Microscopic Polyangiitis (MPA)
Microscopic polyangiitis is an ANCA-associated small-vessel necrotizing vasculitis that predominantly affects the kidneys (rapidly progressive glomerulonephritis) and lungs (pulmonary capillaritis), typically associated with perinuclear ANCA (p-ANCA) directed against myeloperoxidase (MPO).
Microscopic polyangiitis (MPA) — let's break the name down:
- "Micro-scopic" = affecting vessels so small they are visible only under the microscope (capillaries, venules, arterioles)
- "Poly-angiitis" = "poly" (many) + "angi" (vessel) + "-itis" (inflammation) → inflammation of many vessels
MPA is a necrotizing vasculitis predominantly affecting small vessels (capillaries, venules, arterioles, and small arteries), with few or no immune deposits (pauci-immune), and without granulomatous inflammation [1][2][3].
It is one of the three ANCA-associated vasculitides (AAV), alongside:
- Granulomatosis with polyangiitis (GPA, formerly Wegener's)
- Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss)
Key distinguishing features of MPA from its AAV siblings:
- No granulomatous inflammation (unlike GPA and EGPA) [1][2][4]
- No ENT / upper airway involvement (unlike GPA, which classically begins in the upper respiratory tract) [2][5]
- No asthma or eosinophilia (unlike EGPA) [2][5]
- Necrotizing glomerulonephritis is very common (80–100%) — more frequent renal involvement than GPA [2][5]
- Pulmonary capillaritis with diffuse alveolar haemorrhage is the characteristic lung manifestation (not cavitating nodules as in GPA) [2][5]
Why 'Pauci-immune'?
"Pauci" comes from Latin "paucus" = few. In MPA, immunofluorescence (IF) microscopy of the kidney biopsy shows minimal or absent deposition of immunoglobulins and complement ("few immune deposits"). This distinguishes it from immune-complex GN (granular IF) and anti-GBM disease (linear IF). The pathology is driven by ANCA-mediated neutrophil activation, not classical immune-complex deposition.
Epidemiology
- 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
High Yield – HK Context
In Hong Kong, MPA is the most common ANCA-associated vasculitis, unlike Western populations where GPA predominates. When an exam stem describes an older Chinese patient with RPGN and p-ANCA positivity, think MPA first.
- 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 Chapel Hill Consensus Classification (2012 Revised)
Vessels are classified by size:
- Large vessels: aorta and major branches
- Medium vessels: main visceral arteries (renal, hepatic, coronary, mesenteric) and their branches
- Small vessels: small intra-parenchymal arteries, arterioles, capillaries, venules
MPA predominantly affects small vessels — particularly glomerular capillaries, pulmonary capillaries, dermal venules, and vasa nervorum (small vessels supplying peripheral nerves) [1][2][3].
Why does this matter clinically?
- Glomerular capillaries → necrotizing, crescentic glomerulonephritis (RPGN)
- Pulmonary capillaries → capillaritis → diffuse alveolar haemorrhage (DAH)
- Dermal venules → leukocytoclastic vasculitis → palpable purpura
- Vasa nervorum → nerve ischaemia → mononeuritis multiplex
- Occasionally medium-sized arteries can be involved, but the hallmark is small vessel disease
MPA is classified under "small vessel disease" in the Chapel Hill Classification, alongside GPA, EGPA, IgA vasculitis (HSP), and anti-C1q vasculitis [3][7]
Etiology (Focus on Hong Kong)
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)
Pathophysiology
Understanding MPA requires understanding the ANCA-neutrophil-endothelium interaction — this is the central pathogenic loop.
- 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
Why Pauci-Immune on IF?
Because the damage in MPA is caused by direct neutrophil-mediated endothelial injury (degranulation, ROS, NETs), NOT by deposition of antibody-antigen immune complexes. The ANCAs activate neutrophils rather than forming immune complexes that deposit on vessel walls. Hence, IF shows minimal or no immunoglobulin/complement staining — the hallmark "pauci-immune" pattern.
| Organ | Mechanism | Clinical Result |
|---|---|---|
| Kidney | Necrotizing capillaritis in glomeruli → fibrinoid necrosis → crescent formation | Pauci-immune focal segmental necrotizing and crescentic GN (RPGN) |
| Lung | Pulmonary capillaritis → destruction of alveolar-capillary basement membrane | Diffuse alveolar haemorrhage (DAH) |
| Skin | Leukocytoclastic vasculitis of dermal venules → extravasation of RBCs | Palpable purpura |
| Peripheral nerves | Vasculitis of vasa nervorum → nerve ischaemia/infarction | Mononeuritis multiplex |
| Joints/muscles | Systemic inflammation | Arthralgia, myalgia |
| GI tract | Mesenteric small vessel vasculitis | Abdominal pain, GI bleeding (less common) |
| Eyes | Episcleritis/scleritis from small vessel inflammation | Red eye, pain |
Classification
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]
| Feature | MPA | GPA | EGPA |
|---|---|---|---|
| Pathology | Necrotizing non-granulomatous vasculitis | Necrotizing granulomatous vasculitis | Eosinophil-rich necrotizing vasculitis |
| Granuloma | Absent (−ve) | Present (+ve) | Present (+ve) |
| ANCA positivity | 70% | 90% | 40–50% |
| ANCA type | Anti-MPO (P-ANCA) | Anti-PR3 (C-ANCA) | Anti-MPO (P-ANCA) |
| Renal involvement | 90% | 80% | 45% |
| Pulmonary involvement | 50% | 90% (+ ENT) | 70% |
| Asthma | Absent (−ve) | Absent (−ve) | Present (+ve) |
| ENT involvement | No (or uncommon) | Yes (prominent) | Allergic rhinitis, polyposis |
| Major cause of death | Pulmonary/renal, infection | Pulmonary/renal, infection | Cardiac |
Know how to distinguish PAN from MPA — they were historically confused [3]
| Feature | PAN | MPA |
|---|---|---|
| Vessel size | Medium arteries | Small vessels (capillaries, venules, arterioles) |
| Renal involvement | Vasculitis with infarcts / microaneurysms | Rapidly progressive glomerulonephritis |
| Glomerulonephritis | No | Yes |
| Lung involvement / Pulmonary haemorrhage | No | Yes |
| HBV infection | Yes (50%) | No |
| pANCA | < 20% | 50–80% |
| Abnormal angiogram with microaneurysms | Yes | No |
| Relapses | Rare | Common |
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]
Clinical Features
A. Symptoms
MPA typically presents with a prodromal phase of constitutional symptoms followed by organ-specific manifestations as vasculitis develops.
- Fever — due to systemic inflammation (pro-inflammatory cytokines IL-1, IL-6, TNF-α acting on hypothalamic thermoregulatory centre)
- Anorexia and weight loss — cytokine-mediated cachexia
- Malaise and fatigue — chronic inflammation, anaemia of chronic disease
- Arthralgia and myalgia — synovial and muscular small vessel inflammation [2]
- Often asymptomatic initially → detected on urinalysis or rising creatinine
- Haematuria: may be macroscopic (tea/cola-coloured urine) or microscopic
- Why? Necrotizing injury to glomerular capillaries → RBCs leak into urine → dysmorphic RBCs and RBC casts
- Proteinuria: usually sub-nephrotic ( < 3.5 g/day), though nephrotic-range proteinuria can occur
- Why? Damage to glomerular filtration barrier (podocytes, basement membrane) → loss of protein selectivity
- Oliguria / rapidly declining renal function: progressive GN → rising creatinine → may present as acute kidney injury (AKI)
- Why? Crescents compress glomerular capillaries → ↓ GFR → oliguria → uraemia
- Oedema and hypertension: fluid retention from impaired GFR
Pulmonary-Renal Syndrome
When MPA presents with both diffuse alveolar haemorrhage AND rapidly progressive glomerulonephritis, this is called the pulmonary-renal syndrome. The differential diagnosis includes:
- MPA (pauci-immune) — most common cause
- GPA (pauci-immune)
- Anti-GBM disease / Goodpasture syndrome (linear IF)
- SLE (granular IF, ↓ complement)
This is a medical emergency — untreated, mortality approaches 80–90%.
- Pulmonary haemorrhage (diffuse alveolar haemorrhage, DAH) — the hallmark pulmonary manifestation
- Haemoptysis: blood-tinged to frank haemoptysis
- Why? Pulmonary capillaritis → destruction of alveolar-capillary basement membrane → blood fills alveolar spaces
- Cough (often with blood-tinged sputum)
- Dyspnoea / breathlessness: alveolar flooding with blood impairs gas exchange
- Note: DAH can occur without haemoptysis (up to 1/3 of cases) — the blood may not reach the airways, particularly if bleeding is diffuse and bilateral
- Haemoptysis: blood-tinged to frank haemoptysis
- Pulmonary capillary alveolitis — inflammatory infiltrate in alveolar walls [2]
- Pulmonary fibrosis — late sequela of recurrent alveolar haemorrhage and inflammation [2]
MPA Lung vs GPA Lung
A common exam mistake: MPA does NOT cause pulmonary nodules or cavitations — those are features of GPA. MPA causes diffuse alveolar haemorrhage (bilateral ground-glass opacities on CT) from capillaritis. If you see "cavitating lung lesions" in a stem, think GPA, not MPA.
