Microscopic Polyangiitis (MPA)

• MPA is a rare disease
• Annual incidence: approximately 1–25 per million depending on ethnicity and geography
• Male predominance ^[2]
• Occurs at any age but typically at 50–60 years old ^[2]

• In East Asian populations (including Chinese/Hong Kong), MPA is notably more common than GPA — this is the opposite pattern to Caucasians, where GPA predominates among AAV ^[6]
• The ratio of MPA:GPA in East Asia is approximately 2–3:1, whereas in Northern Europe and North America GPA is more common
• Anti-MPO (p-ANCA) positivity predominates in MPA, and anti-MPO AAV is overall more prevalent in Asian populations
• This epidemiological skew toward MPA and anti-MPO positivity in Hong Kong is high yield for local exams

• Age > 50 years — peak incidence in 6th–7th decade
• Male sex (slight predominance)
• Environmental exposures: silica dust, hydrocarbons, and farming have been associated with increased AAV risk
• Drug-related: certain drugs (hydralazine, propylthiouracil, minocycline, levamisole-adulterated cocaine) can induce ANCA formation (especially anti-MPO) and trigger a drug-induced AAV that can mimic MPA
• Genetic susceptibility: HLA associations (HLA-DPB1 for anti-PR3; HLA-DQ for anti-MPO); susceptibility loci in SERPINA1 (α1-antitrypsin gene) and PRTN3

The exact cause of MPA is unknown. It is considered a primary autoimmune vasculitis driven by pathogenic ANCAs (particularly anti-MPO antibodies).

• Propylthiouracil (PTU) — especially relevant in Hong Kong where hyperthyroidism (Graves' disease) is common and PTU is used. PTU is the most well-established drug trigger for anti-MPO ANCA and can cause a clinical syndrome indistinguishable from MPA
• Hydralazine, minocycline, penicillamine, levamisole (adulterated cocaine)
• Drug-induced cases are typically anti-MPO positive and often have multi-ANCA specificity (anti-MPO + anti-elastase + anti-lactoferrin)

• Infections (e.g., Staphylococcus aureus nasal carriage, other infections) have been proposed as environmental triggers through molecular mimicry and superantigen-mediated activation
• However, this is more established for GPA than MPA

• HLA-DQ associations with anti-MPO AAV
• Polymorphisms in genes encoding MPO itself
• The genetic predisposition differs from GPA (which associates more with HLA-DP and SERPINA1/PRTN3)

• In genetically susceptible individuals, an environmental trigger (infection, drug, silica) leads to the loss of immune tolerance to neutrophil granule proteins, specifically myeloperoxidase (MPO)
• B cells produce anti-MPO antibodies (detected as p-ANCA on indirect immunofluorescence, confirmed as anti-MPO on ELISA)
• Why p-ANCA? On ethanol-fixed neutrophils (the standard IF substrate), MPO redistributes from the cytoplasmic granules to the perinuclear area during fixation, giving a "perinuclear" staining pattern

• For ANCAs to access their target antigens (MPO sits inside neutrophil granules and is normally inaccessible on the cell surface), neutrophils must first be primed
• Priming is caused by pro-inflammatory cytokines (TNF-α, IL-1, C5a) — which may be released during a concurrent infection or other inflammatory stimulus
• Priming causes translocation of MPO from intracellular granules to the neutrophil cell surface, making it accessible to circulating anti-MPO antibodies

• Anti-MPO antibodies bind to surface-expressed MPO and also engage Fc receptors on the neutrophil
• This dual signal (antigen binding + Fc receptor crosslinking) causes full neutrophil activation:
  • Degranulation: release of reactive oxygen species (ROS), proteases, and MPO → direct endothelial damage
  • Neutrophil extracellular traps (NETs): NETosis exposes more MPO and PR3, creating a vicious cycle
  • Firm adhesion to endothelium: activated neutrophils adhere to vessel walls via β2-integrins

• Activated neutrophils adherent to vessel walls release their toxic cargo directly onto endothelial cells → fibrinoid necrosis of the vessel wall
• This is a pauci-immune process: the damage is caused by neutrophil-mediated injury, NOT by immune complex deposition → hence minimal immunoglobulin/complement on IF

