Anca Associated Vasculitis

Overview

• Definition: ANCA-associated vasculitis (AAV) refers to a group of systemic autoimmune diseases characterized by necrotizing inflammation of small-to-medium-sized blood vessels, with few or no immune deposits, and the presence of circulating autoantibodies against neutrophil cytoplasmic antigens (ANCAs). The three main types are Granulomatosis with Polyangiitis (GPA), Microscopic Polyangiitis (MPA), and Eosinophilic Granulomatosis with Polyangiitis (EGPA, formerly Churg-Strauss syndrome).

• Epidemiology:

  • Incidence: Varies geographically, generally 10-20 cases per million per year.
  • Prevalence: Approximately 40-100 cases per million.
  • Age: Can occur at any age, but most common in individuals aged 50-70 years.
  • Sex: No significant sex predilection, though GPA may have a slight male predominance, and EGPA a slight female predominance.
  • Race/Ethnicity: More common in Caucasian populations, less common in individuals of African or Asian descent.

• Classification:

  • Granulomatosis with Polyangiitis (GPA): Formerly Wegener's granulomatosis. Characterized by necrotizing granulomatous inflammation of the upper and lower respiratory tracts, necrotizing vasculitis affecting small to medium-sized vessels (capillaries, venules, arterioles, rarely small arteries), and frequently necrotizing glomerulonephritis. Typically associated with PR3-ANCA (cANCA pattern).
  • Microscopic Polyangiitis (MPA): Necrotizing vasculitis affecting small vessels, particularly capillaries, venules, and arterioles, with few or no immune deposits. Necrotizing glomerulonephritis and pulmonary capillaritis are common. Typically associated with MPO-ANCA (pANCA pattern). Granulomatous inflammation is absent.
  • Eosinophilic Granulomatosis with Polyangiitis (EGPA): Formerly Churg-Strauss syndrome. Characterized by eosinophil-rich granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small-to-medium-sized vessels, associated with asthma and eosinophilia. Neuropathy, cardiac involvement, and skin lesions are common. Approximately 30-40% of patients are MPO-ANCA positive.
  • Renal-limited vasculitis: A variant presenting solely with glomerulonephritis.
  • Drug-induced AAV: Rare, often associated with propylthiouracil, hydralazine, minocycline, d-penicillamine, and allopurinol.

Pathophysiology

• Mechanism: AAV is primarily an autoimmune disease where ANCAs play a key pathogenic role.

  • Neutrophil Priming: Pro-inflammatory cytokines (e.g., TNF-alpha, IL-1beta) circulating during infections or inflammation prime neutrophils, causing ANCA antigens (proteinase 3 [PR3] or myeloperoxidase [MPO]) to translocate from intracellular granules to the cell surface.
  • ANCA Binding: ANCAs bind to these surface-expressed antigens on primed neutrophils.
  • Neutrophil Activation: ANCA binding triggers neutrophil activation, leading to:
    • Degranulation and release of proteolytic enzymes (e.g., PR3, MPO) and reactive oxygen species (ROS), which damage endothelial cells.
    • Upregulation of adhesion molecules (e.g., CD11b/CD18), promoting neutrophil adherence to the endothelium.
    • Formation of neutrophil extracellular traps (NETs), which contribute to inflammation and expose ANCA antigens.
  • Endothelial Damage: Activated neutrophils damage endothelial cells, leading to vasculitis, vessel wall necrosis, and thrombosis.
  • Complement Activation: The alternative complement pathway is activated in AAV, contributing to inflammation and neutrophil recruitment. C5a, a potent anaphylatoxin, enhances neutrophil priming and ANCA-mediated activation.
  • T-cell Involvement: T-lymphocytes, particularly Th17 cells, are also implicated in driving inflammation and granuloma formation in GPA.
  • Genetic Susceptibility: Associations with HLA-DP and SERPINA1 (alpha-1 antitrypsin deficiency) for PR3-ANCA AAV, and HLA-DQ for MPO-ANCA AAV.

