Residency · Residency · Rheumatology

ANCA-Associated Vasculitis

Introduction

The ANCA-associated vasculitides are necrotizing small-vessel vasculitides characterized by few or no immune deposits, a pattern termed pauci-immune vasculitis. Three distinct entities are encompassed within this category: granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis. ANCA specificity is increasingly recognized as defining distinct disease phenotypes, with PR3-ANCA and MPO-ANCA conferring different clinical features, relapse risks, and prognostic implications that may ultimately prove more relevant than the traditional disease labels. Major therapeutic advances in recent years have fundamentally altered the treatment landscape, including the RAVE trial establishing rituximab for induction, the ADVOCATE trial introducing avacopan as a glucocorticoid-sparing complement inhibitor, and the PEXIVAS trial reshaping approaches to glucocorticoid dosing and plasma exchange.

ANCA Antibodies

PR3-ANCA (c-ANCA pattern)

PR3-ANCA targets proteinase 3, a serine protease stored in neutrophil azurophilic granules, and produces a cytoplasmic immunofluorescence pattern on indirect immunofluorescence assay. PR3-ANCA is predominantly associated with GPA, present in approximately 75 to 80 percent of GPA cases. Patients with PR3-ANCA have a higher relapse rate compared to those with MPO-ANCA, reflecting a more relapse-prone disease phenotype. PR3-ANCA disease tends toward more granulomatous manifestations with prominent upper airway involvement. While PR3-positive patients may demonstrate better initial responses to induction therapy, their higher relapse rate necessitates more prolonged maintenance immunosuppression.

MPO-ANCA (p-ANCA pattern)

MPO-ANCA targets myeloperoxidase, a lysosomal enzyme in neutrophils, and produces a perinuclear immunofluorescence pattern on indirect immunofluorescence assay. MPO-ANCA is predominantly associated with MPA, present in approximately 60 to 70 percent of cases. MPO-ANCA disease is characteristically more renal-predominant and is associated with a higher incidence of pulmonary fibrosis. While the relapse rate is lower than in PR3-ANCA disease, patients may accumulate more chronic organ damage. MPO-ANCA is more common in East Asian and Southern European populations compared to Northern European populations where PR3-ANCA predominates.

Testing Methodology

The 2017 Revised International Consensus recommends antigen-specific immunoassays, either ELISA or fluorescent enzyme immunoassay for PR3 and MPO, as the preferred primary screening method over indirect immunofluorescence assay. Indirect immunofluorescence alone carries an approximately 10 percent false positive rate, as the p-ANCA pattern can be caused by numerous non-vasculitis conditions including inflammatory bowel disease, autoimmune hepatitis, and infections. An IFA pattern should always be confirmed with antigen-specific testing. A critically important clinical principle is that ANCA titers do not reliably predict relapse, and rising titers in the absence of clinical disease activity should not be used as the sole basis for treatment escalation.

Granulomatosis with Polyangiitis (GPA)

Clinical Manifestations

Upper airway involvement occurs in approximately 90 percent of GPA patients and represents the most common initial symptom presentation. Chronic sinusitis refractory to standard antibiotic therapy is often the earliest manifestation. Saddle-nose deformity results from granulomatous destruction of the nasal septum. Subglottic stenosis occurs in up to 16 percent of patients and presents with stridor and dyspnea, often requiring endoscopic dilation. Otitis media, either serous or destructive, and oral ulcers with strawberry gingivitis, a pathognomonic finding, are additional upper airway manifestations.

Pulmonary involvement affects 85 to 90 percent of patients. Pulmonary nodules with cavitation are the most characteristic radiographic finding. Diffuse alveolar hemorrhage is a life-threatening complication presenting with hemoptysis, diffuse bilateral infiltrates, dropping hemoglobin, and paradoxically elevated DLCO reflecting the presence of intra-alveolar blood. Tracheobronchial stenosis and pleural effusions occur less commonly.

Renal involvement affects 70 to 80 percent of patients and typically manifests as rapidly progressive glomerulonephritis with a pauci-immune crescentic pattern on biopsy. The urinary sediment is characteristically active with dysmorphic red blood cells and red blood cell casts, accompanied by proteinuria that is usually sub-nephrotic in range. Without treatment, renal disease may progress to dialysis-dependent renal failure.

Ocular manifestations occur in approximately 50 percent of patients and include orbital pseudotumor presenting as a granulomatous mass, proptosis, scleritis, episcleritis, and retinal vasculitis. Neurologic involvement in 30 to 50 percent includes peripheral neuropathy with mononeuritis multiplex being the characteristic pattern, cranial neuropathy, and rarely CNS vasculitis. Cutaneous manifestations in 40 to 50 percent include palpable purpura, ulcers, nodules, and pyoderma gangrenosum-like lesions. Musculoskeletal symptoms of arthralgias, myalgias, and non-erosive arthritis are common. Constitutional symptoms including fever, weight loss, and fatigue frequently accompany active disease.

