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Vasculitis - Complete Clinical Review
Definition
Vasculitis is a general term for vessel wall inflammation. The two most common pathogenic mechanisms are immune-mediated inflammation and direct vascular invasion by infectious pathogens. Physical/chemical injury (radiation, toxins, trauma) also causes vasculitis. Some 20 primary forms are recognized, classified by vessel size, immune mechanism, autoantibody profile, granuloma formation, organ specificity, and demographics.
- Robbins & Kumar Basic Pathology, p. 328
Classification by Vessel Size
Large-Vessel Vasculitis
Predominantly affects the aorta and its major branches.
| Disease | Key Feature |
|---|---|
| Giant Cell Arteritis | Granulomatous; age >50; temporal/ophthalmic arteries |
| Takayasu Arteritis | Granulomatous; age <50; aortic arch and branches |
Medium-Vessel Vasculitis
Predominantly affects main visceral arteries and their branches; aneurysms and stenoses are common.
| Disease | Key Feature |
|---|---|
| Polyarteritis Nodosa (PAN) | Necrotizing; no ANCA; no pulmonary involvement |
| Kawasaki Disease | Anti-endothelial cell antibodies; coronary arteries; children |
Small-Vessel Vasculitis
Predominantly affects arterioles, capillaries, and venules.
ANCA-associated (pauci-immune):
| Disease | ANCA | Hallmark |
|---|---|---|
| Microscopic Polyangiitis (MPA) | MPO-ANCA | Necrotizing GN + pulmonary capillaritis; no granulomas |
| Granulomatosis with Polyangiitis (GPA / Wegener) | PR3-ANCA (95%) | Upper + lower airway granulomas + GN |
| Eosinophilic GPA (EGPA / Churg-Strauss) | MPO-ANCA (>50%) | Asthma + eosinophilia + granulomatous inflammation |
Immune complex-mediated:
| Disease | Immune Complex |
|---|---|
| IgA Vasculitis (HSP) | IgA deposits |
| Cryoglobulinemic Vasculitis | Cryoglobulin complexes |
| SLE Vasculitis | Nuclear antigen complexes |
| Anti-GBM Disease (Goodpasture) | Anti-GBM antibody |
Pathogenesis
1. Immune Complex Deposition
Immune complexes deposit in vessel walls, activate complement, and recruit neutrophils. Seen in drug hypersensitivity vasculitis (e.g., penicillin), SLE, and HBsAg-associated PAN (up to 30% of PAN cases).
2. ANCA-Associated Mechanisms
ANCAs are autoantibodies directed against neutrophil cytoplasmic antigens. Two main types:
- PR3-ANCA (c-ANCA): Neutrophil azurophilic granule constituent; shares homology with microbial peptides
- MPO-ANCA (p-ANCA): Myeloperoxidase
Pathogenic sequence:
- Drugs or cross-reactive microbial antigens induce ANCA formation
- Inflammatory stimuli (e.g., TNF) upregulate surface expression of PR3/MPO on neutrophils
- ANCAs bind these cytokine-activated cells, causing further neutrophil activation
- ANCA-activated neutrophils release granule contents and reactive oxygen species, injuring endothelial cells
- Lesions are "pauci-immune" - no circulating immune complexes, no antibody/complement in vessel walls
ANCA titers generally mirror clinical severity; a rise after quiescence predicts relapse.
3. Anti-Endothelial Cell Antibodies
Underlie Kawasaki disease.
4. Autoreactive T Cells
Cause granulomatous vasculitis (GCA, Takayasu). Both Th1 (IFN-γ) and Th17 (IL-17) pathways are involved in GCA.
- Robbins & Kumar Basic Pathology, pp. 328-332
Individual Vasculitis Entities
Giant Cell (Temporal) Arteritis
The most common vasculitis in the United States.
Vessels affected: Temporal arteries, ophthalmic arteries, vertebral arteries, aorta.
Risk factors: Age >50, North European descent; strong MHC class II HLA association.
Morphology:
- Patchy granulomatous inflammation of the inner media
- T lymphocytes and macrophages with multinucleate giant cells
- Fragmentation of the internal elastic lamina
- Nodular intimal thickening reducing lumen diameter
- In 25% of cases: non-specific panarteritis without giant cells
Clinical features:
- Fever, fatigue, weight loss
- Facial pain/headache along the temporal artery; tender to palpation
- Ocular symptoms in ~50% (ophthalmic artery involvement) - diplopia to complete vision loss (an ophthalmologic emergency)
- ESR markedly elevated
- Often associated with polymyalgia rheumatica
Diagnosis: Temporal artery biopsy (negative biopsy does not exclude - inflammation is patchy)
Treatment: Corticosteroids (mainstay). Anti-IL-6 receptor therapy (tocilizumab) for steroid-resistant cases; recent evidence supports tocilizumab for glucocorticoid-sparing.
