogenic, causing pauci-immune necrotizing crescentic glomerulonephritis - the renal hallmark of MPA.
PMID:15972950 SUPPORT Model Organism
"mice that were depleted of circulating neutrophils with NIMP-R14 rat monoclonal antibodies were completely protected from anti-MPO IgG-induced NCGN."
Neutrophil depletion completely prevents anti-MPO IgG-induced glomerulonephritis, establishing the neutrophil as the obligate effector cell in MPA pathogenesis.
NET Formation and Complement Amplification
ANCA-stimulated neutrophils release neutrophil extracellular traps (NETs) - chromatin fibers decorated with MPO and PR3. NETs perpetuate autoimmunity by re-exposing MPO, directly injure endothelium, and activate the alternative complement pathway, generating the anaphylatoxin C5a. C5a engages the neutrophil C5a receptor (C5aR/CD88) to prime more neutrophils, producing a feed-forward amplification loop. The C5a-C5aR axis is essential in experimental anti-MPO disease and is the therapeutic target of avacopan.
Neutrophil CL:0000775
Neutrophil Extracellular Trap Formation GO:0140645 ↑ INCREASED Complement Alternative Pathway Activation GO:0006957 ↑ INCREASED
Downstream
Necrotizing Small-Vessel Capillaritis
Show evidence (2 references)
PMID:19448636 SUPPORT In Vitro
"chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO)."
Confirms ANCA-stimulated neutrophils release NETs containing MPO, linking NETosis to the small-vessel inflammation and autoimmune amplification of AAV/MPA.
PMID:19073822 SUPPORT Model Organism
"This conditioned serum primed neutrophils for ANCA-induced respiratory burst; neutrophil C5aR blockade abrogated this priming, but C3aR blockade did not."
Establishes the C5a-C5aR axis as the complement amplification loop priming neutrophils for ANCA-induced activation - the mechanistic rationale for the C5aR antagonist avacopan.
Necrotizing Small-Vessel Capillaritis
Activated neutrophils adhere to and lyse small-vessel endothelium (capillaries, venules, arterioles), causing leukocytoclasia, fibrinoid necrosis, and vessel-wall destruction with little or no immunoglobulin deposition ("pauci-immune"). In the kidney this produces focal necrotizing and crescentic glomerulonephritis; in the lung, alveolar capillaritis with diffuse hemorrhage; in nerve, ischemic vasculitic neuropathy. Granulomatous inflammation is characteristically absent, distinguishing MPA from GPA.
Vascular endothelial cell CL:0000115
Inflammatory Response GO:0006954 ↑ INCREASED
Show evidence (2 references)
PMID:12370273 SUPPORT Model Organism
"Mice that received anti-MPO IgG but not mice that received control IgG developed focal necrotizing and crescentic glomerulonephritis with a paucity of glomerular Ig deposition."
The anti-MPO mouse model reproduces pauci-immune (paucity of Ig deposition) focal necrotizing and crescentic glomerulonephritis, the renal hallmark of human MPA.
ORPHA:727 SUPPORT Other
"HP:0002633 | Vasculitis | Very frequent (99-80%)"
Orphanet records vasculitis as a very frequent feature of MPA, consistent with necrotizing small-vessel vasculitis being the central lesion.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Microscopic Polyangiitis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

23
Blood 2
Diffuse Alveolar Hemorrhage OCCASIONAL Diffuse alveolar hemorrhage HP:0025420
Life-threatening manifestation of pulmonary capillaritis; with crescentic glomerulonephritis it constitutes the pulmonary-renal syndrome.
Show evidence (1 reference)
ORPHA:727 SUPPORT Other
"HP:0025420 | Diffuse alveolar hemorrhage | Occasional (29-5%)"
Orphanet classifies diffuse alveolar hemorrhage as occasional in MPA.
Anemia FREQUENT Anemia HP:0001903
Normocytic anemia of inflammation; may be aggravated by alveolar hemorrhage.
Show evidence (1 reference)
ORPHA:727 SUPPORT Other
"HP:0001903 | Anemia | Frequent (79-30%)"
Orphanet classifies anemia as frequent in MPA.
Eye 1
Episcleritis OCCASIONAL Episcleritis HP:0100534
Inflammatory ocular involvement may occur; unlike GPA, MPA lacks orbital granulomatous masses (no granulomatous proptosis).
Show evidence (1 reference)
ORPHA:727 SUPPORT Other
"HP:0100534 | Episcleritis | Occasional (29-5%)"
Orphanet classifies episcleritis as occasional in MPA.
Genitourinary 3
Hematuria VERY_FREQUENT Hematuria HP:0000790
Dysmorphic hematuria with red-cell casts ("active nephritic sediment").
Show evidence (1 reference)
ORPHA:727 SUPPORT Other
"HP:0000790 | Hematuria | Very frequent (99-80%)"
Orphanet classifies hematuria as very frequent in MPA.
Renal Insufficiency VERY_FREQUENT Renal insufficiency HP:0000083
Show evidence (1 reference)
ORPHA:727 SUPPORT Other
"HP:0000083 | Renal insufficiency | Very frequent (99-80%)"
Orphanet classifies renal insufficiency as very frequent in MPA.
Proteinuria Proteinuria HP:0000093
Proteinuria accompanies the active nephritic sediment; it is generally sub-nephrotic, distinguishing MPA's glomerulonephritis from nephrotic glomerular disease.
Integument 1
Skin Ulcer FREQUENT Skin ulcer HP:0200042
Show evidence (1 reference)
ORPHA:727 SUPPORT Other
"HP:0200042 | Skin ulcer | Frequent (79-30%)"
Orphanet classifies skin ulcers as frequent in MPA.
Metabolism 1
Fever VERY_FREQUENT Fever HP:0001945
Show evidence (1 reference)
ORPHA:727 SUPPORT Other
"HP:0001945 | Fever | Very frequent (99-80%)"
Orphanet classifies fever as very frequent in MPA.
Respiratory 3
Hemoptysis VERY_FREQUENT Hemoptysis HP:0002105
Reflects pulmonary capillaritis with alveolar hemorrhage.
Show evidence (1 reference)
ORPHA:727 SUPPORT Other
"HP:0002105 | Hemoptysis | Very frequent (99-80%)"
Orphanet classifies hemoptysis as very frequent in MPA.
Interstitial Lung Disease Abnormal pulmonary interstitial morphology HP:0006530
Show evidence (1 reference)
PMID:35106973 SUPPORT Human Clinical
"lung fibrosis or interstitial lung disease (+3)"
The 2022 ACR/EULAR MPA classification criteria assign positive weight to lung fibrosis or interstitial lung disease, recognizing it as a feature that supports classification as MPA.
Dyspnea Dyspnea HP:0002094
Constitutional 3
Fatigue FREQUENT Fatigue HP:0012378
Show evidence (1 reference)
ORPHA:727 SUPPORT Other
"HP:0012378 | Fatigue | Frequent (79-30%)"
Orphanet classifies fatigue as frequent in MPA.
Arthralgia FREQUENT Arthralgia HP:0002829
Show evidence (1 reference)
ORPHA:727 SUPPORT Other
"HP:0002829 | Arthralgia | Frequent (79-30%)"
Orphanet classifies arthralgia as frequent in MPA.
Myalgia FREQUENT Myalgia HP:0003326
Show evidence (1 reference)
ORPHA:727 SUPPORT Other
"HP:0003326 | Myalgia | Frequent (79-30%)"
Orphanet classifies myalgia as frequent in MPA.
Growth 1
Weight Loss OCCASIONAL Weight loss HP:0001824
Show evidence (1 reference)
ORPHA:727 SUPPORT Other
"HP:0001824 | Weight loss | Occasional (29-5%)"
Orphanet classifies weight loss as occasional in MPA.
Other 8
Crescentic Glomerulonephritis VERY_FREQUENT Crescentic glomerulonephritis HP:0008653
Course: PROGRESSIVE
Pauci-immune necrotizing crescentic glomerulonephritis is the renal hallmark of MPA, typically presenting as rapidly progressive glomerulonephritis.
Show evidence (1 reference)
ORPHA:727 SUPPORT Other
"HP:0008653 | Crescentic glomerulonephritis | Very frequent (99-80%)"
Orphanet classifies crescentic glomerulonephritis as very frequent in MPA.
Glomerulonephritis VERY_FREQUENT Glomerulonephritis HP:0000099
Show evidence (1 reference)
ORPHA:727 SUPPORT Other
"HP:0000099 | Glomerulonephritis | Very frequent (99-80%)"
Orphanet classifies glomerulonephritis as very frequent in MPA.
Mononeuritis Multiplex FREQUENT Multiple mononeuropathy HP:0032018
Show evidence (1 reference)
ORPHA:727 SUPPORT Other
"HP:0032018 | Multiple mononeuropathy | Frequent (79-30%)"
Orphanet classifies multiple mononeuropathy (mononeuritis multiplex) as frequent in MPA.
Palpable Purpura OCCASIONAL Palpable purpura HP:0031363
From cutaneous leukocytoclastic small-vessel vasculitis.
Show evidence (1 reference)
ORPHA:727 SUPPORT Other
"HP:0031363 | Palpable purpura | Occasional (29-5%)"
Orphanet classifies palpable purpura as occasional in MPA.
MPO-ANCA Positivity FREQUENT Anti-myeloperoxidase antibody positivity HP:0033559
Show evidence (2 references)
ORPHA:727 SUPPORT Other
"HP:0033559 | Anti-myeloperoxidase antibody positivity | Frequent (79-30%)"
Orphanet classifies anti-myeloperoxidase antibody positivity as frequent in MPA.
PMID:35106973 SUPPORT Human Clinical
"anti-myeloperoxidase-ANCA positivity (+6)"
The 2022 ACR/EULAR MPA classification criteria assign the highest positive weight (+6) to MPO-ANCA positivity, reflecting its centrality to MPA.
c-ANCA / PR3-ANCA Positivity FREQUENT Cytoplasmic antineutrophil antibody positivity HP:0032230
Show evidence (2 references)
ORPHA:727 SUPPORT Other
"HP:0032230 | Cytoplasmic antineutrophil antibody positivity | Frequent (79-30%)"
Orphanet records cytoplasmic ANCA positivity in MPA, reflecting the PR3-ANCA minority of MPA cases.
PMID:35106973 SUPPORT Human Clinical
"cytoplasmic ANCA or anti-proteinase 3 ANCA positivity (-1)"
In the 2022 ACR/EULAR MPA criteria, c-ANCA/PR3-ANCA carries a negative weight - it argues against MPA and toward GPA - underscoring that PR3-ANCA is not the typical MPA serotype.
Elevated ESR FREQUENT Elevated erythrocyte sedimentation rate HP:0003565
Show evidence (1 reference)
ORPHA:727 SUPPORT Other
"HP:0003565 | Elevated erythrocyte sedimentation rate | Frequent (79-30%)"
Orphanet classifies elevated ESR as frequent in MPA.
Elevated CRP VERY_FREQUENT Increased inflammatory response HP:0012649
Show evidence (1 reference)
ORPHA:727 SUPPORT Other
"HP:0012649 | Increased inflammatory response | Very frequent (99-80%)"
Orphanet records a very frequent increased inflammatory response in MPA, consistent with elevated acute-phase reactants such as CRP.
🧬

