Vasculitis

Definition and epidemiology

Vasculitis is defined by inflammation and necrosis of blood vessel walls, leading to vessel damage, stenosis, thrombosis, aneurysm formation, or rupture. The resulting clinical manifestations depend on the size, location, and distribution of affected vessels.

The Chapel Hill Consensus Conference (CHCC) classification organizes vasculitides by predominant vessel size:

Large-vessel vasculitis:

• Giant cell arteritis (GCA): most common systemic vasculitis in adults >50 years; incidence 15-25 per 100,000, higher in Northern European populations
• Takayasu arteritis (TAK): affects women <40 years in 80-90% of cases; more common in Asia, India, and Latin America

Medium-vessel vasculitis:

• Polyarteritis nodosa (PAN): rare, affects adults in 4th-6th decade
• Kawasaki disease (KD): most common vasculitis in children; peak age 1-2 years, more common in Asian populations

Small-vessel vasculitis:

• ANCA-associated vasculitis (AAV): includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA); annual incidence 10-20 per million
• Immune complex vasculitis: includes IgA vasculitis (Henoch-Schönlein purpura), cryoglobulinemic vasculitis, and anti-GBM disease

Overall prevalence of systemic vasculitis is approximately 40-50 per 100,000. Many forms affect adults, but IgA vasculitis and Kawasaki disease predominantly affect children.

Etiology and risk factors

Vasculitis can be primary (idiopathic) or secondary to infection, drugs, malignancy, or connective tissue disease.

Primary vasculitis risk factors:

• Genetic predisposition: HLA-B51 in Behçet disease, certain HLA-DR alleles in GCA
• Age: GCA >50 years, TAK <40 years
• Sex: female predominance in TAK and GCA; male predominance in PAN and Kawasaki disease
• Ethnicity: higher GCA in Northern Europeans, higher TAK in Asians, higher Kawasaki in East Asians

Secondary vasculitis triggers:

Infections:

• Hepatitis B: associated with PAN (10-30% of PAN cases historically)
• Hepatitis C: most common cause of cryoglobulinemic vasculitis (>80% of cases)
• HIV, parvovirus B19, CMV: various vasculitic syndromes
• Post-streptococcal: IgA vasculitis trigger in children

Drugs:

• Hydralazine, propylthiouracil, minocycline: drug-induced ANCA-associated vasculitis
• Cocaine (especially levamisole-contaminated): cutaneous vasculitis with ANCA positivity
• Penicillins, cephalosporins, NSAIDs: hypersensitivity vasculitis

Autoimmune diseases:

• Systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome: secondary vasculitis in 10-30%

Malignancy:

• Paraneoplastic vasculitis: hematologic malignancies (especially hairy cell leukemia with PAN-like picture)

Most primary vasculitides have no identifiable trigger and are thought to result from dysregulated immune responses in genetically predisposed individuals.

Pathophysiology

Vasculitis pathogenesis involves immune-mediated vessel wall injury through multiple mechanisms:

ANCA-associated vasculitis

Anti-neutrophil cytoplasmic antibodies (ANCA) activate primed neutrophils, causing degranulation and release of reactive oxygen species and proteases. Two main patterns:

• c-ANCA (PR3-ANCA): targets proteinase-3; classic for GPA
• p-ANCA (MPO-ANCA): targets myeloperoxidase; typical of MPA and EGPA

Activated neutrophils adhere to vessel walls, undergo NETosis (neutrophil extracellular trap formation), and cause necrotizing inflammation. The alternative complement pathway (especially C5a) amplifies neutrophil activation.

Immune complex-mediated vasculitis

Deposition of antigen-antibody complexes in vessel walls activates complement, recruits inflammatory cells, and causes leukocytoclastic vasculitis. Classic histologic finding: neutrophil infiltration with nuclear debris (leukocytoclasis). Examples include IgA vasculitis (IgA-dominant deposits) and cryoglobulinemic vasculitis (cryoglobulin-containing complexes).

Large-vessel vasculitis

GCA and TAK involve granulomatous inflammation of the vessel wall, likely initiated by dendritic cells presenting vessel wall antigens to CD4+ T cells. Activated T cells drive macrophage and giant cell formation in the media and adventitia. Intimal hyperplasia leads to stenosis; medial destruction can cause aneurysm.

Direct antibody-mediated injury

Anti-GBM disease: antibodies against type IV collagen in basement membranes cause pulmonary hemorrhage and glomerulonephritis.

