ANCA-Associated Vasculitis: A Practical Guide for the Internist

Dr Neeraj Manikath , claude.ai

Abstract

ANCA-associated vasculitides (AAV) represent a group of life-threatening systemic diseases that demand prompt recognition and treatment. This review provides a systematic approach to diagnosis, classification, and management of AAV, with practical clinical pearls for internists managing these complex patients.

Introduction

ANCA-associated vasculitides comprise granulomatosis with polyangiitis (GPA, formerly Wegener's), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss). These necrotizing vasculitides affect small-to-medium vessels and share the presence of antineutrophil cytoplasmic antibodies, though their clinical presentations differ significantly.

Epidemiology and Pathogenesis

The annual incidence of AAV ranges from 13-20 cases per million, with peak onset in the sixth decade. GPA is more common in Caucasians, while MPA shows higher prevalence in Asian populations.

Pearl #1: The pathogenic role of ANCAs has been conclusively demonstrated. PR3-ANCA and MPO-ANCA directly activate primed neutrophils, causing endothelial damage and vessel wall necrosis. This understanding has revolutionized both diagnosis and targeted therapy.

The current paradigm suggests a "two-hit" mechanism: genetic susceptibility combined with environmental triggers (silica exposure, infections) leads to ANCA production, which then precipitates clinical vasculitis in the presence of additional inflammatory stimuli.

Clinical Recognition: When to Suspect AAV

The Red Flags

Suspect AAV when patients present with:

1. Multisystem involvement affecting kidneys, lungs, and upper airways
2. Rapidly progressive glomerulonephritis (RPGN) with constitutional symptoms
3. Pulmonary-renal syndrome
4. Treatment-resistant sinusitis with systemic features
5. Peripheral neuropathy (mononeuritis multiplex) with systemic illness

Oyster #1: Not all patients present with classic multisystem disease. Up to 30% present with limited disease affecting single organs. A high index of suspicion is crucial.

Organ-Specific Manifestations

Upper Respiratory Tract (predominantly GPA):

• Chronic sinusitis, nasal crusting, epistaxis
• Saddle-nose deformity (septal perforation)
• Subglottic stenosis (2-4% of GPA patients)

Hack #1: In patients with "chronic sinusitis" resistant to antibiotics, always check inflammatory markers and consider ANCA testing. Plain sinus films showing bony destruction suggest vasculitis rather than infection.

Pulmonary Disease:

• Pulmonary nodules (cavitary or non-cavitary)
• Alveolar hemorrhage presenting as hemoptysis, anemia, and diffuse infiltrates
• Pulmonary capillaritis

Pearl #2: The absence of hemoptysis does NOT exclude alveolar hemorrhage. Look for unexplained anemia with falling hemoglobin and new pulmonary infiltrates. Bronchoalveolar lavage showing progressively bloodier returns clinches the diagnosis.

Renal Disease:

• RPGN with hematuria, red cell casts, and rising creatinine
• Typically minimal proteinuria (<1.5g/day) distinguishes it from nephrotic syndrome
• Biopsy shows pauci-immune crescentic glomerulonephritis

Hack #2: Serial creatinine measurements are essential. A doubling of creatinine over 2-4 weeks warrants urgent evaluation. Don't wait for oliguria—by then, significant irreversible damage has occurred.

Neurological Manifestations:

• Mononeuritis multiplex (60% of peripheral neuropathy in AAV)
• Cranial neuropathies
• Pachymeningitis (hypertrophic dura)

Skin and Other Organs:

• Palpable purpura (most common)
• Livedo reticularis, ulcers
• Ocular involvement: scleritis, episcleritis, orbital pseudotumor

Diagnostic Approach: Where and What to Test

Step 1: Initial Laboratory Evaluation

Essential First-Line Tests:

• Complete blood count (anemia, thrombocytosis)
• Comprehensive metabolic panel
• Urinalysis with microscopy (essential—don't rely on dipstick alone)
• Inflammatory markers (ESR, CRP)
• ANCA testing (both immunofluorescence and antigen-specific ELISA)

Pearl #3: Always order BOTH immunofluorescence (IF) and ELISA. IF patterns (c-ANCA, p-ANCA) combined with antigen specificity (PR3, MPO) provide maximum diagnostic accuracy. Approximately 10% of patients are ANCA-negative, particularly those with limited disease.