• Risk Factors:

  • Genetic Predisposition: HLA-DPB1*0401, SERPINA1 Z allele.
  • Environmental Factors:
    • Infections: Especially Staphylococcal aureus nasal carriage in GPA, potentially triggering flares.
    • Silica exposure: Associated with an increased risk of AAV.
    • Drug Exposure: Propylthiouracil, hydralazine, minocycline, d-penicillamine, allopurinol (causing drug-induced AAV).
    • Smoking: Increased risk of GPA.

• Protective Factors: None definitively proven. Early diagnosis and aggressive treatment are crucial for preventing disease progression and improving outcomes.

Clinical Presentation

Signs and Symptoms

AAV can present with a wide range of non-specific symptoms, often delaying diagnosis. Organ involvement varies by disease type.

• Cardinal Features:

  • Renal: Necrotizing glomerulonephritis (rapidly progressive glomerulonephritis, RPGN). Hematuria, proteinuria, elevated creatinine. Present in >80% of MPA and GPA.
  • Pulmonary: Alveolar hemorrhage (hemoptysis, dyspnea, diffuse infiltrates on imaging), nodules, cavitating lesions (GPA), interstitial lung disease (MPA, EGPA).
  • Upper Airway (GPA dominant): Chronic sinusitis, otitis media, nasal crusting/ulceration, saddle nose deformity, subglottic stenosis.
  • Skin: Palpable purpura, livedo reticularis, ulcers, nodules, digital ischemia.
  • Neurological: Mononeuritis multiplex (foot drop, wrist drop), cranial neuropathy, stroke, rarely CNS vasculitis. Common in EGPA.
  • Constitutional: Fever, malaise, fatigue, weight loss, arthralgia/myalgia.

• Early Signs:

  • Persistent sinusitis, nasal crusting, nosebleeds (GPA).
  • Persistent cough, dyspnea, pleuritic chest pain.
  • Microscopic hematuria and proteinuria (often asymptomatic).
  • Skin rash (palpable purpura).
  • Unexplained fatigue, fever, weight loss.
  • Arthralgias.
  • Asthmatic symptoms (EGPA).

• Advanced Signs:

  • Rapidly progressive renal failure requiring dialysis.
  • Massive pulmonary hemorrhage with acute respiratory failure.
  • Saddle nose deformity due to cartilaginous destruction (GPA).
  • Blindness due to orbital pseudotumor or scleritis (GPA).
  • Significant neurological deficit from mononeuritis multiplex.
  • Cardiac failure or arrhythmias from myocarditis (EGPA).

• Atypical Presentations:

  • Pure ocular involvement (e.g., scleritis, orbital mass).
  • Isolated subglottic stenosis.
  • Myositis.
  • Gastrointestinal vasculitis (abdominal pain, bleeding).
  • Endocardial involvement mimicking endocarditis.

Physical Examination

Findings depend on the organs involved.

• Inspection:

  • Skin: Palpable purpura (most common), petechiae, ulcers (especially lower extremities), livedo reticularis.
  • Nose: Nasal crusting, septal perforation, saddle nose deformity (GPA).
  • Eyes: Conjunctivitis, episcleritis, scleritis, proptosis (orbital pseudotumor in GPA).
  • Lungs: Tachypnea, crackles/rales (diffuse alveolar hemorrhage).
  • Musculoskeletal: Joint effusions, muscle wasting.
  • General: Cachexia, pallor (anemia).

• Palpation:

  • Sinuses: Tenderness (sinusitis).
  • Lymph nodes: Lymphadenopathy (less common).
  • Abdomen: Tenderness (mesenteric ischemia/infarction).
  • Peripheral nerves: Tenderness along nerve distribution (mononeuropathy multiplex).

• Special Tests:

  • Neurological Exam: Evaluate for motor and sensory deficits consistent with peripheral neuropathy (e.g., foot drop, wrist drop), cranial nerve palsies.
  • Head and Neck Exam: Anterior rhinoscopy to assess nasal septum, turbinates, and identify ulcerations or perforations. Otoscopy for serous otitis media.
  • Ophthalmologic Exam: Fundoscopy for retinal vasculitis, episcleritis/scleritis.