• In the kidney, necrotizing injury to glomerular capillaries allows fibrin and plasma proteins to leak into Bowman's space
• This provokes proliferation of parietal epithelial cells and macrophage infiltration → formation of crescents (cellular crescents → fibrocellular → fibrous)
• This is the histological hallmark of rapidly progressive (crescentic) glomerulonephritis (RPGN) — Type III (pauci-immune) RPGN

• Recent research has established that the alternative complement pathway plays a crucial role in amplifying ANCA-mediated injury
• C5a generated by complement activation further primes neutrophils → positive feedback loop
• This is the rationale for avacopan (C5a receptor inhibitor) as a newer targeted therapy

MPA sits under:

• Primary vasculitis → Small vessel vasculitis → ANCA-associated vasculitis

Classification of primary vasculitis:

• Large vessel disease: Giant cell arteritis, Takayasu's arteritis
• Medium / small vessel disease: Polyarteritis nodosa (PAN) (Viral hepatitis B related), Kawasaki disease, Granulomatosis with polyangiitis (ANCA related), Eosinophilic granulomatosis with polyangiitis (ANCA related), Microscopic polyangiitis (ANCA related), IgA vasculitis (Henoch Schönlein Purpura) ^[3]

This comparison table is extremely high yield for exams — know it cold ^{[1][2][3][4][5]}

^{[1][2][3][4][5]}

Know how to distinguish PAN from MPA — they were historically confused ^[3]

^[3]

When MPA presents as rapidly progressive glomerulonephritis:

• Type III RPGN (Pauci-immune) — this is the classical RPGN type for MPA
• ANCA +ve vasculitis accounts for 40–45% of all RPGN ^[4]
• Minimal staining in immunofluorescence (Pauci-immune) ^[4]
• Treatment: pulse steroids (IV methylprednisolone 1 g/day for 3 days) + cyclophosphamide (or rituximab) ± plasma exchange ^[4]

^[4][8]

Why might you confuse it with MPA?

• Both cause pauci-immune RPGN, palpable purpura, mononeuritis multiplex, and constitutional symptoms
• Both are ANCA-positive

How to distinguish GPA from MPA:

GC lecture-slide key point: "Triad of sinusitis, pulmonary infiltrates and nephritis suggest Wegener's" ^[7][8]. If you see ENT destruction + lung nodules/cavities + RPGN, that is GPA, not MPA.

Why might you confuse it with MPA?

• Both can be p-ANCA (anti-MPO) positive
• Both can cause palpable purpura and mononeuritis multiplex

How to distinguish EGPA from MPA:

GC lecture-slide high yield: EGPA features — "Allergy, bronchial asthma: Frequent; Eosinophilia: > 10% of peripheral white cells; ANCA: pANCA (anti-MPO) 66%; Histology: Eosinophilic necrotising granuloma; Major cause of death: Cardiac" ^[3]

• Microscopic polyangiitis (MPA)
• Granulomatosis with polyangiitis (GPA)
• Eosinophilic granulomatosis with polyangiitis (EGPA)
• Idiopathic pauci-immune GN (ANCA-negative, < 5%) ^[10][11]
• Renal-limited vasculitis (considered part of MPA/GPA spectrum — many eventually develop extrarenal manifestations) ^[6]

• Goodpasture syndrome (anti-GBM + pulmonary haemorrhage)
• Anti-GBM disease (renal-limited, no pulmonary involvement)

Further stratified by complement level:

^[4][7][8]

This is a critically important differential because PAN and MPA were historically considered the same disease and were only separated by the Chapel Hill Consensus.

