Vasculitis
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"vasculitis"[MeSH Terms] AND "classification"
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Vasculitis
Vasculitis refers to a heterogeneous group of conditions characterized by inflammation of the vessel wall, leading to narrowing or occlusion of the lumen, aneurysm formation, and impairment of distal organ function. Each type has a distinct pathogenesis, natural history, and therapeutic approach.
Definition and General Concept
The vasculitides are rare diseases. In the US, a condition is "orphan" if it affects fewer than 200,000 persons; in Europe, prevalence < 5 per 10,000 qualifies. Incidence and prevalence vary with age, time, ethnicity, and geography, generating hypotheses about etiology. - Rheumatology (2022, Elsevier), p. 1454
Classification Framework
Historical Background
Classification began with Zeek (1952), who recognized five types based on vessel size using the term "necrotizing angiitis." All modern systems build on this vessel-size framework. The 1994 Chapel Hill Consensus Conference (CHCC) standardized nomenclature; a revised version was issued in 2012. Key name changes include:
- Wegener's granulomatosis → Granulomatosis with polyangiitis (GPA)
- Henoch-Schönlein purpura → IgA vasculitis (IgAV)
The 2012 CHCC Classification by Vessel Size
| Category | Definition | Diseases |
|---|---|---|
| Large-vessel vasculitis (LVV) | Affects aorta and major branches | Giant cell arteritis (GCA), Takayasu arteritis |
| Medium-vessel vasculitis (MVV) | Affects main visceral arteries (renal, mesenteric, coronary) | Polyarteritis nodosa (PAN), Kawasaki disease |
| Small-vessel vasculitis (SVV) | Affects arterioles, capillaries, venules | ANCA-associated, immune complex-mediated |
| Variable-vessel vasculitis | Any vessel size | Behçet's disease, Cogan's syndrome |
| Single-organ vasculitis | One organ only | Primary CNS angiitis, cutaneous vasculitis |
- Rheumatology (2022, Elsevier), p. 1455; Firestein & Kelley's Textbook of Rheumatology, p. 1948
Large-Vessel Vasculitis
Giant Cell Arteritis (GCA)
- Granulomatous arteritis of the aorta and branches, with predilection for carotid and vertebral artery branches (especially the temporal artery)
- Onset usually > 50 years, often associated with polymyalgia rheumatica
- Risk of visual loss (ischemic optic neuropathy), jaw claudication, headache
Takayasu Arteritis
- Granulomatous arteritis of the aorta and major branches
- Onset usually < 50 years
- Limb claudication, pulse deficits, renovascular hypertension
Medium-Vessel Vasculitis
Polyarteritis Nodosa (PAN)
- Necrotizing arteritis of medium or small arteries without glomerulonephritis, arterioles, capillaries, or venules involvement
- Not ANCA-associated
- Associated with hepatitis B virus infection in some cases
- Features: mononeuritis multiplex, renal infarcts, mesenteric ischemia, skin nodules, livedo reticularis
Kawasaki Disease
- Predominantly medium and small arteries; coronary artery aneurysms are the major concern
- Usually in infants and young children; associated with mucocutaneous lymph node syndrome
Small-Vessel Vasculitis
ANCA-Associated Vasculitis (AAV)
AAV is defined by necrotizing vasculitis with few or no immune deposits, predominantly affecting small vessels, and association with ANCA (MPO or PR3). - Firestein & Kelley's, p. 1949
Granulomatosis with Polyangiitis (GPA)
- Necrotizing granulomatous inflammation of upper and lower respiratory tract + necrotizing small-to-medium vessel vasculitis
- Typically PR3-ANCA / C-ANCA positive
- Classic triad: sinusitis/epistaxis, pulmonary infiltrates/nodules/cavities, glomerulonephritis
- 2022 ACR/EULAR criteria (score ≥ 5): nasal involvement (+3), cartilaginous involvement (+2), PR3/C-ANCA (+5), pulmonary nodule/mass/cavitation (+2), granuloma on biopsy (+2), pauci-immune GN (+1); MPO/P-ANCA (-1), eosinophilia ≥ 1×10⁹/L (-4). Sensitivity 93%, specificity 94%
Microscopic Polyangiitis (MPA)
- Necrotizing vasculitis, no granulomatous inflammation
- MPO-ANCA / P-ANCA typically positive
- Necrotizing glomerulonephritis is very common; pulmonary capillaritis occurs
Eosinophilic Granulomatosis with Polyangiitis (EGPA, formerly Churg-Strauss)
- Distinguished by: asthma, blood eosinophilia, eosinophil-rich tissue inflammation
- ANCA positive in 38-73% (usually MPO-ANCA)
- Three phases: allergic (asthma/rhinitis) → eosinophilic (tissue infiltration) → vasculitic
