What is the approach to diagnosing and treating vasculitis in a patient presenting with symptoms such as fever, fatigue, weight loss, or skin lesions?

Diagnostic Approach to Vasculitis

When vasculitis is suspected based on fever, fatigue, weight loss, or skin lesions, immediately obtain ANCA testing (both indirect immunofluorescence and antigen-specific ELISA for MPO and PR3), inflammatory markers (ESR/CRP), complete blood count, comprehensive metabolic panel, and urinalysis with microscopy—then pursue tissue biopsy of the most affected organ while simultaneously initiating high-dose glucocorticoids (40-60 mg/day prednisone-equivalent) if clinical suspicion is high and the patient has organ-threatening disease. 1, 2

Initial Clinical Assessment

Key Clinical Features by Vessel Size

Large Vessel Vasculitis (Giant Cell Arteritis/Takayasu Arteritis):

• New-onset persistent localized headache (often temporal), constitutional symptoms (weight loss >2 kg, low-grade fever, fatigue, night sweats), jaw/tongue claudication, acute visual symptoms (amaurosis fugax, acute visual loss, diplopia), limb claudication 1
• Physical examination: temporal artery tenderness/thickening with reduced pulsation, scalp tenderness, bruits (particularly axillary), reduced pulses/blood pressure in upper limbs, hypertension (>140/90 mmHg), new loss of pulses, pulse inequality, carotidynia 1

Small Vessel Vasculitis (ANCA-Associated):

• Palpable purpura, infiltrated erythema, nodular erythema, livedo racemosa, deep ulcers, or digital gangrene 3
• Renal involvement (hematuria, proteinuria, red cell casts), pulmonary involvement (hemoptysis, infiltrates), upper/lower respiratory tract disease 1

Essential Laboratory Evaluation

Immediate laboratory workup must include: 2, 4

• ANCA testing: Use antigen-specific immunoassays (MPO-ANCA and PR3-ANCA ELISA) as the preferred screening methodology rather than indirect immunofluorescence alone, as they have higher diagnostic accuracy 1, 2
• Inflammatory markers: ESR and CRP (though nonspecific and cannot distinguish vasculitis activity from infection) 1
• Complete blood count with differential: Assess for anemia, leukocytosis, thrombocytosis, or cytopenias 2, 4
• Comprehensive metabolic panel: Including serum creatinine to evaluate renal function 2, 4
• Urinalysis with microscopy: Critical at every visit to detect hematuria, proteinuria, and red cell casts suggesting glomerulonephritis 1, 2, 4
• Anti-nuclear antibodies (ANA): To assess for connective tissue diseases that can present with secondary vasculitis 2, 4

Critical caveat: Approximately 10% of patients with ANCA-associated vasculitis are ANCA-negative, requiring tissue biopsy for definitive diagnosis. 5, 2, 4 Normal ESR/CRP should raise suspicion for an alternative diagnosis in suspected giant cell arteritis. 1

Imaging Studies

Large vessel vasculitis:

• Temporal artery ultrasound shows 88% sensitivity and 97% specificity for diagnosing giant cell arteritis 1, 2
• MRI/MRA or PET can assist diagnosis and document extent of arterial involvement in Takayasu arteritis, though these require formal validation 1
• Conventional angiography should be considered when advanced imaging is unavailable 1

Small vessel vasculitis:

• Chest imaging (X-ray or CT) to evaluate for pulmonary involvement, granulomas, infiltrates, or cavitary lesions 2, 4
• MRI brain for suspected CNS vasculitis (abnormal in >90% of cases) 2

Important limitation: Cerebral angiography has low specificity with significant overlap with atherosclerosis and reversible cerebral vasoconstriction syndrome; small-vessel vasculitis may present with normal angiograms. 5

Tissue Biopsy Strategy

Biopsy is the gold standard but has critical limitations: 1, 5

• For giant cell arteritis: Temporal artery biopsy should be performed whenever diagnosis is suspected, but this should not delay treatment; obtain at least 1 cm length to enable examination of multiple sections 1
• For small vessel vasculitis: Target biopsy to areas demonstrably abnormal on imaging; kidney biopsy provides both diagnostic and prognostic information with diagnostic yield over 70% 1, 2
• Biopsy technique: Extend to subcutis from the most tender, reddish or purpuric lesional skin; serial sections often required for identifying the main vasculitic lesion 3
• Direct immunofluorescence: Perform concomitant biopsy to distinguish IgA-associated vasculitis (Henoch-Schönlein purpura) from IgG-/IgM-associated vasculitis 3

Critical pitfall: A negative biopsy does not exclude vasculitis due to the focal, patchy nature of vascular inflammation; biopsy yield varies significantly by organ sampled and operator skill. 5 Treatment with glucocorticoids prior to biopsy is unlikely to affect results if biopsy is performed within 1-2 weeks. 1

Treatment Initiation Algorithm

When to Start Treatment Before Biopsy Confirmation

Immediate treatment (40-60 mg/day prednisone-equivalent) is indicated when: 1, 2

1. Giant cell arteritis with visual symptoms: Patients with typical symptoms, increased CRP/ESR, and acute visual disturbance should be treated immediately, as delaying glucocorticoid therapy when visual loss is present is the strongest risk factor for permanent blindness 1

2. Suspected large vessel vasculitis without visual symptoms: High-dose glucocorticoids should be commenced on strong clinical suspicion prior to biopsy due to risk of irreversible ocular involvement 1

3. ANCA-positive small vessel vasculitis with organ-threatening disease: In patients with positive PR3-ANCA or MPO-ANCA serology and clinical presentation compatible with small-vessel vasculitis, start immunosuppressive therapy immediately without waiting for biopsy results, especially if rapidly deteriorating 2

Disease Categorization for Treatment Planning

Categorize ANCA-associated vasculitis patients into: 2

• Localized: Upper/lower respiratory tract disease without systemic involvement
• Early systemic: Any manifestation without organ-threatening disease
• Generalized: Renal or organ-threatening disease with serum creatinine <500 μmol/L (5.6 mg/dL)
• Severe: Renal or vital organ failure with serum creatinine >500 μmol/L (5.6 mg/dL)
• Refractory: Progressive disease unresponsive to glucocorticoids and cyclophosphamide

Specific Treatment Recommendations

Large vessel vasculitis (Giant Cell Arteritis/Takayasu Arteritis):

• Initiate high-dose glucocorticoids (40-60 mg/day prednisone-equivalent) immediately 1, 2
• Taper to 15-20 mg/day within 2-3 months, then to ≤5 mg/day (GCA) or ≤10 mg/day (TAK) after 1 year 1
• Add tocilizumab for refractory/relapsing disease or patients at increased risk for glucocorticoid-related adverse events 2
• For Takayasu arteritis specifically, give non-biological glucocorticoid-sparing agents in combination with glucocorticoids to all patients 2

ANCA-associated vasculitis (generalized or severe disease):

• Initiate combination therapy with glucocorticoids (1 mg/kg/day, maximum 60 mg/day) plus either rituximab or cyclophosphamide 2, 6
• Prefer cyclophosphamide when severe glomerulonephritis with serum creatinine >4 mg/dL (>354 μmol/L) 2
• Prefer rituximab (375 mg/m² once weekly for 4 weeks) for younger patients with fertility concerns, relapsing disease, or PR3-ANCA positive disease 2, 6

Mandatory Referral and Monitoring

All patients with suspected vasculitis must be referred to centers with vasculitis expertise for multidisciplinary management. 1, 5, 2, 4 The rarity of primary systemic vasculitis makes it difficult to maintain expertise, and specialized centers provide access to rapid biopsy interpretation and advanced imaging. 5, 2

For suspected giant cell arteritis: Referral to a specialized centre ("fast-track clinic") for diagnostic work-up within 24 hours can reduce the rate of permanent visual impairment. 1

Ongoing monitoring should include: 2

• Urinalysis at every clinic visit to screen for infection, renal relapse
• Inflammatory markers and renal function every 1-3 months
• Complete blood count and liver function tests at similar intervals to screen for drug toxicity