Takayasu Arteritis ("Pulseless Disease")
Vessels: Aorta, aortic arch branches (carotid, subclavian, renal arteries), pulmonary artery.
Demographics: Age <50; young Asian women predominantly.
Morphology: Granulomatous inflammation of the aorta and its main branches; irregular thickening of the aortic wall, intimal wrinkling; "tree-bark" aorta. Lesions histologically resemble GCA.
Clinical features:
- Ocular disturbances (visual field defects, retinal hemorrhage)
- Absent/asymmetric pulses in upper extremities - "pulseless disease"
- Neurologic deficits (syncope, strokes)
- Hypertension (renovascular involvement)
- Pulmonary hypertension
- Systemic inflammation (fever, arthritis, myalgia)
- Pooled prevalence of stroke: 8.9% per meta-analysis
Treatment: Corticosteroids; methotrexate, azathioprine, or biologics as steroid-sparing agents. Vascular surgery/stenting for critical stenoses.
Polyarteritis Nodosa (PAN)
Vessels: Medium and small arteries - spares pulmonary circulation, glomeruli, arterioles, capillaries, and venules (key distinguishing feature from MPA).
Associations: Hepatitis B (HBsAg immune complexes in ~30% of cases). No ANCA.
Morphology:
- Segmental transmural necrotizing inflammation
- Lesions at different stages of development in same patient (unlike MPA)
- Inflammatory aneurysms; thrombosis; infarction of supplied organs
- Healing with fibrous scarring
Clinical features:
- Multisystem disease: kidney (hypertension, hematuria), heart, liver, peripheral nervous system (mononeuritis multiplex)
- GI tract involvement - mesenteric arteritis causing pain/bleeding
- Skin: livedo reticularis, nodules, ulcers, digital infarcts
Treatment: Corticosteroids + cyclophosphamide for severe cases; antiviral therapy (interferon + antivirals) for HBV-associated PAN.
Kawasaki Disease
Demographics: Infants and young children; Asian descent; most common under 5 years.
Pathogenesis: Anti-endothelial cell antibodies. Likely triggered by an uncharacterized infectious agent.
Morphology: Necrotizing arteritis affecting coronary arteries in 80% of symptomatic cases; coronary artery aneurysms (risk of thrombosis and rupture).
Clinical features (mucocutaneous lymph node syndrome):
- Fever >5 days (required)
- Bilateral conjunctival injection (non-purulent)
- Oral changes: strawberry tongue, red cracked lips, pharyngeal erythema
- Rash (polymorphous)
- Extremity changes: erythema/edema of hands/feet, periungual desquamation
- Cervical lymphadenopathy
- Coronary aneurysms in untreated cases - most important complication
Treatment: IV immunoglobulin (IVIG) + aspirin (dramatically reduces coronary aneurysm risk). Infliximab for refractory cases.
Granulomatosis with Polyangiitis (GPA / Wegener)
Vessels: Small to medium vessels; upper and lower respiratory tract + kidneys.
Antibody: PR3-ANCA present in ~95% of cases.
Classic triad:
- Necrotizing granulomas of the upper respiratory tract (sinusitis, nasal septal perforation, "saddle-nose" deformity)
- Necrotizing vasculitis of pulmonary vessels
- Focal necrotizing glomerulonephritis (crescentic GN)
Clinical features:
- Chronic sinusitis, epistaxis, nasal/oral ulcers
- Hemoptysis, dyspnea
- Hematuria, proteinuria (renal failure if untreated)
- Constitutional symptoms
- c-ANCA/PR3-ANCA is the key diagnostic marker
Treatment: Rituximab or cyclophosphamide + glucocorticoids for remission induction. Rituximab or azathioprine/methotrexate for maintenance. Close monitoring mandatory.
Microscopic Polyangiitis (MPA)
Vessels: Capillaries, arterioles, venules (and small arteries) - the smallest vessels.
Antibody: MPO-ANCA (most cases). Pauci-immune (no immune complexes).
Distinguishes from PAN: Affects capillaries/venules; all lesions are the same age; involves pulmonary capillaries and glomeruli (PAN does not).
Morphology: Segmental fibrinoid necrosis; focal transmural necrotizing lesions; leukocytoclastic vasculitis (neutrophil karyorrhexis in postcapillary venules); no granulomas.
