ANCA Associated Vasculitis
Antineutrophil cytoplasm antibody (ANCA) associated vasculitis (AAV) describes a family of small to medium vessel systemic vasculitis that shares many overlapping features including clinical manifestations and therapies but also has distinct differences among each condition (granulomatosis with polyangiitis [GPA], microscopic polyangiitis [MPA], and eosinophilic granulomatosis with polyangiitis [EGPA]).
These vasculitides are characterized by necrotizing, pauci-immune small vessel vasculitis with GPA and without MPA granulomatous inflammation.
Most patients present with both renal and pulmonary involvement, but the skin, nervous system, and gastrointestinal tract can also be affected.
In a limited form of GPA, disease is generally confined to the upper respiratory tract and can be managed less aggressively.
- Antineutrophil cetoplasmic antibody-associated vasculitis
- Antineutrophil cytoplasmic antibody positive vasculitis
- Granulomatosis with polyangiitis
- Wegener granulomatosis (WG)
- Microscopic polyangiitis
- Eosinophilic granulomatosis with polyangiitis
How common is ANCA Associated Vasculitis
10 to 20 cases per million per year in most parts of the world
Varies between 94 to 160 per million
Predominant Gender and Age
Slightly higher incidence in males, peak 60 to 70 yr
Increases with age, peak 60 to 70 yr of age
Who are at risk for ANCA Associated Vasculitis
Infections (e.g., S. aureus), silica exposure, hydrocarbon exposure, cigarette smoking, pesticides, medications (e.g., hydralazine, minocycline, propylthiouracil, levamisole-cocaine, allopurinol)
Familial forms have been described but are rare; GPA associated with SNP in HLA-DP, PRTN3, SERPINA1; MPA associated with HLA-DQ polymorphisms
Symptoms of ANCA Associated Vasculitis
- •Constitutional symptoms: Fever, fatigue, weight loss, myalgia, arthralgia
- •Upper respiratory tract (URT): Chronic sinusitis, chronic otitis media, mastoiditis, nasal crusting, obstruction and epistaxis, nasal septal perforation, nasal lacrimal duct stenosis, saddle nose deformities, tracheal and subglottic stenosis. Up to 90% of patients with GPA have one or more URT manifestations
- Eyes: Conjunctivitis, ulcerative keratosis, episcleritis or scleritis, optic neuropathy, nasolacrimal duct obstruction, retinal vasculitis, uveitis, proptosis
- •Ears: Sensorineural and conductive hearing loss, otorrhea, and polychondritis
- •Mouth: Chronic ulcerative lesions of the oral mucosa, “mulberry” gingivitis, can be seen in GPA
- •Pulmonary: Dyspnea, hemoptysis, pleuritic chest pain. Imaging may show nodules, infiltrates, cavitary lesions, effusion, or alveolar hemorrhage
- •Gastrointestinal: Ischemic abdominal pain, peritonitis, bloody diarrhea, bowel ulceration or perforation, most commonly in MPA
- •Renal: Most commonly affected organ in GPA and MPA. Elevated blood pressure, edema, decreased urine output. Rapidly progressive glomerulonephritis (38% to 70%), microscopic hematuria with or without red cell casts, and proteinuria
- •Nervous system: Mononeuritis multiplex and peripheral neuropathies (15% to 50% in both), meningeal inflammation (pachymeningitis), headaches, and rarely CNS involvement with seizures or strokes
- •Skin: Cutaneous nodules over extensor surfaces of joints, necrotizing skin lesions, palpable purpura (30% to 46%), urticaria, livedo reticularis, and digital gangreneFLOA
Causes of ANCA Associated Vasculitis
Unclear etiology of this complex immune-mediated disorder. ANCAs play a major role in the pathogenesis.
When PR3 and MPO are expressed on cell surfaces of neutrophils, they can cause endothelial damage as well as local tissue necrosis if activated in extravascular tissue.
Other risk factors including genetic, environmental exposure to silica or certain strains of Staphylococcus aureus have been proposed.
•Other granulomatous lung diseases for GPA (e.g., sarcoidosis, lymphomatoid granulomatosis, EGPA, necrotizing bronchocentric granulomatosis). The differential diagnosis of granulomatous lung disease is described in Section II. The below table describes differential diagnostic features of ANCA-associated vasculitis.
Differential Diagnostic Features of the Antineutrophil Cytoplasm Antibody–Associated Vasculitides
From Firestein GS et al: Kelly’s textbook of rheumatology, ed 9, Philadelphia, 2013, Saunders.
|Feature||Microscopic Polyangiitis (MPA)||GPA (Wegener Granulomatosis)||EGPA (Churg-Strauss Syndrome)||Comments|
|Glomerulonephritis||+++||+++||+||Progressive renal failure uncommon in EGPA|
|Pulmonary infiltrates or nodules||++||+++||+++||Asthma and eosinophilia in EGPA|
|Upper airway disease||+||+++||++||Ear, nose, and throat disease usually favors GPA|
|Peripheral nerve involvement||+||++||+++||Often a prominent feature of EGPA|
|Central nervous system involvement||+||+||+|
+++, Very commonly seen; ++, seen often; +, uncommon finding; EGPA, eosinophilic granulomatosis with polyangiitis; GPA, granulomatosis with polyangiitis.