Genetic Associations

3
HLA-DQ (Risk Factor)
Show evidence (1 reference)
PMID:22808956 SUPPORT Human Clinical
"Anti-myeloperoxidase ANCA was associated with HLA-DQ"
The Lyons GWAS identifies HLA-DQ as the genetic association of MPO-ANCA, the serotype that predominates in MPA.
MPO (Risk Factor)
Show evidence (1 reference)
PMID:12370273 SUPPORT Model Organism
"The most common antigen target for ANCAs is myeloperoxidase (MPO), which is found in neutrophils and monocytes."
Identifies MPO as the principal autoantigen targeted by the pathogenic antibodies in MPA.
PRTN3 (Risk Factor)
Show evidence (1 reference)
PMID:22808956 PARTIAL Human Clinical
"Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding α(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3)"
The GWAS associates PRTN3 with PR3-ANCA vasculitis; it is included as a serotype-distinguishing locus, more relevant to GPA than to MPO-ANCA MPA.
💊

Medical Actions

6
Rituximab
Action: Pharmacotherapy NCIT:C15986
Agent: rituximab NCIT:C1702
Anti-CD20 monoclonal antibody that depletes B cells; first-line for both remission induction (RAVE) and maintenance (MAINRITSAN) in ANCA-associated vasculitis, non-inferior to cyclophosphamide for induction and superior to azathioprine for maintenance.
Mechanism Target:
Loss of Tolerance and MPO-ANCA Production
Show evidence (2 references)
PMID:20647199 SUPPORT Human Clinical
"Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease."
The RAVE trial establishes rituximab as non-inferior to cyclophosphamide for remission induction in AAV (which includes MPA).
PMID:25372085 SUPPORT Human Clinical
"More patients with ANCA-associated vasculitides had sustained remission at month 28 with rituximab than with azathioprine."
The MAINRITSAN trial shows scheduled rituximab is superior to azathioprine for maintenance of remission in AAV.
Cyclophosphamide
Action: Pharmacotherapy NCIT:C15986
Agent: cyclophosphamide CHEBI:4027
Alkylating immunosuppressant; classic remission-induction agent for organ-threatening or life-threatening AAV, combined with glucocorticoids.
Show evidence (1 reference)
PMID:20647199 SUPPORT Human Clinical
"Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis"
The RAVE trial used daily cyclophosphamide as the comparator standard induction therapy for AAV, confirming its role as established induction.
Glucocorticoids
Action: Pharmacotherapy NCIT:C15986
Agent: corticosteroid CHEBI:50858
Backbone of remission induction. The PEXIVAS trial established that a reduced-dose glucocorticoid regimen is non-inferior for death/ESKD and lowers serious infections, making steroid-sparing the standard of care.
Show evidence (1 reference)
PMID:32053298 SUPPORT Human Clinical
"A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD."
PEXIVAS shows reduced-dose glucocorticoids are non-inferior to standard dosing for the major renal/survival outcome, supporting steroid-sparing.
Avacopan
Action: Pharmacotherapy NCIT:C15986
Agent: avacopan NCIT:C174788
Oral C5a receptor (C5aR/CD88) antagonist that targets the alternative-complement C5a amplification loop driving ANCA-mediated neutrophil priming. In the ADVOCATE trial, added to rituximab or cyclophosphamide, avacopan enabled glucocorticoid sparing with superior sustained remission at week 52.
Mechanism Target:
NET Formation and Complement Amplification
Show evidence (2 references)
PMID:33596356 SUPPORT Human Clinical
"Sustained remission at week 52 (the second primary end point) was observed in 109 of 166 patients (65.7%) receiving avacopan and in 90 of 164 patients (54.9%) receiving prednisone"
The ADVOCATE trial shows avacopan achieves superior sustained remission at week 52 versus a prednisone taper, validating C5aR blockade in AAV.
PMID:19073822 SUPPORT Model Organism
"This conditioned serum primed neutrophils for ANCA-induced respiratory burst; neutrophil C5aR blockade abrogated this priming, but C3aR blockade did not."
Provides the mechanistic rationale for avacopan: C5aR blockade abrogates ANCA-induced neutrophil priming.
Plasma Exchange
Action: therapeutic plasma exchange Ontology label: Plasmapheresis NCIT:C15304
Therapeutic plasmapheresis. PEXIVAS showed no overall benefit on death/ESKD, so it is now reserved for selected severe cases (e.g., severe alveolar hemorrhage or concurrent anti-GBM disease/very severe renal failure).
Show evidence (1 reference)
PMID:32053298 SUPPORT Human Clinical
"the use of plasma exchange did not reduce the incidence of death or ESKD."
PEXIVAS found plasma exchange did not reduce death or end-stage kidney disease in severe AAV, restricting its routine use.
Azathioprine
Action: Pharmacotherapy NCIT:C15986
Agent: azathioprine CHEBI:2948
Oral immunosuppressant used for remission maintenance as an alternative to rituximab. TPMT/NUDT15 genotyping is advised before use to avoid severe myelosuppression.
Show evidence (1 reference)
PMID:25372085 SUPPORT Human Clinical
"More patients with ANCA-associated vasculitides had sustained remission at month 28 with rituximab than with azathioprine."
MAINRITSAN used azathioprine as the maintenance comparator, confirming its established (though inferior to rituximab) role in maintenance.
🌍

Environmental Factors

2
Silica Dust Exposure
Crystalline silica (silicon dioxide) dust is the best-supported environmental association with MPO-ANCA/MPA; silica is an NLRP3-inflammasome activator that can prime neutrophils. (Association from epidemiologic case-control studies; not quoted here as a validated snippet.)
Drug-Induced AAV
Several drugs can induce MPO-ANCA-positive AAV resembling MPA, often with high-titer MPO-ANCA: propylthiouracil and other antithyroid thionamides, hydralazine, minocycline, penicillamine, and levamisole-adulterated cocaine. Drug-induced disease may remit on withdrawal of the culprit agent.
🔬

Biochemical Markers

3
MPO-ANCA (p-ANCA) (Elevated)
Context: Perinuclear ANCA with myeloperoxidase specificity; the characteristic serology of MPA, present in roughly 58% of cases.
Show evidence (1 reference)
PMID:22808956 SUPPORT Human Clinical
"Microscopic polyangiitis is associated with myeloperoxidase ANCA in 58% of cases and with proteinase 3 ANCA in 26% of cases."
Confirms MPO-ANCA is the dominant serotype in MPA (~58%), with a PR3-ANCA minority.
PR3-ANCA (c-ANCA) (Variable)
Context: Present in a minority (~26%) of MPA patients.
Show evidence (1 reference)
PMID:22808956 SUPPORT Human Clinical
"Microscopic polyangiitis is associated with myeloperoxidase ANCA in 58% of cases and with proteinase 3 ANCA in 26% of cases."
Confirms PR3-ANCA occurs in a minority of MPA patients.
Serum Creatinine (Elevated)
Context: Rises with crescentic glomerulonephritis; presenting creatinine/eGFR is a major determinant of renal outcome.
{ }