Step 2: ANCA Testing Interpretation

The Modern Approach:

• PR3-ANCA (c-ANCA pattern): 90% specific for GPA
• MPO-ANCA (p-ANCA pattern): Associated with MPA, less commonly GPA
• ANCA titers correlate poorly with disease activity—don't chase numbers

Oyster #2: A positive ANCA doesn't diagnose vasculitis. ANCAs occur in infections (endocarditis, tuberculosis), inflammatory bowel disease, and drug-induced conditions (propylthiouracil, cocaine adulterated with levamisole). Clinical context is paramount.

Hack #3: In ANCA-negative patients with high clinical suspicion, repeat testing in 2-4 weeks. Some patients seroconvert during disease evolution. Consider alternative diagnoses including anti-GBM disease, lupus, and cryoglobulinemia.

Step 3: Tissue Diagnosis

When Biopsy is Crucial: Tissue confirmation should be pursued in nearly all cases before initiating immunosuppression, unless life-threatening disease necessitates empiric treatment.

Biopsy Site Selection:

1. Kidney: Highest yield (90%), shows pauci-immune crescentic GN
2. Lung: Via bronchoscopy or surgical biopsy for nodules
3. Sinus/nasal: Limited value (only 20% show vasculitis)
4. Skin: High yield for cutaneous lesions

Pearl #4: The histologic triad of necrotizing granulomas, vasculitis, and geographic necrosis is pathognomonic for GPA but seen in only 15% of biopsies. Most specimens show only one or two features.

Step 4: Imaging

Chest CT: Essential for all patients

• Nodules, cavities, infiltrates
• Establishes baseline for monitoring

Sinus CT: For upper airway disease

• Bony erosion suggests vasculitis versus infection

Hack #4: PET-CT is increasingly used to identify occult disease sites and guide biopsy location. Particularly useful in fever of unknown origin with suspected vasculitis.

Disease Activity Assessment

Use validated scoring systems:

• Birmingham Vasculitis Activity Score (BVAS): Quantifies active disease
• Five Factor Score (FFS): Predicts mortality in EGPA and MPA

Pearl #5: The 2022 ACR/EULAR classification criteria provide weighted scores for AAV diagnosis but are designed for clinical trials, not individual diagnosis. Don't rely solely on scoring systems—clinical judgment remains essential.

Treatment: The Step-by-Step Approach

Phase 1: Remission Induction (3-6 months)

Severe/Organ-Threatening Disease:

Standard Regimen:

• Cyclophosphamide 15 mg/kg IV every 2-4 weeks (preferred over daily oral) OR Rituximab 375 mg/m² weekly × 4 doses (or 1g × 2 doses)
• Glucocorticoids: 1 mg/kg/day (max 80mg) prednisone, tapered over 3-6 months
• Pneumocystis prophylaxis (trimethoprim-sulfamethoxazole)

Hack #5: Rituximab is non-inferior to cyclophosphamide and preferred for relapsing disease or in young patients concerned about fertility. The RAVE trial established equivalence, with rituximab showing superiority in relapsing disease.

Plasma Exchange Adjunct: Reserved for:

• Dialysis-requiring renal failure
• Diffuse alveolar hemorrhage
• Combined ANCA and anti-GBM disease

Oyster #3: The PEXIVAS trial showed plasma exchange doesn't reduce death or end-stage renal disease. Use judiciously, primarily for dual-positive (ANCA + anti-GBM) disease or life-threatening alveolar hemorrhage.

Limited Disease (Non-Organ Threatening):

• Methotrexate 20-25 mg weekly + glucocorticoids
• Reserve for patients without renal or pulmonary involvement

Phase 2: Maintenance Therapy (18-24 months minimum)

First-Line Options:

• Rituximab 500 mg every 6 months (preferred based on MAINRITSAN trials)
• Azathioprine 2 mg/kg/day
• Methotrexate 20-25 mg weekly

Pearl #6: The MAINRITSAN2 trial demonstrated rituximab's superiority over azathioprine for maintaining remission (70% vs 42% relapse-free at 28 months). Rituximab is now the gold standard for maintenance.