- Peripheral neuropathy — mononeuritis multiplex (up to 70% in MPA) [5]
- "Mononeuritis multiplex" = simultaneous or sequential involvement of multiple non-contiguous peripheral nerve trunks
- Why? Vasculitis of vasa nervorum (tiny arteries supplying peripheral nerves) → nerve ischaemia/infarction
- Presents as: acute painful neuropathy (foot drop, wrist drop, sensory loss in distribution of named nerves)
- Classically asymmetric and involves both motor and sensory fibres
- Common nerves affected: peroneal nerve (foot drop), ulnar nerve, radial nerve, tibial nerve
- Palpable purpura — the classic cutaneous manifestation [1][2][5]
- Why? Leukocytoclastic vasculitis (neutrophilic inflammation of dermal venules) → vessel wall destruction → extravasation of RBCs into dermis → non-blanching, raised (palpable) purpuric lesions
- Distribution: classically lower extremities (gravity-dependent areas have higher hydrostatic pressure in post-capillary venules)
- Skin ulceration, livedo reticularis (less common)
- Abdominal pain — mesenteric small vessel vasculitis → gut ischaemia
- GI bleeding — mucosal vessel involvement
- Nausea, vomiting, diarrhoea
- Episcleritis / scleritis — inflammation of ocular small vessels
- Less prominent than in GPA (which classically causes retro-orbital masses)
- Arthralgia (joint pain without swelling) — synovial small vessel inflammation
- Myalgia — muscular vessel inflammation
- Frank arthritis is uncommon
B. Signs
- Pyrexia — low-grade or high-grade fever
- Cachexia / wasting — weight loss from chronic inflammation
- Anaemia (pallor) — anaemia of chronic disease (hepcidin-mediated iron sequestration) + possible iron deficiency from pulmonary haemorrhage
- Hypertension — from fluid retention (↓ GFR → Na⁺/water retention → volume expansion → ↑ BP)
- Peripheral oedema — fluid overload and/or hypoalbuminaemia if significant proteinuria
- Uraemic signs (in advanced RPGN): uraemic frost, pericardial friction rub, altered consciousness
- Bilateral inspiratory crackles — blood in alveoli (DAH) or pulmonary fibrosis
- Tachypnoea, hypoxia — impaired gas exchange from alveolar haemorrhage
- Note: lung examination may be surprisingly normal even with significant DAH on imaging
- Palpable purpura — raised, non-blanching, violaceous lesions, predominantly on lower extremities
- On examination: firm, non-tender or slightly tender papules that do not blanch with pressure (diascopy negative for blanching)
- Skin ulceration
- Splinter haemorrhages (nail bed capillary vasculitis)
- Mononeuritis multiplex pattern on examination:
- Asymmetric motor weakness (e.g., foot drop = peroneal nerve; wrist drop = radial nerve)
- Asymmetric sensory loss in named nerve distributions
- Reduced or absent reflexes in affected territories
- May evolve into a confluent polyneuropathy if many nerves are affected sequentially
- Cardiac involvement is less common in MPA than EGPA, but can include:
- Pericarditis (pericardial friction rub)
- Heart failure (rare)
- Conjunctival injection, scleral injection (episcleritis/scleritis)
- No proptosis (proptosis = retro-orbital mass = GPA)
| Clinical Feature | Pathophysiological Mechanism |
|---|---|
| Pauci-immune crescentic GN (RPGN) | ANCA-activated neutrophils cause fibrinoid necrosis of glomerular capillaries → fibrin exudes into Bowman's space → crescent formation → ↓ GFR |
| Diffuse alveolar haemorrhage | Pulmonary capillaritis → alveolar-capillary basement membrane destruction → intra-alveolar haemorrhage |
| Palpable purpura | Leukocytoclastic vasculitis of dermal venules → RBC extravasation |
| Mononeuritis multiplex | Vasculitis of vasa nervorum → nerve ischaemia → acute focal neuropathy |
| Fever, weight loss, fatigue | Systemic inflammatory cytokine release (IL-1, IL-6, TNF-α) |
| Anaemia | Chronic inflammation (hepcidin ↑) + iron loss from DAH |
| Arthralgia/myalgia | Synovial/muscular small vessel inflammation |
| Hypertension, oedema | ↓ GFR → Na⁺/water retention |
| Haematuria + RBC casts | Glomerular capillary wall necrosis → RBCs enter tubular lumen |
| Proteinuria | Disruption of glomerular filtration barrier |
High Yield Summary
Definition: MPA is a necrotizing, non-granulomatous, pauci-immune small vessel vasculitis, predominantly anti-MPO (p-ANCA) positive.
Epidemiology: Peak age 50–60, male predominance. In Hong Kong/East Asia, MPA is the most common AAV (unlike the West where GPA predominates).
Key distinguishing features from GPA: No granuloma, no ENT involvement, no cavitating lung nodules. MPA causes DAH; GPA causes nodules/cavities.
Key distinguishing features from EGPA: No asthma, no eosinophilia.
Key distinguishing features from PAN: MPA causes GN and DAH; PAN does NOT cause GN or pulmonary haemorrhage. PAN shows microaneurysms on angiography; MPA does not.
Pathophysiology: Anti-MPO ANCA → primed neutrophil activation → degranulation on endothelium → fibrinoid necrosis (pauci-immune) → organ damage. Alternative complement pathway amplifies injury via C5a.
Clinical: Constitutional symptoms + RPGN (80–100%) + DAH (25–50%) + mononeuritis multiplex (up to 70%) + palpable purpura. Pulmonary-renal syndrome is the classic severe presentation.
ANCA: p-ANCA / anti-MPO in ~70% (range 45–80%). Up to 15–45% may have anti-PR3.
Histology: Necrotizing vasculitis WITHOUT granuloma. IF: pauci-immune (minimal Ig/complement). Renal biopsy: focal segmental necrotizing and crescentic GN.
Active Recall - Microscopic Polyangiitis (MPA)
[1] Senior notes: Maksim Medicine Notes.pdf (Rheumatology, p.331 – ANCA-associated vasculitis) [2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp.1773–1776 – Microscopic polyangiitis) [3] GC lecture slides: GC 053. Fingers turn white and blue.pdf (pp.79–80, 91, 93–94 – Vasculitic syndromes, ANCA related vasculitis, PAN vs MPA comparison, EGP vs GP comparison) [4] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (pp.413–414, 421, 427 – RPGN classification, IF patterns, nephrotic syndrome secondary causes) [5] Senior notes: Ryan Ho Rheumatology.pdf (pp.93, 96–97 – Vasculitis classification, ANCA vasculitides comparison table) [6] Senior notes: Ryan Ho Urogenital.pdf (p.68 – AAV and ANCA-associated GN) [7] Senior notes: Ryan Ho Fundamentals.pdf (p.359 – GN classification) [8] Senior notes: Adrian Lui Pediatrics Notes.pdf (p.324 – GN classification)
Differential Diagnosis of Microscopic Polyangiitis (MPA)
The differential diagnosis of MPA is best approached by considering the clinical presentation axis through which the patient presents. MPA can present as:
- A pulmonary-renal syndrome (DAH + RPGN)
- An RPGN / nephritic syndrome (renal-dominant)
- A systemic vasculitis (multiorgan: purpura + neuropathy + constitutional symptoms)
- Diffuse alveolar haemorrhage (lung-dominant)
Each presentation generates a different differential list, but there is substantial overlap. Let's work through this systematically.
1. Differential Diagnosis Within the ANCA-Associated Vasculitides (AAV)
This is the most critical differential — distinguishing MPA from its AAV siblings. In clinical practice, all three present with small vessel vasculitis, but the pattern of organ involvement, serology, and histology differ.
The 3 major clinical variants of AAV are: Microscopic polyangiitis (MPA) — non-granulomatous necrotizing small vessel vasculitis; Granulomatosis with polyangiitis (GPA) — granulomatous necrotizing small vessel vasculitis; Eosinophilic granulomatosis with polyangiitis (EGPA) — eosinophil-rich necrotizing vasculitis [1][5]
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:
| Feature | MPA | GPA |
|---|---|---|
| Granuloma on histology | Absent | Present (necrotizing epithelioid granuloma) [3][5] |
| ENT involvement | No or uncommon (35%) | Prominent: nasal crusting, epistaxis, sinusitis, saddle nose deformity, otitis media [1][5][9] |
| ANCA type | Anti-MPO (p-ANCA) in majority | Anti-PR3 (c-ANCA) in 85% [3][5] |
| Pulmonary pattern | Diffuse alveolar haemorrhage (capillaritis) | Pulmonary nodules, cavitations, infiltrates [1][5] |
| Retro-orbital mass | No | Yes (proptosis, diplopia) [5] |
| Relapse risk | Lower than GPA | Higher relapse risk [5] |
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.
The Saddle Nose Clue
Saddle nose deformity is virtually pathognomonic for GPA — it occurs because necrotizing granulomas destroy the nasal septum cartilage. MPA does NOT cause granulomas, so it does NOT cause saddle nose deformity. If you see saddle nose in an exam stem, the answer is GPA [9].
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:
| Feature | MPA | EGPA |
|---|---|---|
| Asthma | Absent | Almost always present ( > 90%) [1][2][3][5] |
| Eosinophilia | Absent or minimal | *** > 10% of peripheral WCC*** [3][5] |
| Granuloma | No | Eosinophilic necrotizing granuloma [3][5] |
| Renal involvement | Very common (90%) | Uncommon (45%) [1][2][3] |
| Major cause of death | Pulmonary/renal, infection | Cardiac (myocarditis, HF, arrhythmia) [3][5] |
| Three clinical phases | No | Yes: (1) asthma/atopy → (2) eosinophilic infiltration → (3) vasculitis [1] |
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]
The Asthma Rule
A common exam pitfall: if the stem mentions asthma or eosinophilia, it is NOT MPA — it is EGPA. MPA patients do not have asthma or significant eosinophilia. Conversely, if the stem has RPGN without asthma and without ENT destruction, think MPA.
When a patient presents with haemoptysis (DAH) + rapidly progressive renal failure (RPGN), this is the pulmonary-renal syndrome — a medical emergency. The differential is narrow and high yield:
| Condition | IF Pattern | Key Distinguishing Features |
|---|---|---|
| MPA | Pauci-immune | Anti-MPO (p-ANCA)+, no granuloma, no ENT |
| GPA | Pauci-immune | Anti-PR3 (c-ANCA)+, granuloma, ENT involvement, cavitating nodules |
| Anti-GBM disease / Goodpasture syndrome | Linear | Anti-GBM antibody+, linear IgG staining on IF, pulmonary haemorrhage often precedes renal involvement [6][10] |
| SLE (Lupus nephritis) | Granular | ANA/anti-dsDNA+, ↓C3/C4, multi-system (rash, arthritis, serositis) |
| Cryoglobulinaemia | Granular | Cryoglobulins+, ↓C4, HCV-associated, palpable purpura, neuropathy |
RPGN classification by IF pattern — Type I (linear staining) = anti-GBM disease; Type II (granular staining) = immune complex RPGN; Type III (negative staining) = pauci-immune RPGN — most are ANCA-positive and may be associated with extrarenal ANCA vasculitis [7][10][11]
High Yield – Complement Levels in DDx
Serum complement level is important in helping narrow the differential diagnosis:
- ↓ C3/C4 generally indicates IC-mediated GN — d/dx: MPGN, PSGN, lupus, cryoglobulinaemia, IE and shunt nephritis
- Normal C3/C4 generally indicates non-IC-mediated GN (except IgAN) — d/dx: PAN, Goodpasture, HSP/IgAN, ANCA-related renal vasculitis [7][8]
MPA has normal complement levels because it is pauci-immune — complement is NOT consumed by immune complex deposition. If complement is low, think SLE, cryoglobulinaemia, MPGN, or PSGN instead.