Diagnostic Approach

History Taking

• Key Questions:

  • Systemic Symptoms: Fever, night sweats, weight loss, fatigue, malaise.
  • Upper Airway: Chronic sinusitis, epistaxis, nasal crusting, hearing changes, hoarseness.
  • Pulmonary: Cough, dyspnea, hemoptysis, pleuritic chest pain.
  • Renal: Changes in urine color (dark/red), frequency, foamy urine, lower extremity edema.
  • Skin: Rash (type, location, evolution), ulcers.
  • Neurological: Numbness, tingling, weakness (especially distal), foot drop, wrist drop, headache, vision changes.
  • Gastrointestinal: Abdominal pain, diarrhea, bloody stools.
  • Cardiac (EGPA): Chest pain, palpitations, syncope.
  • Musculoskeletal: Joint pain, muscle pain or weakness.
  • Past Medical History: Asthma, allergies, medication use (especially propylthiouracil, hydralazine), history of infections (Staph aureus).
  • Travel History/Exposures: Silica, other environmental agents.

• Red Flags: Suggestive of severe, active vasculitis requiring urgent evaluation:

  • Rapidly progressive renal failure (creatinine rise >50% within 3 months).
  • Hemoptysis (suggestive of diffuse alveolar hemorrhage).
  • Acute neurological deficits (mononeuritis multiplex, stroke).
  • Severe gastrointestinal bleeding or ischemia.
  • New onset, severe peripheral neuropathy.
  • Evidence of cardiovascular compromise (in EGPA particularly).

Laboratory Tests

• First-Line:

  • ANCA testing:
    • Indirect Immunofluorescence (IIF): Screens for cANCA (cytoplasmic pattern, usually PR3-ANCA) and pANCA (perinuclear pattern, usually MPO-ANCA).
    • Antigen-Specific ELISA: Confirms and quantifies PR3-ANCA and MPO-ANCA. AAV diagnosis generally requires positive ANCA by ELISA. IIF alone is not sufficient.
    • Note: Approximately 10-20% of GPA and MPA patients can be ANCA-negative, especially in localized disease. In EGPA, ~30-40% are MPO-ANCA positive.
  • Complete Blood Count (CBC): Anemia (chronic disease, hemorrhage), leukocytosis (inflammation, eosinophilia in EGPA), thrombocytosis.
  • Erythrocyte Sedimentation Rate (ESR) & C-Reactive Protein (CRP): Often markedly elevated in active disease.
  • Kidney Function Tests: Serum creatinine, BUN, electrolytes. Urinalysis with microscopy for hematuria (dysmorphic red blood cells), proteinuria, red blood cell casts (highly suggestive of glomerulonephritis).
  • Liver Function Tests: May be elevated in systemic disease.
  • Complement levels (C3, C4): Usually normal or elevated in AAV, whereas low levels suggest other vasculitides (e.g., cryoglobulinemic vasculitis, SLE).
  • Hepatitis B and C serology: Exclusion of viral vasculitis.
  • HIV test: Exclusion of HIV-associated vasculitis.
  • Anti-GBM antibodies: To rule out anti-glomerular basement membrane disease (Goodpasture's syndrome), which can present similarly to RPGN.

• Confirmatory:

  • Biopsy of involved organ: Gold standard for diagnosis.
    • Kidney: Renal biopsy showing necrotizing glomerulonephritis with crescents and scant immune deposits (pauci-immune glomerulonephritis) is highly characteristic.
    • Lung: Biopsy (e.g., thoracoscopic) showing necrotizing granulomatous inflammation and vasculitis (GPA), or capillaritis (MPA).
    • Upper Airway: Nasal or sinus biopsy showing necrotizing granulomatous inflammation.
    • Skin: Biopsy of purpuric lesions showing leukocytoclastic vasculitis.
    • Nerve: Sural nerve biopsy showing necrotizing vasculitis.
    • Muscle: Biopsy demonstrating vasculitis.

