Microscopic Polyangiitis

• Antigen Presentation and ANCA Generation: In genetically predisposed individuals (HLA-DPB1*04 association), environmental triggers (infections, medications, silica exposure) activate pattern recognition receptors on dendritic cells and innate lymphoid cells. These cells cross-present myeloperoxidase (MPO) and proteinase-3 (PR3), neutrophil primary granule constituents, to CD4+ and CD8+ T cells. MPO-specific and PR3-specific T cells differentiate into Th1 and Th17 phenotypes, producing IFN-γ and IL-17. Concurrently, germinal center reactions in secondary lymphoid organs generate antigen-specific B cells producing IgG anti-MPO or anti-PR3 autoantibodies (ANCAs). MPO-ANCA is detected in approximately 60-70% of MPA cases (MPO-ANCA/p-ANCA pattern on immunofluorescence), while PR3-ANCA occurs in 20-30% (PR3-ANCA/c-ANCA pattern); approximately 5-10% are ANCA-negative. The predominance of MPO-ANCA in MPA distinguishes it from GPA, where PR3-ANCA predominates.

• Neutrophil Activation and Endothelial Damage: Circulating ANCAs bind to their respective antigens on primed neutrophil surfaces, crosslinking Fc receptors (FcγRIIa, FcγRIIIb) and triggering robust intracellular signaling cascades through Syk kinase and PI3K. This causes rapid degranulation, releasing proteolytic enzymes (elastase, cathepsin G, collagenase), reactive oxygen species (superoxide, hydroxyl radicals), and additional ANCA autoantigens in microvesicles, amplifying the immune response. Simultaneously, complement activation (particularly alternative pathway priming by properdin-independent mechanisms and direct lectin pathway activation by ANCA-immune complexes) generates C5a, a potent neutrophil chemotactic factor further recruiting and priming additional neutrophils. Activated neutrophils bind to endothelial cells via integrin-selectin interactions and transmigrate into the vessel wall, where they cause direct cytotoxic damage through proteolytic enzyme release and oxidative burst, resulting in vessel wall necrosis. The hallmark fibrinoid necrosis (homogeneous, eosinophilic wall infiltration with loss of normal architecture) occurs predominantly in small vessels of kidneys, lungs, and skin.

• Organ-Specific Manifestations Through Selective Vessel Targeting: The glomerulonephritis in MPA results from necrotizing inflammation of the capillary walls within the glomerulus. Crescentic glomerulonephritis develops when the parietal epithelium is denuded by necrosis; fibrin and platelets deposit in this area, and parietal epithelial cells undergo proliferation and differentiation into fibroblast-like cells forming cellular crescents (predominantly cellular or fibrocellular, rather than fibrinous crescents seen in immune complex disease). Progressive crescent formation leads to capillary obliteration, glomerular sclerosis, and declining glomerular filtration rate (GFR). Pulmonary capillaritis causes acute pulmonary hemorrhage through similar mechanisms; disruption of the alveolar-capillary barrier allows RBC extravasation into alveoli, clinically manifesting as hemoptysis and diffuse alveolar infiltrates. The diffuse nature of pulmonary involvement (versus GPA, which typically has focal nodular infiltrates) reflects the capillaritis pathology. Cutaneous vasculitis produces palpable purpura through necrotizing inflammation of dermal and subdermal vessels, typically affecting lower extremities and buttocks due to hydrostatic pressure effects and gravity-dependent leukocyte sedimentation. Peripheral neuropathy results from vasculitis of the vasa nervorum supplying peripheral nerves, causing ischemic nerve injury; this typically manifests as mononeuritis multiplex (asymmetric, multifocal neuropathy affecting different nerve territories sequentially) rather than polyneuropathy.

• Absence of Granulomas and Immune Complex Deposition: MPA is distinguished from GPA by the absence of necrotizing granulomatous inflammation; the pathologic hallmark is necrotizing vasculitis alone. Additionally, the vasculitis is pauci-immune (minimal immunoglobulin and complement deposition on immunofluorescence microscopy), contrasting with immune complex vasculitides where granular immunoglobulin and complement deposits are prominent. This pauci-immune pattern, combined with ANCA positivity, is essentially diagnostic. The pauci-immune pattern likely results from the small size of ANCA-immune complexes or their rapid clearance compared to larger immune complexes in classic immune complex disease.