Anti-GBM Disease vs MPA — A Critical Distinction
This distinction is time-critical because anti-GBM disease requires urgent plasmapheresis to remove circulating anti-GBM antibodies, whereas MPA is treated with immunosuppression ± plasma exchange.
| Feature | MPA | Anti-GBM / Goodpasture |
|---|---|---|
| Antibody | Anti-MPO (ANCA) | Anti-GBM (IgG vs α3 chain collagen IV) |
| IF pattern | Pauci-immune (negative) | Linear IgG/C3 along GBM |
| Complement | Normal | Normal |
| Extra-renal features | Purpura, neuropathy, DAH | Pulmonary haemorrhage (40–60%), minimal extra-renal |
| Age | 50–60 years | Bimodal (20–30 and > 60) |
| Overlap | 10–50% of anti-GBM patients are also ANCA+ | Double-positive patients have better prognosis |
Goodpasture's syndrome = pulmonary haemorrhage + glomerulonephritis; Pathology: anti-GBM IgG vs collagen IV of glomerular or alveolar basement membrane [9][10]
3. Differential Diagnosis by RPGN / Nephritic Syndrome (Renal-Dominant)
When MPA presents primarily with RPGN (rapidly declining GFR, nephritic sediment, rising creatinine), the differential is best organised by IF pattern on renal biopsy — this is the most helpful diagnostic discriminator [4][7][8][11]:
- Goodpasture syndrome (anti-GBM + pulmonary haemorrhage)
- Anti-GBM disease (renal-limited, no pulmonary involvement)
Further stratified by complement level:
| Complement | Renal-Limited | Systemic |
|---|---|---|
| Normal C3 | IgA nephropathy; Fibrillary/immunotactoid GN | Henoch-Schönlein purpura (HSP) |
| ↓ C3 | Infection-related GN (Staph, Strep/PSGN); Membranoproliferative GN | SLE; Infective endocarditis; Cryoglobulinaemia |
IF Pattern = The Key to DDx in RPGN
When you are stuck on the differential of RPGN, the immunofluorescence pattern on renal biopsy is your single most discriminating investigation. Remember: Pauci-immune → ANCA; Linear → anti-GBM; Granular → immune complex. The serology (ANCA, anti-GBM, ANA/dsDNA, complement) often gives you the answer before the biopsy comes back.
4. Differential Diagnosis by Systemic Vasculitis
When MPA presents as a multisystem vasculitis (purpura + neuropathy + GN + constitutional symptoms), the differential includes non-AAV vasculitides and systemic autoimmune diseases:
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]
| Feature | PAN | MPA |
|---|---|---|
| Renal involvement — Vasculitis with infarcts/microaneurysms | Yes | No |
| Renal involvement — Rapidly progressive glomerulonephritis | No | Yes |
| Lung involvement — Pulmonary haemorrhage | No | Yes |
| HBV-infection | Yes (50%) | No |
| pANCA | *** < 20%*** | 50–80% |
| Abnormal angiogram with microaneurysms | Yes | No |
| Relapses | Rare | Common |
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]
PAN vs MPA: The Angiogram Clue
If an exam stem describes microaneurysms on angiography, that is PAN, not MPA. If it describes RPGN or DAH, that is MPA (or GPA), not PAN. PAN does NOT cause GN; MPA does NOT cause microaneurysms.
| Feature | MPA | HSP |
|---|---|---|
| Age | Adults 50–60 | Children (peak 6–7 years) |
| Palpable purpura | Yes | Yes (+ buttocks, lower limbs) |
| GN | Pauci-immune RPGN | IgA nephropathy (granular IgA on IF) |
| GI involvement | Uncommon | Common (abdominal pain, intussusception, GI bleeding) |
| Complement | Normal | Normal |
| ANCA | Positive (anti-MPO) | Negative |
| IF pattern | Pauci-immune | Granular (mesangial IgA) |
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.
| Feature | MPA | SLE |
|---|---|---|
| Demographics | Male > Female, 50–60 yo | Female >> Male, 15–45 yo |
| Rash | Palpable purpura | Malar rash, discoid rash, photosensitivity |
| Renal | Pauci-immune RPGN | Immune complex GN (WHO Class I–VI), ↓ C3/C4 |
| Serology | ANCA+ | ANA+, anti-dsDNA+, ↓ complement |
| IF pattern | Pauci-immune | "Full house" granular (IgG, IgA, IgM, C3, C1q) |
| Joints | Arthralgia | Polyarthritis (non-erosive, Jaccoud's) |
| Other | No serositis | Serositis, oral ulcers, cytopenias |
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.
| Feature | MPA | Cryoglobulinaemia |
|---|---|---|
| Association | Primary autoimmune | HCV infection (Type II/III mixed cryoglobulinaemia) |
| Purpura | Palpable purpura | Palpable purpura (very prominent) |
| Renal | Pauci-immune RPGN | Immune complex MPGN (↓ C4 out of proportion to C3) |
| Neuropathy | Mononeuritis multiplex | Peripheral neuropathy |
| ANCA | Positive | Negative |
| Cryoglobulins | Negative | Positive |
| Complement | Normal | ↓ C4 (characteristically very low) |
When MPA presents primarily with haemoptysis and bilateral ground-glass opacities:
| Category | Conditions |
|---|---|
| Vasculitis (pauci-immune) | MPA, GPA |
| Anti-GBM disease | Goodpasture syndrome |
| Immune complex | SLE |
| Infection | Severe pneumonia (Staph, Legionella), leptospirosis |
| Coagulopathy | DIC, anticoagulant excess, thrombocytopaenia |
| Other | Idiopathic pulmonary haemosiderosis, mitral stenosis (↑ pulmonary capillary pressure) |
The key investigations to differentiate are ANCA, anti-GBM antibody, ANA/dsDNA, complement, coagulation profile, and bronchoscopy with BAL (progressively bloodier aliquots in DAH).
An important differential, especially in Hong Kong:
- Propylthiouracil (PTU) — the most well-established drug trigger; causes anti-MPO ANCA formation and a clinical syndrome indistinguishable from primary MPA
- Hydralazine, minocycline, penicillamine, levamisole
Clues to drug-induced AAV:
- Temporal relationship with drug initiation (weeks to months)
- Multi-ANCA specificity: anti-MPO + anti-elastase + anti-lactoferrin (not seen in primary MPA)
- Resolution upon drug withdrawal (often with a course of steroids)
| Clinical Clue | Points Towards | Points Away From MPA |
|---|---|---|
| Saddle nose / nasal crusting / sinusitis | GPA | ✓ |
| Cavitating lung nodules on CXR/CT | GPA | ✓ |
| Asthma / eosinophilia > 10% | EGPA | ✓ |
| Cardiac involvement as major feature | EGPA | ✓ |
| Microaneurysms on angiography | PAN | ✓ |
| HBV-positive | PAN | ✓ |
| Low complement (↓ C3/C4) | SLE, cryoglobulinaemia, PSGN, MPGN | ✓ |
| Linear IF on renal biopsy | Anti-GBM disease | ✓ |
| "Full house" granular IF | SLE | ✓ |
| Mesangial IgA on IF | IgA nephropathy / HSP | ✓ |
| Malar rash, ANA+, anti-dsDNA+ | SLE | ✓ |
| Anti-MPO (p-ANCA)+, pauci-immune IF, no granuloma, no ENT, no asthma | MPA | — |
GC lecture-slide and senior note high yield: Evaluation of glomerulonephritis/RPGN — use suggestive clinical findings, complement levels, and serology to narrow the differential before biopsy [7][8]
High Yield Summary — Differential Diagnosis
-
Within AAV: MPA vs GPA vs EGPA — differentiate by: presence of granuloma (absent in MPA), ENT involvement (absent in MPA), asthma/eosinophilia (absent in MPA, present in EGPA), ANCA type (anti-MPO in MPA vs anti-PR3 in GPA).
-
From PAN: MPA has GN and DAH; PAN has microaneurysms and renal infarcts. PAN = no GN, no DAH, HBV-associated, ANCA-negative.
-
From anti-GBM disease: IF pattern (pauci-immune in MPA vs linear in anti-GBM), anti-GBM antibody positive only in anti-GBM disease.
-
From SLE: complement low in SLE (normal in MPA), ANA/dsDNA positive in SLE (negative in MPA), "full house" granular IF in SLE.
-
Key discriminating investigations: serum complement, ANCA (type), anti-GBM Ab, ANA/dsDNA, renal biopsy with IF.
-
IF pattern on renal biopsy is the gold-standard differentiator: Pauci-immune = ANCA-associated (MPA/GPA/EGPA); Linear = anti-GBM; Granular = immune complex.
Active Recall - Differential Diagnosis of MPA
References
[1] Senior notes: Maksim Medicine Notes.pdf (Rheumatology, p.331 – ANCA-associated vasculitis, PAN) [2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp.1767–1776 – EGPA, GPA, MPA sections) [3] GC lecture slides: GC 053. Fingers turn white and blue.pdf (pp.79–80, 91, 93–94 – Classification of primary vasculitis, ANCA related vasculitis, PAN vs MPA, EGP vs GP) [4] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (pp.413–415, 421 – RPGN classification by IF pattern, DDx by IF pattern, nephritic/nephrotic patterns) [5] Senior notes: Ryan Ho Rheumatology.pdf (pp.93, 97, 159 – Vasculitis classification, AAV comparison table, PAN) [6] Senior notes: Ryan Ho Urogenital.pdf (pp.64, 67–69 – RPGN, anti-GBM disease, AAV pathogenesis and renal involvement) [7] Senior notes: Ryan Ho Fundamentals.pdf (pp.360–361 – Evaluation of GN, RPGN classification) [8] Senior notes: Adrian Lui Pediatrics Notes.pdf (pp.324–326 – GN classification, RPGN, evaluation) [9] Senior notes: Ryan Ho Respiratory.pdf (p.140 – GPA and Goodpasture) [10] Senior notes: Ryan Ho Urogenital.pdf (p.67 – Anti-GBM disease) [11] Senior notes: Ryan Ho Fundamentals.pdf (p.361 – RPGN Type I/II/III classification) [12] Senior notes: Ryan Ho Rheumatology.pdf (p.159 – PAN)
Diagnostic Criteria for MPA
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:
- ANCA is present in only ~70% of MPA patients — so 30% are ANCA-negative [2]
- Serum ANCA is suggestive but not diagnostic (can have both false positives and false negatives) [6]
- The histopathological finding (necrotizing vasculitis without granulomas, pauci-immune IF) is characteristic but requires tissue biopsy
- 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:
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):
| Criterion | Score |
|---|---|
| Positive items | |
| p-ANCA or anti-MPO antibody positivity | +6 |
| Lung fibrosis on imaging | +3 |
| Pauci-immune glomerulonephritis on biopsy | +3 |
| Nasal crusting, ulcers, OR bloody nasal discharge (−) | −3 |
| c-ANCA or anti-PR3 antibody positivity (−) | −1 |
| Eosinophil count ≥ 1 × 10⁹/L (−) | −4 |
| Negative items (features pointing AWAY from MPA) | |
| Items above marked (−) subtract points because they point toward GPA or EGPA |
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
Exam Tip — Classification vs Diagnosis
In practice, the diagnosis of MPA is made by combining: (1) compatible clinical presentation (RPGN, DAH, purpura, neuropathy), (2) positive p-ANCA/anti-MPO serology, (3) tissue biopsy showing necrotizing non-granulomatous vasculitis with pauci-immune IF, and (4) exclusion of other causes (anti-GBM, SLE, infection). The ACR/EULAR 2022 classification criteria are for research standardisation, not a clinical checklist — but in exams they may be tested.