Clinical features:
- Palpable purpura (skin, most common)
- Necrotizing GN (90% of patients) - hematuria, proteinuria
- Pulmonary capillaritis - hemoptysis, diffuse alveolar hemorrhage
- Abdominal pain/bleeding; muscle pain; weakness
Treatment: Corticosteroids + cyclophosphamide or rituximab. Remission maintenance with azathioprine/rituximab.
Eosinophilic Granulomatosis with Polyangiitis (EGPA / Churg-Strauss)
Vessels: Small to medium vessels; respiratory tract.
Classic triad: Asthma + eosinophilia + granulomatous vasculitis.
Antibody: MPO-ANCA in >50% (ANCA more frequent when glomerulonephritis is present).
Clinical features:
- Long history of adult-onset asthma
- Peripheral eosinophilia (>10% on differential)
- Mononeuritis multiplex
- Skin lesions; cardiac involvement (eosinophilic myocarditis - major cause of death)
- GN (less common than GPA or MPA)
Treatment: High-dose glucocorticoids; cyclophosphamide for severe/refractory disease. Mepolizumab (anti-IL-5) approved for steroid-sparing in EGPA.
IgA Vasculitis (Henoch-Schönlein Purpura / HSP)
Vessels: Small vessels (IgA immune complex deposits in vessel walls).
Most common systemic vasculitis in children. Often follows a respiratory infection.
Classic tetrad:
- Palpable purpura (lower extremities/buttocks) - non-thrombocytopenic
- Arthralgia/arthritis
- Colicky abdominal pain (GI vasculitis)
- Renal involvement (IgA nephropathy pattern - hematuria/proteinuria)
Pathology: IgA and C3 deposits in small vessel walls on immunofluorescence (identical pattern to IgA nephropathy in the kidney).
Treatment: Mostly self-limiting in children. Supportive care. Corticosteroids for severe GI/renal involvement.
Behçet Disease
Vessels: Any size - veins as well as arteries (one of few vasculitides to prominently involve veins).
Pathogenesis: Strongly associated with HLA-B51. T-cell-mediated with neutrophil hyperactivation.
Clinical features (classic triad):
- Recurrent oral aphthous ulcers (virtually universal)
- Genital ulcers
- Uveitis (may lead to blindness)
Additional features: skin lesions (erythema nodosum, pseudofolliculitis), venous thrombosis, CNS involvement, arthritis.
Pathergy test: Nonspecific skin hyperreactivity to needle prick.
Treatment: Colchicine, azathioprine, cyclosporine, anti-TNF agents for refractory disease.
Shared Clinical Manifestations
Regardless of specific type, vasculitis commonly presents with:
- Constitutional: Fever, malaise, myalgia, arthralgia, weight loss
- Skin: Palpable purpura, livedo reticularis, ulcers, digital infarcts
- Renal: Hematuria, proteinuria, progressive renal failure (glomerulonephritis)
- Neurologic: Mononeuritis multiplex, headache, stroke
- Pulmonary: Hemoptysis, diffuse alveolar hemorrhage, nodules
- GI: Abdominal pain, GI bleeding, bowel infarction
Diagnosis
Laboratory
| Test | Utility |
|---|---|
| ANCA (PR3/MPO) | GPA (PR3), MPA/EGPA (MPO) |
| ESR / CRP | Disease activity marker (markedly elevated in GCA) |
| CBC | Eosinophilia (EGPA), anemia of inflammation |
| Urinalysis | RBC casts, proteinuria (renal vasculitis) |
| Serum creatinine | Renal function |
| HBsAg / HCV antibody | PAN, cryoglobulinemic vasculitis |
| ANA, anti-dsDNA | SLE-associated vasculitis |
| Complement (C3, C4, CH50) | Low in immune-complex vasculitis |
| Cryoglobulins | Cryoglobulinemic vasculitis |
| IgA levels | IgA vasculitis |
Imaging
- Angiography (DSA): Gold standard for medium/large vessel vasculitis; shows stenoses, occlusions, aneurysms. Angiography can be negative in small vessel CNS vasculitis.