• Monitoring:

  • ANCA titers: Can be used in some centers to monitor disease activity and predict relapse, though their utility is debated and not universally recommended for routine monitoring. Changes in titer should be interpreted in context of clinical presentation.
  • ESR/CRP: Trend with disease activity.
  • CBC, Renal function tests, Urinalysis: Regularly to monitor organ involvement and drug toxicity.

Imaging

• Recommended:

  • Chest X-ray (CXR): May show infiltrates, nodules, cavities, pleural effusions.
  • High-resolution Computed Tomography (HRCT) of Chest: More sensitive for detecting pulmonary nodules, infiltrates, ground-glass opacities (alveolar hemorrhage), cavities, bronchiectasis. Essential for evaluating lung involvement.
  • CT Sinuses: For evaluation of GPA involving the upper respiratory tract (mucosal thickening, bone erosion, orbital invasion).
  • MRI Brain/Spine: If neurological symptoms suggest CNS involvement or cranial neuropathy.
  • Peripheral nerve ultrasound/MRI: To help localize affected nerves for biopsy or to assess nerve damage.

• Advanced:

  • PET/CT: Can be useful for identifying inflammatory lesions, especially in cases with unclear sites of active disease or to differentiate between active inflammation and fibrotic changes.
  • Bronchoscopy with BAL: If diffuse alveolar hemorrhage is suspected, to confirm hemorrhagic alveolitis and rule out infection.
  • Angiography: Rarely needed, as AAV typically affects small vessels not well visualized by conventional angiography. In cases of suspected large vessel involvement, CTA/MRA may be considered.

Management

Acute Management

AAV is a medical emergency, especially when involving rapidly progressive glomerulonephritis, pulmonary hemorrhage, or severe neurological compromise.

• Immediate:

  • High-dose Glucocorticoids: Methylprednisolone 500-1000 mg IV daily for 3 days, then transition to oral prednisone (1 mg/kg/day, max 60-80 mg/day).
  • Plasmapheresis: Considered in severe disease with rapidly progressive renal failure (creatinine >5.7 mg/dL or need for dialysis) or diffuse alveolar hemorrhage. The PEXIVAS trial indicated no overall survival benefit but reduced ESRF and severe relapse with plasmapheresis, at the cost of more serious adverse events. Discuss with nephrology/critical care.
  • Intubation/Ventilatory support: For severe hypoxemic respiratory failure from alveolar hemorrhage.
  • Hemodialysis: For acute renal failure.

• Stabilization:

  • Induction Therapy: Critical for achieving remission.
    • Cyclophosphamide (CYC) + Glucocorticoids:
      • Oral CYC: 2 mg/kg/day (usual maximum 150-200 mg/day), adjusted for renal function. Disadvantages include cumulative toxicity (hemorrhagic cystitis, myelosuppression, malignancy, infertility).
      • IV Pulse CYC: 15 mg/kg IV (max 1.2 g) every 2 weeks for 3 doses, then every 3 weeks for 3-6 months. Less cumulative toxicity but potentially less effective in very severe disease.
    • Rituximab (RTX) + Glucocorticoids:
      • Standard dose: 375 mg/m² IV once weekly for 4 weeks. Or, lower fixed dose of 500 mg IV on Day 1 and Day 15 (Rituximab in ANCA-Associated Vasculitis [RAVE] trial protocol was 375 mg/m² weekly for 4 weeks, PEXIVAS used 375 mg/m² weekly for 4 doses or 1g initial dose, followed by 1g a week later).
      • Rituximab vs Cyclophosphamide: RAVE trial showed RTX non-inferior to CYC for induction of remission in newly diagnosed or relapsing AAV, with better outcomes in relapsing patients and those with PR3-ANCA disease. RTX is now a first-line alternative to CYC.
  • Infection Prophylaxis:
    • Pneumocystis jirovecii Pneumonia (PJP): Trimethoprim/sulfamethoxazole (e.g., one single-strength tablet daily or one double-strength tablet three times weekly) should be given with CYC or high-dose glucocorticoids.
    • Herpes virus: Acyclovir or valacyclovir may be considered, especially with high-dose steroids or concurrent immunosuppression.