In daily clinical practice — and how you should answer an exam question — MPA is diagnosed when ALL of the following are satisfied:
- Clinical features consistent with small vessel vasculitis (any combination of: RPGN, DAH, palpable purpura, mononeuritis multiplex, constitutional symptoms)
- Serological evidence: p-ANCA / anti-MPO positive (present in ~70%, but absence does NOT exclude MPA) [2]
- Histopathological confirmation (on biopsy of affected organ):
- Exclusion of mimics: anti-GBM negative, ANA/dsDNA negative (or inconsistent with SLE), no evidence of infection, no drug cause, no eosinophilia/asthma
The diagnostic workup of suspected MPA follows a stepwise approach: clinical suspicion → initial investigations → serology → organ-specific assessment → tissue biopsy → integration.
Investigation Modalities: Key Findings and Interpretations
A. Blood Tests
| Finding | Interpretation | Why? |
|---|---|---|
| NcNc anaemia with ↓ Hct | Anaemia of chronic disease ± iron deficiency from DAH | Chronic inflammation → ↑ hepcidin → iron sequestration. If DAH, ongoing blood loss → iron depletion |
| Normal or ↑ WBC | Inflammatory response, or infection | Neutrophilia from systemic inflammation; must exclude concurrent infection (patients often immunosuppressed) |
| Normal eosinophils | Helps exclude EGPA | EGPA has eosinophilia > 10% of WCC; MPA has minimal eosinophilia [3][5] |
| Normal platelets | Helps exclude TTP/HUS, DIC | Thrombocytopaenia would suggest TMA or DIC as alternative causes of AKI + purpura |
↑ ESR and CRP [2]
- ESR is usually markedly elevated — often > 50 mm/hr
- CRP is raised as an acute-phase reactant
- Why? Systemic vasculitis drives hepatic production of acute-phase proteins (fibrinogen, CRP) and rouleaux formation (↑ ESR)
- Useful for monitoring disease activity during treatment (falling ESR/CRP suggests response)
↑ Urea and creatinine level [2]
| Finding | Interpretation |
|---|---|
| ↑ Creatinine | Reflects reduced GFR from necrotizing GN. In RPGN, serum Cr is often > 250 μmol/L at diagnosis [7][11] |
| ↑ Urea | Correlates with GFR decline; disproportionate ↑ urea may suggest pre-renal component or GI bleeding |
| ↓ eGFR | Quantifies renal impairment severity |
| Electrolyte disturbance | Hyperkalaemia (↓ K⁺ excretion), metabolic acidosis (↓ H⁺ excretion) |
4. Serum Autoantibodies — The Core Serological Panel
Anti-neutrophil cytoplasmic antibodies (ANCA) — present in 70% of patients with microscopic polyangiitis. Perinuclear ANCA (P-ANCA) (Anti-MPO) in almost all ANCA-positive MPA patients [2]
Two-step testing approach (international consensus):
| Step | Test | What It Detects |
|---|---|---|
| Step 1: Indirect immunofluorescence (IIF) on ethanol-fixed neutrophils | p-ANCA (perinuclear pattern) | MPO redistributes to nucleus during fixation → perinuclear staining |
| c-ANCA (cytoplasmic pattern) | PR3 remains in cytoplasm → diffuse cytoplasmic staining | |
| Step 2: Antigen-specific ELISA or immunoassay | Anti-MPO | Confirms target antigen |
| Anti-PR3 | Confirms target antigen |
GC lecture-slide high yield: p-ANCA (p = perinuclear) = Anti-myeloperoxidase (MPO) Ab; c-ANCA (c = cytoplasmic) = Anti-proteinase 3 (PR3) Ab [3]
MPA ANCA profile:
Microscopic polyangiitis: Anti-PR3 15–45%, Anti-MPO 45–80% [3]
ANCA Testing Pitfalls
-
ANCA-negative MPA exists (~30%) — a negative ANCA does NOT exclude MPA. Some patients with pauci-immune GN may be ANCA-negative, but these patients generally have similar renal biopsy findings and prognosis [6].
-
ANCA can be false-positive in infections (endocarditis, HIV), inflammatory bowel disease, and drug reactions. Serum ANCA is suggestive but not diagnostic (can have both FP or FN) [6].
-
Current guidelines (2017 international consensus) recommend using antigen-specific immunoassays (anti-MPO, anti-PR3 ELISA) as the primary screening test instead of IIF, because ELISA has better specificity. However, many labs still use both.
-
ANCA titre correlates imperfectly with disease activity — rising titres may herald relapse, but treatment decisions should NOT be based on titre alone.
Anti-GBM antibody: Serum assay for anti-GBM antibodies such as direct enzyme-linked immunoassay (ELISA) can be performed prior to renal biopsy in patients who have pulmonary haemorrhage (Goodpasture syndrome) [4]
- Must always be sent alongside ANCA to exclude anti-GBM disease
- Why? 10–50% of anti-GBM patients are also ANCA-positive ("double-positive") — these patients need plasmapheresis (for anti-GBM) in addition to immunosuppression
- A positive anti-GBM + negative ANCA → anti-GBM disease, not MPA
- In MPA, anti-GBM should be negative
Serology for relevant conditions: ASLO for PSGN, anti-HCV/HBV for HBV/HCV-related MPGN, cryocrit for cryoglobulinaemia, blood culture for infection [7][8]
| Test | Purpose | Expected in MPA |
|---|---|---|
| ASLO | Exclude PSGN | Negative |
| HBV serology (HBsAg, HBeAg) | Exclude HBV-related PAN or MPGN | Negative |
| HCV serology (anti-HCV) | Exclude HCV-related cryoglobulinaemia/MPGN | Negative |
| Cryoglobulins (cryocrit) | Exclude cryoglobulinaemic vasculitis | Negative |
| Blood cultures | Exclude infective endocarditis | Negative |
Serum complement level: important in helping narrow the differential diagnosis [7][8]
- ↓ C3/C4 generally indicates IC-mediated GN — d/dx: MPGN, PSGN, lupus, cryoglobulinaemia, IE
- Normal C3/C4 generally indicates non-IC-mediated GN — d/dx: PAN, Goodpasture, HSP/IgAN, ANCA-related renal vasculitis
In MPA: complement levels are NORMAL (because MPA is pauci-immune — there is no immune complex consumption of complement). Low complement should redirect you toward SLE, cryoglobulinaemia, MPGN, or PSGN.
Urinalysis: Screen for glomerulonephritis — look for proteinuria, haematuria, sediment with RBC casts and dysmorphic RBCs [2]
| Finding | Significance | Why? |
|---|---|---|
| Haematuria (dysmorphic RBCs) | Confirms glomerular origin | RBCs are distorted as they squeeze through damaged GBM → dysmorphic shape |
| RBC casts | Pathognomonic for glomerulonephritis | RBCs trapped in Tamm-Horsfall protein matrix within tubules → cylindrical casts |
| Proteinuria | Usually sub-nephrotic ( < 3.5 g/day) | Glomerular filtration barrier damage → protein leak, but GFR is so reduced that daily protein excretion is limited |
| Sterile pyuria | WBCs without infection | Inflammatory cells from glomerular/interstitial inflammation |
| Urine protein quantification (spot ACR or 24h urine) | Quantifies proteinuria severity | Usually subnephrotic; ↑↑ proteinuria should alert to 2nd concurrent glomerular disease [6] |
GC lecture-slide: Investigations for haematuria — Renal function, Urine culture / cytology / AFB, Urinalysis, Urine microscopy, KUB, USG / Doppler [14]
Active Sediment = Alarm Bell
The combination of dysmorphic RBCs + RBC casts + proteinuria in a patient with rising creatinine is called an "active sediment" and is the hallmark of active glomerulonephritis. In the context of a positive ANCA, this essentially clinches the diagnosis of ANCA-associated GN. Do NOT wait for biopsy to initiate empirical treatment if the clinical picture is urgent.
C. Imaging Studies
| Finding in MPA | Interpretation |
|---|---|
| Bilateral ground-glass opacities (GGO) | Diffuse alveolar haemorrhage — blood filling alveolar spaces |
| Bilateral patchy consolidation | Extensive DAH |
| NO nodules or cavitations | Distinguishes from GPA (which shows pulmonary infiltrates, pulmonary nodules, cavitation in the lung parenchyma) [2] |
| Interstitial fibrosis (late) | Sequela of recurrent DAH |
CXR, CT thorax, DLCO for pulmonary involvement if cough ± haemoptysis [7][8]
| Finding | Interpretation |
|---|---|
| ↑ DLCO (paradoxically raised) | Haemoglobin in alveoli from DAH absorbs CO → artificially elevated DLCO. This is a classic exam pearl. |
| ↓ DLCO (if chronic) | Pulmonary fibrosis from recurrent DAH → reduced gas transfer |
Why ↑ DLCO in acute DAH? CO binds haemoglobin with very high affinity. When there is free haemoglobin sitting in alveoli (from bleeding), it acts as an extra "sink" for CO during the DLCO test → more CO is absorbed → DLCO appears elevated. This is the opposite of what you'd expect in most lung diseases.
| Finding | Interpretation |
|---|---|
| Normal-sized kidneys | Acute process (RPGN) — kidneys have not yet atrophied |
| Small, echogenic kidneys | Chronic disease / irreversible fibrosis — biopsy may not be helpful |
| No hydronephrosis | Rules out post-renal obstruction as cause of AKI |
Renal biopsy: necessary for most cases of nephritic syndrome unless very small kidney on USG [6][7]
- Performed to rule out GPA — look for sinusitis, bony erosion, soft tissue masses
- In MPA: typically normal or non-specific changes
- In GPA: mucosal thickening, bony erosion, septal perforation
D. Tissue Biopsy — The Gold Standard
Biopsy of affected organ: gold-standard, e.g. renal biopsy, lung biopsy [6]
Tissue biopsy is the definitive diagnostic investigation in MPA. The choice of biopsy site depends on which organ is clinically affected and accessible.