Glucocorticoid Minimization: Taper to discontinuation by 6 months when possible. Chronic low-dose steroids increase infection and cardiovascular risk without proven benefit.

Phase 3: Monitoring and Relapse Management

Surveillance Schedule:

• Monthly during induction
• Every 3 months during maintenance
• Monitor: CBC, creatinine, urinalysis, inflammatory markers
• ANCA titers: Not for routine monitoring

Hack #6: Clinical and laboratory monitoring trumps ANCA titers. Rising ANCA without clinical/laboratory activity doesn't warrant treatment escalation. Conversely, 10% of relapses occur with negative ANCA.

Relapse Definition:

• Major relapse: Organ-threatening recurrence requiring induction therapy
• Minor relapse: Non-organ threatening, manageable with increased steroids or maintenance agent adjustment

Pearl #7: Relapses are common (50% at 5 years). PR3-ANCA positivity, pulmonary disease, and GPA diagnosis increase relapse risk. Consider extended maintenance (>24 months) in high-risk patients.

Special Scenarios

ANCA-Negative AAV

• 10-20% of patients, more common in limited disease
• Diagnosis requires tissue confirmation
• Treatment identical to ANCA-positive disease

Refractory Disease (5-10% of patients)

• Consider alternative diagnoses
• Options: switch cyclophosphamide to rituximab (or vice versa), add IVIG, or consider avacopan (C5a receptor antagonist)

Oyster #4: The ADVOCATE trial showed avacopan (C5a receptor blocker) as an effective steroid-sparing agent. FDA-approved in 2021, it represents a targeted therapy approach, though cost and limited long-term data require consideration.

Drug-Induced ANCA Vasculitis

• Propylthiouracil, hydralazine, levamisole-adulterated cocaine
• Usually MPO-ANCA positive
• Often resolves with drug discontinuation

Complications and Their Management

Infection Risk: The leading cause of early mortality in AAV. Prophylaxis is essential:

• Pneumocystis: TMP-SMX or alternatives
• Consider antifungal prophylaxis in prolonged immunosuppression
• Vaccinations (inactivated) before or after immunosuppression

Hack #7: Hold rituximab if CD19+ B cells haven't recovered (<0.01 × 10⁹/L) to reduce infection risk, but balance against relapse risk.

Cardiovascular Disease: Two-fold increased risk. Address traditional risk factors aggressively.

Venous Thromboembolism: Consider prophylaxis during active disease and prolonged immobility.

Chronic Kidney Disease: ~25% progress to ESRD. Kidney transplantation is successful after sustained remission (≥12 months).

Prognosis and Long-Term Outcomes

Modern therapy has dramatically improved outcomes:

• 5-year survival: >80%
• Complete remission: 75-90%
• Major causes of death: infection (early), cardiovascular disease (late), active vasculitis

Pearl #8: The "damage" concept is crucial. The Vasculitis Damage Index (VDI) quantifies permanent organ damage from disease or treatment. Once remission is achieved, minimizing damage from therapy becomes the priority.

Conclusion: The Practical Internist's Checklist

When you suspect AAV:

1. Document multisystem involvement
2. Urinalysis (with microscopy) and renal function
3. ANCA testing (IF + ELISA)
4. Chest imaging
5. Pursue tissue diagnosis
6. Early rheumatology/nephrology consultation

When you diagnose AAV:

1. Risk-stratify (organ-threatening vs limited)
2. Choose appropriate induction (rituximab vs cyclophosphamide)
3. High-dose steroids with rapid taper plan
4. Infection prophylaxis
5. Plan maintenance strategy (preferably rituximab)
6. Long-term monitoring protocol

Final Pearl: AAV is no longer the uniformly fatal disease of decades past. With prompt recognition, aggressive initial therapy, and vigilant long-term management, most patients achieve sustained remission and acceptable quality of life. The key is thinking of it early, testing appropriately, and treating decisively.

References

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