• Emergency:

  • Cardiac Tamponade: Due to pericarditis (rare, but can occur, especially in EGPA).
  • Acute CNS events: Stroke or seizures requiring neurosurgical/neurological intervention.
  • Airway obstruction: Due to subglottic stenosis (GPA) requiring urgent tracheostomy.

Chronic Management

• Pharmacological:

  • Maintenance Therapy: After inducing remission, duration is typically 18-24 months, sometimes longer.
    • Azathioprine (AZA): 2 mg/kg/day (max 150-200 mg/day). Preferred in the PEXIVAS maintenance arm.
    • Mycophenolate Mofetil (MMF): 1-2 g/day in two divided doses. Less evidence than AZA for maintenance but an option, especially if AZA intolerant.
    • Rituximab (RTX):
      • Relapse prevention: 500 mg IV every 6 months for at least 18-24 months (longer in high-risk patients, e.g., PR3-ANCA, history of relapse). Maintained remission better than AZA in MAINRITSAN and RITUXVAS studies.
      • Fixed-interval vs. ANCA-driven: Fixed interval (every 6 months) often preferred.
    • Methotrexate (MTX): 15-25 mg weekly. Can be used for maintenance in non-severe disease, but generally less effective than AZA or RTX.
    • Leflunomide: 20-30 mg daily. Alternative for maintenance, particularly in CYC-intolerant patients.
  • Glucocorticoid Taper: Gradual reduction of prednisone over 6-9 months, aiming for discontinuation if possible. Rapid taper increases relapse risk.
  • Ancillary Medications:
    • Bisphosphonates and Calcium/Vitamin D: For steroid-induced osteoporosis prevention.
    • Gastric protection: PPI or H2 blocker with high-dose steroids.
    • Blood pressure control: ACE inhibitors/ARBs for renal protection if proteinuria present.

• Non-pharmacological:

  • Lifestyle modifications: Smoking cessation (critical for pulmonary involvement), healthy diet, regular exercise.
  • Infection prevention: Vaccinations (influenza, pneumococcal, COVID-19).
  • Psychological support: For chronic illness adjustment.
  • Staphylococcus aureus eradication: In GPA patients with nasal carriage, intranasal mupirocin may reduce relapse risk.

• Monitoring:

  • Regular clinical evaluation: Monthly during induction, then every 3-6 months based on stability.
  • Laboratory: CBC, creatinine, urinalysis, ESR/CRP monthly during active disease and early maintenance, then less frequently.
  • Organ-specific monitoring: Repeat CXR/CT chest, PFTs, ENT exams as needed.
  • Immunosuppressant monitoring: TPMT genotyping before AZA, drug levels for MMF in select cases, B-cell count for RTX efficacy.
  • Adverse events: Monitoring for infections, malignancy, medication toxicities.

Treatment Algorithms

• First-Line for Induction (Severe, Organ-threatening disease):

  1. Glucocorticoids: Methylprednisolone IV pulse for 3 days, followed by oral prednisone 1 mg/kg/day.
  2. PLUS one of the following:
     • Rituximab (RTX): 375 mg/m² IV weekly for 4 doses OR 1g IV on Day 1 and Day 15. Considered first-line for most patients.
     • Cyclophosphamide (CYC): Oral 2 mg/kg/day OR IV pulse (e.g., 15 mg/kg every 2-3 weeks). Often preferred if rapid B-cell depletion is less critical or for specific contraindications to RTX.

• First-Line for Induction (Non-organ-threatening/early disease):

  • Oral Prednisone + Methotrexate or Mycophenolate Mofetil. Note: For GPA/MPA, even "non-organ threatening" can progress rapidly, so many centers still opt for CYC/RTX for induction due to high relapse rates.

• Maintenance Therapy (After 3-6 months of induction):

  1. Glucocorticoids: Tapered slowly over 6-9 months.
  2. PLUS one of the following for 18-24 months (or longer for high-risk patients):
     • Rituximab (RTX): 500 mg IV every 6 months. Strongly recommended, especially for PR3-ANCA patients or a history of relapse.
     • Azathioprine (AZA): 2 mg/kg/day.
     • Mycophenolate Mofetil (MMF): 1-2 g/day (often used when AZA intolerant).
     • Methotrexate (MTX): 15-25 mg/week (for long-term use in non-severe disease).