- MRA/CTA: Useful for large vessel disease; inferior to DSA for small peripheral vessels
- High-resolution MRI vessel wall imaging: Circumferential vessel wall enhancement in CNS vasculitis
- PET-CT: Inflammatory activity in large vessel vasculitis (GCA, Takayasu)
- CXR/CT chest: Nodules, cavities, diffuse alveolar hemorrhage (GPA, MPA, EGPA)
Biopsy
- Temporal artery biopsy: GCA (skip lesions mean negative biopsy does not exclude)
- Renal biopsy: Necrotizing GN with pauci-immune pattern (ANCA vasculitis)
- Skin biopsy: Leukocytoclastic vasculitis; IgA staining (HSP)
- Brain/meningeal biopsy: Often necessary for primary CNS vasculitis (angiography frequently negative)
- Nasal/sinus biopsy: GPA
Treatment Overview
General Principles
Treatment is guided by disease type, severity, and organ involvement:
- Severe: CNS, cardiac, renal, peripheral nerve - aggressive immunosuppression
- Not severe: Skin/musculoskeletal - may use glucocorticoids alone or watchful waiting
- Always exclude infectious vasculitis before starting immunosuppression
- "Watchful waiting" is appropriate when diagnosis is uncertain, etiology is reversible (drug/toxin), or disease is self-limited
A common error is treating patients too long with high-dose immunosuppressive agents.
Remission Induction
| Drug | Use |
|---|---|
| High-dose glucocorticoids | All severe vasculitis (first-line) |
| Cyclophosphamide | GPA, MPA, EGPA, PAN (severe) |
| Rituximab | GPA, MPA (non-inferior to cyclophosphamide; preferred when fertility preservation matters) |
| IVIG + aspirin | Kawasaki disease |
Remission Maintenance
| Drug | Use |
|---|---|
| Azathioprine | GPA, MPA, EGPA |
| Methotrexate | GPA (mild-moderate) |
| Mycophenolate mofetil (MMF) | Alternative to azathioprine |
| Rituximab | GPA, MPA maintenance |
| Low-dose prednisone | GCA, Takayasu |
Biologic Agents
| Agent | Use |
|---|---|
| Tocilizumab (IL-6R inhibitor) | GCA (glucocorticoid-sparing), Takayasu |
| Mepolizumab (anti-IL-5) | EGPA (eosinophil-targeted) |
| Infliximab (anti-TNF) | Refractory Kawasaki, Behçet |
Monitoring
Vasculitis has high relapse rates. Regular clinical, laboratory, and radiographic monitoring is mandatory - not just at disease onset, but for years after diagnosis. ANCA titers correlate with disease activity; a rising titer predicts relapse.
Infection Prophylaxis
Pneumocystis jiroveci pneumonia (PJP) prophylaxis is required for patients on cyclophosphamide + glucocorticoid regimens.
Cardiovascular Risk
Vasculitis carries significantly increased cardiovascular risk:
-
ANCA-associated vasculitis: 3-fold increased CVD risk; 8-fold increased cerebrovascular event risk
-
GCA / Takayasu: Increased stroke and cardiovascular mortality; meta-analysis shows pooled stroke prevalence of 8.9% in Takayasu
-
Platelet inhibitor use should follow general population guidelines (aspirin for secondary, not primary, CVD prevention)
-
Firestein & Kelley's Textbook of Rheumatology; Robbins & Kumar Basic Pathology, pp. 328-336; Fitzpatrick's Dermatology, p. 2586; Murray & Nadel's Respiratory Medicine
Quick Reference Summary Table
| Vasculitis | Vessel Size | Key Ab/Marker | Classic Feature | Treatment |
|---|---|---|---|---|
| Giant Cell Arteritis | Large | ESR↑, IL-6↑ | Age >50, temporal HA, blindness | Steroids ± tocilizumab |
| Takayasu | Large | ESR↑ | Age <50, pulseless, Asian women | Steroids ± methotrexate |
| PAN | Medium | HBsAg (30%) | No lung, no ANCA, renal/gut infarcts | Steroids ± CYC; antivirals if HBV |
| Kawasaki | Medium | Anti-EC Ab | Children, coronary aneurysms | IVIG + aspirin |
| GPA (Wegener) | Small-Med | PR3-ANCA (95%) | Sinusitis + hemoptysis + GN | Steroids + rituximab/CYC |
| MPA | Small | MPO-ANCA | GN (90%) + pulm capillaritis | Steroids + rituximab/CYC |
| EGPA (Churg-Strauss) | Small-Med | MPO-ANCA (>50%) | Asthma + eosinophilia | Steroids ± mepolizumab |
| IgA Vasculitis (HSP) | Small | IgA deposits | Children: purpura + arthritis + GI | Supportive; steroids if severe |
| Behçet | Variable | HLA-B51 | Oral + genital ulcers + uveitis | Colchicine, azathioprine, anti-TNF |
| Cryoglobulinemic | Small | Cryoglobulins, HCV | Purpura + GN + peripheral neuropathy | Treat HCV; steroids; rituximab |
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