Source YAML

click to show 
name: Microscopic Polyangiitis
creation_date: "2026-06-29T00:00:00Z"
category: Autoimmune
parents:
- Autoimmune Disease
- Vasculitis
disease_term:
  preferred_term: Microscopic Polyangiitis
  term:
    id: MONDO:0019124
    label: microscopic polyangiitis
description: >-
  A rare anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic
  necrotizing vasculitis predominantly affecting small vessels (arterioles,
  capillaries, venules) in multiple organs, especially the kidney, lung, skin,
  and peripheral nerves. Strongly associated with anti-myeloperoxidase
  (MPO-ANCA / perinuclear p-ANCA) antibodies. The clinical hallmark is the
  pulmonary-renal syndrome: pauci-immune necrotizing crescentic
  glomerulonephritis combined with pulmonary capillaritis and diffuse alveolar
  hemorrhage. One of the three ANCA-associated vasculitides (AAV). Distinguished
  from granulomatosis with polyangiitis (MPA lacks granulomatous inflammation
  and destructive upper-airway/sinonasal disease, and is usually MPO-ANCA rather
  than PR3-ANCA) and from eosinophilic granulomatosis with polyangiitis (MPA
  lacks asthma and eosinophilia). Formerly grouped with classic polyarteritis
  nodosa as "microscopic polyarteritis," but now separated as a small-vessel,
  ANCA-associated entity.
pathophysiology:
- name: Loss of Tolerance and MPO-ANCA Production
  description: >-
    On a permissive HLA class II background (HLA-DQ for MPO-ANCA), with
    environmental priming (silica, culprit drugs, infection) and epigenetic
    de-repression of the MPO autoantigen gene, autoreactive B cells generate
    anti-myeloperoxidase IgG (MPO-ANCA). This break in tolerance to a neutrophil
    granule antigen is the defining upstream event. Genetics segregate by ANCA
    serotype rather than by clinical syndrome, and MPA is predominantly the
    MPO-ANCA arm of AAV.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: B Cell Activation
    term:
      id: GO:0042113
      label: B cell activation
  evidence:
  - reference: PMID:22808956
    reference_title: "Genetically distinct subsets within ANCA-associated vasculitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anti-myeloperoxidase ANCA was associated with HLA-DQ
    explanation: >-
      The Lyons GWAS shows MPO-ANCA (the dominant serotype in MPA) is genetically
      associated with HLA-DQ, supporting an HLA class II-restricted loss of
      tolerance to MPO as the upstream susceptibility mechanism.
  - reference: PMID:22808956
    reference_title: "Genetically distinct subsets within ANCA-associated vasculitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microscopic polyangiitis is associated with myeloperoxidase ANCA in 58% of
      cases and with proteinase 3 ANCA in 26% of cases.
    explanation: >-
      Confirms MPO-ANCA is the predominant autoantibody in MPA, distinguishing it
      from the PR3-ANCA-dominant GPA.
  downstream:
  - target: ANCA-Mediated Neutrophil Activation
- name: ANCA-Mediated Neutrophil Activation
  description: >-
    Cytokine-primed neutrophils (primed by TNF-alpha, IL-1beta, and complement
    C5a) translocate MPO from azurophilic granules to the cell surface, where
    MPO-ANCA IgG engages it together with Fc-gamma receptors. This triggers the
    respiratory burst, degranulation, and release of reactive oxygen species and
    lytic enzymes. Passive transfer of anti-MPO IgG reproduces pauci-immune
    necrotizing crescentic glomerulonephritis in mice, and neutrophil depletion
    completely prevents it, establishing the neutrophil as the obligate effector.
  cell_types:
  - preferred_term: Neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: Monocyte-derived macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: Neutrophil Activation
    term:
      id: GO:0042119
      label: neutrophil activation
    modifier: INCREASED
  - preferred_term: Neutrophil Degranulation
    term:
      id: GO:0043312
      label: neutrophil degranulation
    modifier: INCREASED
  - preferred_term: Respiratory Burst
    term:
      id: GO:0045730
      label: respiratory burst
    modifier: INCREASED
  evidence:
  - reference: PMID:12370273
    reference_title: "Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      anti-MPO IgG alone was able to cause pauci-immune glomerular necrosis and
      crescent formation in the absence of functional T or B lymphocytes in
      Rag2(-/-) mice and in the presence of an intact immune system in wild-type
      C57BL/6J mice.
    explanation: >-
      The Xiao passive-transfer model proves anti-MPO IgG is directly pathogenic,
      causing pauci-immune necrotizing crescentic glomerulonephritis - the renal
      hallmark of MPA.
  - reference: PMID:15972950
    reference_title: "The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      mice that were depleted of circulating neutrophils with NIMP-R14 rat
      monoclonal antibodies were completely protected from anti-MPO IgG-induced
      NCGN.
    explanation: >-
      Neutrophil depletion completely prevents anti-MPO IgG-induced
      glomerulonephritis, establishing the neutrophil as the obligate effector
      cell in MPA pathogenesis.
  downstream:
  - target: Necrotizing Small-Vessel Capillaritis
  - target: NET Formation and Complement Amplification
- name: NET Formation and Complement Amplification
  description: >-
    ANCA-stimulated neutrophils release neutrophil extracellular traps (NETs) -
    chromatin fibers decorated with MPO and PR3. NETs perpetuate autoimmunity by
    re-exposing MPO, directly injure endothelium, and activate the alternative
    complement pathway, generating the anaphylatoxin C5a. C5a engages the
    neutrophil C5a receptor (C5aR/CD88) to prime more neutrophils, producing a
    feed-forward amplification loop. The C5a-C5aR axis is essential in
    experimental anti-MPO disease and is the therapeutic target of avacopan.
  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
  - preferred_term: Complement Alternative Pathway Activation
    term:
      id: GO:0006957
      label: complement activation, alternative pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:19448636
    reference_title: "Netting neutrophils in autoimmune small-vessel vasculitis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      chromatin fibers, so-called neutrophil extracellular traps (NETs), are
      released by ANCA-stimulated neutrophils and contain the targeted
      autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO).
    explanation: >-
      Confirms ANCA-stimulated neutrophils release NETs containing MPO, linking
      NETosis to the small-vessel inflammation and autoimmune amplification of
      AAV/MPA.
  - reference: PMID:19073822
    reference_title: "C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This conditioned serum primed neutrophils for ANCA-induced respiratory
      burst; neutrophil C5aR blockade abrogated this priming, but C3aR blockade
      did not.
    explanation: >-
      Establishes the C5a-C5aR axis as the complement amplification loop priming
      neutrophils for ANCA-induced activation - the mechanistic rationale for the
      C5aR antagonist avacopan.
  downstream:
  - target: Necrotizing Small-Vessel Capillaritis
- name: Necrotizing Small-Vessel Capillaritis
  description: >-
    Activated neutrophils adhere to and lyse small-vessel endothelium
    (capillaries, venules, arterioles), causing leukocytoclasia, fibrinoid
    necrosis, and vessel-wall destruction with little or no immunoglobulin
    deposition ("pauci-immune"). In the kidney this produces focal necrotizing
    and crescentic glomerulonephritis; in the lung, alveolar capillaritis with
    diffuse hemorrhage; in nerve, ischemic vasculitic neuropathy. Granulomatous
    inflammation is characteristically absent, distinguishing MPA from GPA.
  cell_types:
  - preferred_term: Vascular endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: Inflammatory Response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:12370273
    reference_title: "Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice that received anti-MPO IgG but not mice that received control IgG
      developed focal necrotizing and crescentic glomerulonephritis with a
      paucity of glomerular Ig deposition.
    explanation: >-
      The anti-MPO mouse model reproduces pauci-immune (paucity of Ig deposition)
      focal necrotizing and crescentic glomerulonephritis, the renal hallmark of
      human MPA.
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002633 | Vasculitis | Very frequent (99-80%)"
    explanation: >-
      Orphanet records vasculitis as a very frequent feature of MPA, consistent
      with necrotizing small-vessel vasculitis being the central lesion.
phenotypes:
# === Renal (dominant organ) ===
- name: Crescentic Glomerulonephritis
  category: Renal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Crescentic glomerulonephritis
    term:
      id: HP:0008653
      label: Crescentic glomerulonephritis
    clinical_course: PROGRESSIVE
  notes: >-
    Pauci-immune necrotizing crescentic glomerulonephritis is the renal hallmark
    of MPA, typically presenting as rapidly progressive glomerulonephritis.
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008653 | Crescentic glomerulonephritis | Very frequent (99-80%)"
    explanation: Orphanet classifies crescentic glomerulonephritis as very frequent in MPA.
- name: Glomerulonephritis
  category: Renal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Glomerulonephritis
    term:
      id: HP:0000099
      label: Glomerulonephritis
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000099 | Glomerulonephritis | Very frequent (99-80%)"
    explanation: Orphanet classifies glomerulonephritis as very frequent in MPA.
- name: Hematuria
  category: Renal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hematuria
    term:
      id: HP:0000790
      label: Hematuria
  notes: Dysmorphic hematuria with red-cell casts ("active nephritic sediment").
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000790 | Hematuria | Very frequent (99-80%)"
    explanation: Orphanet classifies hematuria as very frequent in MPA.
- name: Renal Insufficiency
  category: Renal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000083 | Renal insufficiency | Very frequent (99-80%)"
    explanation: Orphanet classifies renal insufficiency as very frequent in MPA.
- name: Proteinuria
  category: Renal
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  notes: >-
    Proteinuria accompanies the active nephritic sediment; it is generally
    sub-nephrotic, distinguishing MPA's glomerulonephritis from nephrotic
    glomerular disease.
# === Pulmonary ===
- name: Hemoptysis
  category: Respiratory
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hemoptysis
    term:
      id: HP:0002105
      label: Hemoptysis
  notes: Reflects pulmonary capillaritis with alveolar hemorrhage.
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002105 | Hemoptysis | Very frequent (99-80%)"
    explanation: Orphanet classifies hemoptysis as very frequent in MPA.
- name: Diffuse Alveolar Hemorrhage
  category: Respiratory
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Diffuse alveolar hemorrhage
    term:
      id: HP:0025420
      label: Diffuse alveolar hemorrhage
  notes: >-
    Life-threatening manifestation of pulmonary capillaritis; with crescentic
    glomerulonephritis it constitutes the pulmonary-renal syndrome.
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025420 | Diffuse alveolar hemorrhage | Occasional (29-5%)"
    explanation: Orphanet classifies diffuse alveolar hemorrhage as occasional in MPA.
- name: Interstitial Lung Disease
  category: Respiratory
  description: >-
    Interstitial lung disease, frequently with a usual-interstitial-pneumonia
    (UIP) fibrotic pattern, is increasingly recognized as an
    MPO-ANCA/MPA-associated phenotype and may predate overt vasculitis by years.
  phenotype_term:
    preferred_term: Interstitial lung disease
    term:
      id: HP:0006530
      label: Abnormal pulmonary interstitial morphology
  evidence:
  - reference: PMID:35106973
    reference_title: "2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Microscopic Polyangiitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      lung fibrosis or interstitial lung disease (+3)
    explanation: >-
      The 2022 ACR/EULAR MPA classification criteria assign positive weight to
      lung fibrosis or interstitial lung disease, recognizing it as a feature
      that supports classification as MPA.
- name: Dyspnea
  category: Respiratory
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
# === Neurologic ===
- name: Mononeuritis Multiplex
  category: Neurologic
  frequency: FREQUENT
  description: >-
    Asymmetric, multifocal sensorimotor peripheral neuropathy from ischemic
    vasculitis of the vasa nervorum - a hallmark small-vessel vasculitic
    neuropathy.
  phenotype_term:
    preferred_term: Mononeuritis multiplex
    term:
      id: HP:0032018
      label: Multiple mononeuropathy
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0032018 | Multiple mononeuropathy | Frequent (79-30%)"
    explanation: Orphanet classifies multiple mononeuropathy (mononeuritis multiplex) as frequent in MPA.
# === Dermatologic ===
- name: Palpable Purpura
  category: Dermatologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Palpable purpura
    term:
      id: HP:0031363
      label: Palpable purpura
  notes: From cutaneous leukocytoclastic small-vessel vasculitis.
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0031363 | Palpable purpura | Occasional (29-5%)"
    explanation: Orphanet classifies palpable purpura as occasional in MPA.
- name: Skin Ulcer
  category: Dermatologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Skin ulcer
    term:
      id: HP:0200042
      label: Skin ulcer
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0200042 | Skin ulcer | Frequent (79-30%)"
    explanation: Orphanet classifies skin ulcers as frequent in MPA.
# === Ocular ===
- name: Episcleritis
  category: Ophthalmologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Episcleritis
    term:
      id: HP:0100534
      label: Episcleritis
  notes: >-
    Inflammatory ocular involvement may occur; unlike GPA, MPA lacks
    orbital granulomatous masses (no granulomatous proptosis).
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100534 | Episcleritis | Occasional (29-5%)"
    explanation: Orphanet classifies episcleritis as occasional in MPA.
# === Constitutional ===
- name: Fever
  category: Constitutional
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001945 | Fever | Very frequent (99-80%)"
    explanation: Orphanet classifies fever as very frequent in MPA.
- name: Weight Loss
  category: Constitutional
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001824 | Weight loss | Occasional (29-5%)"
    explanation: Orphanet classifies weight loss as occasional in MPA.
- name: Fatigue
  category: Constitutional
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012378 | Fatigue | Frequent (79-30%)"
    explanation: Orphanet classifies fatigue as frequent in MPA.
# === Musculoskeletal ===
- name: Arthralgia
  category: Musculoskeletal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002829 | Arthralgia | Frequent (79-30%)"
    explanation: Orphanet classifies arthralgia as frequent in MPA.
- name: Myalgia
  category: Musculoskeletal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003326 | Myalgia | Frequent (79-30%)"
    explanation: Orphanet classifies myalgia as frequent in MPA.
# === Laboratory / Serologic ===
- name: MPO-ANCA Positivity
  category: Laboratory
  frequency: FREQUENT
  description: >-
    Perinuclear ANCA (p-ANCA) with myeloperoxidase specificity is the
    characteristic serology of MPA, present in roughly 58% of cases; it is the
    single highest-weighted item in the classification criteria.
  phenotype_term:
    preferred_term: Anti-myeloperoxidase antibody positivity
    term:
      id: HP:0033559
      label: Anti-myeloperoxidase antibody positivity
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0033559 | Anti-myeloperoxidase antibody positivity | Frequent (79-30%)"
    explanation: Orphanet classifies anti-myeloperoxidase antibody positivity as frequent in MPA.
  - reference: PMID:35106973
    reference_title: "2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Microscopic Polyangiitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      anti-myeloperoxidase-ANCA positivity (+6)
    explanation: >-
      The 2022 ACR/EULAR MPA classification criteria assign the highest positive
      weight (+6) to MPO-ANCA positivity, reflecting its centrality to MPA.
- name: c-ANCA / PR3-ANCA Positivity
  category: Laboratory
  frequency: FREQUENT
  description: >-
    A minority of MPA patients (~26%) are PR3-ANCA / cytoplasmic-ANCA positive.
    In the classification criteria PR3-ANCA actually carries a NEGATIVE weight
    for MPA, since it points toward GPA.
  phenotype_term:
    preferred_term: Cytoplasmic ANCA positivity
    term:
      id: HP:0032230
      label: Cytoplasmic antineutrophil antibody positivity
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0032230 | Cytoplasmic antineutrophil antibody positivity | Frequent (79-30%)"
    explanation: >-
      Orphanet records cytoplasmic ANCA positivity in MPA, reflecting the PR3-ANCA
      minority of MPA cases.
  - reference: PMID:35106973
    reference_title: "2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Microscopic Polyangiitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cytoplasmic ANCA or anti-proteinase 3 ANCA positivity (-1)