• Refractory Cases:

  • Failure to achieve remission OR severe relapse despite appropriate induction:
    • Consider switching induction agent (e.g., from CYC to RTX, or vice versa, or adding RTX after CYC).
    • Increased immunosuppression: Higher dose of current monotherapy, or adding a synergistic agent.
    • Alemtuzumab: Anti-CD52 monoclonal antibody, used in highly refractory cases, particularly if RTX is ineffective. High risk of infection and cytopenias.
    • Intravenous Immunoglobulin (IVIG): May be considered as an add-on therapy, especially for severe refractory disease or if infection risk precludes escalating conventional immunosuppression.
    • C5a receptor inhibitor (Avacopan): Approved as an add-on to standard therapy (glucocorticoids + RTX or CYC) and allows for reduced glucocorticoid exposure.
    • Eculizumab: A C5 inhibitor, being studied for refractory disease.

Complications

• Common:

  • Infections: Due to immunosuppression (PJP, bacterial, viral, fungal).
  • Glucocorticoid-related side effects: Osteoporosis, diabetes, hypertension, avascular necrosis, cataracts, glaucoma.
  • Drug toxicities: Myelosuppression (CYC, AZA), hemorrhagic cystitis (CYC), liver toxicity (MTX, AZA), infusion reactions (RTX).
  • Relapse: A significant challenge, often triggered by discontinuing maintenance therapy or concurrent infection.

• Serious:

  • End-stage renal disease (ESRD): Requiring dialysis or kidney transplant.
  • Diffuse alveolar hemorrhage: Leading to acute respiratory failure and death.
  • Severe neurological deficits: Permanent nerve damage, stroke.
  • Cardiovascular events: Myocardial infarction, heart failure (especially EGPA).
  • Malignancy: Increased risk, particularly with cyclophosphamide (bladder cancer, lymphomas) and long-term immunosuppression.
  • Sepsis: Leading cause of mortality.

• Long-term:

  • Organ damage: Permanent renal impairment, pulmonary fibrosis, chronic sinusitis, saddle nose deformity, hearing loss, peripheral neuropathy, optic atrophy.
  • Steroid-induced complications: See above.
  • Impaired quality of life: Chronic fatigue, pain, psychological distress.
  • Infertility: Especially with cyclophosphamide, dose-dependent.

Prognosis

• Factors:

  • Disease Severity at presentation: The Five-Factor Score (FFS) or Birmingham Vasculitis Activity Score (BVAS) are used to assess severity and prognosis. Higher FFS (age >65, cardiac, GI, or renal involvement, Cr >1.5 mg/dL) predicts poorer outcomes.
  • Type of ANCA: PR3-ANCA associated with higher relapse rates than MPO-ANCA.
  • Organ involvement: Renal failure, pulmonary hemorrhage, cardiac, or CNS involvement significantly worsen prognosis.
  • Age: Older age associated with poorer prognosis.
  • Response to treatment: Rapid and sustained remission is a positive prognostic indicator.
  • Comorbidities: Presence of other chronic diseases negatively impacts outcomes.

• Survival:

  • Untreated AAV is rapidly fatal, with 1-year survival around 10-20%.
  • With modern immunosuppressive therapy, 5-year survival is 70-80%.
  • Mortality is highest in the first year due to active disease, severe infection, or side effects of treatment.
  • Long-term mortality is often due to infections, cardiovascular disease, malignancy, or ESRD.

• Quality of Life:

  • Can be significantly impaired by chronic disease symptoms, organ damage, and side effects of treatment.
  • Fatigue, pain, and psychological distress are common.
  • Functional limitations can lead to reduced employment and social participation.

Prevention

• Primary: No known methods to prevent the initial occurrence of AAV.