• Genetic Predisposition: HLA associations, particularly **HLA-DPB1*04, confer increased susceptibility to ANCA-associated vasculitides. Genome-wide association studies (GWAS) have identified additional loci including variants in PRTN3 (proteinase-3 gene), MPO, SERPINA1 (alpha-1 antitrypsin), PTPN22**, and immune regulatory genes (IL23R, CTLA4). However, genetic factors alone are insufficient for disease development; concordance in identical twins is <5%, emphasizing the importance of environmental triggers. The explanation for why some genetically predisposed individuals develop MPA specifically (MPO-ANCA associated) versus GPA (PR3-ANCA associated) remains incompletely understood but may relate to differential antigen presentation or specific environmental exposures.

• Environmental Triggers and Infection: Respiratory tract infections, particularly with Staphylococcus aureus, Streptococcus pneumoniae, and various viral pathogens, frequently precede ANCA-AAV onset by weeks to months. The proposed mechanism involves molecular mimicry between bacterial antigens and neutrophil proteins (MPO or PR3) or bystander activation of autoreactive T cells through pattern recognition receptor stimulation in the context of local inflammation. Chronic infections such as hepatitis C (HCV) have been historically associated with cryoglobulinemia but can also trigger ANCA production, though the temporal relationship to MPA development is variable. Upper respiratory tract infection is the most frequently reported preceding infection.

• Chemical and Occupational Exposures: Silica dust exposure (occupational or environmental) has been consistently associated with ANCA-AAV, including MPA. The mechanism likely involves silica-induced macrophage activation, production of pro-inflammatory cytokines (TNF-α, IL-1, IL-6), and enhanced Th1/Th17 differentiation. Organic solvents (particularly hydrocarbons) have also been implicated in case-control studies. Anti-TNF-α therapy paradoxically triggers de novo ANCA-AAV in 0.5-2% of treated patients, particularly in those with rheumatoid arthritis or inflammatory bowel disease receiving such agents; these typically present with MPO-ANCA-positive disease.

• Medication-Induced ANCA Vasculitis: Specific drugs are associated with drug-induced ANCA-associated vasculitis, most commonly antithyroid agents (propylthiouracil, methimazole), hydralazine, and levamisole-adulterated cocaine. Propylthiouracil is particularly notable as it causes MPO-ANCA-positive vasculitis in approximately 0.1-0.3% of treated patients, with a latency of months to years; this is now a leading cause of drug-induced ANCA-AAV in developed countries. Levamisole-adulterated cocaine causes a distinct phenotype of necrotizing vasculitis with necrotizing glomerulonephritis, often presenting with atypical serology (anti-neutrophil cytoplasmic antibodies directed against MPO-levamisole-neutrophil complexes). Anti-TNF-α agents are implicated in approximately 90% of drug-induced ANCA-AAV cases.

• Secondary ANCA-AAV in Underlying Systemic Disease: While MPA is primary vasculitis, ANCA positivity and vasculitic manifestations can occur secondary to malignancy (particularly hematologic malignancies), inflammatory bowel disease, or other chronic inflammatory conditions. In these settings, the presence of ANCA should not automatically be attributed to secondary disease; primary ANCA-AAV may coexist.

• Glomerulonephritis and Renal Insufficiency: The most common and diagnostically critical manifestation, present in >90% of patients at diagnosis. Patients may present with asymptomatic microscopic or macroscopic hematuria detected on urinalysis, often accompanied by proteinuria (typically in the nephrotic range, >3.5 g/24 hours, in approximately 50% of cases). Rapidly progressive glomerulonephritis (RPGN) defines the acute presentation in many patients, characterized by rapid decline in GFR over days to weeks, typically accompanied by rising serum creatinine and oliguria (urine output <400 mL/day). Dysmorphic RBCs and RBC casts on urinalysis are hallmark findings reflecting glomerular origin of hematuria. The pathophysiology of RPGN in MPA involves crescentic glomerulonephritis with capillary necrosis; as crescents progress to sclerosis, irreversible renal insufficiency develops, potentially necessitating dialysis if treatment is delayed. Acute kidney injury (AKI) with serum creatinine elevation >50% baseline or requiring renal replacement therapy occurs in approximately 50-60% of patients at presentation. Hypertension occurs in approximately 30-50% of patients, resulting from reduced renal mass, fluid retention from declining GFR, and renin-angiotensin system activation.

