ANCA Associated Vasculitis

Wan-sik Uhm

doi:10.4078/jkra.2010.17.2.108

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Uhm: ANCA Associated Vasculitis

Original Article

J Korean Rheum Assoc 2010;17(2):108-132.

Published online: 23 June 2010

DOI: https://doi.org/10.4078/jkra.2010.17.2.108

ANCA Associated Vasculitis

Wan-sik Uhm

Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea

Received 3 June 20105 June 2010 Accepted 7 June 2010

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Primary antineutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV) constitute a group of small vessel vasculitides that includes Wegener's granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome. Recently, many in vitro and in vivo studies have highlighted the role of ANCA as the main pathophysiological factor in the development of AAV. Two remarkable studies on ANCA pathogenesis were recently reported. One study examined anti-lysosomal membrane protein-2, which supports the ‘shared epitope’ theory. The other examined the neutrophil extracellular trap that is released by neutrophils primed by ANCA. Each disease of AAV shows a broad spectrum of the clinical features and severities, which makes it difficult to diagnose and treat them. Considerable effort has been made in the past decades to improve the treatment outcomes, reduce the incidence of relapse and avoid drug toxicity. This review describes the current understanding of AAV along with a few Korean reports.

Keywords: ANCA associated vasculitis, Small vessel vasculitis, Wegener's granulomatosis, Microscopic polyangiitis, Churg-Strauss syndrome

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Table 1.

Summary of prevalence, incidence and onset age for ANCA associated vasculitis

	Prevalence (/million)	Incidence (/million/year)	Onset age
Wegner's granulomatosis	24~160 (11-15)	3~11 (15, 20-22)	51~66 (11, 13-15)
Microscopic polyangiitis	25~94 (12-15)	2~8 (15, 20-24)	60~71 (11, 13-15)
Churg-Strauss syndrome	11~14 (11, 23, 25)	2~7 (23, 26)	50~61 (11, 13)

Table 2.

ACR classification criteria and CHCC nomenclature of ANCA associated vasculitis

	ACR criteria (1990) (63)	CHCC Nomenclature (1994) (8)
Wegner's granulomatosis	1. Nasal or oral inflammation 2. Chest X-ray showing nodules, infiltrates (fixed) or cavities 3. Microscopic hematuria or red cell casts in urine 4. Granulomatous inflammation on biopsy Two criteria classify WG with a sensitivity of 88.2% and specificity of 92.0%	▪ Granulomatous inflammation involving the upper and lower respiratory tract, and necrotizing vasculitis affecting small to medium-sized vessels ▪ Necrotizing GN is common
Microscopic polyangiitis		▪ Necrotizing vasculitis, with few or no immune deposits, affecting small vessels ▪ Necrotizing arteritis of small and medium-sized arteries may be present. Necrotizing GN is common. Pulmonary capillaritis often occurs.
Churg-Strauss syndrome	1. Asthma 2. Eosinophilia 3. Neuropathy 4. Pulmonary infiltrates (non-fixed) 5. Sinusitis 6. Positive biopsy Four criteria classify CSS with a sensitivity of 85% and specificity of 99.7%	▪ Eosinophil-rich, granulmatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to medium-sized vessels, associated with asthma and eosinophilia

ACR: American College of Rheumatology, CHCC: Chapel Hill Consensus Conference, WG: Wegner's granulomatosis, GN: glomerulonephritis, CSS: Churg-Strauss syndrome

Table 3.

Clinical manifestations of ANCA associated vasculitis

	WG (100,101)	MPA (102)	CSS (62,103-106)
ANCA positivity ANCA antigen Specificity∗ (107) Fundamental histology	80~95% PR3: 70~80% MPO: 10~15% Leukocytoclastic vasculitis; necrotizing granulomatous inflammation (rarely seen in renal biopsy specimen)	70% PR3: 15~30% MPO: 50~70% Leukocytoclastic vasculitis; no granulomatous inflammation	50% PR3: 15~20% MPO: 30~40% Eosinophilic tissue infiltrates and vasculitis: granulomas have eosinophilic necrosis
ENT	79~94% Nasal septal perforation, saddle-nose deformity, sinusitis, conductive or sensorineural hearing loss, subglottic stenosis	11% Absent or mild	50~60% Nasal polyps, allergic rhinitis, sinusitis, conductive hearing loss
Eye	29~65% Orbital pseudotumor, scleritis (risk of scleromalacia perforans), episcleritis, uveitis	<5% Occasional eye disease, scleritis, episcleritis, uveitis	<5% Occasional eye disease, scleritis, episcleritis, uveitis
Lung	53~83% Nodules, infiltrates or cavitary lesions; alveolar hemorrhage	25% Alveolar hemorrhage	90~100% Asthma, fleeting infiltrates, alveolar hemorrhage
Kidney	23~77% Segmental necrotizing GN, rare granulomatous features	79% Segmental necrotizing GN	25~58% Segmental necrotizing GN
Heart	13% Occasional valvular lesions	<5% Rare	8~47% Heart failure
Peripheral nerve	20% Vasculitic neuropathy	58% Vasculitic neuropathy	66~76% Vasculitic neuropathy
Eosinophilia	Mild eosinophilia occasionally	None	90~100% All

∗These percentages come from studies of Europe and the United States

Table 4.

