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Basic Information ⬇

AUTHORS: Omar Karim, BS, and Manuel f Dasilva, MD

Definition

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) describes a family of small to medium vessel systemic vasculitides 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.

Synonyms

Anti-neutrophil cytoplasm antibody-associated vasculitis

Anti-neutrophil cytoplasmic antibody-positive vasculitis

Granulomatosis with polyangiitis

GPA

Wegener granulomatosis (WG)

MPA

Microscopic polyangiitis

Eosinophilic granulomatosis with polyangiitis

EGPA

ICD-10CM CODES
I77.6Arteritis, unspecified
M31.3Granulomatosis with polyangiitis
M31.7Microscopic polyangiitis
M30.1EGPA
Epidemiology & Demographics
Incidence

6 to 12 cases per million per year in Western Europe and Japan, but statistics vary globally1

Prevalence

Varies between 94 and 160 per million1

Predominant Sex & Age

Slightly higher incidence in males, peak 60 to 70 yr1

Peak Incidence

Increases with age, peak 60 to 70 yr of age1

Risk Factors

Infections (e.g., Staphylococcus aureus), silica exposure, hydrocarbon exposure, cigarette smoking, pesticides, medications (e.g., hydralazine, minocycline, propylthiouracil, levamisole-cocaine, allopurinol)

Genetics

Familial forms have been described but are rare; GPA associated with single nucleotide polymorphisms (SNP) in HLA-DP, PRTN3, SERPINA1; MPA associated with HLA-DQ polymorphisms.

Physical Findings & Clinical Presentation (

  • 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 (Fig. 1), 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 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 central nervous system (CNS) involvement with seizures or strokes.
  • Skin: Cutaneous nodules over extensor surfaces of joints, necrotizing skin lesions (Fig. E2), palpable purpura (30% to 46%), urticaria, livedo reticularis, and digital gangrene.

Figure 1 Saddle-nose deformity in a patient with Wegener granulomatosis.

From Kelley’s textbook of rheumatology, ed 8, Philadelphia, 2009, Elsevier.

TABLE 1 Preliminary Criteria for the Classification of Catastrophic Antiphospholipid Syndrome (APS)

  • Evidence of involvement of three or more organs, systems, or tissuesa
  • Development of manifestations simultaneously or in <1 wk
  • Confirmation by histopathology of small vessel occlusion in at least one organ or tissueb
  • Laboratory confirmation of the presence of antiphospholipid antibody (lupus anticoagulant or anticardiolipin or anti-β2-glycoprotein I antibodies)c
Definite Catastrophic APS
All four criteria
Probable Catastrophic APS
Criteria 2 through 4 and two organs, systems, or tissues involved
Criteria 1 through 3, except no confirmation 6 wk apart owing to early death of patient not tested before catastrophic episode
Criteria 1, 2, and 4
Criteria 1, 3, and 4 and development of a third event more than 1 wk but less than 1 mo after the first, despite anticoagulation

a Usually, clinical evidence of vessel occlusions, confirmed by imaging techniques when appropriate. Renal involvement is defined by a 50% rise in serum creatinine, severe systemic hypertension, proteinuria, or some combination of these.

b For histopathologic confirmation, significant evidence of thrombosis must be present, although vasculitis may coexist occasionally.

c If the patient has not been diagnosed previously with APS, laboratory confirmation requires that the presence of antiphospholipid antibody be detected on two or more occasions at least 6 wk apart (not necessarily at the time of the event), according to proposed preliminary criteria for the classification of APS.

From Asherson RA et al: Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines, Lupus 12:530-534, 2003.