Immune Complex Small-Vessel Vasculitis
| Disease | Key Feature |
|---|---|
| IgA Vasculitis (HSP) | IgA immune complex deposits; palpable purpura, arthritis, abdominal pain, nephritis |
| Cryoglobulinemic vasculitis | Type II (monoclonal IgM + polyclonal IgG) most often from HCV; purpura, neuropathy, membranoproliferative GN |
| Hypocomplementemic urticarial vasculitis (HUV/HUVS) | Low C1q, anti-C1q antibodies; urticarial skin vasculitis ± systemic features |
| Anti-GBM disease (Goodpasture syndrome) | Anti-GBM antibodies; glomerulonephritis + pulmonary hemorrhage; 10-50% also ANCA-positive |
Secondary Vasculitis
Many autoimmune diseases are associated with vasculitis:
- SLE, Sjögren's syndrome, rheumatoid arthritis, relapsing polychondritis
- Drug-induced: hydralazine and propylthiouracil are classic causes of MPO-ANCA small-vessel vasculitis with alveolar hemorrhage/GN
- Immune checkpoint inhibitor (ICI) therapy is an emerging cause - typically resolves with glucocorticoids or drug withdrawal
- Infections: hepatitis B (PAN), hepatitis C (cryoglobulinemia)
Pathology
- Large vessel: granulomatous inflammation with multinucleated giant cells, intimal thickening
- Medium vessel: necrotizing arteritis, fibrinoid necrosis, transmural inflammation
- Small vessel (ANCA): pauci-immune (few/no immunoglobulin deposits), neutrophil-predominant necrosis
- Small vessel (immune complex): immune complex deposits detectable by immunofluorescence or electron microscopy
Key Investigations
| Test | Relevance |
|---|---|
| ANCA (PR3, MPO) | AAV diagnosis/classification |
| Anti-GBM antibody | Goodpasture syndrome |
| Cryoglobulins | Cryoglobulinemic vasculitis |
| Complement (C3, C4, C1q) | Immune complex vasculitis (low in SLE-vasculitis, HUVS) |
| Hepatitis B/C serology | PAN, cryoglobulinemia |
| Biopsy | Gold standard for most vasculitides |
| Imaging (CTA, PET-CT, MRA) | LVV - aortic/branch involvement |
Treatment
Induction of Remission (AAV)
Standard induction combines corticosteroids with an immunomodulatory agent. - Comprehensive Clinical Nephrology, 7th Ed., p. 362
- Cyclophosphamide (oral 2 mg/kg/day or IV 0.35-1 g/m²): remission in ~75% at 3 months, ~90% at 6 months
- Rituximab (anti-CD20): FDA and EMA approved for AAV induction; non-inferior to cyclophosphamide (RAVE and RITUXVAS trials). Preferred in younger patients, women of childbearing age, and relapsing disease
- The PEXIVAS trial demonstrated that reduced corticosteroid dosing (60% less exposure) is non-inferior for ESKD and all-cause mortality
- Avacopan (C5a receptor inhibitor): Phase III ADVOCATE trial showed 72.3% remission vs. 70.1% with prednisone - now used to reduce corticosteroid exposure
Maintenance of Remission
- Azathioprine or rituximab (preferred over cyclophosphamide for maintenance due to lower toxicity)
- Low-dose corticosteroids during maintenance, with gradual taper
- Maintenance typically continued for at least 24 months
Large-Vessel Vasculitis
- High-dose glucocorticoids (prednisone 40-60 mg/day) are the cornerstone for GCA and Takayasu
- Tocilizumab (IL-6 receptor inhibitor) is approved for GCA as a steroid-sparing agent
- Aspirin for GCA (reduces risk of ischemic complications)
Kawasaki Disease
- IV immunoglobulin (IVIG) + high-dose aspirin in acute phase
Pulmonary Manifestations of Vasculitis
Vasculitis is the most common cause of diffuse alveolar hemorrhage (DAH). In a retrospective review of 34 cases, systemic vasculitis accounted for 14 cases (predominantly GPA), followed by pulmonary-renal syndromes, anti-GBM disease, and idiopathic causes. - Murray & Nadel's Respiratory Medicine, p. 4843
Pulmonary-involved vasculitides include:
- GPA (necrotizing granulomas, cavities)
- MPA (pulmonary capillaritis)
- EGPA (eosinophilic infiltrates)
- IgA vasculitis
- Isolated pulmonary capillaritis
Recent Evidence
A 2025 Lancet review on large-vessel vasculitis (PMID 40939604) provides updated evidence on GCA and Takayasu arteritis management. A 2024 review covers IgA vasculitis (PMID 38281080) with updated classification criteria. The 2022 ACR/EULAR classification criteria for cranial GCA involvement are also recently updated.
Summary mnemonic for vessel-size categories:
- Large - GCA, Takayasu (Granulomas + Giant cells)
- Medium - PAN, Kawasaki (No ANCA, No glomerulonephritis in PAN)
- Small ANCA - GPA, MPA, EGPA (Pauci-immune)
- Small IC - IgAV, Cryo, anti-GBM (Immune complex deposits)
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