• Pulmonary Involvement and Hemoptysis: Present in 40-60% of patients at diagnosis, pulmonary manifestations reflect capillaritis causing alveolar hemorrhage. Hemoptysis, while dramatic and concerning, occurs in only 10-25% of patients; many patients with pulmonary capillaritis present with dyspnea and cough without hemoptysis. The pathophysiology involves disruption of the alveolar-capillary interface with RBC extravasation into alveolar spaces; patients may expectorate blood-tinged or grossly bloody sputum. Diffuse alveolar infiltrates on chest radiography or CT are characteristically bilateral and multifocal, reflecting the diffuse nature of capillaritis (distinguished from the focal nodular infiltrates typical of GPA). Alveolar infiltrates may progress rapidly over hours to days, and if extensive, can cause acute respiratory distress syndrome (ARDS)—a medical emergency. Diffusion capacity (DLCO) elevation is characteristic of acute alveolar hemorrhage (elevated DLCO results from increased hemoglobin in the alveolar space, which enhances carbon monoxide uptake). Chest radiography may show ill-defined ground-glass opacities, air-space consolidation, or diffuse interstitial opacities depending on the extent of hemorrhage and associated interstitial inflammation. Pulmonary function testing typically reveals a restrictive pattern with reduced FVC and FEV1, though these may normalize if the vasculitis is controlled.

• Systemic Constitutional Symptoms: Fever, malaise, and weight loss occur in 40-50% of patients, reflecting systemic inflammation. Constitutional symptoms may precede specific organ involvement by weeks and can be nonspecific, leading to diagnostic delay. Myalgias and arthralgias affect approximately 30-40% of patients; true arthritis (synovitis with joint swelling) occurs less frequently than in GPA, occurring in approximately 15-20% of patients.

• Cutaneous Manifestations: Palpable purpura, the most common skin finding, occurs in approximately 40-50% of patients. The purpura typically appears on lower extremities and buttocks (gravity-dependent distribution), reflects necrotizing vasculitis of dermal and subdermal vessels, and may be accompanied by pain rather than pruritus (distinguishing it from viral exanthems). Lesions may be few or numerous, occasionally involving the face, trunk, and upper extremities. Ulcers and necrosis can develop in severe cases as purpuric lesions evolve. Skin biopsy showing necrotizing vasculitis of small vessels is confirmatory; direct immunofluorescence typically reveals pauci-immune pattern (minimal immunoglobulin and complement deposition).

• Peripheral Neuropathy: Occurs in approximately 50-60% of patients, typically manifesting as mononeuritis multiplex (asymmetric, multifocal neuropathy). Patients may present with acute foot drop (anterior tibial nerve involvement), wrist drop (radial nerve), or other focal motor deficits developing over days to weeks. Sensory symptoms include localized paresthesias in the distribution of affected nerves. The asymmetric, multifocal pattern (affecting different nerves at different times) distinguishes mononeuritis multiplex from distal symmetric polyneuropathy. Electromyography (EMG) and nerve conduction studies (NCS) reveal axonal degeneration pattern, confirming the vasculitic etiology (vasculitis causes ischemic nerve injury with axonal loss rather than demyelination). Importantly, peripheral neuropathy in MPA is typically not a presenting manifestation but develops during the course of disease, though it can be present at diagnosis in approximately 5-10% of cases.

• Gastrointestinal Involvement: Occurs in 10-15% of patients, less frequently than in GPA. Manifestations include abdominal pain (mesenteric vasculitis), diarrhea, gastrointestinal bleeding, and rarely perforation. Bowel ischemia represents the pathophysiology, resulting from vasculitis of small vessels in the gastrointestinal tract.