All pathways converge on vessel wall inflammation → endothelial injury → thrombosis, hemorrhage, or ischemia → end-organ damage. The clinical syndrome reflects which organs' vessels are affected.

Clinical features

Vasculitis presentations vary by vessel size and organs involved. Constitutional symptoms (fever, weight loss, malaise) are common to most systemic forms.

Large-vessel vasculitis

Giant cell arteritis:

• Headache (often temporal), scalp tenderness
• Jaw claudication (chewing pain), tongue claudication
• Visual symptoms: transient monocular vision loss (amaurosis fugax), diplopia, irreversible blindness if untreated (anterior ischemic optic neuropathy)
• Polymyalgia rheumatica in 40-60%: shoulder and hip girdle pain and stiffness
• Temporal artery: thickened, tender, non-pulsatile

Takayasu arteritis:

• Limb claudication, pulse discrepancies ("pulseless disease")
• Blood pressure discrepancies between arms (>10 mmHg)
• Vascular bruits (subclavian, carotid)
• Hypertension (renal artery stenosis), aortic regurgitation
• Retinopathy, stroke, myocardial ischemia in advanced disease

Medium-vessel vasculitis

Polyarteritis nodosa:

• Cutaneous: livedo reticularis, subcutaneous nodules, ulcers
• Renal: hypertension, renal infarcts (NO glomerulonephritis—distinguishes from AAV)
• GI: postprandial abdominal pain (mesenteric ischemia), GI bleeding, perforation
• Neurologic: mononeuritis multiplex (asymmetric peripheral neuropathy), stroke
• Cardiac: coronary arteritis, myocardial infarction

Kawasaki disease:

• High fever >5 days, bilateral non-exudative conjunctivitis, oral mucositis (strawberry tongue, cracked lips)
• Polymorphous rash, erythema and edema of hands/feet with subsequent desquamation
• Cervical lymphadenopathy
• Coronary artery aneurysms (most serious complication, 25% if untreated)

Small-vessel vasculitis

Granulomatosis with polyangiitis (GPA):

• Upper respiratory: chronic sinusitis, nasal crusting, septal perforation (saddle-nose deformity)
• Lower respiratory: pulmonary nodules, infiltrates, alveolar hemorrhage (hemoptysis, dyspnea)
• Renal: rapidly progressive glomerulonephritis (RPGN), hematuria, proteinuria, renal failure
• Classic triad: upper airway + lung + kidney

Microscopic polyangiitis (MPA):

• Pulmonary-renal syndrome: alveolar hemorrhage + RPGN
• NO upper airway involvement (vs. GPA)
• NO granulomas on biopsy (vs. GPA)

Eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss):

• Asthma (often adult-onset, severe)
• Eosinophilia (>10% or >1,500/μL)
• Sinusitis, pulmonary infiltrates
• Mononeuritis multiplex, myocarditis (major cause of mortality)
• ANCA positive in only 40-60%

IgA vasculitis (Henoch-Schönlein purpura):

• Palpable purpura on lower extremities and buttocks (mandatory feature)
• Arthritis/arthralgia (knees, ankles)
• Abdominal pain, GI bleeding (intussusception in children)
• IgA nephropathy (hematuria, proteinuria)
• Mostly children, often post-URI

Cryoglobulinemic vasculitis:

• Palpable purpura, arthralgias, weakness
• Peripheral neuropathy, glomerulonephritis
• Associated with hepatitis C in majority

Common cutaneous manifestations across types

• Palpable purpura (small-vessel involvement)
• Livedo reticularis (medium-vessel)
• Digital ischemia/gangrene
• Ulcers, nodules

Diagnosis

Diagnosis requires integration of clinical features, laboratory findings, imaging, and often histopathology.