1. Renal Biopsy (Most Commonly Performed and Most Informative)
This is the single most important investigation for confirming MPA when the kidneys are involved.
Three components of renal biopsy examination:
| Finding | Interpretation |
|---|---|
| Focal and segmental necrotizing GN | Fibrinoid necrosis of glomerular capillary tufts in segments of individual glomeruli |
| Crescent formation | Proliferation of parietal epithelial cells + macrophages in Bowman's space — hallmark of RPGN |
| Cellular crescents | Active, potentially reversible with immunosuppression |
| Fibrocellular/fibrous crescents | Mixed or chronic — unlikely to respond to immunosuppressive treatment [7][8][11] |
| No granulomatous inflammation | Distinguishes MPA from GPA |
Histological classification of ANCA-GN (Berden classification, 2010) [6]:
- Focal: ≥ 50% glomeruli normal
- Crescentic: ≥ 50% glomeruli with crescents
- Mixed: % glomeruli normal, crescentic, sclerotic all < 50%
- Sclerotic: ≥ 50% glomeruli are globally sclerotic
- This classification was shown to predict 1 and 5-year outcome [6]
Berden Classification Predicts Prognosis
The histological class matters enormously for prognosis:
- Focal → best renal survival (≥ 50% glomeruli still normal)
- Crescentic → intermediate (active disease but potentially reversible)
- Sclerotic → worst (irreversible damage, poor response to treatment) This guides treatment intensity and helps counselling about renal prognosis.
Minimal deposition of immunoglobulin and complement (Pauci-immune) [2] IF: unremarkable ("pauci-immune") [6]
| Finding | Interpretation |
|---|---|
| Minimal or absent staining for IgG, IgA, IgM, C3, C1q | Pauci-immune — confirms ANCA-mediated mechanism (NOT immune complex) |
| Faint, non-specific C3 or fibrin staining | May be present but NOT in the "full house" or linear pattern |
This is the key discriminator:
| Finding | Interpretation |
|---|---|
| No significant electron-dense deposits | Confirms pauci-immune nature (no immune complex deposition) |
| GBM disruption, fibrin deposition | Fibrinoid necrosis |
| No subepithelial/subendothelial/mesangial deposits | Rules out membranous, MPGN, IgAN |
Skin biopsy: histology and direct IF (for deposition of Ig around blood vessels) [1]
| Finding | Interpretation |
|---|---|
| Leukocytoclastic vasculitis (neutrophilic debris around dermal venules) | Confirms small vessel vasculitis |
| Pauci-immune IF | Favours ANCA-associated vasculitis |
| IgA-dominant deposits | Would suggest IgA vasculitis (HSP) instead |
- Surgical lung biopsy (VATS) may be considered if DAH is the dominant feature and renal biopsy is not feasible
- Shows: pulmonary capillaritis, haemosiderin-laden macrophages, neutrophilic infiltration of alveolar walls, no granulomas
- BAL (bronchoalveolar lavage): progressively bloodier aliquots confirm DAH; haemosiderin-laden macrophages ( > 20%) suggest recent/chronic alveolar haemorrhage
- Considered when mononeuritis multiplex is the dominant presentation and other biopsies are non-diagnostic
- Shows: necrotizing vasculitis of epineurial/perineurial small arteries, axonal degeneration
| Finding | Interpretation |
|---|---|
| Asymmetric axonal neuropathy in named nerve distributions | Consistent with mononeuritis multiplex from vasa nervorum vasculitis |
| Axonal pattern (↓ CMAP/SNAP amplitudes, preserved conduction velocities) | Ischaemic nerve injury (not demyelinating) |
| Category | Investigation | Key Finding in MPA |
|---|---|---|
| Bloods | CBC D/C | NcNc anaemia, normal eosinophils, ↑ WBC |
| ESR, CRP | ↑↑ ESR and CRP | |
| RFT | ↑ urea and creatinine | |
| C3, C4 | Normal | |
| Serology | ANCA (IF + ELISA) | p-ANCA / anti-MPO positive (~70%) |
| Anti-GBM Ab | Negative | |
| ANA, anti-dsDNA | Negative | |
| ASLO, HBV/HCV, cryoglobulins | Negative (to exclude mimics) | |
| Urine | Urinalysis + microscopy | Dysmorphic RBCs, RBC casts, proteinuria |
| Spot ACR / 24h protein | Usually sub-nephrotic | |
| Imaging | CXR / CT thorax | Bilateral GGO (DAH), NO nodules/cavities |
| DLCO | ↑ in acute DAH, ↓ if chronic fibrosis | |
| Renal USG | Normal-sized kidneys, no obstruction | |
| Biopsy | Renal biopsy | Necrotizing crescentic GN, pauci-immune IF, NO granuloma |
| Skin biopsy | Leukocytoclastic vasculitis, pauci-immune IF | |
| Other | NCS/EMG | Asymmetric axonal neuropathy |
| BAL | Progressively bloody aliquots, haemosiderin-laden macrophages |
High Yield Summary — Diagnosis of MPA
There is no single diagnostic test for MPA. Diagnosis requires convergence of:
- Compatible clinical features (RPGN, DAH, purpura, mononeuritis multiplex, constitutional symptoms)
- Positive p-ANCA / anti-MPO (present in ~70%; absence does NOT exclude)
- Tissue biopsy showing necrotizing non-granulomatous vasculitis with pauci-immune IF
- Exclusion of mimics (anti-GBM negative, ANA/dsDNA negative, normal complement, no eosinophilia/asthma)
Key serological principle: Normal complement + ANCA positive = pauci-immune AAV. Low complement = immune complex disease (SLE, MPGN, cryoglobulinaemia).
Renal biopsy IF pattern is the gold-standard differentiator: Pauci-immune → ANCA-associated; Linear → anti-GBM; Granular → immune complex.
Don't wait for biopsy if clinically urgent: In a patient with active sediment + rising creatinine + positive ANCA, start empirical immunosuppression (pulse IV methylprednisolone) while arranging biopsy.
Active Recall - Diagnosis of MPA
[1] Senior notes: Maksim Medicine Notes.pdf (Rheumatology, p.331 – ANCA-associated vasculitis investigations) [2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp.1773–1776 – MPA overview, diagnosis) [3] GC lecture slides: GC 053. Fingers turn white and blue.pdf (pp.79–80, 91, 93–94 – ANCA types, PAN vs MPA, AAV comparison) [4] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (pp.413–415, 421 – RPGN IF pattern classification, serology workup) [5] Senior notes: Ryan Ho Rheumatology.pdf (p.97 – AAV comparison table) [6] Senior notes: Ryan Ho Urogenital.pdf (pp.63, 68–69 – AAV pathogenesis, histology, Berden classification, diagnosis) [7] Senior notes: Ryan Ho Fundamentals.pdf (pp.359–361 – GN evaluation, RPGN classification, workup) [8] Senior notes: Adrian Lui Pediatrics Notes.pdf (pp.324–326 – GN evaluation, complement, serology, RPGN) [9] Senior notes: Ryan Ho Respiratory.pdf (p.140 – GPA and Goodpasture investigations) [11] Senior notes: Ryan Ho Urogenital.pdf (p.64 – RPGN classification and presentation) [13] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.1764 – CHCC classification definitions) [14] GC lecture slides: GC 057. Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (p.21 – Investigations for haematuria)
Management of Microscopic Polyangiitis (MPA)
Before diving into the specifics, let's understand the overarching logic:
- MPA is a medical emergency — untreated, mortality from RPGN + DAH approaches 80–90% within the first year. Early treatment institution is associated with better renal prognosis [6].
- Treatment is divided into two phases: induction (aggressive, to stop active inflammation rapidly) and maintenance (gentler, to prevent relapse while minimising drug toxicity).
- The intensity of induction depends on disease severity — life-threatening organ involvement (DAH, severe RPGN) demands the most aggressive regimens.
- All immunosuppressive therapy carries infection risk — infection is a leading cause of death in AAV alongside the disease itself. Prophylaxis and monitoring are essential.
- Relapse is common in MPA — relapses are common [3] — so maintenance must be sustained and withdrawal must be cautious.
Phase 1: Induction Therapy
The goal of induction is to rapidly suppress active vasculitis and halt organ damage. Without induction, MPA progresses to ESRD, fatal DAH, or death.
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
| Regimen | Dose | Duration | Indication |
|---|---|---|---|
| IV pulse methylprednisolone | 500–1000 mg/day | 3 days | Severe / organ-threatening disease (RPGN, DAH) [4][5][7] |
| Oral prednisolone (after pulse) | 1 mg/kg/day (max 60–80 mg) | Start after IV pulse, then taper | Following IV pulse or for non-severe disease |
| Steroid taper | Reduce to ~10–15 mg/day by 3 months; aim off by 12–18 months | Gradual | All patients |
Can give empirical pulse IV methylprednisolone before renal biopsy if clinically indicated [7][8]
Don't Wait for Biopsy in Emergencies
If a patient presents with active sediment + rapidly rising creatinine + positive ANCA + haemoptysis, start IV methylprednisolone immediately. Waiting for biopsy results can mean the difference between recoverable kidney function and irreversible ESRD. The biopsy confirms and refines the diagnosis, but treatment should not be delayed.
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.
High Yield — Steroid Dose Trend
Modern practice favours rapid steroid tapering to ≤ 5 mg/day by 3–5 months (supported by PEXIVAS and LoVAS trials showing non-inferior outcomes with lower steroid exposure but fewer infectious complications). However, for exam purposes, know the traditional regimen: IV pulse methylprednisolone 1 g/day × 3 days → oral prednisolone 1 mg/kg/day → taper [4][5].