Limited vs Severe GPA

The distinction between limited and severe GPA is fundamental to treatment selection. Limited or non-organ-threatening disease involves the upper airway, skin, and joints without renal involvement or pulmonary hemorrhage. Severe or organ-threatening disease encompasses rapidly progressive glomerulonephritis, diffuse alveolar hemorrhage, mononeuritis multiplex, and severe scleritis threatening vision.

Microscopic Polyangiitis (MPA)

Clinical Manifestations

Renal involvement dominates the clinical picture of MPA, affecting approximately 90 percent of patients and often serving as the presenting feature. The glomerulonephritis is pauci-immune and crescentic, frequently the most severe manifestation. Pulmonary involvement includes diffuse alveolar hemorrhage, which is more common in MPA than in GPA, and interstitial lung disease with UIP and NSIP patterns, which is increasingly recognized, particularly in association with MPO-ANCA. Indeed, MPA is now established as an important cause of ILD. Cutaneous manifestations in 30 to 60 percent include palpable purpura and livedo reticularis. Neurologic involvement in approximately 30 percent features mononeuritis multiplex and peripheral neuropathy. Gastrointestinal involvement in 10 to 30 percent may present with abdominal pain, GI hemorrhage, or bowel perforation. Constitutional symptoms of fever and weight loss are common. The critical distinguishing feature from GPA is the absence of granulomatous upper airway disease.

<image>A comprehensive comparison diagram of the three ANCA-associated vasculitides (GPA, MPA, EGPA). Use three columns, one for each disease. For each column, show a human body figure with highlighted affected organs. GPA: Upper airway (saddle nose, sinusitis), lungs (cavitary nodules), kidneys (crescentic GN), eyes (orbital mass), skin (purpura). MPA: Kidneys (crescentic GN, most prominent), lungs (DAH, ILD), skin (purpura), nerves (mononeuritis multiplex). EGPA: Lungs (asthma, infiltrates), sinuses (nasal polyposis), skin (purpura, nodules), nerves (mononeuritis multiplex), heart (myocarditis). Below each figure, list: ANCA type (PR3 vs MPO), biopsy findings (granulomatous vs non-granulomatous vs eosinophilic), and key distinguishing features. Use consistent color coding for organ involvement severity.</image>

Eosinophilic Granulomatosis with Polyangiitis (EGPA)

Clinical Phases

EGPA characteristically evolves through three clinical phases, though these may overlap. The prodromal phase, which may span years to decades, features adult-onset asthma present in more than 95 percent of patients, along with allergic rhinitis and nasal polyposis. The eosinophilic phase is marked by peripheral eosinophilia exceeding 10 percent or 1500 cells per microliter and eosinophilic infiltration of organs including the lungs and gastrointestinal tract. The vasculitic phase brings small-vessel vasculitis that may temporally overlap with the eosinophilic phase.

Clinical Manifestations

Asthma is present in more than 95 percent of patients and is typically severe and late-onset, preceding the vasculitic phase by years. ENT involvement includes nasal polyposis and chronic sinusitis that is characteristically non-destructive, unlike the destructive sinusitis of GPA. Pulmonary manifestations include migratory infiltrates and eosinophilic pneumonia, with diffuse alveolar hemorrhage being less common than in GPA or MPA. Cardiac involvement is the most feared complication and the leading cause of death in EGPA, manifesting as eosinophilic myocarditis, pericarditis, and coronary vasculitis, and is more common in ANCA-negative EGPA. Neurologic involvement, particularly mononeuritis multiplex affecting approximately 70 percent of patients, is the most common vasculitic manifestation. Gastrointestinal involvement includes eosinophilic gastroenteritis, mesenteric vasculitis, and bowel perforation. Cutaneous manifestations include purpura, nodules, and urticaria. Renal involvement is less common and less severe than in GPA or MPA, affecting approximately 25 percent of patients, and may manifest as eosinophilic interstitial nephritis or pauci-immune glomerulonephritis.

EGPA Subtypes

EGPA is increasingly recognized as comprising two distinct subtypes defined by ANCA status. ANCA-positive EGPA, occurring in approximately 40 percent of patients and usually positive for MPO-ANCA, features more vasculitic manifestations including glomerulonephritis, palpable purpura, and mononeuritis multiplex. ANCA-negative EGPA, accounting for approximately 60 percent, demonstrates more eosinophilic tissue infiltration with a predilection for cardiac disease and pulmonary infiltrates.