Laboratory investigations

Inflammatory markers:

• ESR and CRP: elevated in most active vasculitides (ESR often >50 mm/hr in GCA)
• Complete blood count: anemia of chronic disease, leukocytosis, thrombocytosis (GCA), eosinophilia (EGPA)

Autoantibodies:

• ANCA testing: immunofluorescence (c-ANCA, p-ANCA) plus antigen-specific ELISA (PR3, MPO)
• GPA: c-ANCA (PR3) in 85-90%
• MPA: p-ANCA (MPO) in 60-80%
• EGPA: p-ANCA (MPO) in 40-60%
• Cryoglobulins: for cryoglobulinemic vasculitis
• Anti-GBM antibodies: for anti-GBM disease
• ANA, RF, complement (C3, C4): to assess for secondary vasculitis

Organ-specific tests:

• Urinalysis: RBC casts (glomerulonephritis), proteinuria
• Renal function: creatinine, BUN
• Hepatitis B and C serology
• Chest X-ray: pulmonary infiltrates, nodules, hemorrhage

Imaging

Large-vessel vasculitis:

• CT angiography or MR angiography: vessel wall thickening, stenosis, aneurysms; preferred for TAK
• PET-CT: increased FDG uptake in inflamed vessel walls; useful for GCA and TAK
• Doppler ultrasound: "halo sign" (hypoechoic wall thickening) in temporal arteries for GCA
• Conventional angiography: shows stenoses, aneurysms, vessel irregularity in PAN and TAK

Medium/small-vessel vasculitis:

• Chest CT: nodules, infiltrates, hemorrhage in GPA/MPA
• Echocardiography: coronary artery assessment in Kawasaki disease

Histopathology

Biopsy is gold standard when accessible:

• Temporal artery biopsy: for GCA; shows transmural granulomatous inflammation, giant cells, fragmented internal elastic lamina; requires adequate length (≥1 cm) due to skip lesions
• Kidney biopsy: for AAV and immune complex vasculitis; shows necrotizing glomerulonephritis (pauci-immune in AAV, immune deposits in IgA vasculitis)
• Skin biopsy: shows leukocytoclastic vasculitis; immunofluorescence can identify IgA deposits (IgA vasculitis)
• Lung biopsy: in GPA shows necrotizing granulomas, vasculitis; rarely needed if clinical picture and ANCA strongly suggest diagnosis
• Nerve/muscle biopsy: for suspected PAN or mononeuritis multiplex

Diagnostic criteria

American College of Rheumatology (ACR) criteria and CHCC definitions guide classification. Key points:

• GCA: age >50, new headache, temporal artery abnormality, ESR >50, positive biopsy (3 of 5 criteria)
• GPA: nasal/oral inflammation, abnormal chest X-ray, urinary sediment, granulomatous inflammation on biopsy (2 of 4 criteria in ACR; modern diagnosis often based on ANCA + typical features)
• Kawasaki: fever ≥5 days plus 4 of 5 principal features (conjunctivitis, oral changes, rash, extremity changes, lymphadenopathy)

Biopsy is not always required if clinical and serologic features are classic, especially when biopsy carries significant risk or would delay critical treatment (e.g., GCA with vision loss).

Differential diagnosis

The differential depends on the presentation pattern:

Systemic illness with multiorgan involvement

• Systemic lupus erythematosus: ANA positive, low complement, malar rash, serositis
• Endocarditis: positive blood cultures, cardiac murmur, embolic phenomena
• Thrombotic thrombocytopenic purpura (TTP): microangiopathic hemolytic anemia, thrombocytopenia, fever, renal dysfunction, neurologic changes; schistocytes on smear
• Antiphospholipid syndrome: arterial/venous thrombosis, recurrent miscarriage, positive aPL antibodies
• Sepsis/disseminated intravascular coagulation: prolonged PT/PTT, low fibrinogen, elevated D-dimer

Pulmonary-renal syndrome

• Goodpasture syndrome (anti-GBM disease): anti-GBM antibodies, linear IgG on kidney biopsy
• Systemic lupus erythematosus: ANA, anti-dsDNA, low complement
• Infection: pneumonia with acute kidney injury from sepsis or ATN

Palpable purpura

• Hypersensitivity vasculitis: drug-induced, self-limited, confined to skin
• Septic emboli: endocarditis, gonococcemia (associated pustules)
• Thrombocytopenia: petechiae rather than palpable purpura, no vessel inflammation
• Cholesterol emboli: livedo reticularis, eosinophilia, post-vascular procedure

Peripheral neuropathy

• Diabetic neuropathy: symmetric, distal, gradual onset
• Guillain-Barré syndrome: ascending, areflexia, post-infectious
• Lyme disease: history of tick bite, erythema migrans, positive serology
• Amyloidosis: systemic features, carpal tunnel syndrome, Congo red staining

Temporal headache in elderly

• Migraine/tension headache: no systemic symptoms, normal ESR
• Intracranial mass: focal neurologic signs, imaging shows lesion
• Temporal arteritis (GCA): elevated ESR/CRP, jaw claudication, visual symptoms