GC lecture-slide high yield — PAN vs MPA comparison: ^[3]

Why the distinction matters:

• PAN affects medium arteries → causes organ infarction and microaneurysms (seen on angiography), but does NOT cause glomerulonephritis (no capillary-level involvement)
• MPA affects small vessels (capillaries) → causes glomerulonephritis and pulmonary capillaritis/DAH, but NOT microaneurysms
• PAN is associated with HBV infection (50%) whereas MPA is NOT ^{[1][3][5][12]}
• PAN is ANCA-negative (or very low positivity < 20%); MPA is p-ANCA positive in 50–80% ^[3]

Why they overlap: both cause palpable purpura + GN + arthralgia. But the age, IF pattern (IgA deposits in HSP vs pauci-immune in MPA), and ANCA status separate them.

The key discriminators are complement levels (low in SLE, normal in MPA), autoantibody profile (ANA/dsDNA in SLE, ANCA in MPA), and IF pattern on renal biopsy.

Before diving into criteria, let's be clear about something important: MPA has no single pathognomonic test. Unlike, say, anti-GBM disease (where a positive anti-GBM antibody + linear IF is essentially diagnostic), MPA is diagnosed through a convergence of clinical features, serology, histopathology, and exclusion of mimics. This is because:

1. ANCA is present in only ~70% of MPA patients — so 30% are ANCA-negative ^[2]
2. Serum ANCA is suggestive but not diagnostic (can have both false positives and false negatives) ^[6]
3. The histopathological finding (necrotizing vasculitis without granulomas, pauci-immune IF) is characteristic but requires tissue biopsy
4. There is no universally accepted "diagnostic criteria" set in the way ACR criteria exist for SLE — instead, the 2012 Revised Chapel Hill Consensus Conference (CHCC) definitions provide classification definitions, and newer ACR/EULAR 2022 classification criteria have been developed for clinical studies

This is the international standard definition used to classify MPA. Note: classification criteria are designed for research (to ensure homogeneous study populations), whereas diagnostic criteria are for clinical practice. However, in exams you will be expected to know the CHCC definition.

MPA is defined as: "Necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels (i.e. capillaries, venules, or arterioles). Necrotizing arteritis involving small and medium arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs. Granulomatous inflammation is absent." ^[2][13]

Key points from this definition:

• Few or no immune deposits → pauci-immune
• Small vessels predominantly (but medium artery involvement allowed)
• Necrotizing GN is very common
• Pulmonary capillaritis often occurs
• Granulomatous inflammation is ABSENT — this is the defining negative criterion that separates MPA from GPA ^[1][2][5]

These are the most recent validated criteria (published 2022) and supersede the older 1990 ACR criteria (which did not even include MPA as a separate entity). For exams, the CHCC definition remains the primary teaching point, but knowledge of the 2022 criteria is increasingly expected.

Entry criterion: The patient must have a diagnosis of small- or medium-vessel vasculitis (i.e., clinical features consistent with vasculitis).

Weighted scoring system (items carry positive or negative points):

A score ≥ 5 classifies as MPA (sensitivity ~91%, specificity ~94%)

Why certain items subtract points:

• Nasal crusting/ulcers → suggests GPA (upper airway granulomatous disease)
• c-ANCA / anti-PR3 → more typical of GPA
• Eosinophilia ≥ 1 × 10⁹/L → suggests EGPA

In daily clinical practice — and how you should answer an exam question — MPA is diagnosed when ALL of the following are satisfied:

1. Clinical features consistent with small vessel vasculitis (any combination of: RPGN, DAH, palpable purpura, mononeuritis multiplex, constitutional symptoms)
2. Serological evidence: p-ANCA / anti-MPO positive (present in ~70%, but absence does NOT exclude MPA) ^[2]
3. Histopathological confirmation (on biopsy of affected organ):
   • Necrotizing NON-granulomatous inflammation of small vessels ^[2]
   • Minimal deposition of immunoglobulin and complement (pauci-immune) ^[2]
4. Exclusion of mimics: anti-GBM negative, ANA/dsDNA negative (or inconsistent with SLE), no evidence of infection, no drug cause, no eosinophilia/asthma

Urinalysis: Screen for glomerulonephritis — look for proteinuria, haematuria, sediment with RBC casts and dysmorphic RBCs ^[2]

GC lecture-slide: Investigations for haematuria — Renal function, Urine culture / cytology / AFB, Urinalysis, Urine microscopy, KUB, USG / Doppler ^[14]