- Other ANCA-associated vasculitides and systemic vasculitis.
- •Goodpasture disease, other causes of glomerulonephritis (e.g., poststreptococcal nephritis)
- •Neoplasms (especially lymphoproliferative disease).
- •Bacterial or fungal sinusitis for GPA
- •Viral infections.
- •Cocaine-induced midline destructive lesions and levamisole-induced vasculitis.
How is ANCA Associated Vasculitis diagnosed
- •Thorough medical history and physical examination. Suspect GPA/MPA if patient has pulmonary and renal symptoms and is refractory to conventional treatment. Suspect GPA if sinus disease.
- •Chest x-ray, laboratory evaluation, PFTs, and tissue (lung or kidney) biopsy for granulomatous lesions in GPA or nongranulomatous vasculitis in MPA.FLOAT NOT FOUND
- •ANCA serology: Most patients with GPA have a cytoplasmic pattern of ANCA (c-ANCA) which are predominantly directed against proteinase 3 (PR3). Whereas in MPA, the majority of patients have a perinuclear pattern (p-ANCA) directed against myeloperoxidase (MPO). Up to 15% of GPA patients have p-ANCA/MPO and about 25% of MPA patients have c-ANCA/PR3. Approximately 10% to 15% of AAV patients are ANCA negative
- •CBC: Anemia, leukocytosis, thrombocytosis (>400,000/μL)
- •Chemistry: Elevated serum creatinine, decreased creatinine clearance
- •Urinalysis: May reveal hematuria, RBC casts, and proteinuria
- •Inflammatory markers: Increased ESR, positive rheumatoid factor, and elevated C-reactive protein may be found
- •Liver function, hepatitis serologies, cryoglobulins, HIV screens, ANA, C3, C4, anti-GBM, and cultures to exclude other processes with similar constitutional symptoms
- •Chest radiograph: Pulmonary infiltrates, nodules, pleural effusions, and cavitary lesions
Computed tomography of sinuses, computed tomography of chest, mesenteric angiography (if renal function permits), MRI of brain depending on symptoms
Fiber optic bronchoscopy with BAL and endoscopic ENT examination: Nasal crusting (“golden crusts”) are typical on evaluation FLOAT NOT FOUND
•Electromyography/nerve conduction study: Sensorimotor peripheral neuropathy
•Biopsy of one or more affected organs should be attempted, including the lung, skin, nasopharynx, or kidneys
How is ANCA Associated Vasculitis treated
- •Ensure proper airway drainage
- •Give nutritional counseling
Acute General Rx
- •Immunosuppressive therapy should be considered in all patients with GPA.
- •Induction therapy consists of glucocorticoid with either cyclophosphamide or rituximab. Selected patients with severe disease including alveolar hemorrhage or rapidly progressive glomerulonephritis may benefit from the addition of plasma exchange to this regimen.
- •The gold standard for treatment is pulse methylprednisolone followed by prednisone 60 to 80 mg/day. Based on PEXIVAS trial, a reduced dose glucocorticoid regimen demonstrated equal efficacy as compared to the standard dose glucocorticoid regimen.
- •Based on the RAVE trial, rituximab (375 mg/m2/wk ×4 wk) appears to be more effective than traditional therapy in treating GPA/MPA that presents with disease flares and is at least as effective as traditional therapy for the induction of remission. The RITUXVAS trial concluded that a combined cyclophosphamide-rituximab regimen was not inferior to pulse cyclophosphamide alone. Both of these studies used concurrent methylprednisolone followed by prednisone. If cyclophosphamide is used, MESNA can be given to prevent cyclophosphamide-induced hemorrhagic cystitis.
- •Methotrexate and glucocorticoids alone may be used with mild extrarenal disease or little to no renal involvement, or with limited sinus and upper airway involvement.
- •The initial MEPEX trial demonstrated that plasma exchange in addition to cyclophosphamide and glucocorticoids may enhance renal function recovery. However, the more recent PEXIVAS trials showed no additional benefit in reducing mortality or progression to end stage renal disease with plasma exchange.
- •Ongoing ADVOCATE trial of investigating the oral C5a receptor blocker, avacopan as a steroid sparing agent, in addition to rituximab or cyclophosphamide shows promising preliminary results of comparable remission rate and serious adverse events.
- •Potentially useful agents for maintenance therapy include rituximab, methotrexate, azathioprine, and mycophenolate mofetil. The MAINRITSAN trial showed that rituximab may be preferable for maintenance therapy. A recent trial 1Charles P et al: Long-term rituximab use to maintain remission of antineutrophil cytoplasmic antibody-associated vasculitis, (Ann Intern Med 173:179-187, 2020).demonstrated that extended therapy with biannual rituximab infusions over 18 mo is associated with a lower incidence of antineutrophil cytoplasmic antibody-associated vasculities (AAV).
- •The CYCAZAREM (for azathioprine) and LEM (for leflunomide) trials showed that these agents can also be used. The WEGENT study showed oral methotrexate and azathioprine were noninferior for maintenance than intravenous cyclophosphamide.
- •Maintenance therapy should generally be continued for at least 18 to 24 mo, and ultimate duration of immunosuppression is decided on a case-by-case basis.
- •Mepolizumab, an anti-IL5 monoclonal antibody, is approved for the treatment of EGPA and is used in patients who are not controlled with oral steroids alone.
- •Treatment with TMP-SMX (160 mg/800 mg bid) may reduce the incidence of relapses in patients with granulomatosis with polyangiitis in remission. It is also useful in preventing Pneumocystis jiroveci pneumonia (PJP), which occurs in 10% of patients receiving induction therapy. Dose of TMP-SMX (160 mg/800 mg) for prophylaxis is 1 tablet three times/wk. If the patient is unable to tolerate TMP-SMX, PJP prophylaxis can also be achieved with dapsone, atovaquone, or inhaled pentamidine.
- •5-yr survival with prompt initiation and aggressive treatment is approximately 80%; without treatment 2-yr survival is 20%.
- •Renal failure and pulmonary involvement are major causes of morbidity and mortality. Age over 50 yr and lack of ENT changes at diagnosis are also associated with worse outcomes and increased mortality in GPA.
- •Remission rate can be achieved in the majority of patients, but relapse is frequent.
What research says
Rituximab (RTX) is non-inferior to cyclophosphamide (CYC) followed by azathioprine (AZA) for remission-induction in severe ANCA-associated vasculitis (AAV), but renal outcomes are unknown.
A post hoc analysis study of patients enrolled in the Rituximab for ANCA-Associated Vasculitis (RAVE) Trial who had renal involvement (biopsy proven pauci-immune GN, red blood cell casts in the urine, and/or a rise in serum creatinine concentration attributed to vasculitis).
Remission-induction regimens were RTX at 375 mg/m2 × 4 or CYC at 2 mg/kg/d. CYC was replaced by AZA (2 mg/kg/d) after 3–6 months.
Both groups received glucocorticoids. Complete remission (CR) was defined as Birmingham Vasculitis Activity Score/Wegener’s Granulomatosis (BVAS/WG)=0 off prednisone.
Fifty-two percent (102 of 197) of the patients had renal involvement at entry. Of these patients, 51 were randomized to RTX, and 51 to CYC/AZA.
Mean eGFR was lower in the RTX group (41 versus 50 ml/min per 1.73 m2; P=0.05); 61% and 75% of patients treated with RTX and 63% and 76% of patients treated with CYC/AZA achieved CR by 6 and 18 months, respectively.
No differences in remission rates or increases in eGFR at 18 months were evident when analysis was stratified by ANCA type, AAV diagnosis (granulomatosis with polyangiitis versus microscopic polyangiitis), or new diagnosis (versus relapsing disease) at entry.
There were no differences between treatment groups in relapses at 6, 12, or 18 months.
No differences in adverse events were observed.
In conclusion, patients with AAV and renal involvement respond similarly to remission induction with RTX plus glucocorticoids or CYC plus glucocorticoids.
- •Rheumatology referral for continued treatment.
- •Multidisciplinary consultation including nephrology, ENT, pulmonary, dermatology may be required depending on other organ involvement.
The goal with treatment of ANCA Associated Vasculitis is to achieve rapid, long-standing remission, based on induction therapy and then maintenance regimens. Without treatment there is very high mortality, and treatment is complicated by serious infections and renal disease.
Patient & Family Education
Support can be found with the Vasculitis Foundation.
- Bossuyt X., et al.: Position paper: revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis. Nat Rev Rheumatol 2017; 13 (11): pp. 683-692.
- Charles P., et al.: Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: results of a multicenter, randomized controlled, phase III trial (MAINRITSAN2). Annals Rheum Dis 2018; 77 (8): pp. 1143-1149.
- Guillevin L., et al.: Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med 2014; 371 (19): pp. 1771-1780.
- Hiemstra T.F., et al.: Mycophenolate mofetil vs. azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis. JAMA 2010; 304 (21): pp. 2381-2388.
- Holle J.U., et al.: Clinical manifestations and treatment of Wegener’s granulomatosis. Rheum Dis Clin North Am 2010; 36 (3): pp. 507-526.
- Pagnoux C., et al.: Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med 2008; 359 (26): pp. 2790-2803.
- Stone J.H., et al.: Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010; 363: pp. 221-232.
- Villiger P.M., et al.: Microscopic polyangiitis: clinical presentation. Autoimmune Rev 2010; 9: pp. 812-819.
- Walsh M., et al.: Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. N Engl J Med 2020; 382 (7): pp. 622-631.