Stroke/TIA in young patient

• Atherosclerosis: risk factors (smoking, hypertension, dyslipidemia)
• Cardiac embolism: atrial fibrillation, valvular disease, PFO
• Dissection: trauma, connective tissue disorder
• Hypercoagulable state: protein C/S deficiency, Factor V Leiden, malignancy
• Vasculitis (TAK, primary CNS vasculitis): inflammatory markers, angiography findings

Management

Treatment depends on vasculitis type, severity, and organ involvement. General principles include inducing remission with immunosuppression, then maintaining remission with less toxic agents. Specific drug doses are not given here; dosing follows current guideline protocols and should be individualized.

Giant cell arteritis

Immediate treatment:

• High-dose glucocorticoids (oral, or intravenous pulse glucocorticoids if vision loss is present)
• Start treatment immediately if clinical suspicion is high; do not delay for biopsy (biopsy remains diagnostic for weeks after starting steroids)

Maintenance:

• Gradual taper over 12-18 months, guided by symptoms and inflammatory markers
• Tocilizumab (IL-6 inhibitor): steroid-sparing agent, allows faster taper and reduces relapses
• Low-dose aspirin for vascular protection
• Bone protection: calcium, vitamin D, bisphosphonate if prolonged steroid use anticipated

Takayasu arteritis

Induction:

• Weight-based glucocorticoids, tapered over months
• Add methotrexate, azathioprine, or mycophenolate mofetil for steroid-sparing
• Biologic agents (tocilizumab, TNF inhibitors) for refractory disease

Revascularization:

• Surgical bypass or angioplasty for critical stenoses, preferably during inactive disease phase
• Antiplatelet therapy

ANCA-associated vasculitis (GPA, MPA, EGPA)

Severe/organ-threatening disease (renal, pulmonary hemorrhage, CNS):

Induction (3-6 months):

• Glucocorticoids: intravenous pulse glucocorticoids followed by oral weight-based glucocorticoids, then tapered
• Cyclophosphamide (pulse IV or daily oral) OR rituximab (both equally effective; rituximab preferred by many due to better toxicity profile)
• Plasma exchange: considered for severe renal disease or diffuse alveolar hemorrhage (benefit debated in recent trials)

Maintenance (18-24 months minimum):

• Rituximab (periodic re-dosing) OR azathioprine OR methotrexate
• Low-dose glucocorticoids, tapered to discontinuation if possible

Non-severe/limited disease (no organ-threatening features):

• Glucocorticoids plus methotrexate or mycophenolate mofetil
• Rituximab for relapsing disease

Adjunctive:

• Trimethoprim-sulfamethoxazole for GPA to prevent infections and possibly reduce relapses
• Pneumocystis jirovecii prophylaxis during intensive immunosuppression

Polyarteritis nodosa

HBV-negative PAN:

• Glucocorticoids plus cyclophosphamide for severe disease
• Glucocorticoids alone or plus methotrexate/azathioprine for milder disease

HBV-associated PAN:

• Short-course glucocorticoids plus plasma exchange
• Antiviral therapy (tenofovir or entecavir) to treat underlying HBV
• Avoid prolonged immunosuppression (can worsen viral replication)

Kawasaki disease

Acute phase (first 10 days of fever):

• Intravenous immunoglobulin (IVIG): single infusion, given within 10 days of fever onset
• High-dose aspirin: anti-inflammatory dose during acute phase, then low-dose for antiplatelet effect
• Reduces coronary aneurysm risk from 25% to <5%

Refractory disease (persistent fever after IVIG):

• Second IVIG dose, or infliximab, or glucocorticoids

Follow-up:

• Echocardiography to monitor for coronary aneurysms
• Long-term aspirin if aneurysms present

IgA vasculitis (Henoch-Schönlein purpura)

Mild disease (rash, arthritis, mild abdominal pain):

• Supportive care: hydration, NSAIDs for arthritis
• Usually self-limited in 4-6 weeks

Severe abdominal or renal involvement:

• Glucocorticoids
• Immunosuppression (cyclophosphamide, mycophenolate) for severe nephritis

Cryoglobulinemic vasculitis

HCV-associated (most common):

• Treat underlying hepatitis C with direct-acting antivirals (DAAs)
• Rituximab for severe vasculitis (cryoglobulin levels often drop with HCV clearance)