Requires pulse steroids (IV methylprednisolone 1 g/day for 3 days) + cyclophosphamide (or rituximab) ± plasma exchange ^[4]

Why steroids first? Glucocorticoids have the fastest onset of immunosuppression — they suppress inflammatory gene transcription within hours by:

• Binding intracellular glucocorticoid receptors → translocating to the nucleus → inhibiting NF-κB and AP-1 transcription factors → ↓ pro-inflammatory cytokines (IL-1, IL-6, TNF-α)
• Inducing lymphocyte apoptosis and reducing neutrophil adhesion to endothelium

Can give empirical pulse IV methylprednisolone before renal biopsy if clinically indicated ^[7][8]

KDIGO 2024 / CanVasc 2025 guideline shift — reduced steroid exposure: Recent guidelines strongly recommend a reduced-dose glucocorticoid regimen (as used in the PEXIVAS and LoVAS trials), aiming to minimise steroid-related toxicity (infection, diabetes, osteoporosis, avascular necrosis). The trend is to taper prednisolone more rapidly — down to ~5 mg/day by 3 months rather than the traditional slower taper.

"Cyclo-phosph-amide" → "cyclo" = cyclic, "phosph" = phosphorus-containing, "amide" = nitrogen mustard derivative. It is an alkylating agent that cross-links DNA → prevents cell division → kills rapidly dividing immune cells (B cells, T cells).

Induction: high-dose steroid + cyclophosphamide / rituximab ^[5]

Side effects — know these well:

Contraindications to CYC:

• Active infection (including TB — screen with CXR/IGRA before starting)
• Pregnancy / breastfeeding (teratogenic)
• Severe pre-existing cytopenias
• Relative: previous high cumulative CYC exposure, young patients desiring fertility (→ consider rituximab instead)

"Rituxi-mab" → "-mab" = monoclonal antibody; "rituxi-" targets CD20 on B cells. It is a chimeric anti-CD20 monoclonal antibody that depletes B cells through:

• Antibody-dependent cellular cytotoxicity (ADCC)
• Complement-dependent cytotoxicity (CDC)
• Direct induction of apoptosis

Why target B cells? B cells are the precursors of plasma cells that produce pathogenic anti-MPO ANCA. Depleting B cells removes the source of ANCA production.

Induction: high-dose steroid + cyclophosphamide / rituximab ^[5]

Evidence: The RAVE (2010) and RITUXVAS (2010) trials demonstrated that rituximab is non-inferior to cyclophosphamide for induction of remission in AAV. For relapsing disease, rituximab is superior to CYC.

Advantages over CYC:

• No gonadal toxicity
• No haemorrhagic cystitis
• No increased malignancy risk
• Preferred for: younger patients, relapsing disease, patients who have reached cumulative CYC limits

Side effects of rituximab:

Contraindications:

• Active severe infection
• HBV carriers without antiviral prophylaxis
• Severe hypogammaglobulinaemia with recurrent infections
• Pregnancy / breastfeeding

"Plasma-pheresis" → "plasma" = blood plasma, "apheresis" (Greek) = "to take away". The procedure physically removes circulating pathogenic antibodies (ANCA, anti-GBM if double-positive), complement factors, and inflammatory mediators.

± plasma exchange ^[4][5]

Regimen: Typically 7 sessions over 14 days, exchanging 60 mL/kg per session with 5% albumin (or FFP if active bleeding)

Evidence update: The PEXIVAS trial (2020) showed that plasma exchange did NOT reduce the composite endpoint of death or ESRD in AAV overall. However, subgroup analyses and expert opinion still support PLEX for:

• Severe DAH (life-threatening)
• Anti-GBM overlap
• Selected cases with very severe renal failure (Cr > 500) — though evidence is now weaker

Side effects of PLEX:

• Hypotension (fluid shifts)
• Bleeding (removal of clotting factors)
• Infection (removal of immunoglobulins)
• Line-related complications (central venous catheter required)

"Ava-copan" → targets the C5a receptor (C5aR1) on neutrophils. Recall from the pathophysiology section: the alternative complement pathway generates C5a, which primes neutrophils and amplifies the ANCA-neutrophil-endothelium injury loop.