• Secondary:

  • Early diagnosis: Crucial to prevent irreversible organ damage and improve outcomes. High index of suspicion for AAV in patients with multi-system involvement, atypical presentations, or RPGN.
  • Aggressive induction therapy: To achieve rapid and sustained remission.
  • Regular screening for infections: Especially during initiation of immunosuppression.

• Tertiary:

  • Relapse prevention: Adherence to maintenance therapy is critical. Regular follow-up for early detection of relapse.
  • Management of comorbidities and complications: Aggressive treatment of infections, optimal management of hypertension, diabetes, and bone health to minimize long-term damage.
  • Patient education: Empowering patients to recognize symptoms of relapse or treatment side effects.
  • Staphylococcus aureus eradication: In GPA patients with persistent nasal carriage, mupirocin reduces relapse risk.

Special Populations

• Pediatric:

  • AAV in children is rare but can be severe.
  • Diagnosis may be delayed due to non-specific symptoms.
  • Treatment principles are similar to adults, but careful attention to growth, development, and long-term toxicity (e.g., infertility with CYC) is paramount.
  • Close collaboration with pediatric nephrology, rheumatology, and pulmonology is essential.
  • Rituximab is increasingly used in children.

• Geriatric:

  • Older patients tend to have more severe disease and higher rates of renal involvement.
  • Increased risk of infections and treatment-related toxicities (e.g., myelosuppression, cardiovascular events).
  • Lower doses of cyclophosphamide or more cautious use of rituximab may be required, guided by comorbidities and renal function.
  • Co-management with geriatricians can be beneficial.

• Pregnancy:

  • AAV in pregnancy is rare. Ideally, conception should occur during sustained remission (>12 months).
  • Contraindicated medications: Cyclophosphamide, methotrexate, mycophenolate mofetil are teratogenic.
  • Safe medications: Glucocorticoids, azathioprine, and rituximab (often avoided in first trimester unless benefits outweigh risks, or for severe flares) are generally considered safer.
  • Management: Close monitoring of disease activity and fetal well-being throughout pregnancy. Higher risk of flare during pregnancy and postpartum.
  • Postpartum: Resume standard maintenance therapy.

• Comorbidities:

  • Renal impairment: Requires dose adjustment of many immunosuppressants (e.g., cyclophosphamide, azathioprine). Increases risk of complications.
  • Infection: Common trigger for relapse and major cause of mortality. Aggressive infection management. Immunosuppression dose often needs to be temporarily reduced or held during severe infections.
  • Cardiovascular disease: Increased risk with chronic inflammation and steroid use. Aggressive risk factor modification.
  • Diabetes/Osteoporosis: Managed similar to other chronic steroid users.

Clinical Pearls

• Diagnostic:

  • "If you don't think of it, you won't diagnose it." Maintain a high index of suspicion in patients with unexplained multi-organ involvement, particularly with renal or pulmonary abnormalities.
  • ANCA testing is crucial, but a negative ANCA does not rule out AAV, especially in localized disease or EGPA. Consider biopsy even with negative ANCA.
  • Biopsy is the gold standard; aim for fresh tissue for optimal diagnosis, especially for small vessel vasculitis.
  • AAV can mimic infection, malignancy, or other autoimmune diseases, thorough workup is key.

• Treatment:

  • Aggressive induction: Critical to prevent irreversible organ damage. Do not delay treatment awaiting biopsy results if clinical suspicion is high and organ-threatening disease is present (e.g., RPGN, DAH).
  • Glucocorticoid sparing: Aim to reduce cumulative steroid dose as early as possible to minimize side effects, especially with availability of agents like avacopan.
  • PJP prophylaxis: Do not forget PJP prophylaxis for all patients on cyclophosphamide or high-dose glucocorticoids.
  • Relapse management: Relapses are common, especially with PR3-ANCA. Consider returning to induction therapy for severe relapses. Rituximab is often favored for preventing subsequent relapses.
  • Shared decision-making: Discuss risks (infection, malignancy) and benefits of immunosuppression with patients.