TABLE 2 Clinical Findings in the ANCA-Associated Vasculitides9-36

GPAEGPAMPA
ConstitutionalCommon. Includes fatigue, malaise, fevers, and weight loss.Common. Weight loss, fatigue, fevers, myalgias and arthralgias.Very common. Generally precedes renal disease by months.
Pulmonary70%-95% of patients with respiratory symptoms or chest imaging abnormalities. Tracheobronchial and endobronchial disease in 10%-50%.Asthma essentially universal. Patchy, heterogenous radiographic infiltrates in >70%.10%-30% with diffuse alveolar hemorrhage.
Renal50%-90% of patients.20%-50% of patients.RPGN almost universal.
Upper airway70%-95% of patients. Destructive or ulcerating lesions are suggestive.Sinusitis, polyposis, and/or rhinitis in ≥70% of patients. Generally not destructive.5%-30%, with sinus disease most common.
MusculoskeletalArthralgias, synovitis, and myalgias in up to 80%.Arthralgias and myalgias in up to 50%.Arthralgias and myalgias in at least 50% of patients.
Eyes25%-60% of patients. Vision-threatening disease including uveitis, ocular ulcers.<5%.0%-30% of patients. May be clinically silent.
Cardiac5%-25% of patients. Conduction delays or other ECG abnormality, systolic or diastolic dysfunction, pericarditis, or coronary artery vasculitis.30%-50% of patients and a major cause of mortality. Conduction delays or other ECG abnormality, systolic or diastolic dysfunction, pericarditis, or coronary artery vasculitis.10%-20%. CHF and pericarditis have been described.
Gastrointestinal<10%30%-50% of patients and a major cause of morbidity and mortality. Hemorrhage, abdominal pain, infarct or perforated viscus.35%-55% of patients. Findings similar to PAN. Pain, bleeding, and ischemia. Rare visceral aneurysms.
DermatologicUp to 60%. Palpable purpura, ulcers, nodules or vesicles.50%-70% purpura, nodules, papules, leukocytoclastic vasculitis with or without eosinophils.35%-60% of patients with purpura common.
NeurologicBoth central and peripheral nervous system involvement.Mononeuritis multiplex in 50%-75%.
CNS in 5%-40%.		Mononeuritis multiplex in 10%-50%.
Chest imagingAbnormal in >80%. Alveolar, interstitial or mixed infiltrates, often with nodular and/or cavitary disease.Infiltrates in >70%. Airways disease common (airway wall thickening, hyperinflation).Infiltrates in 10%-30%. Pleural effusions in 5%-20%.
ANCAANCA positive >90% (PR3-ANCA 75%,
MPO-ANCA 20%).		ANCA positive in 50% (PR3-ANCA 5%,
MPO-ANCA 45%).		ANCA positive in 90% (PR3-ANCA 30%,
MPO-ANCA 60%).

ANCA, Antineutrophil cytoplasmic antibodies; CHF, congestive heart failure; CNS, central nervous system; ECG, electrocardiography; EGPA, eosinophilic granulomatosis with polyangiitis; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; MPO, myeloperoxidase; PAN, polyarteritis nodosa; PR3, proteinase 3; RPGN, rapidly progressive glomerulonephritis.

From Broaddus VC et al: Murray & Nadel’s textbook of respiratory medicine, ed 7, Philadelphia 2022, Elsevier.

Figure E2 Granulomatosis with Polyangiitis (GPA; Formerly Known as Wegener Granulomatosis)

Painful, ulcerative, necrotic plaques on the ankle (A) and elbow (B) of a female patient with GPA.

From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology: a textbook of skin disorders of childhood and adolescence, ed 5, Edinburgh, 2016, Elsevier.

Etiology

The etiology of this complex immune-mediated disorder remains unclear and is likely multifactorial in nature. 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 S. aureus have been proposed.

Diagnosis ⬆ ⬇

Differential Diagnosis

  • 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. Table 3 describes differential diagnostic features of ANCA-associated vasculitis.
  • 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.

TABLE 3 Differential Diagnostic Features of the Anti-Neutrophil Cytoplasm Antibody-Associated Vasculitides

FeatureMicroscopic 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
Alveolar hemorrhage+++++
Upper airway disease++++++Ear, nose, and throat disease usually favors GPA
Skin, purpura++++++
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.

From Firestein GS et al: Kelly’s textbook of rheumatology, ed 9, Philadelphia, 2013, Saunders.

Workup (Table 4

  • 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, pulmonary function tests, and tissue (lung or kidney) biopsy for granulomatous lesions in GPA (Fig. E3) or non-granulomatous vasculitis in MPA.