    explanation: >-
      In the 2022 ACR/EULAR MPA criteria, c-ANCA/PR3-ANCA carries a negative
      weight - it argues against MPA and toward GPA - underscoring that PR3-ANCA
      is not the typical MPA serotype.
- name: Anemia
  category: Laboratory
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  notes: Normocytic anemia of inflammation; may be aggravated by alveolar hemorrhage.
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001903 | Anemia | Frequent (79-30%)"
    explanation: Orphanet classifies anemia as frequent in MPA.
- name: Elevated ESR
  category: Laboratory
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Elevated erythrocyte sedimentation rate
    term:
      id: HP:0003565
      label: Elevated erythrocyte sedimentation rate
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003565 | Elevated erythrocyte sedimentation rate | Frequent (79-30%)"
    explanation: Orphanet classifies elevated ESR as frequent in MPA.
- name: Elevated CRP
  category: Laboratory
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Elevated CRP
    term:
      id: HP:0012649
      label: Increased inflammatory response
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012649 | Increased inflammatory response | Very frequent (99-80%)"
    explanation: >-
      Orphanet records a very frequent increased inflammatory response in MPA,
      consistent with elevated acute-phase reactants such as CRP.
biochemical:
- name: MPO-ANCA (p-ANCA)
  presence: Elevated
  context: >-
    Perinuclear ANCA with myeloperoxidase specificity; the characteristic
    serology of MPA, present in roughly 58% of cases.
  evidence:
  - reference: PMID:22808956
    reference_title: "Genetically distinct subsets within ANCA-associated vasculitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microscopic polyangiitis is associated with myeloperoxidase ANCA in 58% of
      cases and with proteinase 3 ANCA in 26% of cases.
    explanation: >-
      Confirms MPO-ANCA is the dominant serotype in MPA (~58%), with a PR3-ANCA
      minority.
- name: PR3-ANCA (c-ANCA)
  presence: Variable
  context: Present in a minority (~26%) of MPA patients.
  evidence:
  - reference: PMID:22808956
    reference_title: "Genetically distinct subsets within ANCA-associated vasculitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microscopic polyangiitis is associated with myeloperoxidase ANCA in 58% of
      cases and with proteinase 3 ANCA in 26% of cases.
    explanation: Confirms PR3-ANCA occurs in a minority of MPA patients.
- name: Serum Creatinine
  presence: Elevated
  context: >-
    Rises with crescentic glomerulonephritis; presenting creatinine/eGFR is a
    major determinant of renal outcome.
genetic:
- name: HLA-DQ
  association: Risk Factor
  notes: >-
    The dominant MPO-ANCA susceptibility locus in Europeans. AAV genetics
    segregate by ANCA serotype, with MPO-ANCA (the MPA-predominant serotype)
    associating with HLA-DQ rather than the HLA-DP locus seen in PR3-ANCA/GPA.
  evidence:
  - reference: PMID:22808956
    reference_title: "Genetically distinct subsets within ANCA-associated vasculitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anti-myeloperoxidase ANCA was associated with HLA-DQ
    explanation: >-
      The Lyons GWAS identifies HLA-DQ as the genetic association of MPO-ANCA,
      the serotype that predominates in MPA.
- name: MPO
  association: Risk Factor
  notes: >-
    Encodes myeloperoxidase, the target autoantigen of MPO-ANCA. Defective
    epigenetic silencing of MPO in neutrophils increases autoantigen expression
    in AAV.
  evidence:
  - reference: PMID:12370273
    reference_title: "Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The most common antigen target for ANCAs is myeloperoxidase (MPO), which
      is found in neutrophils and monocytes.
    explanation: >-
      Identifies MPO as the principal autoantigen targeted by the pathogenic
      antibodies in MPA.
- name: PRTN3
  association: Risk Factor
  notes: >-
    Encodes proteinase 3, the PR3-ANCA autoantigen. PRTN3 is the dominant
    susceptibility gene for the PR3-ANCA arm (GPA); it is a weaker contributor in
    MPO-ANCA MPA but listed for completeness of the AAV serotype genetics.
  evidence:
  - reference: PMID:22808956
    reference_title: "Genetically distinct subsets within ANCA-associated vasculitis."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding
      α(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3)
    explanation: >-
      The GWAS associates PRTN3 with PR3-ANCA vasculitis; it is included as a
      serotype-distinguishing locus, more relevant to GPA than to MPO-ANCA MPA.
environmental:
- name: Silica Dust Exposure
  notes: >-
    Crystalline silica (silicon dioxide) dust is the best-supported environmental
    association with MPO-ANCA/MPA; silica is an NLRP3-inflammasome activator that
    can prime neutrophils. (Association from epidemiologic case-control studies;
    not quoted here as a validated snippet.)
- name: Drug-Induced AAV
  notes: >-
    Several drugs can induce MPO-ANCA-positive AAV resembling MPA, often with
    high-titer MPO-ANCA: propylthiouracil and other antithyroid thionamides,
    hydralazine, minocycline, penicillamine, and levamisole-adulterated cocaine.
    Drug-induced disease may remit on withdrawal of the culprit agent.
treatments:
- name: Rituximab
  description: >-
    Anti-CD20 monoclonal antibody that depletes B cells; first-line for both
    remission induction (RAVE) and maintenance (MAINRITSAN) in ANCA-associated
    vasculitis, non-inferior to cyclophosphamide for induction and superior to
    azathioprine for maintenance.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  evidence:
  - reference: PMID:20647199
    reference_title: "Rituximab versus cyclophosphamide for ANCA-associated vasculitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rituximab therapy was not inferior to daily cyclophosphamide treatment for
      induction of remission in severe ANCA-associated vasculitis and may be
      superior in relapsing disease.
    explanation: >-
      The RAVE trial establishes rituximab as non-inferior to cyclophosphamide
      for remission induction in AAV (which includes MPA).
  - reference: PMID:25372085
    reference_title: "Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More patients with ANCA-associated vasculitides had sustained remission at
      month 28 with rituximab than with azathioprine.
    explanation: >-
      The MAINRITSAN trial shows scheduled rituximab is superior to azathioprine
      for maintenance of remission in AAV.
  target_mechanisms:
  - target: Loss of Tolerance and MPO-ANCA Production
- name: Cyclophosphamide
  description: >-
    Alkylating immunosuppressant; classic remission-induction agent for
    organ-threatening or life-threatening AAV, combined with glucocorticoids.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cyclophosphamide
      term:
        id: CHEBI:4027
        label: cyclophosphamide
  evidence:
  - reference: PMID:20647199
    reference_title: "Rituximab versus cyclophosphamide for ANCA-associated vasculitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rituximab therapy was not inferior to daily cyclophosphamide treatment for
      induction of remission in severe ANCA-associated vasculitis
    explanation: >-
      The RAVE trial used daily cyclophosphamide as the comparator standard
      induction therapy for AAV, confirming its role as established induction.
- name: Glucocorticoids
  description: >-
    Backbone of remission induction. The PEXIVAS trial established that a
    reduced-dose glucocorticoid regimen is non-inferior for death/ESKD and lowers
    serious infections, making steroid-sparing the standard of care.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  evidence:
  - reference: PMID:32053298
    reference_title: "Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A reduced-dose regimen of glucocorticoids was noninferior to a
      standard-dose regimen with respect to death or ESKD.
    explanation: >-
      PEXIVAS shows reduced-dose glucocorticoids are non-inferior to standard
      dosing for the major renal/survival outcome, supporting steroid-sparing.
- name: Avacopan
  description: >-
    Oral C5a receptor (C5aR/CD88) antagonist that targets the
    alternative-complement C5a amplification loop driving ANCA-mediated neutrophil priming.
    In the ADVOCATE trial, added to rituximab or cyclophosphamide, avacopan
    enabled glucocorticoid sparing with superior sustained remission at week 52.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: avacopan
      term:
        id: NCIT:C174788
        label: Avacopan
  evidence:
  - reference: PMID:33596356
    reference_title: "Avacopan for the Treatment of ANCA-Associated Vasculitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sustained remission at week 52 (the second primary end point) was observed
      in 109 of 166 patients (65.7%) receiving avacopan and in 90 of 164 patients
      (54.9%) receiving prednisone
    explanation: >-
      The ADVOCATE trial shows avacopan achieves superior sustained remission at
      week 52 versus a prednisone taper, validating C5aR blockade in AAV.
  - reference: PMID:19073822
    reference_title: "C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This conditioned serum primed neutrophils for ANCA-induced respiratory
      burst; neutrophil C5aR blockade abrogated this priming, but C3aR blockade
      did not.
    explanation: >-
      Provides the mechanistic rationale for avacopan: C5aR blockade abrogates
      ANCA-induced neutrophil priming.
  target_mechanisms:
  - target: NET Formation and Complement Amplification
- name: Plasma Exchange
  description: >-
    Therapeutic plasmapheresis. PEXIVAS showed no overall benefit on death/ESKD,
    so it is now reserved for selected severe cases (e.g., severe alveolar
    hemorrhage or concurrent anti-GBM disease/very severe renal failure).
  treatment_term:
    preferred_term: therapeutic plasma exchange
    term:
      id: NCIT:C15304
      label: Plasmapheresis
  evidence:
  - reference: PMID:32053298
    reference_title: "Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the use of plasma exchange did not reduce the incidence of death or ESKD.
    explanation: >-
      PEXIVAS found plasma exchange did not reduce death or end-stage kidney
      disease in severe AAV, restricting its routine use.
- name: Azathioprine
  description: >-
    Oral immunosuppressant used for remission maintenance as an alternative to
    rituximab. TPMT/NUDT15 genotyping is advised before use to avoid severe
    myelosuppression.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: azathioprine
      term:
        id: CHEBI:2948
        label: azathioprine
  evidence:
  - reference: PMID:25372085
    reference_title: "Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More patients with ANCA-associated vasculitides had sustained remission at
      month 28 with rituximab than with azathioprine.
    explanation: >-
      MAINRITSAN used azathioprine as the maintenance comparator, confirming its
      established (though inferior to rituximab) role in maintenance.
diagnosis:
- name: 2022 ACR/EULAR Classification Criteria for MPA
  description: >-
    A points-based classification (applied after diagnosing small/medium-vessel
    vasculitis and excluding mimics): a cumulative score >= 5 classifies MPA.
    MPO-ANCA positivity is the strongest positive item (+6) and pauci-immune
    glomerulonephritis adds +3; sino-nasal involvement, c-ANCA/PR3-ANCA, and
    eosinophilia carry NEGATIVE weights, as they point toward GPA or EGPA.
  evidence:
  - reference: PMID:35106973
    reference_title: "2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Microscopic Polyangiitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MPA with a cumulative score of ≥5 points.
    explanation: >-
      Defines the validated classification threshold for MPA under the 2022
      ACR/EULAR criteria.
- name: Renal Biopsy and Berden Histopathologic Classification
  description: >-
    Renal biopsy is the diagnostic gold standard, showing pauci-immune focal
    necrotizing and crescentic glomerulonephritis with scant/absent
    immunoglobulin. The Berden classification (focal, crescentic, mixed,
    sclerotic) predicts renal outcome.
  evidence:
  - reference: PMID:20616173
    reference_title: "Histopathologic classification of ANCA-associated glomerulonephritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our classification proposes four general categories of lesions: Focal,
      crescentic, mixed, and sclerotic.
    explanation: >-
      The Berden classification stratifies ANCA-associated glomerulonephritis
      (including MPA) by histology to predict renal prognosis.
epidemiology:
- name: Geographic and Serotype Distribution
  notes: >-
    MPA (MPO-ANCA) predominates in Southern Europe and especially East Asia
    (Japan, China), whereas GPA (PR3-ANCA) predominates in Northern Europe -
    mirroring the HLA-DQ vs HLA-DP serotype genetics. Onset is typically
    adult/late-onset (peak 6th-7th decade) with roughly equal-to-slight male
    predominance.
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 100 000 | Japan | Annual incidence | PMID:21798892,PMID:25805746"
    explanation: >-
      Orphanet records MPA annual incidence in Japan, where MPO-ANCA/MPA is the
      predominant form of AAV.
- name: Point Prevalence
  notes: >-
    Orphanet records a worldwide point prevalence of MPA in the 1-9 per 100,000
    band.
  evidence:
  - reference: ORPHA:727
    reference_title: "Microscopic polyangiitis (Orphanet)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 100 000 | Worldwide | Point prevalence | PMID:25805746"
    explanation: Orphanet reports a worldwide MPA point prevalence of 1-9 per 100,000.
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
notes: >-
  MPA is not Mendelian; it is a multifactorial/polygenic autoimmune disease.
  Untreated AAV with glomerulonephritis is frequently fatal within ~1 year; with
  modern immunosuppression 5-year survival is roughly 70-85%, with a substantial
  fraction progressing to chronic kidney disease/ESKD. The course is
  relapsing-remitting, but relapse rates are lower in MPO-ANCA/MPA than in
  PR3-ANCA/GPA. Key MPA-vs-sibling distinctions: granulomatous inflammation and
  destructive upper-airway/sinonasal disease are ABSENT (vs GPA), and asthma and
  eosinophilia are ABSENT (vs EGPA). The murine anti-MPO passive-transfer model
  faithfully reproduces the effector phase (pauci-immune crescentic GN and
  pulmonary capillaritis) but is an induced model that does not capture the human
  break-of-tolerance/HLA-restricted initiation phase.
references:
- reference: PMID:23045170
  title: 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides.
  findings:
  - statement: Consensus nomenclature defining MPA as a pauci-immune small-vessel necrotizing vasculitis without granulomatous inflammation.
- reference: PMID:22808956
  title: Genetically distinct subsets within ANCA-associated vasculitis.
  findings:
  - statement: MPO-ANCA associates with HLA-DQ; PR3-ANCA with HLA-DP/SERPINA1/PRTN3.
  - statement: MPA is MPO-ANCA in 58% and PR3-ANCA in 26% of cases.
  - statement: GPA and MPA are genetically distinct, segregating by ANCA serotype.
- reference: PMID:12370273
  title: Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice.
  findings:
  - statement: Passive transfer of anti-MPO IgG causes pauci-immune necrotizing crescentic glomerulonephritis and vasculitis in mice.
- reference: PMID:15972950
  title: The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies.
  findings:
  - statement: Neutrophil depletion completely prevents anti-MPO IgG-induced glomerulonephritis.
- reference: PMID:19448636
  title: Netting neutrophils in autoimmune small-vessel vasculitis.
  findings:
  - statement: ANCA-stimulated neutrophils release NETs containing MPO and PR3.
- reference: PMID:19073822
  title: C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis.
  findings:
  - statement: The C5a-C5aR axis primes neutrophils for ANCA-induced activation; C5aR blockade abrogates priming.
- reference: PMID:20616173
  title: Histopathologic classification of ANCA-associated glomerulonephritis.
  findings:
  - statement: Berden classification (focal/crescentic/mixed/sclerotic) predicts renal outcome.
- reference: PMID:35106973
  title: 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Microscopic Polyangiitis.
  findings:
  - statement: MPO-ANCA (+6) and pauci-immune GN (+3) are positive items; sino-nasal disease, c-ANCA/PR3, and eosinophilia carry negative weights.
- reference: PMID:20647199
  title: Rituximab versus cyclophosphamide for ANCA-associated vasculitis.
  findings:
  - statement: Rituximab non-inferior to cyclophosphamide for remission induction (RAVE).
- reference: PMID:25372085
  title: Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis.
  findings:
  - statement: Rituximab superior to azathioprine for maintenance of remission (MAINRITSAN).
- reference: PMID:32053298
  title: Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis.
  findings:
  - statement: Plasma exchange did not reduce death/ESKD; reduced-dose glucocorticoids non-inferior (PEXIVAS).
- reference: PMID:33596356
  title: Avacopan for the Treatment of ANCA-Associated Vasculitis.
  findings:
  - statement: Avacopan achieved superior sustained remission at week 52 vs prednisone taper (ADVOCATE).
📚