• Cardiac Involvement: Rare, occurring in <5% of patients at diagnosis. Pericarditis, myocarditis, and coronary vasculitis have been reported. Coronary vasculitis can precipitate acute myocardial infarction, though this is uncommon.

• Central Nervous System (CNS) Involvement: Infrequent (<5%), but well-documented. Manifestations include cerebral vasculitis, intracerebral hemorrhage, and stroke. The rarity of primary CNS involvement in MPA contrasts with a higher frequency in GPA.

• Important Clinical Variants: "Pulmonary-Renal" Syndrome is the classic presentation in approximately 40-50% of patients presenting with the triad of pulmonary hemorrhage (hemoptysis and/or dyspnea with diffuse alveolar infiltrates), glomerulonephritis (hematuria, proteinuria, declining GFR), and constitutional symptoms—this combination demands urgent evaluation for ANCA-AAV. ANCA-Negative MPA (5-10% of MPA cases) presents identically to seropositive disease but requires tissue diagnosis to confirm the diagnosis, as the pathologic findings (necrotizing glomerulonephritis, pauci-immune pattern) are required to distinguish ANCA-negative MPA from other causes of RPGN.

Immediate stabilization (before serology or biopsy returns)

• Airway and oxygenation: diffuse alveolar hemorrhage with hypoxemia may require intubation and lung-protective ventilation; transfuse for symptomatic anemia and reverse any coagulopathy, since bleeding is capillaritic rather than coagulopathic.
• Pulse IV glucocorticoids: methylprednisolone is started empirically when rapidly progressive glomerulonephritis or alveolar hemorrhage is suspected — organ loss is measured in days, and treatment should not await biopsy. Dialysis is initiated for standard indications; renal replacement need does not preclude immunosuppression.

Remission induction (ACR/Vasculitis Foundation 2021 AAV guideline; KDIGO 2021 Glomerular Diseases guideline)

• Glucocorticoids plus a B-cell–depleting agent: rituximab (anti-CD20) is favored over cyclophosphamide for severe active MPA, and is clearly preferred in relapsing disease, in younger patients concerned about gonadal toxicity, and where cumulative alkylator exposure is a concern.
• Cyclophosphamide (IV pulse preferred over oral for lower cumulative dose) with mesna and aggressive hydration is the alternative induction agent.
• Reduced-dose oral glucocorticoid taper is now standard, based on PEXIVAS, because infection risk tracks with steroid exposure.
• Avacopan, an oral C5a receptor antagonist, is FDA-approved as adjunctive therapy in severe ANCA-associated vasculitis and is used to spare glucocorticoids; it exploits the C5a-driven neutrophil priming central to MPA pathogenesis.

Escalation / second line

• Plasma exchange is no longer routine. It is reserved for selected patients — very severe kidney injury at high risk of ESKD, alveolar hemorrhage with hypoxemia, or coexisting anti-GBM antibodies ("double-positive" disease, where PLEX is mandatory).

Maintenance (start after remission induced)

• Rituximab at scheduled intervals is preferred over azathioprine; methotrexate is an option but is avoided with significant renal impairment. Maintenance continues for years, guided by relapse risk.

Adjunctive and contraindicated

• Pneumocystis prophylaxis with trimethoprim-sulfamethoxazole, hepatitis B screening before rituximab, bone protection, and non-live vaccines only.
• Avoid cyclophosphamide, methotrexate, and mycophenolate in pregnancy (teratogenic); live vaccines are contraindicated during immunosuppression. In drug-induced ANCA vasculitis, withdrawal of the offending agent is the first therapeutic act.

