What is the classification and treatment approach for vasculitis in patients of different ages, sexes, and ethnicities, with varying medical histories and clinical presentations?

Vasculitis Classification

Primary Classification Framework

Vasculitis classification is fundamentally based on the size of the predominantly affected blood vessels, using the Chapel Hill Consensus Conference (CHCC) definitions in conjunction with American College of Rheumatology (ACR) criteria. 1, 2

The classification system divides vasculitis into three main categories based on vessel caliber:

Large Vessel Vasculitis (LVV)

• Giant Cell Arteritis (GCA): Affects patients >50 years of age, involving the aorta and its first- and second-order branches, particularly extracranial carotid branches including the superficial temporal artery 1, 2
• Takayasu Arteritis (TAK): Predominantly affects young women ≤40 years of age, involving the aorta and main branches, with potential pulmonary and coronary artery involvement 1, 2

Medium Vessel Vasculitis (MVV)

• Polyarteritis Nodosa (PAN): Affects medium and small visceral vessels, particularly renal arteries, with association to hepatitis B virus; presents with subcutaneous nodules and livedo racemosa without glomerulonephritis 1, 2, 3
• Kawasaki Disease: Self-limiting acute necrotizing vasculitis most prevalent in Asian populations <5 years of age, affecting coronary arteries in 15-20% of cases 1, 2

Small Vessel Vasculitis

• ANCA-Associated Vasculitis (AAV): Includes granulomatosis with polyangiitis (GPA/Wegener's), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis 4, 2, 5
• Immune Complex Vasculitis: Includes IgA vasculitis (Henoch-Schönlein purpura) and cryoglobulinemic vasculitis 4, 2, 3

Variable Vessel Vasculitis

• Behçet's Disease and Cogan's Syndrome: Can involve vessels of any size, particularly the aorta 2, 5, 6

Diagnostic Approach by Vessel Size

For Large Vessel Vasculitis

Diagnosis requires imaging confirmation rather than biopsy, as tissue sampling from large vessels is rarely feasible. 1

• CTA or MRA for vessel wall assessment and luminal changes 1
• PET-CT for detecting vessel wall inflammation 1
• Temporal artery ultrasound or biopsy specifically for cranial GCA 1

For Medium and Small Vessel Vasculitis

Biopsy showing typical features (necrotizing vasculitis, granulomatous inflammation, glomerulonephritis) should be obtained in most cases. 1

However, patients without confirmatory biopsy may be classified if they meet either criterion:

1. Specific imaging (angiography, MRI/CT) or surrogate parameters strongly suggest vasculitis, glomerulonephritis, and/or granuloma 1
2. Clinical diagnosis of MPA or GPA with positive anti-PR3/C-ANCA or anti-MPO/P-ANCA 1

Surrogate parameters supporting AAV diagnosis without biopsy include:

• Fixed pulmonary infiltrates/nodules or cavitations 1
• Subglottic stenosis 1
• Retro-orbital granuloma 1
• Red cell casts or dysmorphic erythrocytes in urine 1
• Diffuse alveolar hemorrhage 1
• Mononeuritis multiplex 1
• Episcleritis 1

Essential Laboratory Workup

For ANCA-Associated Vasculitis

ANCA testing using both indirect immunofluorescence and antigen-specific ELISA for MPO and PR3 is mandatory for classification. 1, 4

• Up to 30% of MPA patients are PR3/C-ANCA positive without typical GPA features, so ANCA subtype alone should not determine diagnosis 1
• Serial ANCA measurements should be performed in clinical studies, though insufficient evidence exists for routine clinical monitoring 1

For All Suspected Vasculitis

• Urinalysis for hematuria, proteinuria, or red cell casts indicating renal involvement 4
• Hepatitis B and C serologies to evaluate for cryoglobulinemic vasculitis 4
• CRP and/or ESR as serologic markers of disease activity 1
• Renal function assessment using GFR estimating equations (MDRD or Cockcroft-Gault) 1
• Chest imaging if respiratory symptoms present 4

Disease Activity Classification

Patients must be categorized into clearly defined activity states using standardized terminology: 1

• Remission: BVAS/GPA of 0 and off glucocorticoid therapy 7
• Response: Improvement in disease activity measures
• Refractory disease: Persistent active disease despite treatment
• Relapse: Recurrence of disease activity after remission

Comprehensive disease assessment requires:

• Birmingham Vasculitis Activity Score (BVAS) for disease activity 1
• Disease Extent Index (DEI) for extent of organ involvement 1
• Vasculitis Damage Index (VDI) for permanent damage assessment 1
• Short Form-36 (SF-36) for quality of life measurement 1

Critical Prognostic Considerations

In AAV, 86% of patients develop permanent damage from disease itself and 42% from treatment-related morbidity, including end-stage renal disease, chronic pulmonary dysfunction, diminished hearing, saddle-nose deformities, blindness and death. 1

Strongest predictive factors for mortality include:

• Advanced renal involvement 1
• Cardiomyopathy 1
• Lung hemorrhage 1
• Gut involvement requiring surgery 1
• Male sex 1
• Initial BVAS score 1

Treatment Framework by Disease Severity

For GPA/MPA with Organ-Threatening or Life-Threatening Disease

Induction therapy consists of corticosteroids combined with rituximab (375 mg/m² weekly for 4 weeks) or cyclophosphamide (2 mg/kg daily for 3-6 months). 7

• Rituximab is preferred for relapsing disease 8
• 1000 mg pulse IV methylprednisolone for 1-3 days prior to initial infusion 7
• Oral prednisone 1 mg/kg/day (maximum 80 mg/day) with pre-specified tapering 7
• 64% of rituximab-treated patients achieved complete remission at 6 months versus 53% with cyclophosphamide 7

Maintenance Therapy

Following remission induction, rituximab 500 mg IV every 6 months for 18 months is effective for maintaining remission. 7

Special Population Considerations

Pediatric Patients (6-17 years)

The safety profile in pediatric GPA and MPA patients is consistent with adults, though infusion-related reactions occur in 32% after first infusion, decreasing to 8% by fourth infusion 7

Leukocytoclastic Vasculitis Classification

Distinctions must be made between IgG/IgM-associated and IgA-associated leukocytoclastic vasculitis (Henoch-Schönlein purpura), and between pediatric and adult HSP. 3

• Adult HSP bears the highest risk for complications 3
• IgG/IgM-associated leukocytoclastic vasculitis bears the lowest risk 3
• Approximately 10% of patients with leukocytoclastic vasculitis have underlying systemic vasculitis 4

Secondary Vasculitis

Patients with vasculitis secondary to infections (hepatitis B/C), medications, or systemic diseases (rheumatoid arthritis, systemic lupus erythematosus) should be studied as pathogenetically and clinically separate entities. 1, 2

Common Pitfalls

ACR classification criteria significantly underperform in classifying large-vessel GCA, as they were developed before modern imaging techniques and ANCA testing. 1, 9

Classification criteria are not suitable for primary diagnosis of vasculitis—they distinguish between different forms once vasculitis is established, but do not diagnose vasculitis itself. 1

ANCA-negative patients should not be excluded from AAV diagnosis if clinical presentation and biopsy are compatible, as up to 10-20% of AAV patients may be ANCA-negative. 1