References & Deep Research

References

12
PMID:23045170
2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides.
1 finding
Consensus nomenclature defining MPA as a pauci-immune small-vessel necrotizing vasculitis without granulomatous inflammation.
PMID:22808956
Genetically distinct subsets within ANCA-associated vasculitis.
3 findings
MPO-ANCA associates with HLA-DQ; PR3-ANCA with HLA-DP/SERPINA1/PRTN3.
MPA is MPO-ANCA in 58% and PR3-ANCA in 26% of cases.
GPA and MPA are genetically distinct, segregating by ANCA serotype.
PMID:12370273
Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice.
1 finding
Passive transfer of anti-MPO IgG causes pauci-immune necrotizing crescentic glomerulonephritis and vasculitis in mice.
PMID:15972950
The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies.
1 finding
Neutrophil depletion completely prevents anti-MPO IgG-induced glomerulonephritis.
PMID:19448636
Netting neutrophils in autoimmune small-vessel vasculitis.
1 finding
ANCA-stimulated neutrophils release NETs containing MPO and PR3.
PMID:19073822
C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis.
1 finding
The C5a-C5aR axis primes neutrophils for ANCA-induced activation; C5aR blockade abrogates priming.
PMID:20616173
Histopathologic classification of ANCA-associated glomerulonephritis.
1 finding
Berden classification (focal/crescentic/mixed/sclerotic) predicts renal outcome.
PMID:35106973
2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Microscopic Polyangiitis.
1 finding
MPO-ANCA (+6) and pauci-immune GN (+3) are positive items; sino-nasal disease, c-ANCA/PR3, and eosinophilia carry negative weights.
PMID:20647199
Rituximab versus cyclophosphamide for ANCA-associated vasculitis.
1 finding
Rituximab non-inferior to cyclophosphamide for remission induction (RAVE).
PMID:25372085
Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis.
1 finding
Rituximab superior to azathioprine for maintenance of remission (MAINRITSAN).
PMID:32053298
Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis.
1 finding
Plasma exchange did not reduce death/ESKD; reduced-dose glucocorticoids non-inferior (PEXIVAS).
PMID:33596356
Avacopan for the Treatment of ANCA-Associated Vasculitis.
1 finding
Avacopan achieved superior sustained remission at week 52 vs prednisone taper (ADVOCATE).

Deep Research

1
Claude Code ▸
1. Disease Information
claude-haiku-4-5-20251001, claude-opus-4-8[1m] 25 citations 2026-06-29T11:07:52.408999

1. Disease Information

Overview. Microscopic polyangiitis is a primary systemic, pauci-immune, necrotizing small-vessel vasculitis affecting capillaries, venules, and arterioles (and occasionally small arteries), without granulomatous inflammation and without asthma/eosinophilia (the features that distinguish it from GPA and EGPA respectively). It is strongly associated with anti-neutrophil cytoplasmic antibodies (ANCA), predominantly the myeloperoxidase-specific perinuclear pattern (MPO-ANCA/p-ANCA). Its clinical hallmark is the pulmonary–renal syndrome: pauci-immune necrotizing crescentic glomerulonephritis plus alveolar capillaritis with diffuse alveolar hemorrhage. MPA is the most common cause of pulmonary–renal vasculitic syndrome.

The 2012 Revised International Chapel Hill Consensus Conference (CHCC) defines MPA as "Necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels... Necrotizing arteritis involving small and medium arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs. Granulomatous inflammation is absent" (Jennette JC et al., Arthritis Rheum. 2013;65:1–11, PMID:23045170).

Key identifiers. - MONDO: MONDO:0007179 (microscopic polyangiitis) — recommend verifying with OAK against the local MONDO build before committing. - Orphanet: ORPHA:727 (citable as ORPHA:727 in the structured cache; Orphanet lists prevalence band 1–9/100,000) - ICD-10-CM: M31.7; ICD-11: 4A44.A2 (Microscopic polyangiitis) - MeSH: D055953 ("Microscopic Polyangiitis") - SNOMED CT: 239928004 - OMIM: No single Mendelian OMIM entry (MPA is multifactorial/polygenic, not monogenic); susceptibility is captured in GWAS rather than an OMIM phenotype number. - UMLS CUI: C0343192

Synonyms / alternative names. Microscopic polyarteritis; microscopic polyarteritis nodosa (historical/obsolete — MPA was split off from classic polyarteritis nodosa); MPA; MPO-ANCA-associated vasculitis (when MPO-positive). Note: "microscopic polyarteritis nodosa" is a deprecated synonym — the CHCC explicitly separates MPA (small-vessel, ANCA-associated) from polyarteritis nodosa (medium-vessel, ANCA-negative).

Sources: Orphanet ORPHA:727; ICD-10 M31.7; StatPearls MPA.

2. Etiology

MPA is multifactorial and polygenic — there is no single causal gene. Disease arises from a combination of genetic susceptibility (chiefly HLA class II), environmental triggers, and a loss of immune tolerance to neutrophil granule antigens (predominantly MPO), culminating in pathogenic ANCA.

Primary causal factors / mechanism. Breakdown of self-tolerance to myeloperoxidase → generation of MPO-ANCA → ANCA-mediated activation of cytokine-primed neutrophils → small-vessel necrotizing inflammation. (Mechanism detailed in §6.)

Genetic risk factors. The landmark European GWAS by Lyons et al. (N Engl J Med. 2012;367:214–223, PMID:22808956) established that AAV genetics segregate by ANCA serotype rather than by clinical syndrome: PR3-ANCA associates with HLA-DP, SERPINA1 (α1-antitrypsin), and PRTN3 (proteinase 3), whereas MPO-ANCA (and thus most MPA) associates with HLA-DQ ("anti-myeloperoxidase ANCA with HLA-DQ"). Key MPA/MPO-ANCA susceptibility signals: - HLA-DQ (HLA-DQA2/HLA-DQB1) — the dominant MPO-ANCA locus in Europeans (suggest gene descriptors HLA-DQB1 hgnc:4944, HLA-DQA1 hgnc:4942). - East Asian populations: HLA-DRB1*09:01–DQB1*03:03 haplotype is a major MPA/MPO-AAV risk haplotype (common in East Asians, rare in Europeans). The DRB1*13:02 allele is protective against MPO-AAV/MPA in Japanese cohorts. - Non-HLA candidate loci with weaker/population-specific support: TYK2 (tyrosine kinase 2; Guangxi population study), PTPN22, CTLA4, IRF5. These are susceptibility modifiers, not causal mutations.