• Pitfalls:

  • Delayed diagnosis: Leading to irreversible organ damage.
  • Under-treatment: Not using potent enough induction therapy for severe disease.
  • Over-treatment: Unnecessary use of high-dose steroids or prolonged immunosuppression, increasing toxicity.
  • Ignoring side effects: Failing to monitor for and manage infections, bone health, cardiovascular risks.
  • Mistaking infection for flare: Exacerbation of systemic inflammatory markers in AAV can be due to either infection or disease flare. Distinguishing these is crucial, as treatment differs significantly.

Recent Updates

• Guidelines:
  • 2021 EULAR/ERA-EDTA recommendations: Updated recommendations for the management of AAV, emphasizing rituximab as a first-line induction agent, the role of plasma exchange in severe cases, and a preference for rituximab or azathioprine for maintenance.
  • Role of Avacopan: New therapeutic option, a C5aR inhibitor, approved for AAV. The ADVOCATE trial demonstrated that avacopan, in conjunction with standard therapy, allows for reduced glucocorticoid exposure while maintaining efficacy, and potentially leading to better renal outcomes. It is used as an adjunctive therapy, not a replacement for cytotoxic agents/rituximab.
• Evidence:
  • PEXIVAS trial (2020): Showed that plasma exchange did not improve overall survival but reduced ESRF and severe relapse in patients with severe AAV. Reduced-dose glucocorticoid regimen was non-inferior to standard-dose.
  • MAINRITSAN studies (2010s): Confirmed superiority of rituximab over azathioprine for maintenance of remission, especially in patients with PR3-ANCA vasculitis.
• Controversies:
  • Optimal duration of maintenance therapy: Still debated, especially in PR3-ANCA patients who have a higher relapse risk. Some advocate for longer, indefinite rituximab maintenance in high-risk groups.
  • Role of ANCA titers in monitoring: While decreases in titers are often seen with treatment, routine use to guide treatment decisions (e.g., increasing immunosuppression based solely on rising titers in an asymptomatic patient) remains controversial due to lack of strong evidence to improve outcomes and potential for overtreatment.
  • Management of ANCA-negative AAV: Diagnosis and management can be challenging. Biopsy remains essential. Treatment generally follows ANCA-positive AAV principles.

Key References

• Guidelines:
  • Hellmich, B., et al. (2021). EULAR recommendations for the management of ANCA-associated vasculitis: 2021 update. Annals of the Rheumatic Diseases, 80(3), 315-322.
  • KDIGO Clinical Practice Guideline for the Management of Glomerular Diseases (2021). Kidney International. (Specific section on AAV).
• Studies:
  • Stone, J. H., et al. (2010). Rituximab versus cyclophosphamide for ANCA-associated vasculitis. New England Journal of Medicine, 363(3), 221-232 (RAVE trial).
  • Jayne, D. R. W., et al. (2020). Randomized trial of plasma exchange or high-dosage glucocorticoids for anti-neutrophil cytoplasmic antibody-associated vasculitis. New England Journal of Medicine, 382(21), 1986-1997 (PEXIVAS trial).
  • Terrier, B., et al. (2016). Rituximab versus Azathioprine for Maintenance of ANCA-Associated Vasculitis. New England Journal of Medicine, 374(17), 1636-1646 (MAINRITSAN trial).
  • Jayne, D. R. W., et al. (2021). Avacopan for the treatment of ANCA-associated vasculitis. New England Journal of Medicine, 384(7), 599-609 (ADVOCATE trial).
• Reviews:
  • Kitching, A. R., et al. (2022). ANCA-associated vasculitis. Nature Reviews Disease Primers, 8(1), 1-20.
  • Jennette, J. C., & Falk, R. J. (2022). Pathogenesis of ANCA-associated vasculitis. Nature Reviews Nephrology, 18(9), 565-582.

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Disclaimer: This information is intended for educational purposes only and should not be considered medical advice. Clinical decisions for individual patients must be made based on the clinician's independent medical judgment, taking into account the patient's specific circumstances, current clinical practice guidelines, and available evidence. Always consult with a qualified healthcare professional for diagnosis and treatment of any medical condition.