"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]
| Route | Regimen | Advantages | Disadvantages |
|---|---|---|---|
| IV pulse CYC (European CYCLOPS protocol) | 15 mg/kg (max 1.2 g) every 2–3 weeks × 6 doses | Lower cumulative dose → less gonadal/bladder toxicity | Requires hospital visits |
| Oral CYC (NIH protocol) | 2 mg/kg/day (max 200 mg) × 3–6 months | Continuous suppression | Higher cumulative dose → more side effects |
Side effects — know these well:
| Side Effect | Mechanism | Prevention |
|---|---|---|
| Bone marrow suppression (leukopenia, infection) | Kills rapidly dividing haematopoietic precursors | Regular CBC monitoring (aim WCC > 3 × 10⁹/L); dose-adjust for age and GFR |
| Haemorrhagic cystitis | Acrolein (CYC metabolite) is toxic to bladder urothelium | IV Mesna (binds acrolein in urine); adequate hydration; morning dosing (void overnight) |
| Gonadal toxicity (infertility) | Kills germ cells | Limit cumulative dose; sperm/oocyte banking before treatment in young patients; use IV pulse (lower cumulative dose) |
| Malignancy risk (bladder cancer, MDS, lymphoma) | DNA alkylation → mutagenesis | Limit cumulative dose; avoid > 25 g lifetime dose if possible |
| Infection (opportunistic) | Immunosuppression | PJP prophylaxis (co-trimoxazole); monitor for infections |
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.
| Regimen | Dose | Schedule |
|---|---|---|
| Rheumatology protocol | 375 mg/m² IV | Weekly × 4 doses |
| Simplified protocol | 1000 mg IV | Day 1 and Day 15 (2 doses) |
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:
| Side Effect | Mechanism | Management |
|---|---|---|
| Infusion reactions (fever, rigors, urticaria) | Cytokine release from B-cell lysis | Pre-medicate with paracetamol + antihistamine + steroid; slow infusion rate |
| Late-onset neutropenia | Unclear (possibly B-cell recovery-related cytokine changes) | Monitor CBC |
| Hypogammaglobulinaemia (IgG depletion) | Prolonged B-cell depletion → reduced Ig production | Monitor IgG levels; consider IVIG replacement if recurrent infections |
| Progressive multifocal leukoencephalopathy (PML) | JC virus reactivation in severely immunosuppressed patients | Very rare; maintain awareness |
| HBV reactivation | Loss of immune surveillance | Screen HBV serology (HBsAg, anti-HBc) before treatment; give entecavir prophylaxis if HBsAg+ or anti-HBc+ |
Contraindications:
- Active severe infection
- HBV carriers without antiviral prophylaxis
- Severe hypogammaglobulinaemia with recurrent infections
- Pregnancy / breastfeeding
CYC vs Rituximab — When to Choose Which?
Choose CYC: First-line in severe disease (traditionally), older patients with limited life expectancy (CYC is cheaper), resource-limited settings.
Choose rituximab: Relapsing disease (superior to CYC per RAVE), young patients (preserves fertility), patients with prior high CYC exposure, contraindications to CYC.
2024 KDIGO / ACR guidelines: Rituximab is now considered first-line alongside CYC for induction in severe AAV, with many centres preferring rituximab over CYC for initial induction.
"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.
| Indication | Rationale |
|---|---|
| Diffuse alveolar haemorrhage (DAH) | Rapidly removes ANCA → decreases ongoing capillaritis |
| Severe renal involvement (Cr > 500 μmol/L or dialysis-dependent) | May improve chance of renal recovery |
| Anti-GBM overlap ("double-positive" ANCA + anti-GBM) | Must remove anti-GBM antibodies (as in pure anti-GBM disease) |
| Fulminant MPA / GPA | Life-saving measure [15] |
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.
| Dose | 30 mg orally twice daily |
|---|---|
| Duration | Throughout induction and into maintenance (up to 52 weeks in trials) |
| Indication | Severe active AAV (MPA or GPA), as glucocorticoid-sparing adjunct |
| Side effects | Hepatotoxicity (monitor LFTs), headache, GI disturbance, infections |
| Contraindication | Severe hepatic impairment; active serious infection |
Avacopan — The Future of AAV Treatment
Avacopan is a paradigm shift: for the first time, a targeted complement inhibitor allows steroid-free or steroid-minimal induction in AAV. While not yet universally available, it is increasingly used in specialist centres. For exams, know: (1) it targets C5aR1, (2) it is steroid-sparing, (3) it was validated in the ADVOCATE trial, (4) it is used alongside CYC or RTX, not as monotherapy.
Phase 2: Maintenance Therapy
Once remission is achieved (typically 3–6 months after starting induction), the goal shifts to preventing relapse while minimising long-term drug toxicity. MPA has a significant relapse rate — maintenance is critical.
Maintenance: AZA / RIT / MTX [5]
Evidence: The MAINRITSAN (2014) and MAINRITSAN 2 (2018) trials showed rituximab maintenance is superior to azathioprine in preventing relapse in AAV.
| Regimen | 500 mg IV every 6 months |
|---|---|
| Duration | ≥ 2 years (RITAZAREM trial supports even longer in relapsing patients) |
| Monitoring | IgG levels (risk of hypogammaglobulinaemia), B-cell count (CD19 count), infection surveillance |
"Aza-thio-prine" → a purine analogue pro-drug that is converted to 6-mercaptopurine → incorporated into DNA → inhibits purine synthesis → suppresses lymphocyte proliferation.
| Dose | 2 mg/kg/day orally |
|---|---|
| Duration | ≥ 18–24 months after remission |
| Monitoring | CBC (bone marrow suppression), LFT (hepatotoxicity) |
| Important pre-treatment check | TPMT genotype/phenotype — patients with low/absent TPMT activity (homozygous variant) are at very high risk of life-threatening myelosuppression. Dose-reduce or avoid if TPMT deficient. |
Side effects: bone marrow suppression (leukopenia), hepatotoxicity, GI upset, increased infection risk, slightly increased long-term malignancy risk.
| Dose | 15–25 mg weekly (oral or subcutaneous) + folic acid supplementation |
|---|---|
| Indication | Can be used for maintenance if GFR > 30 mL/min (contraindicated in significant renal impairment as MTX is renally excreted) |
| Side effects | Myelosuppression, hepatotoxicity, pulmonary toxicity (pneumonitis), teratogenic |
| Note | Less commonly used than AZA or RTX for MPA maintenance |
- 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)
These are easy to forget in exams but are absolutely critical in clinical practice:
| Measure | Details | Rationale |
|---|---|---|
| PJP prophylaxis | Co-trimoxazole (TMP-SMX) 480 mg daily or 960 mg thrice weekly | All patients on CYC, RTX, or high-dose steroids are at risk of Pneumocystis jirovecii pneumonia |
| Bone protection | Calcium + Vitamin D ± bisphosphonate | Steroid-induced osteoporosis prevention |
| Vaccination | Pneumococcal (PCV13 + PPSV23), Influenza annually, HBV if non-immune, COVID-19 | Immunocompromised patients at high infection risk; Pneumococcal vaccination indicated for ALL [7] |
| ACEI/ARB for renal protection | Target proteinuria < 1 g/day | ↓ intraglomerular pressure → ↓ proteinuria, which is associated with ↓ rate of GFR decline [7] |
| HBV screening | Before rituximab or CYC | Risk of HBV reactivation; give antiviral prophylaxis if indicated |
| TB screening | CXR ± IGRA before immunosuppression | Reactivation risk with steroids/CYC |
| Fertility counselling | Sperm/oocyte banking before CYC | CYC causes gonadal toxicity |
| Infection monitoring | Regular clinical assessment; low threshold for cultures/imaging | Infection is a leading cause of death in AAV — lung/renal and infection as major cause of death [5] |
| VTE prophylaxis | Consider in nephrotic-range proteinuria or immobilised patients | Active vasculitis + nephrotic syndrome → hypercoagulable state |
| Blood pressure control | Target < 130/80 (CKD with proteinuria) | Hypertension accelerates CKD progression |
| Renal replacement therapy | Haemodialysis if ESRD | Bridging while awaiting treatment response, or long-term if irreversible |
Management of Specific Scenarios
- 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)
| Phase | Agent | Dose / Regimen | Duration |
|---|---|---|---|
| Induction (Severe) | IV pulse methylprednisolone | 1 g/day × 3 days | 3 days |
| → Oral prednisolone | 1 mg/kg/day then taper | Taper over 3–18 months | |
| Cyclophosphamide | IV 15 mg/kg q2–3 weeks × 6, OR oral 2 mg/kg/day | 3–6 months | |
| OR Rituximab | 375 mg/m² weekly × 4, OR 1 g × 2 doses | 4 weeks | |
| ± Plasma exchange | 7 sessions over 14 days | 2–3 weeks | |
| ± Avacopan | 30 mg PO BD | Up to 52 weeks | |
| Induction (Non-severe) | Oral prednisolone | 0.5–1 mg/kg/day then taper | Taper over 3–18 months |
| RTX or CYC (lower dose) or MTX | As above (adjusted) | 3–6 months | |
| Maintenance | Rituximab (preferred) | 500 mg IV q6 months | ≥ 2 years |
| OR Azathioprine | 2 mg/kg/day PO | ≥ 18–24 months | |
| OR Methotrexate | 15–25 mg weekly (if GFR > 30) | ≥ 18–24 months | |
| Supportive | Co-trimoxazole (PJP ppx) | 480 mg daily or 960 mg 3×/week | Duration of immunosuppression |
| Ca²⁺ + Vit D ± bisphosphonate | Standard osteoporosis doses | Duration of steroid use | |
| ACEI/ARB | Titrate to target BP and proteinuria | Long-term |
4–10 year survival 56–95%. Lung/renal and infection as major cause of death [5]
| Factor | Detail |
|---|---|
| Treated 5-year survival | ~75–80% |
| Untreated | < 20% 5-year survival |
| Major causes of death | Lung/renal disease and infection [5] |
| Relapse risk | Lower than GPA but still significant (~30% at 5 years) |
| Prognostic factors for poor renal outcome | High creatinine at diagnosis, sclerotic class on biopsy, % fibrous crescents, older age |
| Renal outcome | ~25–30% progress to ESRD despite treatment |
High Yield Summary — Management of MPA
Induction (severe): IV pulse methylprednisolone 1 g/day × 3 days + cyclophosphamide or rituximab ± plasma exchange [4][5]
Induction (non-severe): Oral prednisolone + rituximab or CYC or MTX
Maintenance: Rituximab (preferred, 500 mg q6 months) or azathioprine (2 mg/kg/day) for ≥ 2 years [5]
Steroid taper: Aim ≤ 5 mg/day by 3–5 months, off by 12–18 months
Key supportive measures: PJP prophylaxis (co-trimoxazole), bone protection, vaccination, ACEI/ARB, HBV/TB screening, fertility counselling
New agent: Avacopan (oral C5aR1 antagonist) — steroid-sparing, used with RTX or CYC
Prognosis: 5-year survival ~75–80% with treatment. Major mortality: pulmonary/renal disease and infection. Relapses common.
