Microscopic Polyangiitis

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)

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)