Severe disease:

• Plasma exchange, rituximab, glucocorticoids

Monitoring and supportive care

• Regular monitoring of inflammatory markers, ANCA titers (trends, not absolute values), renal function, urinalysis
• Cardiovascular risk modification
• Infection surveillance (major cause of morbidity/mortality)
• Vaccination (before starting rituximab if possible; avoid live vaccines during immunosuppression)
• Address steroid adverse effects: bone density, glucose, blood pressure, mood

Complications and prognosis

Acute complications

Organ-threatening:

• Irreversible blindness (GCA): occurs in 15-20% if untreated; rarely bilateral if treatment started promptly
• Renal failure (AAV, anti-GBM): dialysis dependence in 20-30% of severe cases; early treatment critical
• Pulmonary hemorrhage (AAV, anti-GBM): life-threatening; mortality 10-30% in severe cases
• Stroke (large-vessel vasculitis, CNS vasculitis)
• Myocardial infarction (coronary arteritis, Kawasaki disease, GCA, TAK)
• Bowel perforation (PAN, IgA vasculitis with severe GI involvement)
• Peripheral gangrene (digital ischemia requiring amputation)

Infection:

• Leading cause of early mortality in AAV, due to intense immunosuppression combined with vasculitis-related immune dysfunction
• Opportunistic infections: Pneumocystis jirovecii pneumonia, cytomegalovirus, fungal infections

Chronic complications

Disease-related:

• Chronic kidney disease or end-stage renal disease
• Chronic respiratory impairment from lung fibrosis (GPA, EGPA)
• Cardiovascular disease from vessel damage and chronic inflammation
• Peripheral neuropathy (often incompletely reversible)
• Hearing loss, chronic sinusitis, saddle-nose deformity (GPA)
• Limb claudication, vascular stenoses (TAK, GCA)

Treatment-related:

• Glucocorticoid toxicity: osteoporosis, fractures, diabetes, hypertension, cataracts, avascular necrosis
• Cyclophosphamide: hemorrhagic cystitis, bladder cancer, infertility, myelodysplasia
• Rituximab: hypogammaglobulinemia, progressive multifocal leukoencephalopathy (rare)
• Infection (all immunosuppressants)

Relapse:

• AAV: 30-50% relapse within 5 years, especially after stopping maintenance therapy
• GCA and TAK: relapses common during steroid taper
• Monitoring for relapse requires clinical vigilance plus laboratory and imaging surveillance

Prognosis

Overall:

• Prognosis has improved dramatically with modern immunosuppression. Historically, untreated systemic vasculitis had >80% 1-year mortality; now 5-year survival exceeds 70-80% for most forms.

By vasculitis type:

GCA:

• Excellent prognosis if treated promptly; mortality not increased vs. age-matched controls
• Vision loss is preventable with early treatment
• Aortic aneurysm risk increased long-term (requires surveillance)

TAK:

• Variable; 5-year survival >95% but significant morbidity from vascular complications
• Outcomes depend on extent of vascular damage at diagnosis and disease activity control

AAV (GPA, MPA, EGPA):

• 5-year survival 75-85% with treatment
• Poor prognostic factors: older age, renal failure at presentation, pulmonary hemorrhage, cardiac involvement
• Five-Factor Score (FFS) predicts mortality: includes renal insufficiency, proteinuria >1 g/day, cardiomyopathy, GI involvement, CNS involvement

PAN:

• Untreated 5-year survival <15%; with treatment, 5-year survival >80%
• Poor prognosis with renal, cardiac, GI, or CNS involvement

Kawasaki disease:

• Excellent prognosis if IVIG given within 10 days: <1% mortality
• Coronary aneurysms in <5% with treatment (25% without)
• Giant aneurysms (>8 mm) carry risk of thrombosis and myocardial infarction

IgA vasculitis:

• Self-limited in most children; 95% full recovery
• Renal involvement in 20-50%: 1-2% progress to ESRD
• Adults have worse renal prognosis than children

Key predictors of poor outcome across vasculitides:

• Delayed diagnosis and treatment
• Renal failure at presentation
• Pulmonary hemorrhage
• Cardiac or CNS involvement
• Older age
• Infection during treatment

Practice questions

Frequently asked questions

Key drugs

Related conditions and differentials

Sources and further reading

StatPearls (NCBI Bookshelf)MedlinePlusWHO ICD-10: M31

Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.