TABLE 4 Clinical Settings in Which It Is Appropriate to Check ANCA and in Which Positive Testing for Antiproteinase 3 or Antimyeloperoxidase Antibodies Could Be Considered Diagnostic of GPA or MPAa

DiseaseManifestationExamination TechniqueLaboratory and Other TestingImagingProblems With Biopsy
GPA >MPAScleritisOphthalmologic examination
GPAOrbital pseudotumorRoutine inspection, or with measurement toolCT or MRI
GPA >MPASensorineural hearing lossAudiographyImpossible
GPASinonasal inflammationOtoscope or fiberoptic examinationCT of sinusesAll three characteristic featuresb seen in only 10% of GPA
GPASubglottic inflammationLaryngoscopyCT of neckCorrelates poorly with examination or outcome
GPAPulmonary nodule(s)CT of chest1. Transbronchial: All three diagnostic featuresb are seldom seen. 2. Surgical biopsy: Invasive
GPA/MPAAlveolar hemorrhageInspection (witnessed hemoptysis) or bronchoscopy with BALCT of chestInvasive, and patient is often critically ill
GPA/MPADigit ischemiaRoutine inspectionAngiographyImpossible
GPA/MPAPeripheral neuropathyNeurologic examination: Sensory and motorNerve conduction studies/electromyographyLikely to result in an area of permanent sensory deficit; small chance of chronic pain
GPA/MPANephritisUrine sediment: RBC casts

BAL, Bronchoalveolar lavage; EGPA, eosinophilic granulomatosis with polyangiitis; GPA, granulomatosis with polyangiitis (Wegener’s); MPA, microscopic polyangiitis.

a If accompanied by marked peripheral eosinophilia, then EGPA would be the most probable diagnosis. Biopsy is often unnecessary to diagnose scleritis or alveolar hemorrhage, is often nonspecific or nondiagnostic for GPA in sinonasal or subglottic or orbital disease, and is impossible in digit ischemia or sensorineural hearing loss. The value of biopsy of a pulmonary nodule or peripheral nerve depends on how typical or atypical the overall presentation is for anti-neutrophil cytoplasmic antibodies-associated vasculitides. Some experts recommend a kidney biopsy for all patients with suspected nephritis. Skin disease is not included in the table because the appearances of cutaneous vasculitis are nonspecific; skin biopsy is therefore particularly valuable for diagnosing vasculitis, although differentiation from other causes of cutaneous vasculitis is often impossible.

b Granulomatous inflammation, necrosis, and small vessel vasculitis.

From Firestein GS et al: Firestein & Kelley’s textbook of rheumatology, ed 11, Philadelphia 2021, Elsevier.

Figure E3 A, Chest CT Scan of a Patient with Granulomatosis with Polyangiitis (GPA) Shows Typical Nodular Lung Infiltrate with Cavitation

B, Low-Power View of Granulomatous Inflammation and Geographic Necrosis (Arrow) in a Lung Biopsy from a Patient with GPA. C, Granulomatous Vasculitis Involving a Small Pulmonary Artery in the Lung of a Patient with GPA. The Vessel Wall is Markedly Thickened with an Inflammatory Infiltrate that Includes Multinucleated Giant Cells. D, Glomeruli Showing Segmental Necrosis with Early Crescent Formation (Arrows).

From Adkinson NF et al: Middleton’s allergy principles and practice, ed 8, Philadelphia, 2014, Saunders.

Laboratory Tests

  • ANCA serology (see Table 4): 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, red blood cell (RBC) casts, and proteinuria
  • Inflammatory markers: Increased erythrocyte sedimentation rate (ESR), positive rheumatoid factor, and elevated C-reactive protein may be found
  • Liver function, hepatitis serologies, cryoglobulins, HIV screens, ANA, C3, C4, anti-glomerular basement membrane, and cultures to exclude other processes with similar constitutional symptoms
Imaging Studies

  • Chest x-ray: Pulmonary infiltrates, nodules, pleural effusions, and cavitary lesions (Fig. 4)
  • CT of sinuses (Fig. 5), CT of chest, mesenteric angiography (if renal function permits), MRI of brain depending on symptoms
  • Fiber optic bronchoscopy with bronchoalveolar lavage (BAL) and endoscopic ear, nose, and throat (ENT) examination: Nasal crusting (“golden crusts”) are typical on evaluation
  • Electromyography/nerve conduction study: Sensorimotor peripheral neuropathy
  • Biopsy of one or more affected organs should be attempted, including the lung, skin, nasopharynx, or kidneys

Figure 5 CT scans of the sinuses.

A, Normal maxillary sinuses in a patient recently diagnosed with granulomatosis with polyangiitis. B, Sinus CT scan of a patient with long-standing Wegener granulomatosis. Nasal septal deviation to the left, destruction of the medial walls of the right maxillary sinus, opacification of both sinuses with soft tissue densities (arrows), and neo-ossification of all maxillary bony structures due to chronic inflammation.

From Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.

Figure 4 Pulmonary hemorrhage in microscopic polyangiitis.

From Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.

Treatment ⬆ ⬇

Nonpharmacologic Therapy

  • Ensure proper airway drainage
  • Give nutritional counseling
Acute General Rx (Fig. 7

  • 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 the 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/m/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.2 The RITUXVAS trial concluded that a combined cyclophosphamide-rituximab regimen was not inferior to pulse cyclophosphamide alone. Both studies used concurrent methylprednisolone followed by prednisone. If cyclophosphamide is used, MESNA can be given to prevent cyclophosphamide-induced hemorrhagic cystitis.3
  • 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.4
  • 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.5
Figure 7 Treatment Algorithm for the Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitides (Aav)

AZA,Azathioprine; Cr, serum creatinine; CYC, cyclophosphamide; EGPA, eosinophilic granulomatosis with polyangiitis; GI, gastrointestinal; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; MTX, methotrexate; PEX, plasma exchange; RTX, rituximab.

From Firestein GS et al: Firestein & Kelley’s textbook of rheumatology, ed 11, Philadelphia 2021, Elsevier.

Chronic Rx

  • 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. MAINRITSAN2 further demonstrated that patients who received tailored rituximab injections that corresponded with elevated CD19+ B lymphocyte or ANCA counts, rather than fixed-scheduled administrations, demonstrated similar relapse presentation rates, even with the former receiving much lower doses of rituximab.6 A recent trial demonstrated that extended therapy with biannual rituximab infusions over 18 mo is associated with a lower incidence of AAV.6
  • 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.7
  • 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-interleukin-5 (IL-5) monoclonal antibody, is approved for the treatment of EGPA and is used in patients who are not controlled with oral steroids alone.8
  • Treatment with TMP-SMX (160 mg/800 mg bid) may reduce the incidence of relapses in patients with GPA in remission. It is also useful in preventing Pneumocystis jiroveci pneumonia (PJP), which occurs in 10% of patients receiving induction therapy. Dose of trimethoprim-sulfamethoxazole (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.1
Disposition

  • 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.
Referral

  • Rheumatology referral for continued treatment.
  • Multidisciplinary consultation including nephrology, ENT, pulmonary, and dermatology may be required depending on other organ involvement.

Pearls & Considerations ⬆ ⬇

Comments

The goal with treatment of AAV is to achieve rapid, long-standing remission, based on induction therapy and then maintenance regimens. Without treatment there is a very high rate of mortality, and treatment is complicated by serious infections and renal disease.

Patient & Family Education

Support can be found with the Vasculitis Foundation.

Related Content

Systemic Vasculitis (Related Key Topic)

Related Content ⬆

    1. JU Holle : Clinical manifestations and treatment of Wegener’s granulomatosisRheum Dis Clin North Am. ;36(3):507-526, 2010.
    2. Stone J.H. : Rituximab versus cyclophosphamide for ANCA-associated vasculitisN Engl J Med. ;363:221-232, 2010.
    3. Jones R.B. : Rituximab versus cyclophosphamide in ANCA-associated renal vasculitisN Engl J Med. ;363(3):211-220, 2010.
    4. Walsh M. : Plasma exchange and glucocorticoids in severe ANCA-associated vasculitisN Engl J Med. ;382(7):622-631, 2020.
    5. Jayne D.R.W. : Avacopan for the treatment of ANCA-associated vasculitisN Engl J Med. ;384(7):599-609, 2021.
    6. Charles P. : 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)Ann Rheum Dis. ;77(8):1143-1149, 2018.
    7. Guillevin L. : Rituximab versus azathioprine for maintenance in ANCA-associated vasculitisN Engl J Med. ;371(19):1771-1780, 2014.
    8. Puéchal X. : Targeted immunotherapy strategies in ANCA-associated vasculitisJoint Bone Spine. ;86(3):321-326, 2019.
    9. Cordier J.-F. : Pulmonary Wegener’s granulomatosis: a clinical and imaging study of 77 casesChest. ;97:906-912, 1990.
    10. Frankel S.K. : Vasculitis: Wegener granulomatosisChurg-Strauss syndrome. ;18:855-879, 2002.
    11. Hoffman G.S. : Wegener’s granulomatosis: an analysis of 158 patientsAnn Intern Med. ;116(6):488-498, 1992.
    12. Jennette J.C., Falk R.J. : The pathology of vasculitis involving the kidneyAm J Kidney Dis. ;24(1):130-141, 1994.
    13. Anderson G. : Wegener’s granulomatosis: a series of 265 British cases seen between 1975 and 1985: a report by a sub-committee of the British Thoracic Society Research CommitteeQ J Med. ;83:427-438, 1992.
    14. Guillevin L. : Churg-Strauss syndrome: clinical study and long-term follow-up of 96 patientsMedicine. ;78(1):26-37, 1999.
    15. Lanham J. : Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndromeMedicine. ;63:65-81, 1984.
    16. Comarmond C. : Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and long-term followup of the 383 patients enrolled in the French Vasculitis Study Group cohortArthritis Rheum. ;65(1):270-281, 2013.
    17. Keogh K.A., Specks U. : Churg-Strauss syndrome: clinical presentation, antineutrophil cytoplasmic antibodies, and leukotriene receptor antagonistsAm J Med. ;115(4):284-290, 2003.
    18. Guillevin L. : Microscopic polyangiitis: clinical and laboratory findings in eighty-five patientsArthritis Rheum. ;42(3):421-430, 1999.
    19. Lhote F., Guillevin L. : Polyarteritis nodosa, microscopic polyangiitis and Churg-Strauss syndromeSemin Respir Crit Care Med. ;19(1):27-45, 1998.
    20. Reinhold-Keller E. : An interdisciplinary approach to the care of patients with Wegener’s granulomatosisArthritis Rheum. ;43(5):1021-1032, 2000.
    21. Romas E. : Wegener’s granulomatosis: clinical features and prognosis in 37 patientsAust N Z J Med. ;23(2):168-175, 1993.
    22. Fauci A.S. : Wegener’s granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 yearsAnn Intern Med. ;98:76-85, 1983.
    23. Frankel S.K. : Small vessel vasculitis of the lungChron Respir Dis. ;2(2):75-84, 2005.
    24. Hoffman G.S., Specks U. : Antineutrophil cytoplasmic antibodiesArthritis Rheum. ;41(9):1521-1537, 1998.
    25. Solans R. : Churg-Strauss syndrome: outcome and long-term follow-up of 32 patientsRheumatology. ;40(7):763-771, 2001.
    26. Guillevin L. : Systemic necrotizing angiitis with asthma: causes and precipitating factors in 43 casesLung 1987;. ;165:165-172, 1987.
    27. Guillevin L. : Clinical findings and prognosis of polyarteritis nodosa and Churg-Strauss angiitis: a study in 165 patientsBr J Rheumatol. ;27:258-264, 1988.
    28. Guillevin L. : Microscopic polyangiitisArthritis Rheum. ;42(3):421-430, 1999.
    29. Guillevin L. : Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome: a prospective study in 342 patientsMedicine. ;75(1):17-28, 1996.
    30. Savage C.O. : Microscopic polyarteritis: presentation, pathology and prognosisQ J Med. ;56(220):467-483, 1985.
    31. Adu D. : Polyarteritis and the kidneyQ J Med. ;62(239):221-237, 1987.
    32. Serra A. : Vasculitis affecting the kidney: presentation, histopathology and long-term outcomeQ J Med. ;53(210):181-207, 1984.
    33. D’Agati V. : Idiopathic microscopic polyarteritis nodosa: ultrastructural observations on the renal vascular and glomerular lesionsAm J Kidney Dis. ;7(1):95-110, 1986.
    34. Chumbley L.C. : Allergic granulomatosis and angiitis (Churg-Strauss syndrome): report and analysis of 30 casesMayo Clin Proc. (8):477-484, 1977.
    35. Sinico R.A. : Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndromeArthritis Rheum. ;52(9):2926-2935, 2005.
    36. Geetha D., Jefferson J.A. : ANCA-associated vasculitis: core Curriculum 2020Am J Kidney Dis. ;75(1):124-137, 2020.
    37. Charles P. : Long-term rituximab use to maintain remission of antineutrophil cytoplasmic antibody-associated vasculitisAnn Intern Med. ;173:179-187, 2020.
    38. lliger P.M. : Microscopic polyangiitis: clinical presentationAutoimmun Rev. ;9:812-819, 2010.