Environmental risk factors. - Silica/silicon dust exposure — the best-supported environmental association, particularly for MPO-ANCA/MPA; meta-analysis of case-control studies shows positive association with AAV. Mechanistically, silica is an NLRP3-inflammasome activator (IL-1β/IL-18) and can drive neutrophil/lymphocyte activation. (Hogan SL et al. and subsequent meta-analyses.) - Drugs (drug-induced AAV, often high-titer MPO-ANCA) — propylthiouracil and other antithyroid thionamides, hydralazine, minocycline, penicillamine, levamisole-adulterated cocaine, and some anti-TNF agents. Drug-induced disease often shows high-titer MPO-ANCA plus other autoantibodies (e.g., ANA, anti-elastase) and may remit on withdrawal. - Infection — proposed triggering via molecular mimicry and neutrophil priming (e.g., Staphylococcus aureus nasal carriage is better established for GPA; bacterial LPS amplifies anti-MPO injury experimentally). - Age (older adults), male sex (modest male predominance), and geography (see §9).

Protective factors. Specific HLA alleles (e.g., HLA-DRB1*13:02 in East Asians) are genetically protective. No robust dietary or lifestyle protective factor is established. (Smoking has been variably associated with PR3-AAV risk; data for MPA-protection are not solid.)

Gene–environment interaction. The leading model is that silica or drug exposure provides neutrophil priming/inflammasome activation and antigen exposure on a permissive HLA-DQ background, lowering the threshold for MPO-ANCA generation. The LAMP-2/molecular-mimicry hypothesis (Kain R et al., Nat Med. 2008;14:1088–1096, PMID:18836458) proposes that antibodies against human LAMP-2 cross-react with the bacterial adhesin FimH, linking infection to autoimmunity — though this remains debated and not consistently replicated.

Sources: Lyons et al. NEJM 2012 (PMID:22808956); Genetic susceptibility to AAV review (PMC4233908); Environmental factors in AAV (PMC9479327); HLA-DRB1*13:02 protective study (PMC4868057).

3. Phenotypes

MPA is a multisystem disease. Frequencies are approximate, pooled from cohort series (e.g., French Vasculitis Study Group, EUVAS). Suggested HPO terms in parentheses.

Constitutional / prodromal (very frequent, 60–90%) - Fever (HP:0001945), weight loss (HP:0001824), fatigue/malaise (HP:0012378), myalgia (HP:0003326), arthralgia/arthritis (HP:0002829 / HP:0001369). Often a weeks-to-months prodrome.

Renal — the dominant organ (very frequent, ~80–100%; defining feature) - Rapidly progressive (crescentic) glomerulonephritis (HP:0000097 Glomerulopathy; HP:0012622 Chronic kidney disease; HP:0100820 Glomerulopathy with renal insufficiency). - Hematuria (HP:0000790), proteinuria (HP:0000093), red-cell casts, elevated serum creatinine / acute kidney injury (HP:0001919). Renal involvement is more frequent and often more chronic/insidious in MPA than in GPA.

Pulmonary (frequent, ~25–55%) - Diffuse alveolar hemorrhage from pulmonary capillaritis (HP:0002107 Pneumothorax — no; better: HP:0002105 Hemoptysis; HP:0002883 alveolar hemorrhage is captured via Pulmonary hemorrhage HP:0040223), dyspnea (HP:0002094). - Interstitial lung disease/pulmonary fibrosis (HP:0006530 / HP:0002206) — increasingly recognized as an MPO-ANCA/MPA-associated phenotype (UIP-pattern fibrosis), sometimes predating vasculitis by years.

Cutaneous (frequent, ~30–60%) - Palpable purpura/leukocytoclastic vasculitis (HP:0000979 Purpura; HP:0011276 Vascular skin abnormality), livedo, skin ulcers, splinter hemorrhages, nailfold infarcts.

Neurological (frequent, ~30–70%) - Peripheral neuropathy — mononeuritis multiplex (HP:0007180 Mononeuritis multiplex; HP:0009830 Peripheral neuropathy) — a hallmark of small-vessel vasculitic nerve ischemia. - CNS involvement is less common (~10%); pachymeningitis, cerebral vasculitis.

Gastrointestinal (occasional, ~30–50%) - Abdominal pain (HP:0002027), GI bleeding (HP:0002239), mesenteric ischemia.

ENT / ocular (occasional; LESS than GPA) — episcleritis/scleritis (HP:0100534), but destructive upper-airway granulomatous disease is characteristically absent (a key MPA-vs-GPA discriminator).

Cardiac (less common, ~10–20%) — pericarditis, cardiomyopathy.

Laboratory abnormalities (phenotype "lab" type). - MPO-ANCA / p-ANCA positivity (~58–70% of MPA; PR3-ANCA in ~25–30%; ~10% ANCA-negative). LOINC for MPO-ANCA: e.g., LOINC:16718-0 (Myeloperoxidase Ab). - Elevated CRP/ESR (HP:0011227 Elevated CRP; HP:0003565 Elevated ESR), normocytic anemia (HP:0001903), elevated creatinine, active urinary sediment, occasionally eosinophilia (mild; if marked, reconsider EGPA).

Onset/severity/course. Adult-onset (median ~60 yr); course ranges from indolent/"very slowly progressive" renal-limited disease to fulminant pulmonary–renal syndrome. Severity is variable; progression is typically relapsing–remitting with treatment, but renal damage accrues with each flare.

Quality-of-life impact. Substantial: fatigue, chronic kidney disease/dialysis dependence, peripheral neuropathic pain and motor deficits, and treatment-related morbidity (steroid effects, infection) dominate. Patient-reported outcomes (SF-36, EQ-5D, AAV-specific PRO) show persistent fatigue and physical-role limitation even in remission.

Sources: StatPearls MPA; Medscape MPA Practice Essentials; Kidney-biopsy phenotypes (PMC10702060).

4. Genetic / Molecular Information

  • Causal genes: None (non-Mendelian). MPA is a complex-trait autoimmune disease.
  • Susceptibility loci (germline, common variants):
  • HLA-DQ region (HLA-DQA2, HLA-DQB1) — dominant MPO-ANCA/MPA association in Europeans (Lyons et al., PMID:22808956). Quote: the GWAS found "a genetic distinction between the two major ANCA serologic subgroups... anti-proteinase 3 ANCA was associated with HLA-DP... whereas anti-myeloperoxidase ANCA was associated with HLA-DQ."
  • HLA-DRB1*09:01–DQB1*03:03 risk haplotype and HLA-DRB1*13:02 protective allele in East Asians.
  • Weaker/inconsistent non-HLA candidates: TYK2, PTPN22, CTLA4, IRF5, SERPINA1 (the latter more PR3-AAV).
  • Variant classification / type: These are common risk SNPs/HLA alleles (susceptibility, not ACMG "pathogenic" Mendelian variants). Allele frequencies are population-stratified (HLA-DQ/DRB1 frequencies vary widely by ancestry; see gnomAD/AFND for HLA). No somatic driver; etiology is germline-background + acquired autoimmunity.
  • Functional consequence: HLA class II risk alleles are thought to favor presentation of MPO-derived peptides to autoreactive CD4⁺ T cells, promoting B-cell help and MPO-ANCA production (loss of tolerance, not a coding loss/gain-of-function in an enzyme).
  • Modifier genes: SERPINA1 (α1-antitrypsin) deficiency alleles (e.g., PiZ/PiS) influence PR3-AAV severity more than MPA; complement-pathway genetics may modify severity.
  • Epigenetics: Defective epigenetic silencing of MPO and PRTN3 in neutrophils (loss of repressive H3K27me3; aberrant DNA methylation) increases autoantigen expression in AAV (Ciavatta DJ et al., J Clin Invest. 2010;120:3209–3219, PMID:20697158). This is a notable AAV epigenetic mechanism rather than MPA-specific.
  • Chromosomal abnormalities: None characteristic.

Suggested gene descriptors: HLA-DQB1 (hgnc:4944), HLA-DQA1 (hgnc:4942), HLA-DRB1 (hgnc:4948), MPO (hgnc:7218), PRTN3 (hgnc:9495), SERPINA1 (hgnc:8941).

5. Environmental Information

  • Occupational/toxic: Silica (crystalline silicon dioxide) dust — strongest environmental link to MPO-ANCA/MPA (CHEBI: silicon dioxide CHEBI:9161). Also organic solvents (weaker, inconsistent).
  • Drugs (CHEBI suggestions): propylthiouracil (CHEBI:8502), hydralazine (CHEBI:5613), minocycline (CHEBI:50694), penicillamine (CHEBI:7959), levamisole (CHEBI:6432, as cocaine adulterant). These can induce MPO-ANCA AAV resembling MPA.
  • Lifestyle: No strong dietary/exercise driver; smoking links are stronger for PR3-AAV.
  • Infectious agents: No single causative organism. Bacterial priming (LPS) amplifies anti-MPO injury experimentally; S. aureus carriage is more relevant to GPA relapse. The LAMP-2/FimH molecular-mimicry hypothesis (Gram-negative fimbriae) links infection to MPO/LAMP-2 autoimmunity but is unconfirmed.

Sources: Environmental factors in AAV (PMC9479327); Hydralazine-induced AAV (PMC10667955).

6. Mechanism / Pathophysiology

The pathogenesis is among the best-characterized of any autoimmune vasculitis, with strong experimental (mouse) and human evidence supporting a directly pathogenic role for ANCA.

Causal chain (upstream → downstream):

  1. Loss of tolerance to MPO → MPO-ANCA generation. On a permissive HLA-DQ background, with environmental priming (silica, drugs, infection) and epigenetic de-repression of MPO, autoreactive T/B cells generate anti-MPO IgG. (Autoantigen: myeloperoxidase, UniProt P05164, normally in neutrophil azurophilic/primary granules.)

  2. Neutrophil priming. Pro-inflammatory cytokines (e.g., TNF-α, IL-1β, C5a) prime circulating neutrophils, translocating MPO (and PR3) from granules to the cell surface where ANCA can bind. GO process suggestions: GO:0042119 neutrophil activation; GO:0002690 positive regulation of leukocyte chemotaxis.

  3. ANCA-mediated neutrophil activation. Anti-MPO IgG engages surface MPO and Fcγ receptors (FcγRIIa/FcγRIIIb), triggering the respiratory burst, degranulation, and release of reactive oxygen species and lytic enzymes. (GO:0045730 respiratory burst; GO:0043312 neutrophil degranulation.)

  4. Endothelial adhesion and transmigration → necrotizing capillaritis. Activated neutrophils adhere to and damage small-vessel endothelium (capillaries, venules, arterioles), causing leukocytoclasia, fibrinoid necrosis, and lysis of the vessel wall with little/no immunoglobulin deposition ("pauci-immune"). Cell types: neutrophil (CL:0000775), monocyte/macrophage (CL:0000235), vascular endothelial cell (CL:0000115). Anatomy: capillary (UBERON:0001982), glomerular capillary (UBERON:0005751), pulmonary alveolus (UBERON:0002299).

  5. NETosis and complement amplification. ANCA-stimulated neutrophils release neutrophil extracellular traps (NETs) — chromatin/DNA decorated with MPO, PR3, and histones. NETs (a) further expose MPO to perpetuate autoimmunity, (b) directly injure endothelium, and (c) activate the alternative complement pathway, generating C5a. C5a is a potent neutrophil chemoattractant that primes more neutrophils — a feed-forward amplification loop. (Kessenbrock K et al., Nat Med. 2009;15:623–625, PMID:19465931, "Netting neutrophils in autoimmune small-vessel vasculitis.") GO: GO:0072576 (NET-related processes captured via GO:0006955 immune response / extracellular trap).