Mechanism: Avacopan is an oral C5a receptor antagonist — it blocks C5a from binding to C5aR1 on neutrophils → prevents neutrophil priming and activation → breaks the amplification loop.

Evidence: The ADVOCATE trial (2021) showed that avacopan was non-inferior to oral prednisone taper at inducing remission and superior at sustaining remission at 52 weeks. Key benefit: allows steroid-sparing or steroid-free induction regimens, reducing steroid-related side effects.

Current status: Approved by FDA (2021) and EMA (2022) as an adjunctive treatment for severe AAV, used in combination with rituximab or CYC to replace or reduce glucocorticoid use.

Evidence: The MAINRITSAN (2014) and MAINRITSAN 2 (2018) trials showed rituximab maintenance is superior to azathioprine in preventing relapse in AAV.

"Aza-thio-prine" → a purine analogue pro-drug that is converted to 6-mercaptopurine → incorporated into DNA → inhibits purine synthesis → suppresses lymphocyte proliferation.

Side effects: bone marrow suppression (leukopenia), hepatotoxicity, GI upset, increased infection risk, slightly increased long-term malignancy risk.

• An alternative to AZA, but the IMPROVE trial showed MMF was inferior to AZA for preventing relapse in AAV
• Reserved for patients intolerant of AZA
• Dose: 1–2 g/day orally divided into BD dosing
• Side effects: GI (diarrhoea, nausea), myelosuppression, infection, teratogenic

Taper glucocorticoids ^[1]

• Aim to reduce and stop oral prednisolone during maintenance
• Target: ≤ 5 mg/day by 3–5 months → off entirely by 12–18 months if possible
• Why taper? Long-term steroids cause: Cushingoid features, osteoporosis, AVN, diabetes, cataracts, hypertension, infections, adrenal suppression
• Bone protection: all patients on ≥ 3 months steroids should receive calcium + vitamin D ± bisphosphonate (if osteoporosis risk)

• Prognosis is guarded — many patients do not recover renal function
• Biopsy findings guide aggressiveness: if predominantly cellular crescents (potentially reversible) → aggressive induction worthwhile; if predominantly fibrous crescents/sclerosis → less likely to respond
• Consider PLEX (though evidence weakened post-PEXIVAS)
• Start dialysis as bridge

• Relapses are common in MPA ^[3]
• Rituximab is the preferred re-induction agent for relapse (RAVE trial showed superiority over CYC for relapsing AAV)
• Reassess maintenance strategy — consider longer maintenance duration, higher rituximab frequency
• Investigate for drug non-compliance, infection triggers, or drug-induced AAV

• If no response to CYC + steroids → switch to rituximab (or vice versa)
• Consider IV immunoglobulin (IVIG) as a bridging agent
• Avacopan may be added as adjunct
• Very rarely: experimental agents (anti-complement, anti-IL-5 receptor)

Frequency: ~25–30% of MPA patients progress to ESRD despite treatment

Why does this happen?

• Necrotizing glomerulonephritis is the hallmark of MPA (present in 80–100%) ^[2]. ANCA-activated neutrophils cause fibrinoid necrosis of glomerular capillaries → crescent formation compresses the glomerular tuft → nephron loss
• Once a crescent progresses from cellular → fibrocellular → fibrous, that glomerulus is irreversibly destroyed. Fibrous crescents are unlikely to respond to immunosuppressive treatment ^[7][8]
• Even after successful induction of remission, the kidney may have sustained too much damage to recover. The Berden classification predicts this: sclerotic class (≥ 50% globally sclerotic glomeruli) has the worst prognosis ^[6]
• Each relapse episode causes further cumulative nephron loss

Consequences of ESRD:

• Requirement for renal replacement therapy (haemodialysis or peritoneal dialysis)
• Renal transplantation may be considered once disease is in sustained remission (typically require ≥ 12 months remission and undetectable ANCA before transplant); recurrence in transplant is possible but uncommon in MPA (~10%)
• All the complications of CKD stage 5: uraemia, hyperkalaemia, metabolic acidosis, renal osteodystrophy, anaemia (EPO deficiency), fluid overload, accelerated cardiovascular disease

Frequency: Respiratory involvement in 25–50% ^[2]; DAH is the most feared pulmonary complication

Why is DAH life-threatening?