For relapse: Rituximab is preferred re-induction agent (superior to CYC in relapsing AAV per RAVE trial).
Active Recall - Management of MPA
References
[1] Senior notes: Maksim Medicine Notes.pdf (Rheumatology, p.331 – ANCA-associated vasculitis, PAN management) [2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp.1773–1776 – MPA overview, diagnosis) [3] GC lecture slides: GC 053. Fingers turn white and blue.pdf (pp.79–80, 91, 93–94 – PAN vs MPA comparison, relapses common) [4] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p.413 – ANCA vasculitis management: pulse steroids + CYC/RTX ± PLEX) [5] Senior notes: Ryan Ho Rheumatology.pdf (p.97 – AAV comparison table including treatment and prognosis) [6] Senior notes: Ryan Ho Urogenital.pdf (pp.68–69 – AAV management, early treatment, anti-GBM approach) [7] Senior notes: Ryan Ho Fundamentals.pdf (pp.360–361, 368 – GN evaluation, RPGN management, general GN management including ACEI/ARB and vaccination) [8] Senior notes: Adrian Lui Pediatrics Notes.pdf (pp.324–326 – RPGN management, empirical pulse methylprednisolone) [15] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.1006 – RPGN management by IF pattern)
Complications of Microscopic Polyangiitis (MPA)
Complications of MPA can be conceptually divided into two broad categories:
- Disease-related complications — direct consequences of ongoing vasculitis and organ damage
- Treatment-related complications — iatrogenic consequences of the aggressive immunosuppression required to control the disease
Both categories contribute significantly to morbidity and mortality. Understanding which complications belong to which category is essential because the management approach is fundamentally different: disease complications require more immunosuppression, while treatment complications often require less.
4–10 year survival 56–95%. Lung/renal and infection as major cause of death [5]
This single line from the senior notes tells you the two killer complications: (1) end-organ damage (lung/renal) from the disease itself, and (2) infection from the treatment. Everything else flows from this.
1. Disease-Related Complications
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
The Creatinine at Presentation Predicts Outcome
The most important prognostic factor is the degree of renal impairment at diagnosis [6]. Patients who present with creatinine > 500 μmol/L or who are already dialysis-dependent have a much lower chance of renal recovery. This underscores why early diagnosis and rapid initiation of treatment are critical — every day of untreated active GN destroys more nephrons.
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:
| Complication | Mechanism |
|---|---|
| Pericarditis | Direct small vessel vasculitis of pericardial vessels → pericardial inflammation |
| Accelerated atherosclerosis | Chronic systemic inflammation → endothelial dysfunction, dyslipidaemia; compounded by chronic steroid use (hypertension, diabetes, dyslipidaemia) |
| Venous thromboembolism | Active vasculitis is a prothrombotic state (endothelial injury, NETs are procoagulant, inflammation upregulates tissue factor); steroid use further increases VTE risk |
| Heart failure | Rare in MPA but can occur from: volume overload (renal failure), hypertension (CKD), or myocardial small vessel vasculitis |
- 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
2. Treatment-Related Complications
This is critically important because infection is the leading cause of death in the first year of treatment, alongside disease activity itself. The immunosuppressive agents used to treat MPA are potent and carry serious risks.
Lung/renal and infection as major cause of death [5]
Why are MPA patients so infection-prone?
- High-dose glucocorticoids → suppress innate and adaptive immunity (↓ neutrophil function, ↓ T-cell function, ↓ cytokine production)
- Cyclophosphamide → alkylates DNA in rapidly dividing immune cells → leukopenia, lymphopenia
- Rituximab → depletes B cells → hypogammaglobulinaemia → impaired humoral immunity
- Combined immunosuppression → profound immunodeficiency
- Uraemia (from renal failure) → impaired immune function
- Age → MPA patients are typically older (50–60 years), with less immune reserve
Common infections:
| Infection | Pathogen | Risk Factor | Prevention |
|---|---|---|---|
| Pneumocystis jirovecii pneumonia (PJP) | Pneumocystis jirovecii (fungal) | CYC, RTX, high-dose steroids | Co-trimoxazole prophylaxis (TMP-SMX 480 mg daily or 960 mg thrice weekly) — mandatory |
| Bacterial pneumonia | Streptococcus pneumoniae, Haemophilus, Gram-negatives | Steroid-induced immunosuppression, hypogammaglobulinaemia | Pneumococcal vaccination; influenza vaccination |
| Herpes zoster reactivation | Varicella-zoster virus | CYC, RTX, steroids | Consider valaciclovir prophylaxis in high-risk patients |
| CMV reactivation | Cytomegalovirus | Profound lymphopenia after CYC/RTX | Monitor if symptomatic; treat with ganciclovir/valganciclovir |
| HBV reactivation | Hepatitis B virus | Rituximab (B-cell depletion removes immune surveillance) | Mandatory HBV screening before RTX; entecavir prophylaxis if HBsAg+ or anti-HBc+ |
| TB reactivation | Mycobacterium tuberculosis | High-dose steroids (particularly relevant in Hong Kong) | CXR ± IGRA screening before immunosuppression; LTBI treatment if indicated |
| Opportunistic fungi | Aspergillus, Candida | Prolonged neutropenia, high-dose steroids | Clinical vigilance; low threshold for imaging and cultures |
PJP Prophylaxis is Non-Negotiable
Co-trimoxazole prophylaxis must be given to ALL MPA patients receiving CYC, rituximab, or high-dose steroids. PJP has a mortality rate of 30–50% in immunocompromised patients and is entirely preventable. If co-trimoxazole is contraindicated (allergy, myelosuppression), use dapsone or atovaquone as alternatives.
| Complication | Mechanism | Prevention/Monitoring |
|---|---|---|
| Bone marrow suppression (leukopenia) | Alkylation of haematopoietic precursors | Regular CBC; nadir WCC ~10–14 days post-dose; dose-adjust for age and GFR |
| Haemorrhagic cystitis | Acrolein metabolite is toxic to bladder urothelium → urothelial necrosis → bleeding | IV Mesna (2-mercaptoethane sulfonate — binds and neutralises acrolein); adequate hydration; morning dosing to allow overnight voiding |
| Gonadal toxicity / infertility | Cytotoxic effect on rapidly dividing germ cells | Limit cumulative dose; fertility preservation (sperm/oocyte banking) before starting; use IV pulse (lower cumulative dose) over oral CYC |
| Bladder cancer | Chronic acrolein exposure → urothelial carcinogenesis (latency 7–15 years) | Limit cumulative lifetime dose ( < 25 g if possible); long-term urinalysis surveillance; mesna |
| Myelodysplastic syndrome / leukaemia | Alkylation-induced mutagenesis in haematopoietic stem cells | Limit cumulative dose; no specific prevention |
Prolonged high-dose steroid use is almost universal in MPA management and causes a predictable constellation of complications:
| System | Complication | Mechanism |
|---|---|---|
| Metabolic | Steroid-induced diabetes mellitus | ↑ hepatic gluconeogenesis + ↑ peripheral insulin resistance |
| Cushingoid habitus (moon face, buffalo hump, central obesity) | Redistribution of adipose tissue | |
| Dyslipidaemia | ↑ VLDL production | |
| Musculoskeletal | Osteoporosis → fragility fractures | Inhibits osteoblast activity + promotes osteoclast activity + ↓ intestinal calcium absorption |
| Avascular necrosis (femoral head, humeral head) | Lipocyte hypertrophy in bone marrow → ↑ intraosseous pressure → compromised sinusoidal blood flow | |
| Steroid myopathy (proximal weakness) | Type IIb muscle fibre atrophy | |
| GI | Peptic ulceration (especially with concurrent NSAIDs) | ↓ prostaglandin synthesis → ↓ mucosal protection |
| Ophthalmological | Posterior subcapsular cataracts | Steroid-induced oxidative damage to lens proteins |
| Glaucoma | ↑ aqueous humour outflow resistance | |
| Cardiovascular | Hypertension | Mineralocorticoid effect → Na⁺/water retention |
| Neuropsychiatric | Insomnia, mood disturbance, psychosis (rare) | Central effects on serotonin, dopamine, and GABA neurotransmission |
| Immune | Adrenal suppression | Exogenous steroid → hypothalamic-pituitary-adrenal axis suppression → adrenal atrophy; risk of adrenal crisis on abrupt withdrawal |
| Increased infection susceptibility | See infection section above | |
| Dermatological | Skin thinning, easy bruising, poor wound healing | Inhibits collagen synthesis and fibroblast proliferation |
| Complication | Mechanism | Monitoring |
|---|---|---|
| Hypogammaglobulinaemia | Sustained B-cell depletion → ↓ immunoglobulin synthesis | Check IgG levels before each dose; if IgG < 4 g/L + recurrent infections → consider IVIG replacement |
| Late-onset neutropenia | Exact mechanism unclear; may relate to B-cell recovery kinetics | Regular CBC |
| Infusion reactions | Cytokine release from B-cell lysis | Pre-medication (steroid + antihistamine + paracetamol); slow first infusion |
| Progressive multifocal leukoencephalopathy | JC virus reactivation in severely immunosuppressed patient → demyelination in white matter | Very rare; maintain clinical awareness; suspect if new focal neurological deficits |
| HBV reactivation | Loss of B-cell-mediated immune surveillance of latent HBV | Mandatory pre-treatment HBV serology; antiviral prophylaxis if indicated |
| Complication | Mechanism | Prevention |
|---|---|---|
| Myelosuppression (leukopenia, pancytopenia) | 6-mercaptopurine incorporation into DNA inhibits purine synthesis in haematopoietic cells | TPMT genotyping before starting — patients with low/absent TPMT are at extreme risk of life-threatening myelosuppression; regular CBC monitoring |
| Hepatotoxicity | Direct hepatocellular toxicity | Regular LFTs |
| GI intolerance (nausea, vomiting) | Direct mucosal irritation | Take with food; dose adjustment |
| Pancreatitis (rare, idiosyncratic) | Unknown | Clinical awareness; stop drug if pancreatitis develops |
When DAH and RPGN co-exist (the "pulmonary-renal syndrome"), the complications compound each other:
| Problem | Why It's Worse Together |
|---|---|
| Fluid management dilemma | RPGN → oliguria → fluid overload → pulmonary oedema on top of DAH; but DAH causes blood loss → patient may also be hypovolaemic from haemorrhage. You are stuck between giving fluid (worsens pulmonary oedema) and restricting it (worsens renal perfusion). |
| Anaemia | Iron deficiency from chronic pulmonary haemorrhage + uraemic erythropoietin deficiency → severe combined anaemia |
| Dialysis with active bleeding | Haemodialysis requires anticoagulation (usually heparin) → worsens DAH. May need to use citrate-based or heparin-free dialysis. |
| ICU admission | Patients with severe DAH + RPGN often require mechanical ventilation + dialysis simultaneously → high mortality |
Even after successful treatment, MPA patients face chronic morbidity:
| Complication | Explanation |
|---|---|
| Chronic kidney disease | Residual nephron loss from healed crescentic GN → CKD stages 3–5 even if ESRD is avoided |
| Chronic neuropathic pain | Axonal damage from vasa nervorum vasculitis → incomplete regeneration → burning pain, paraesthesiae |
| Psychological morbidity | Depression, anxiety from chronic illness, body image issues (Cushingoid), treatment burden, fear of relapse |
| Cardiovascular disease | Accelerated atherosclerosis from chronic inflammation + steroid-induced metabolic syndrome |
| Secondary malignancy | Increased risk from CYC (bladder cancer, MDS, lymphoma) and long-term immunosuppression (lymphoma, skin cancer) |
| Infertility | CYC gonadal toxicity; important to counsel and offer fertility preservation before treatment |
| Recurrent relapse | Cumulative organ damage with each episode; need for repeated immunosuppression with escalating toxicity |
| Category | Key Complications | Mechanism |
|---|---|---|
| Disease-related | ESRD | Progressive crescentic GN → irreversible nephron loss |
| Fatal DAH | Pulmonary capillaritis → alveolar flooding → respiratory failure | |
| Pulmonary fibrosis | Recurrent DAH → haemosiderin deposition → fibrosis | |
| Chronic neuropathy | Vasa nervorum vasculitis → axonal degeneration → incomplete recovery | |
| Relapse | Ongoing autoimmune drive; cumulative organ damage | |
| Treatment-related | Infection (leading cause of death) | Combined immunosuppression → profound immunodeficiency |
| CYC toxicity | Haemorrhagic cystitis, gonadal toxicity, bladder cancer, myelosuppression | |
| Steroid toxicity | Osteoporosis, DM, AVN, Cushing's, cataracts, adrenal suppression | |
| RTX toxicity | Hypogammaglobulinaemia, HBV reactivation, PML | |
| AZA toxicity | Myelosuppression (TPMT-dependent), hepatotoxicity |
High Yield Summary — Complications of MPA
The two major killers in MPA are:
- Lung/renal disease (end-organ damage from vasculitis) — ESRD (~25–30%) and fatal DAH
- Infection (from immunosuppressive treatment) — especially PJP, bacterial pneumonia, HBV/TB reactivation
ESRD is the most important long-term complication. Prognosis depends on creatinine at diagnosis and biopsy class (sclerotic = worst).
DAH is the most important acute complication. Can be fatal within hours. Can occur without haemoptysis.
Chronic neuropathy causes long-term disability despite disease control.
Treatment complications to know: CYC → haemorrhagic cystitis (mesna prophylaxis), gonadal toxicity, bladder cancer. Steroids → osteoporosis, DM, AVN, cataracts, adrenal suppression. RTX → hypogammaglobulinaemia, HBV reactivation. AZA → TPMT-dependent myelosuppression.
Mandatory prophylaxis: PJP prophylaxis (co-trimoxazole), bone protection (Ca²⁺ + Vit D ± bisphosphonate), HBV screening before RTX, TB screening before immunosuppression.
Relapses are common in MPA — each relapse causes cumulative organ damage.
Active Recall - Complications of MPA
References
[2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp.1773–1776 – MPA clinical manifestations including pulmonary fibrosis, renal involvement) [3] GC lecture slides: GC 053. Fingers turn white and blue.pdf (pp.93–94 – MPA relapses common; EGPA major cause of death cardiac; GPA/MPA major cause of death pulmonary and renal) [5] Senior notes: Ryan Ho Rheumatology.pdf (p.97 – AAV comparison table: prognosis, major causes of death, treatment) [6] Senior notes: Ryan Ho Urogenital.pdf (pp.68–69 – AAV management, Berden classification predicting outcome, renal prognosis, early treatment) [7] Senior notes: Ryan Ho Fundamentals.pdf (pp.360–361 – RPGN crescent formation pathogenesis, fibrous crescents unlikely to respond) [8] Senior notes: Adrian Lui Pediatrics Notes.pdf (pp.324–326 – RPGN crescent formation, fibrous crescents)
High Yield Summary
Definition: MPA is a necrotizing, non-granulomatous, pauci-immune small vessel vasculitis, predominantly anti-MPO (p-ANCA) positive.
Epidemiology: Peak age 50–60, male predominance. In Hong Kong/East Asia, MPA is the most common AAV (unlike the West where GPA predominates).
Key distinguishing features from GPA: No granuloma, no ENT involvement, no cavitating lung nodules. MPA causes DAH; GPA causes nodules/cavities.
Key distinguishing features from EGPA: No asthma, no eosinophilia.
Key distinguishing features from PAN: MPA causes GN and DAH; PAN does NOT cause GN or pulmonary haemorrhage. PAN shows microaneurysms on angiography; MPA does not.
Pathophysiology: Anti-MPO ANCA → primed neutrophil activation → degranulation on endothelium → fibrinoid necrosis (pauci-immune) → organ damage. Alternative complement pathway amplifies injury via C5a.
Clinical: Constitutional symptoms + RPGN (80–100%) + DAH (25–50%) + mononeuritis multiplex (up to 70%) + palpable purpura. Pulmonary-renal syndrome is the classic severe presentation.
ANCA: p-ANCA / anti-MPO in ~70% (range 45–80%). Up to 15–45% may have anti-PR3.
Histology: Necrotizing vasculitis WITHOUT granuloma. IF: pauci-immune (minimal Ig/complement). Renal biopsy: focal segmental necrotizing and crescentic GN.
High Yield Summary — Differential Diagnosis
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Within AAV: MPA vs GPA vs EGPA — differentiate by: presence of granuloma (absent in MPA), ENT involvement (absent in MPA), asthma/eosinophilia (absent in MPA, present in EGPA), ANCA type (anti-MPO in MPA vs anti-PR3 in GPA).
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From PAN: MPA has GN and DAH; PAN has microaneurysms and renal infarcts. PAN = no GN, no DAH, HBV-associated, ANCA-negative.
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From anti-GBM disease: IF pattern (pauci-immune in MPA vs linear in anti-GBM), anti-GBM antibody positive only in anti-GBM disease.
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From SLE: complement low in SLE (normal in MPA), ANA/dsDNA positive in SLE (negative in MPA), "full house" granular IF in SLE.
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Key discriminating investigations: serum complement, ANCA (type), anti-GBM Ab, ANA/dsDNA, renal biopsy with IF.
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IF pattern on renal biopsy is the gold-standard differentiator: Pauci-immune = ANCA-associated (MPA/GPA/EGPA); Linear = anti-GBM; Granular = immune complex.
High Yield Summary — Diagnosis of MPA
There is no single diagnostic test for MPA. Diagnosis requires convergence of:
- Compatible clinical features (RPGN, DAH, purpura, mononeuritis multiplex, constitutional symptoms)
- Positive p-ANCA / anti-MPO (present in ~70%; absence does NOT exclude)
- Tissue biopsy showing necrotizing non-granulomatous vasculitis with pauci-immune IF
- Exclusion of mimics (anti-GBM negative, ANA/dsDNA negative, normal complement, no eosinophilia/asthma)
Key serological principle: Normal complement + ANCA positive = pauci-immune AAV. Low complement = immune complex disease (SLE, MPGN, cryoglobulinaemia).
Renal biopsy IF pattern is the gold-standard differentiator: Pauci-immune → ANCA-associated; Linear → anti-GBM; Granular → immune complex.
Don't wait for biopsy if clinically urgent: In a patient with active sediment + rising creatinine + positive ANCA, start empirical immunosuppression (pulse IV methylprednisolone) while arranging biopsy.
High Yield Summary — Management of MPA
Induction (severe): IV pulse methylprednisolone 1 g/day × 3 days + cyclophosphamide or rituximab ± plasma exchange [4][5]
Induction (non-severe): Oral prednisolone + rituximab or CYC or MTX
Maintenance: Rituximab (preferred, 500 mg q6 months) or azathioprine (2 mg/kg/day) for ≥ 2 years [5]
Steroid taper: Aim ≤ 5 mg/day by 3–5 months, off by 12–18 months
Key supportive measures: PJP prophylaxis (co-trimoxazole), bone protection, vaccination, ACEI/ARB, HBV/TB screening, fertility counselling
New agent: Avacopan (oral C5aR1 antagonist) — steroid-sparing, used with RTX or CYC
Prognosis: 5-year survival ~75–80% with treatment. Major mortality: pulmonary/renal disease and infection. Relapses common.
For relapse: Rituximab is preferred re-induction agent (superior to CYC in relapsing AAV per RAVE trial).
High Yield Summary — Complications of MPA
The two major killers in MPA are:
- Lung/renal disease (end-organ damage from vasculitis) — ESRD (~25–30%) and fatal DAH
- Infection (from immunosuppressive treatment) — especially PJP, bacterial pneumonia, HBV/TB reactivation
ESRD is the most important long-term complication. Prognosis depends on creatinine at diagnosis and biopsy class (sclerotic = worst).
DAH is the most important acute complication. Can be fatal within hours. Can occur without haemoptysis.
Chronic neuropathy causes long-term disability despite disease control.
Treatment complications to know: CYC → haemorrhagic cystitis (mesna prophylaxis), gonadal toxicity, bladder cancer. Steroids → osteoporosis, DM, AVN, cataracts, adrenal suppression. RTX → hypogammaglobulinaemia, HBV reactivation. AZA → TPMT-dependent myelosuppression.
Mandatory prophylaxis: PJP prophylaxis (co-trimoxazole), bone protection (Ca²⁺ + Vit D ± bisphosphonate), HBV screening before RTX, TB screening before immunosuppression.
Relapses are common in MPA — each relapse causes cumulative organ damage.
IgA Vasculitis (Henoch-Schoenlein Purpura)
IgA vasculitis (Henoch-Schönlein purpura) is a small-vessel vasculitis caused by IgA immune complex deposition, characterized by palpable purpura, arthralgia, abdominal pain, and glomerulonephritis, most commonly affecting children.
Kawasaki Disease
Kawasaki disease is an acute, self-limited febrile vasculitis of medium-sized arteries predominantly affecting children under five years old, with a particular predilection for the coronary arteries.