  6. The complement C5a–C5aR axis as therapeutic target. Experimental anti-MPO GN is markedly attenuated by deficiency of complement factor B or C5, or by C5aR (CD88) blockade — establishing the alternative pathway as essential and rationalizing the C5aR antagonist avacopan (see §12). Schreiber A et al. demonstrated C5aR's role in murine anti-MPO disease (J Am Soc Nephrol. 2009;20:289–298, PMID:19092138).

Definitive experimental proof (model-organism evidence): Xiao H, Heeringa P, Hu P, ... Falk RJ, Jennette JC. "Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice." J Clin Invest. 2002;110:955–963 (PMID:12370273) — passive transfer of anti-MPO IgG into wild-type and into Rag2⁻/⁻ mice (lacking T and B cells) produced pauci-immune necrotizing crescentic glomerulonephritis, proving ANCA IgG is directly pathogenic. The follow-up (Xiao H et al., Am J Pathol. 2005;167:39–45, PMID:15972950) showed neutrophil depletion completely prevents anti-MPO IgG-induced glomerulonephritis, proving the neutrophil is the obligate effector.

Tissue damage modes: ischemic + inflammatory necrosis (fibrinoid necrosis of vessel wall), oxidative injury (ROS), NET-mediated endothelial cytotoxicity, and downstream crescent formation (parietal epithelial proliferation responding to fibrin/plasma leakage into Bowman's space).

Molecular profiling: Transcriptomic studies of AAV blood/kidney show neutrophil-granule and interferon signatures; granulocyte subsets predict treatment response (RAVE reanalysis). Proteomics confirms circulating MPO, calprotectin (S100A8/A9), and complement Bb/C5a as activity biomarkers.

Sources: Xiao et al. JCI 2002 (PMC151154); Xiao et al. Am J Pathol 2005 (PMID:15972950); Kessenbrock NETs Nat Med 2009; Targeting complement in AAV (PMC12783592).

7. Anatomical Structures Affected

  • Primary organs: Kidney (UBERON:0002113) — glomerulus (UBERON:0000074), glomerular capillary tuft; Lung (UBERON:0002048) — alveolar capillary bed (UBERON:0002299).
  • Secondary/other organs & systems: peripheral nerves (UBERON:0001021; vasa nervorum), skin (UBERON:0002097), gastrointestinal tract (UBERON:0000160), eye (UBERON:0000970), heart/pericardium (UBERON:0002348), CNS meninges (UBERON:0002360).
  • Body systems: renal/urinary, respiratory, peripheral nervous, integumentary, cardiovascular (small vessels systemically), digestive.
  • Vessel level: capillaries, post-capillary venules, arterioles (and small arteries) — i.e., small-vessel vasculitis (UBERON:0001982 capillary; UBERON:0001980 blood vessel).
  • Tissue/cell level: vascular endothelium (endothelial cell CL:0000115), neutrophils (CL:0000775) as effectors, monocytes/macrophages (CL:0000235), glomerular parietal epithelial cells (crescents). Connective tissue of vessel walls undergoes fibrinoid necrosis.
  • Subcellular: neutrophil azurophilic/primary granule (GO:0042582) housing MPO; cell surface (translocated MPO); extracellular space (NETs, GO:0005615).
  • Localization/laterality: systemic and bilateral (e.g., bilateral diffuse alveolar hemorrhage, diffuse glomerular involvement); nerve involvement is typically asymmetric/multifocal (mononeuritis multiplex).

8. Temporal Development

  • Onset: Adult, typically late-onset (peak 6th–7th decade; median ~60 yr); rare in children. Pattern ranges from insidious/subacute (months of constitutional symptoms, slowly rising creatinine) to acute/fulminant (rapidly progressive GN ± alveolar hemorrhage). A "very slowly progressive" MPA subset is increasingly described.
  • Progression / stages: active (induction) → remission → potential relapse → chronic damage (CKD/ESKD, pulmonary fibrosis, neuropathic deficits). Renal histology stratifies prognosis (Berden classification: focal > crescentic > mixed > sclerotic, in order of worsening renal outcome — Berden AE et al., J Am Soc Nephrol. 2010;21:1628–1636, PMID:20616173).
  • Course pattern: relapsing–remitting chronic disease. Relapse rates are lower in MPO-ANCA/MPA than in PR3-ANCA/GPA, but each relapse risks cumulative organ damage.
  • Duration: chronic, lifelong susceptibility; rarely self-limited (except some drug-induced cases that remit on withdrawal).
  • Remission: treatment-induced (immunosuppression); spontaneous remission is uncommon.
  • Critical window: early diagnosis and prompt immunosuppression before irreversible glomerular sclerosis (dialysis-dependent AKI) or fatal alveolar hemorrhage — the chief determinant of long-term renal survival.

9. Inheritance and Population

  • Epidemiology: AAV overall incidence ~1.2–3.3/100,000/yr; MPA incidence ~2.4–10.1 per million/yr depending on region; prevalence in the tens per million. A worldwide systematic review/meta-analysis (Watts/others) reports geographic and serotype gradients.
  • Geographic / ethnic gradient: MPA (MPO-ANCA) predominates in Southern Europe and especially East Asia (Japan, China), whereas GPA (PR3-ANCA) predominates in Northern Europe. In Japan, the great majority of AAV is MPO-ANCA/MPA. This north–south / Europe–Asia gradient mirrors the HLA-DQ vs HLA-DP serotype genetics.
  • Inheritance: Not Mendelian — multifactorial/polygenic with environmental contribution. No defined penetrance, expressivity, anticipation, founder effect, consanguinity role, or carrier frequency in the classical sense.
  • Sex ratio: roughly equal to slight male predominance (~1.0–1.8 : 1, M:F), varying by cohort.
  • Age distribution: strongly age-associated, rising with age, peak 65–74 yr.

Sources: Worldwide incidence/prevalence meta-analysis (PMC9106044); Epidemiology of GPA/MPA in France (PMID:36108505).

10. Diagnostics

Serology (cornerstone). - Indirect immunofluorescence → perinuclear (p-ANCA) pattern; confirmed by antigen-specific MPO-ANCA ELISA (positive in ~58–70% of MPA). PR3-ANCA in a minority; ~10% ANCA-negative. (LOINC: MPO Ab 16718-0; PR3 Ab 14283-7.)

Laboratory. Serum creatinine/eGFR, urinalysis with microscopy (dysmorphic hematuria, RBC casts, proteinuria = active "nephritic" sediment), CRP/ESR, CBC (normocytic anemia), complement (usually normal — helps separate from immune-complex vasculitis), anti-GBM antibody (to exclude/co-diagnose Goodpasture, which can coexist in "double-positive" patients).

Imaging. Chest CT/HRCT for alveolar hemorrhage (ground-glass/consolidation) and interstitial fibrosis (UIP pattern); bronchoscopy with serial bronchoalveolar lavage showing progressively bloodier returns ± hemosiderin-laden macrophages confirms diffuse alveolar hemorrhage.

Biopsy (diagnostic gold standard). - Renal biopsy: pauci-immune focal necrotizing and crescentic glomerulonephritis; immunofluorescence shows scant/absent immunoglobulin and complement (distinguishing from immune-complex and anti-GBM disease). Classified by Berden categories (focal/crescentic/mixed/sclerotic). - Other tissue: skin (leukocytoclastic vasculitis), sural nerve (necrotizing vasculitis of vasa nervorum), lung (capillaritis). Absence of granulomas supports MPA over GPA.

Electrophysiology. Nerve conduction studies/EMG document axonal, asymmetric sensorimotor neuropathy (mononeuritis multiplex).

Genetic testing. Not used for diagnosis (polygenic disease); HLA/GWAS findings are research-grade risk markers, not clinical tests. No WGS/WES/panel/karyotype/repeat-expansion indication.

Classification criteria. The 2022 ACR/EULAR Classification Criteria for MPA (Suppiah R et al., Arthritis Rheumatol. 2022;74:400–406, PMID:35106964; companion Ann Rheum Dis. 2022) — applied only after diagnosing small/medium-vessel vasculitis and excluding mimics; a cumulative score ≥ 5 classifies MPA. Weighted items include + p-ANCA/MPO-ANCA (+6), pauci-immune GN (+3), and negative weights for nasal/sinus involvement, c-ANCA/PR3 (−1), and eosinophilia (−4) — i.e., features that point toward GPA or EGPA reduce the MPA score. (Earlier framework: 2012 CHCC nomenclature and the EMA/Watts algorithm.)

Differential diagnosis. GPA (granulomas, ENT destruction, PR3-ANCA), EGPA (asthma, eosinophilia), anti-GBM/Goodpasture disease, immune-complex small-vessel vasculitis (IgA vasculitis, cryoglobulinemic, lupus nephritis — these are not pauci-immune), polyarteritis nodosa (medium-vessel, ANCA-negative), infective endocarditis, and drug-induced AAV.

Screening. No population screening (uncommon, no presymptomatic test). ANCA testing is targeted to clinical suspicion (renal–pulmonary syndrome, mononeuritis multiplex, etc.).

Sources: 2022 ACR/EULAR MPA criteria (Wiley); Berden histopathologic classification (PMID:20616173).

11. Outcome / Prognosis

  • Survival: Untreated, AAV with GN is frequently fatal within ~1 year; with modern immunosuppression, 5-year survival ~70–85%. Early mortality is driven by active vasculitis (alveolar hemorrhage, sepsis from immunosuppression); later mortality by infection, cardiovascular disease, ESKD, and malignancy.
  • Renal outcome: A major determinant; substantial fraction progress to chronic kidney disease/ESKD (dialysis), especially with crescentic/sclerotic biopsy class and high presenting creatinine.
  • Mortality predictors: older age, higher creatinine/dialysis at presentation, alveolar hemorrhage, higher disease activity (BVAS), and infection. The Five-Factor Score (FFS, 1996/2009 revision; Guillevin L et al.) prognosticates necrotizing vasculitides.
  • Relapse: lower in MPO-ANCA/MPA than PR3-ANCA/GPA; persistent/rising ANCA and PR3 serotype increase relapse risk.
  • Morbidity/QoL: CKD, neuropathic pain/weakness, pulmonary fibrosis, plus treatment toxicity (glucocorticoid effects, infection, infertility/cytopenia from cyclophosphamide). Damage accrual is measured by the Vasculitis Damage Index (VDI).
  • Prognostic biomarkers: ANCA titer trajectory (esp. PR3), renal histology class (Berden), the ANCA Renal Risk Score, and emerging complement activation markers (urinary/plasma C5a, Bb).

Sources: Slowly vs rapidly progressive MPA (PMC11170224); Austrian ÖGN/ÖGR 2023 consensus (PMC10511611).

12. Treatment

Management is split into remission induction and remission maintenance, plus adjuncts. Suggested MAXO/NCIT terms noted.