Disease-related — emergencies first

• Diffuse alveolar hemorrhage with respiratory failure (EMERGENCY): capillaritis disrupts the alveolar–capillary barrier; signaled by falling hemoglobin without external blood loss, new bilateral ground-glass opacities, and progressively bloodier sequential aliquots on bronchoalveolar lavage. Hemoptysis may be absent.
• Rapidly progressive glomerulonephritis to end-stage kidney disease (EMERGENCY): cellular crescents organize into fibrous crescents and glomerulosclerosis within weeks; signaled by a creatinine rising over days with an active urine sediment. Delay in immunosuppression is the main determinant of dialysis dependence.
• Mesenteric vasculitis with bowel infarction or perforation (EMERGENCY): pain out of proportion to exam, peritoneal signs, free air.
• Relapse: ANCA-associated vasculitis is a relapsing disease; PR3-ANCA positivity carries a higher relapse rate than MPO-ANCA. A rising ANCA titer alone is not sufficient to re-treat — clinical or urinary evidence of activity is required.
• MPO-ANCA–associated interstitial lung disease/pulmonary fibrosis: a distinctive association with MPA, sometimes preceding vasculitis by years; signaled by progressive dyspnea with basal reticulation and traction bronchiectasis rather than hemorrhage.
• Irreversible axonal nerve injury: infarcted vasa nervorum leave residual foot drop despite disease control.
• Venous thromboembolism: active vasculitis is prothrombotic; new unilateral leg swelling or pleuritic chest pain in an actively inflamed patient should prompt imaging.

Treatment-related

• Infection: the leading cause of early mortality. Glucocorticoids plus B-cell or alkylator therapy predispose to Pneumocystis jirovecii pneumonia, invasive fungal disease, and hepatitis B reactivation after rituximab. A new fever in a treated patient is infection until proven otherwise, not automatically a flare.
• Cyclophosphamide toxicity: acrolein metabolite causes hemorrhagic cystitis (painless gross hematuria) and later urothelial carcinoma; also gonadal failure, myelosuppression, and myelodysplasia.
• Rituximab toxicity: hypogammaglobulinemia with recurrent sinopulmonary infection, infusion reactions, and rarely progressive multifocal leukoencephalopathy.
• Glucocorticoid toxicity: hyperglycemia, osteoporotic fracture, avascular necrosis, adrenal suppression.
• Avacopan: hepatotoxicity requiring transaminase monitoring.

• The classic stem: an older adult with weeks of fever and weight loss, then hemoptysis or dyspnea plus a creatinine that has doubled, with dysmorphic RBCs and RBC casts on urinalysis — a pulmonary-renal syndrome.
• The serology-to-pathology pairing examiners want: MPO-ANCA / p-ANCA (perinuclear staining) with pauci-immune necrotizing crescentic glomerulonephritis on biopsy. "Pauci-immune" means negative or scant immunofluorescence — that single phrase excludes lupus nephritis, IgA vasculitis, and post-infectious GN.
• Best next step when RPGN plus hemoptysis is suspected: send ANCA and anti-GBM antibodies simultaneously and start pulse IV glucocorticoids empirically; kidney biopsy confirms but should not delay therapy. Roughly a subset of ANCA-positive patients are also anti-GBM positive, and that combination mandates plasma exchange.
• The distractor to avoid — MPA is not GPA: no granulomas, no saddle-nose deformity, no subglottic stenosis, no destructive upper-airway disease, and lung findings are diffuse alveolar infiltrates rather than cavitating nodules. Likewise, no asthma and no eosinophilia — that is EGPA.
• Elevated DLCO in a hypoxemic patient is the buzzword for alveolar hemorrhage: intra-alveolar hemoglobin avidly binds carbon monoxide. Nearly every other cause of infiltrates lowers DLCO.
• Induction is glucocorticoids plus rituximab or cyclophosphamide per the ACR/Vasculitis Foundation 2021 guideline; rituximab is the preferred choice in relapsing disease and in patients of reproductive age. Plasma exchange is not routine after PEXIVAS — selecting it reflexively is a common wrong answer.
• Drug-induced mimics: hydralazine, propylthiouracil, and levamisole-adulterated cocaine produce MPO-ANCA vasculitis, often with very high titers or dual ANCA positivity. Stopping the drug is the first step.
• Do not chase the titer: a rising ANCA without clinical activity is not an indication to reinduce immunosuppression, and new fever in a treated patient is infection until proven otherwise.