• Pulmonary capillaritis → destruction of alveolar-capillary basement membrane → flooding of alveolar spaces with blood → acute hypoxaemic respiratory failure
• Massive DAH can cause haemorrhagic shock (hypovolaemia from blood loss into the lungs)
• DAH can occur without haemoptysis in up to one-third of cases (blood stays in alveoli without reaching the airways), so it can be missed clinically until the patient desaturates
• If not treated emergently (IV pulse steroids + CYC/RTX ± PLEX ± intubation/ventilation), mortality from a single severe DAH episode can exceed 50%

Long-term pulmonary sequelae:

• Pulmonary fibrosis ^[2] — recurrent episodes of DAH cause progressive interstitial fibrosis from:
  • Organisation of intra-alveolar blood and fibrin
  • Haemosiderin deposition (iron from broken-down haemoglobin → oxidative damage → fibrosis)
  • Chronic inflammation of alveolar walls
• Pulmonary fibrosis leads to: restrictive lung disease (↓ FVC, ↓ TLC), impaired gas exchange (↓ DLCO in chronic phase), progressive dyspnoea, and exercise intolerance

Frequency: PNS involvement (70%) especially mononeuritis multiplex ^[5]

Why does neuropathy persist?

• Vasculitis of vasa nervorum causes axonal degeneration (not demyelination) through nerve ischaemia/infarction
• Axonal regeneration is slow (~1 mm/day) and often incomplete — so even after vasculitis is controlled, patients may have persistent:
  • Motor weakness (foot drop, wrist drop)
  • Sensory loss or neuropathic pain (burning, shooting pain, paraesthesiae)
  • Reduced or absent reflexes
• Over time, mononeuritis multiplex can evolve into a confluent sensorimotor polyneuropathy (as more and more nerve territories become affected)

Impact: significant disability and reduced quality of life; neuropathic pain may require gabapentin/pregabalin/duloxetine; physiotherapy and occupational therapy for motor deficits

Although cardiac involvement is less common in MPA than in EGPA (where cardiac is the major cause of death ^[3]), MPA patients still face cardiovascular complications:

• Mesenteric vasculitis → gut ischaemia → abdominal pain, GI bleeding, bowel infarction (rare but potentially life-threatening)
• More common in PAN than MPA, but small vessel GI involvement can occur

• Episcleritis / scleritis → if untreated, scleritis can lead to scleral thinning and perforation (scleromalacia)
• Less severe than the retro-orbital masses and proptosis seen in GPA

Relapses: Common ^[3]

• MPA relapse rate is ~30% at 5 years, somewhat lower than GPA but still clinically significant
• Each relapse episode causes further cumulative organ damage — especially renal
• Risk factors for relapse: anti-PR3 positivity (higher relapse risk than anti-MPO), early steroid withdrawal, short maintenance duration, previous relapse
• Relapse may manifest as: return of nephritic sediment, rising creatinine, new haemoptysis, new purpura, or new neuropathy

Lung/renal and infection as major cause of death ^[5]

Why are MPA patients so infection-prone?

1. High-dose glucocorticoids → suppress innate and adaptive immunity (↓ neutrophil function, ↓ T-cell function, ↓ cytokine production)
2. Cyclophosphamide → alkylates DNA in rapidly dividing immune cells → leukopenia, lymphopenia
3. Rituximab → depletes B cells → hypogammaglobulinaemia → impaired humoral immunity
4. Combined immunosuppression → profound immunodeficiency
5. Uraemia (from renal failure) → impaired immune function
6. Age → MPA patients are typically older (50–60 years), with less immune reserve

Common infections:

Prolonged high-dose steroid use is almost universal in MPA management and causes a predictable constellation of complications: