What are the key considerations and treatment options for vasculitis in patients presenting with symptoms such as fever, fatigue, and organ-specific symptoms across various age groups and demographics?

Vasculitis: When to Consider and How to Treat

When to Consider Vasculitis

Suspect vasculitis in patients presenting with constitutional symptoms (fever, fatigue, weight loss >2 kg) combined with organ-specific manifestations, particularly palpable purpura, rapidly progressive renal failure, pulmonary hemorrhage, or multi-system involvement. 1, 2

Key Clinical Red Flags by Vessel Size:

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

• New persistent temporal headache, jaw/tongue claudication, acute visual symptoms (amaurosis fugax, diplopia, acute vision loss) 1
• Limb claudication, absent pulses, blood pressure asymmetry, bruits (particularly axillary) 1
• Tender/thickened temporal arteries with reduced pulsation 1
• Age >50 years for GCA; age ≤40 years for Takayasu arteritis 1
• Elevated ESR/CRP with appropriate clinical context 1

Small-Medium Vessel Vasculitis (ANCA-Associated):

• Rapidly progressive glomerulonephritis: microscopic hematuria with dysmorphic RBCs, red cell casts, proteinuria 1-3 g/day, declining GFR over days-weeks 1
• Pulmonary-renal syndrome: simultaneous lung hemorrhage and acute kidney injury 1
• Upper/lower respiratory tract involvement: sinusitis, nasal crusting, saddle-nose deformity, hemoptysis 1
• Palpable purpura, infiltrated erythema, nodular lesions, livedo racemosa, digital gangrene 2, 3
• Peripheral/central nervous system involvement, ocular manifestations 1

Diagnostic Workup:

Immediate Laboratory Testing:

• ANCA testing (immunofluorescence + antigen-specific immunoassays for MPO and PR3) - 90% sensitive in small-vessel vasculitis 1
• Complete blood count, ESR/CRP, comprehensive metabolic panel, urinalysis with microscopy 1
• Anti-GBM antibodies if pulmonary-renal syndrome present 1

Tissue Diagnosis:

• Biopsy is strongly recommended to confirm diagnosis - diagnostic yield >70% when appropriate site selected 1
• Renal biopsy: 91.5% diagnostic yield in GPA with renal involvement 1
• Temporal artery biopsy/ultrasound for suspected GCA 1
• Skin biopsy extending to subcutis from most tender, purpuric lesion 2
• Direct immunofluorescence to distinguish IgA-associated (Henoch-Schönlein) from IgG/IgM-associated vasculitis 2

Imaging:

• Fast-track imaging within 24 hours for suspected GCA to reduce permanent visual impairment 1
• Cross-sectional imaging for large-vessel involvement assessment 1

How to Treat Vasculitis

ANCA-Associated Vasculitis (GPA/MPA/EGPA):

Disease Severity Stratification (EUVAS Classification): 1

• Localized: Upper/lower respiratory tract only, no systemic symptoms
• Early systemic: Any involvement without organ/life-threatening disease
• Generalized: Renal or organ-threatening disease, creatinine <500 μmol/L
• Severe: Renal/vital organ failure, creatinine >500 μmol/L
• Refractory: Progressive disease despite glucocorticoids and cyclophosphamide

Remission Induction Treatment:

For Generalized/Severe Disease: 1, 4

• Rituximab 375 mg/m² IV weekly × 4 weeks (preferred) OR cyclophosphamide (2 mg/kg/day oral or IV pulses) 1
• High-dose glucocorticoids: 1 mg/kg/day prednisone (max 60-80 mg/day) with pre-specified tapering 1
• IV methylprednisolone 1000 mg/day × 1-3 days for severe presentations 1, 4
• Plasma exchange should be considered for: diffuse alveolar hemorrhage with hypoxemia, anti-GBM antibody-positive disease, or refractory disease 1

For Early Systemic Disease (Non-Organ Threatening): 1

• Methotrexate 20-25 mg/week + glucocorticoids as alternative to cyclophosphamide 1

Remission Maintenance: 1

• Azathioprine 2 mg/kg/day OR methotrexate OR rituximab for 18-24 months minimum 1
• Continue glucocorticoid taper to ≤5 mg/day by 12 months 1

Relapsing Disease: 1

• Reinduction therapy required, preferably with rituximab 1
• If cyclophosphamide used initially, switch to rituximab for relapse (or vice versa) 1

Refractory Disease: 1

• Increase glucocorticoids (IV or oral) 1
• Add rituximab if cyclophosphamide used previously, or vice versa 1
• Consider plasma exchange 1

Large Vessel Vasculitis (GCA/Takayasu):

Immediate Treatment: 1

• High-dose glucocorticoids 40-60 mg/day prednisone-equivalent immediately upon clinical suspicion 1
• Do NOT delay treatment for diagnostic confirmation if acute visual symptoms present - strongest risk factor for permanent blindness 1
• Fast-track referral to specialized center within 24 hours 1

Glucocorticoid Tapering: 1

• Target 15-20 mg/day within 2-3 months 1
• Target ≤5 mg/day for GCA or ≤10 mg/day for Takayasu by 12 months 1

Critical Supportive Measures:

Prophylaxis: 1

• Pneumocystis jiroveci prophylaxis (co-trimoxazole) during immunosuppression 1
• Osteoporosis prophylaxis with calcium, vitamin D, bisphosphonates 1
• Mesna for bladder protection with cyclophosphamide 1

Drug-Induced Vasculitis: 5

• Discontinuation of offending medication (propylthiouracil, TNF inhibitors, tofacitinib) often sufficient for resolution 5

Common Pitfalls to Avoid:

• Do not wait for ANCA results to treat suspected severe vasculitis - 10% are ANCA-negative 1
• Do not delay temporal artery biopsy/imaging for suspected GCA - features may persist weeks after glucocorticoid initiation 1
• Do not use rituximab 500 mg courses for radiographic outcomes - 1000 mg courses demonstrated superior structural protection 4
• Always exclude drug-induced vasculitis, infection (hepatitis B/C), and thrombotic mimics (antiphospholipid syndrome) before committing to immunosuppression 1, 5, 2
• Recognize that vasculitis is a relapsing disease requiring long-term monitoring and patient education for early relapse recognition 1

Refer all patients to specialized vasculitis centers for multidisciplinary management, as outcomes improve with expert care 1