Remission induction. - Rituximab (anti-CD20 B-cell depletion; therapeutic_modality MONOCLONAL_ANTIBODY) — first-line, non-inferior to cyclophosphamide and superior in relapsing disease. RAVE trial (Stone JH et al., N Engl J Med. 2010;363:221–232, PMID:20647199). NCIT:C2778 (Rituximab); MAXO chemotherapy/immunotherapy term MAXO:0000647 or pharmacotherapy NCIT:C15986. - Cyclophosphamide (alkylating immunosuppressant; CHEBI:4026) — classic induction, with the CYCLOPS pulsed-IV regimen reducing cumulative dose vs oral. Pharmacotherapy NCIT:C15986; cytotoxic. - Glucocorticoids (e.g., prednisone, CHEBI:8378; methylprednisolone pulses) — backbone of induction. PEXIVAS (Walsh M et al., N Engl J Med. 2020;382:622–631, PMID:32053298) showed a reduced-dose glucocorticoid regimen is non-infe­rior for death/ESKD and lowers serious infections — establishing steroid-sparing as standard. MAXO MAXO:0000058-class glucocorticoid therapy. - Avacopan (oral C5a-receptor/CD88 antagonist, ATC, brand TAVNEOS; FDA-approved Oct 2021; CHEBI/NCIT:C168722) — ADVOCATE trial (Jayne DRW et al., N Engl J Med. 2021;384:599–609, PMID:33596356): added to rituximab or cyclophosphamide, avacopan was non-inferior at week 26 and superior for sustained remission at week 52 while enabling glucocorticoid sparing. Mechanism directly targets the C5a–C5aR amplification loop (§6). therapeutic_modality SMALL_MOLECULE. - Plasma exchange (therapeutic plasmapheresis; MAXO:0000063): PEXIVAS showed no overall benefit on death/ESKD; now reserved for selected severe cases (e.g., severe alveolar hemorrhage or concurrent anti-GBM/very severe renal failure), per shared decision-making.

Remission maintenance. - Rituximab maintenance — MAINRITSAN trials (Guillevin L et al., N Engl J Med. 2014;371:1771–1780, PMID:25372085) showed scheduled rituximab superior to azathioprine for preventing relapse; pooled long-term MAINRITSAN data confirm durable benefit (500 mg every 6 months × 18 months). RITAZAREM supports rituximab maintenance after rituximab induction in relapsing disease. - Azathioprine (CHEBI:2948) or methotrexate (non-renal/limited disease; CHEBI:44185) or mycophenolate mofetil as alternatives.

Pharmacogenomics. TPMT/NUDT15 genotyping before azathioprine to avoid severe myelosuppression (CPIC guideline). Cyclophosphamide and glucocorticoid metabolism vary individually but lack actionable routine PGx.

Supportive/prophylactic. Pneumocystis jirovecii prophylaxis (trimethoprim-sulfamethoxazole) during intensive immunosuppression; osteoporosis prophylaxis with steroids; vaccination (non-live) before immunosuppression; dialysis/renal replacement for ESKD; rehabilitation for neuropathy.

Treatment outcomes/adverse events. Induction achieves remission in ~70–85% by 6 months. Major harms: serious infection (leading cause of early death, driven by glucocorticoid + cytotoxic exposure), cytopenias, malignancy (cyclophosphamide, esp. bladder cancer/MDS with high cumulative dose), infertility, and steroid toxicity — all motivating the steroid-/cyclophosphamide-sparing shift toward rituximab + avacopan.

Experimental / pipeline. Complement-pathway and B-cell–directed agents, obinutuzumab (anti-CD20), plasma-cell-directed therapy, and trials registered on ClinicalTrials.gov (e.g., avacopan real-world and combination studies; ITN/EUVAS programs).

Sources: RAVE NEJM 2010 (and design); MAINRITSAN pooled (PMID:37918894); PEXIVAS (PMID:32053298); ADVOCATE/avacopan NEJM 2021.

13. Prevention

  • Primary prevention: No vaccine or established population-level prevention (etiology multifactorial). Modifiable-risk reduction: minimize occupational silica exposure (engineering controls, respiratory protection) and avoid culprit drugs (propylthiouracil, hydralazine, minocycline) in susceptible patients; consider alternative agents and discontinue promptly if drug-induced AAV is suspected.
  • Secondary prevention (early detection): prompt ANCA testing and biopsy in at-risk presentations (renal–pulmonary syndrome, mononeuritis multiplex, unexplained RPGN) to begin therapy before irreversible organ damage. No asymptomatic screening program.
  • Tertiary prevention (complication avoidance): scheduled maintenance immunosuppression to prevent relapse; infection prophylaxis (PJP, vaccination); cardiovascular and bone-health risk management; ANCA/clinical monitoring for early relapse capture.
  • Genetic counseling: not applicable in the Mendelian sense — MPA is not inherited as a single-gene disorder, and familial recurrence is rare; reassurance is generally appropriate.
  • Public health/environmental: workplace silica regulation is the principal population-level lever.

14. Other Species / Natural Disease

  • Taxonomy of natural disease: ANCA-associated vasculitis is fundamentally a human disease; there is no well-established spontaneous MPA in companion animals analogous to the human syndrome. (NCBITaxon:9606 Homo sapiens for the disease; experimental disease is induced in NCBITaxon:10090 Mus musculus.)
  • Orthologous genes: Mpo (mouse, NCBI Gene 17523), enabling the murine anti-MPO model; Prtn3 ortholog exists but the mouse PR3 model is far weaker than the MPO model (a known cross-species limitation).
  • Veterinary/natural relevance: No significant naturally occurring veterinary counterpart catalogued in OMIA; reported animal vasculitides differ mechanistically. No zoonotic potential (autoimmune, non-transmissible).
  • Comparative biology: The conservation of MPO biology and neutrophil effector mechanisms is what makes the mouse passive-transfer model translationally informative, but mice do not spontaneously develop MPA — disease must be induced.

15. Model Organisms

  • Mouse (the workhorse model):
  • Passive-transfer anti-MPO model (Xiao/Falk/Jennette): immunize Mpo⁻/⁻ mice with mouse MPO → transfer anti-MPO IgG (or splenocytes) into wild-type or Rag2⁻/⁻ recipients → pauci-immune necrotizing crescentic glomerulonephritis and small-vessel vasculitis that closely mimics human MPA (PMID:12370273). This model demonstrated direct ANCA pathogenicity and the obligatory role of neutrophils (PMID:15972950).
  • Amplification/induction: bacterial LPS co-administration aggravates injury via TNF-α, supporting the priming/infection link (Huugen D et al., Am J Pathol. 2005, PMC1603449).
  • Mechanistic dissection: factor B–, C5–, and C5aR-deficient mice show attenuated disease, establishing the alternative-complement/C5a axis and validating avacopan's target (Schreiber A et al., PMID:19092138).
  • Genetic model types: knockout (Mpo⁻/⁻ immunization host; complement-gene KOs), and immunodeficient recipients (Rag2⁻/⁻) to isolate the antibody effector arm.
  • Rat: the WKY rat develops experimental anti-MPO crescentic GN and is used to study epitope-specific pathogenicity.
  • In vitro / cellular: human neutrophil activation assays (ANCA-induced respiratory burst, degranulation, NETosis), endothelial co-culture cytotoxicity, and complement-activation assays on NETs.
  • Phenotype recapitulation: the murine anti-MPO model faithfully reproduces pauci-immune necrotizing crescentic GN and pulmonary capillaritis. Limitations: it is an induced (passive-transfer) model rather than spontaneous autoimmunity, does not capture the human break-of-tolerance/HLA-restricted T-cell priming, under-models the chronic relapsing course, and PR3-ANCA disease is poorly modeled — so this is best classified as MODEL_ORGANISM evidence that recapitulates effector mechanisms but not the full human initiation phase (a candidate HUMAN_MODEL_MISMATCH note for the initiation/tolerance arm).
  • Resources: MGI (mouse Mpo, complement KO strains), Frontiers review "Animal Models of ANCA-Associated Vasculitis" (PMC, 2020).

Sources: Animal models of AAV (Frontiers 2020); Xiao JCI 2002; Xiao Am J Pathol 2005.

Key Citations (PMID-anchored, for dismech evidence items)

Claim Reference PMID
CHCC nomenclature / MPA definition Jennette JC et al. Arthritis Rheum. 2013;65:1–11 23045170
MPO-ANCA↔HLA-DQ; PR3-ANCA↔HLA-DP (GWAS) Lyons PA et al. N Engl J Med. 2012;367:214–223 22808956
Anti-MPO IgG directly causes pauci-immune NCGN (mouse) Xiao H et al. J Clin Invest. 2002;110:955–963 12370273
Neutrophils obligatory for anti-MPO GN Xiao H et al. Am J Pathol. 2005;167:39–45 15972950
NETs in AAV pathogenesis Kessenbrock K et al. Nat Med. 2009;15:623–625 19465931
C5aR essential in murine anti-MPO disease Schreiber A et al. J Am Soc Nephrol. 2009;20:289–298 19092138
Renal histopathologic classification Berden AE et al. J Am Soc Nephrol. 2010;21:1628–1636 20616173
LAMP-2/FimH molecular mimicry hypothesis Kain R et al. Nat Med. 2008;14:1088–1096 18836458
Epigenetic autoantigen de-repression Ciavatta DJ et al. J Clin Invest. 2010;120:3209–3219 20697158
2022 ACR/EULAR MPA classification criteria Suppiah R et al. Arthritis Rheumatol. 2022;74:400–406 35106964
Rituximab induction (RAVE) Stone JH et al. N Engl J Med. 2010;363:221–232 20647199
Rituximab maintenance (MAINRITSAN) Guillevin L et al. N Engl J Med. 2014;371:1771–1780 25372085
Reduced-dose steroids / PLEX (PEXIVAS) Walsh M et al. N Engl J Med. 2020;382:622–631 32053298
Avacopan / C5aR blockade (ADVOCATE) Jayne DRW et al. N Engl J Med. 2021;384:599–609 33596356
MAINRITSAN pooled long-term outcome Charles P et al. Ann Rheum Dis. 2023 37918894

Curation caveats for the dismech entry: (1) Verify MONDO:0007179 and all ontology IDs with OAK before committing; the report suggests terms but they must pass just validate-terms-file. (2) Every snippet must be re-fetched and substring-verified via just fetch-reference PMID:XXXX — the abstract quotes paraphrased above are leads, not validated snippets (per the DR-output SOP and NEC preflight). (3) Tag mouse passive-transfer findings as evidence_source: MODEL_ORGANISM; keep them distinct from human-clinical phenotype support. (4) PMID:33596356 is the actual NEJM ADVOCATE paper (one web result showed an adjacent commentary PMID 34042398 — use 33596356 for the primary trial).

Primary web sources used: - Orphanet ORPHA:727 - StatPearls: Microscopic Polyangiitis - Medscape: MPA Practice Essentials - Lyons et al. NEJM 2012 GWAS (PMID:22808956) - Genetic susceptibility to AAV review (PMC4233908) - Environmental factors in AAV (PMC9479327) - Xiao et al. JCI 2002 (PMC151154) - Xiao et al. Am J Pathol 2005 (PMID:15972950) - NETs & alternative complement in AAV (PMC4831636) - Targeting complement in AAV (PMC12783592) - 2022 ACR/EULAR MPA criteria (Suppiah, Wiley) - ADVOCATE / Avacopan NEJM 2021 - PEXIVAS NEJM 2020 (PMID:32053298) - MAINRITSAN pooled analysis (PMID:37918894) - RAVE / rituximab maintenance NEJM - Worldwide AAV incidence/prevalence meta-analysis (PMC9106044) - Epidemiology of GPA/MPA in France (PMID:36108505) - Animal models of AAV (Frontiers 2020) - Kidney-biopsy phenotypes of MPA (PMC10702060) - Austrian ÖGN/ÖGR 2023 GPA/MPA consensus (PMC10511611)