Mimics and secondary causes of vasculitis (108)

Mimics of vasculitis		Secondary causes of vasculitis
Atheroembolic disease	Infections	Tuberculosis
Atheromatous vascular disease		Hepatitis B
Anti-phospholipid syndrome		Hepatitis C
Multiple myeloma		HIV
Infective endocarditis		Parvovirus
Other chronic infections		Cystic fibrosis
Para-neoplastic syndromes
Genetic vascular disorders (e.g. Marfan's syndrome)	Malignancy	Lymphoma
Autoinflammatory syndromes		Solid organ malignancy
Hypersensitivity reactions	Connective tissue disorders	Rheumatoid arthritis
Cocaine and amphetamine abuse		Systemic lupus erythematosus
		Scleroderma
		Sjogren's syndrome
	Drugs	Penicillamine
		Propylthiouracil
		Hydralazine
		Minocycline
		Cocaine
	Environmental exposure	Dusts
		Silica

Table 5.

Definitions for disease stages of ANCA associated vasculitis according to EULAR

Clinical subgroup	Systemic vasculitis outside ENT tract and lung	Threatened vital organ function	Other definitions	Serum creatinine (μ mol/L)	Reference
Localized	No	No	No constitutional symptoms, ANCA typically negative	<120 (1.4 mg/dL)
Early systemic	Yes	Yes	Constitutional symptoms present, ANCA-positive or -negative	<120
Generalized	Yes	Yes	ANCA-positive	<500 (5.6 mg/dL)	Jayne et al (128)
Severe	Yes	Organ failure	ANCA-positive	>500	Jayne (156)
Refractory	Yes	Yes	Refractory to standard therapy	Any	Jayne (156)

ANCA: antineutrophil cytoplasmic antibody, ENT: ear, nose and throat

Table 6.

Recommendation for use and definition of activity states in vasculitis (155)

Activity state	Definition
Remission	Absence of disease activity attributable to active disease qualified by the need for ongoing stable maintenance immunosuppressive therapy. The term “active disease” is not restricted to vasculitis only, but also includes other inflammatory features like granulomatous inflammation in WG or tissue eosinophilia in CSS.
Response	50% reduction of disease activity score and absence of new manifestations
Relapse	Re-occurrence or new onset of disease attributable to active vasculitis
Major	Re-occurrence or new onset of potentially organ- or life-threatening disease
Minor	Re-occurrence or new onset of disease which is neither potentially organ- nor life-threatening
Refractory disease	Unchanged or increased disease activity in acute AAV after 4 weeks of treatment with standard therapy in acute AAV, or Lack of response, defined as ≤ 50% reduction in the disease activity score, after 6 weeks of treatment, or Chronic, persistent disease defined as presence of at least one major or three minor items on the disease activity score list (eg, BVAS or BVAS/WG) after ≥ 12 weeks of treatment
Low-activity disease state	Persistence of minor symptoms (eg, arthalgia, myalgia) that respond to a modest increase of the GC dose and do not warrant an escalation of therapy beyond a modest dose increase inthe current medication

AAV: antineutrophil cytoplasmic antibody-associated vasculitis, BVAS: Birmingham Vasculitis Activity Score, BVAS/WG: Birmingham Vasculitis Activity Score for Wegener's granulomatosis, CSS: Chrug-Strauss syndrome, GC: glucocorticoid, WG: Wegener's granulomatosis

Table 7.

Dose modification of pulsed cyclophosphamide as used in a randomisedcontrolled trial comparing the efficacy of daily oral versus pulsed cyclophosphamide for renal vasculitis (http://www.vasculitis.org/protocols/CYCLOPS.pdf)

Pulsed CYC dose reductions for renal function and age
Age, years	Creatinine (μ mol/litre)
Age, years	<300 (3.4 mg/dL)	300~500 (3.4~5.6 mg/dL)
<60	15 mg/kg/pulse	12.5 mg/kg/pulse
60~70	12.5 mg/kg/pulse	10 mg/kg/pulse
>70	10 mg/kg/pulse	7.5 mg/kg/pulse

The trial did not include a separate regimen for patients with a creatinine of <150 μ mol/litre (1.7 mg/dL). CYC: cyclophosphamide

Table 8.

Alternative remission induction treatments in relapsing, refractory or persistent disease (155)

Drug	Dose	Reference
Intravenous immunoglobulin	2 g/kg over 5 days	Muso et al, Jayne et al (176,177)
15-Deoxyspergualin	0.5 mg/kg/day till white cell count nadir of 3,000/ μ L, then wait until the white cell count returns to ≥ 4,000/ μ L and repeat the dose for six cycles	Burke et al (185)
Anti-thymocyte globulin	2.5 mg/kg/day for 10 days adjusted according to lymphocyte count: no anti-thymocyte globulin if <150/ μ L, 1.5 mg/kg/day if 150~300/ μ L, full dose if >300/ μ L	Schmitt et al (179)
Infliximab	3~5 mg/kg/infusion every 1 to 2 months	Booth et al (180)
Mycophenolate mofetil	2 g/day	Koukoulaki et al, Stassen et al (173,178)
Rituximab	375 mg/m² body surface area weekly for 4 weeks	Keogh et al, Keogh et al, Stasi et al, Brihaye et al, Eriksson et al (69,181-184)

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