Five Factor Score (FFS) - Prognosis

The Five Factor Score provides prognostic stratification in EGPA, with each factor assigned one point: proteinuria exceeding 1 gram per day, serum creatinine above 1.58 milligrams per deciliter, gastrointestinal involvement, cardiomyopathy, and CNS involvement. A score of 0 carries a 5-year mortality of approximately 12 percent, while a score of 1 or greater increases 5-year mortality to approximately 26 percent. The FFS also guides the intensity of initial therapy.

Diagnosis

Laboratory

ANCA testing by immunoassay identifies PR3-ANCA or MPO-ANCA positivity. ESR and CRP are elevated during active disease. The complete blood count may show anemia of chronic disease, and eosinophilia exceeding 1500 per microliter is characteristic of EGPA. An elevated serum creatinine indicates renal involvement. Urinalysis revealing an active sediment with dysmorphic red blood cells, red blood cell casts, and proteinuria is a hallmark of renal vasculitis. Complement levels are characteristically normal, an important finding that distinguishes AAV from SLE and cryoglobulinemic vasculitis, where complement is consumed.

Biopsy

Renal biopsy demonstrates pauci-immune focal necrotizing crescentic glomerulonephritis with few or no immune deposits on immunofluorescence, a finding that distinguishes AAV from lupus nephritis, IgA nephropathy, and anti-GBM disease. Lung biopsy reveals necrotizing granulomatous inflammation in GPA and capillaritis in the setting of diffuse alveolar hemorrhage. Skin biopsy shows leukocytoclastic vasculitis. Nasal or sinus biopsy in GPA demonstrates necrotizing granulomatous inflammation with multinucleated giant cells. Nerve biopsy reveals necrotizing vasculitis of the vasa nervorum in the setting of mononeuritis multiplex.

Management

Remission Induction

Severe/Organ-Threatening AAV (GPA/MPA)

Rituximab, an anti-CD20 monoclonal antibody, is now the preferred first-line induction agent per 2022 ACR/EULAR recommendations. The RAVE trial demonstrated that rituximab 375 milligrams per square meter weekly for 4 doses was non-inferior to cyclophosphamide for induction and superior in patients with relapsing disease. The RITUXVAS trial confirmed that a rituximab-based regimen was non-inferior to cyclophosphamide-based therapy for renal vasculitis. Rituximab dosing follows either the 375 milligrams per square meter weekly for 4 doses protocol or 1000 milligrams intravenously on day 1 and day 15.

Cyclophosphamide remains an alternative induction agent. The CYCLOPS protocol employs intravenous pulse cyclophosphamide at 15 milligrams per kilogram with a maximum of 1.2 grams every 2 to 4 weeks for 3 to 6 months. The CYCLOPS trial established that intravenous pulse dosing is non-inferior to daily oral cyclophosphamide at 2 milligrams per kilogram per day while achieving lower cumulative doses and fewer adverse effects, particularly reduced bladder cancer risk.

Glucocorticoids are given as intravenous methylprednisolone 500 to 1000 milligrams for 1 to 3 days, followed by oral prednisone at 1 milligram per kilogram per day with a maximum of 80 milligrams, tapered over 3 to 6 months. The PEXIVAS trial demonstrated that a reduced-dose glucocorticoid regimen, starting at 50 percent lower doses, was non-inferior to the standard dose, supporting a faster taper approach.

Avacopan, a C5a complement receptor antagonist, was demonstrated in the ADVOCATE trial to be non-inferior to prednisone taper at 26 weeks and superior for sustained remission at 52 weeks when dosed at 30 milligrams twice daily. Avacopan enables glucocorticoid-free or glucocorticoid-reduced induction regimens and received FDA approval in 2021.

Plasma exchange, evaluated definitively in the PEXIVAS trial, demonstrated no overall benefit for mortality or end-stage renal disease. Plasma exchange may still be considered in the setting of diffuse alveolar hemorrhage with respiratory failure or severe renal disease with creatinine above 5.7 milligrams per deciliter, particularly when concurrent anti-GBM disease is present.

Non-Severe/Limited AAV

Non-severe or limited disease can be managed with methotrexate at 20 to 25 milligrams weekly plus glucocorticoids, as supported by the NORAM trial which demonstrated methotrexate non-inferiority to cyclophosphamide for limited GPA. Mycophenolate mofetil at 2 to 3 grams daily plus glucocorticoids is an alternative. Rituximab is increasingly used even for non-severe disease.

EGPA-Specific Induction

For EGPA with a Five Factor Score of 0, indicating no poor prognostic factors, glucocorticoids alone at prednisone 1 milligram per kilogram per day may suffice. When the FFS is 1 or greater, glucocorticoids are combined with cyclophosphamide or rituximab. Mepolizumab, an anti-IL-5 antibody, was demonstrated in the MIRRA trial to reduce relapse rates and allow glucocorticoid tapering in relapsing or refractory EGPA when dosed at 300 milligrams subcutaneously every 4 weeks, receiving FDA approval in 2017. Benralizumab, which targets the IL-5 receptor alpha chain, was shown in the MANDARA trial to be non-inferior to mepolizumab when dosed at 30 milligrams subcutaneously every 4 weeks, and received FDA approval for EGPA in 2024.

Remission Maintenance

GPA/MPA

Rituximab is the preferred maintenance agent based on the MAINRITSAN trial, which demonstrated that rituximab 500 milligrams intravenously every 6 months for 18 months was superior to azathioprine for preventing relapse. The MAINRITSAN-3 trial showed that extended rituximab maintenance for 4 years reduced relapse compared to stopping at 18 months. The RITAZAREM trial demonstrated that rituximab 1000 milligrams every 4 months was superior to azathioprine for maintenance in relapsing AAV. The minimum duration of maintenance therapy is 2 years, with consideration of 4 or more years for PR3-ANCA disease given its higher relapse risk.

Azathioprine at 2 milligrams per kilogram per day remains an alternative maintenance agent, particularly for MPO-ANCA disease with its lower relapse rate. Methotrexate at 20 to 25 milligrams weekly is an alternative for limited GPA. The IMPROVE trial demonstrated that mycophenolate mofetil is less effective than azathioprine for maintenance. Leflunomide is an additional alternative steroid-sparing agent.

<image>A treatment algorithm for ANCA-associated vasculitis (GPA/MPA). Start with "AAV diagnosis confirmed" and branch based on disease severity. Severe/organ-threatening (RPGN, DAH, severe mononeuritis): Induction with rituximab (preferred) or IV CYC + GC (IV methylprednisolone pulses → oral prednisone taper per PEXIVAS reduced-dose protocol) ± avacopan (GC-sparing). Non-severe/limited: MTX or MMF + GC. After 3-6 months of induction, transition to maintenance: RTX 500 mg q6 months (preferred, per MAINRITSAN) or AZA 2 mg/kg/day. Show maintenance duration: minimum 2 years; PR3-ANCA consider 4+ years. Include separate EGPA pathway: FFS 0 → GC ± mepolizumab; FFS ≥1 → GC + CYC/RTX ± mepolizumab. Mark all key trial names at decision points.</image>

Specific Complications Management

Subglottic stenosis requires intralesional glucocorticoid injection combined with endoscopic dilation and may necessitate tracheostomy in severe cases. Orbital pseudotumor responds to systemic immunosuppression with rituximab or cyclophosphamide. Pulmonary hemorrhage demands urgent induction therapy, with consideration of plasma exchange if life-threatening. Progressive renal failure may require dialysis as a bridge, with renal transplantation offering excellent outcomes after sustained remission, as recurrence rates in the transplanted kidney are low.

Monitoring and Relapse

Regular monitoring includes complete blood count, basic metabolic panel, urinalysis, ESR, CRP, and ANCA titers, with the critical caveat that a rise in ANCA titers alone does not mandate treatment change. PR3-ANCA disease carries a higher relapse risk of approximately 60 to 80 percent over 5 years without maintenance therapy, compared to 30 to 40 percent for MPO-ANCA disease. Rising ANCA titers should prompt close clinical follow-up but should not trigger treatment escalation in the absence of clinical evidence of relapse. Immunoglobulin levels should be monitored in patients receiving rituximab, as hypogammaglobulinemia increases infection risk. Patients exposed to cyclophosphamide require long-term malignancy surveillance, particularly for bladder cancer, which is especially associated with oral cyclophosphamide use.

Key Clinical Pearls

• PR3-ANCA (GPA) has higher relapse rates than MPO-ANCA (MPA); requires longer maintenance therapy
• Rituximab is now preferred over cyclophosphamide for induction in most AAV patients (RAVE/RITUXVAS data)
• Avacopan allows GC-free or GC-minimized induction and is superior for sustained remission (ADVOCATE trial)
• PEXIVAS: Reduced-dose GC is non-inferior to standard dose and plasma exchange shows no overall benefit
• ANCA titers should NOT be used alone to guide treatment decisions; always correlate with clinical findings
• EGPA cardiac involvement is the leading cause of death; more common in ANCA-negative EGPA

References

1. Stone JH, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis (RAVE). N Engl J Med. 2010;363(3):221-232.
2. Jayne DRW, et al. Avacopan for the treatment of ANCA-associated vasculitis (ADVOCATE). N Engl J Med. 2021;384(7):599-609.
3. Walsh M, et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis (PEXIVAS). N Engl J Med. 2020;382(7):622-631.
4. Guillevin L, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis (MAINRITSAN). N Engl J Med. 2014;371(19):1771-1780.
5. Wechsler ME, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis (MIRRA). N Engl J Med. 2017;376(20):1921-1932.

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