ANCA Associated Vasculitis

The Discovery of Anti-Neutrophil

Cytoplasmic Antibodies (ANCA)

First described in 1982 by Davies in 8 patients with

necrotizing pauci-immune glomerulonephritis1
Hall and colleagues identified ANCA in four patients with
systemic vasculitis2
In 1985, Van der Woude suggested an association
between ANCA and Wegeners granulomatosis3
ANCA subsequently reported in microscopic polyangiitis
and in Churg Strauss syndrome4

1. Davies DJ, et al: Br Med J 285:606, 1982

2. Hall JB, et al: Aust NZ J Med 14:277, 1984
3. van der Woude FJ, et al: Lancet 1:425, 1985
4. Jennette CJ, Falk R: New Eng J Med 337:1512, 1997

ANCA-Associated Vasculitis

Shared Features of ANCA-Associated

Vasculitides

Wegener's granulomatosis (WG), microscopic

polyangiitis (MPA), and Churg Strauss syndrome (CSS)
Can be considered together in view of a number of
shared pathologic, clinical, and laboratory features

Preferentially involve small vessels (arterioles, capillaries,

venules)
Similar glomerular lesions (crescents, focal necrosis, pauciimmune)
Propensity to present as lung-renal syndromes
Varying prevalence of ANCA positivity

Detection of ANCA

ANCAs were originally described based on their

immunofluorescence patterns

cytoplasmic (c-ANCA) and perinuclear (p-ANCA)

The antigens responsible for these patterns have also

been identified

proteinase 3 (PR3) for c-ANCA

myeloperoxidase (MPO) for p-ANCA

Immunofluorescence and Antigenic

Specificity

In c-ANCA reactivity

PR3 is responsible for more than 90% of such reactions

Other antigens may occasionally contribute
bactericidal permeability-inducing protein (BPI)
rarely MPO

In p-ANCA reactivity

MPO is responsible for ~10% of such reactivity

Other antigens include
elastase, azurocidin, cathepsin G lysozyme, lactoferrin
antinuclear antibodies (ANA) can also have p-anca patterns

ANCA Testing

International Consensus Statement for Testing and

Reporting ANCA recommends

all sera are screened for ANCA by IIF

IIF-positivity is confirmed by direct ELISAs

Some laboratories test by direct ELISA alone

Others screen with direct ELISA and confirm positive
sera by IIF
A few use capture (sandwich) ELISAs

Problems in ANCA Testing

Diversity of antineutrophil cytoplasmic antibody target

antigens
Assay standardization and performance
Application of antineutrophil cytoplasmic antibody testing
in a clinical setting with a low pretest probability
The widespread assumption that antineutrophil
cytoplasmic antibody titers alone may closely reflect
disease activity and therefore may be used to guide
therapy

ANCA Frequencies in Vasculitis

Hagen EC, et al: Kidney Int 53(3):743753, 1998.

ANCA in Other Diseases

Connective tissue diseases:

Infections:

Ulcerative colitis > Crohns disease

Other autoimmune GI diseases

Endocarditis, HIV

Inflammatory bowel disease:

SLE, rheumatoid arthritis, myositis

Sclerosing cholangitis, autoimmune hepatitis

Drug-induced ANCA:

Hydralazine, propylthiouracil, D-penicillamine and minocycline

Schematic concept of proinflammatory

effects of ANCA leading to vasculitis

ANCA and Disease Activity

Pooled analysis studies by Davenport in Am J Nephrol

15(3):201207, 1995

100 patients followed serially for 2 years by Boomsma:

Arthritis Rheum 43(9):20252033, 2000

48% of rises followed by relapse

51% of relapses preceded by rise

92% of flares associated with rises in ANCA

Predictive value higher with ELISA than with IIF

Greatest utility when tests are negative

Wegeners Granulomatosis: History

WG is a granulomatous necrotizing vasculitis

characterized by its predilection to affect the upper and
lower respiratory tracts and the kidneys
First described in 1931 by Heinz Klinger, a German
medical student
In 1936 and 1939, Dr. Friedrich Wegener provided
detailed information about three patients with a similar
illness
Remained relatively unknown in the American literature
until the 1950s, when Godman and Churg published a
detailed description of the disorder

WG: Epidemiology

WG affects both sexes equally

Occurs in patients of all ages (mean age 41 years; range
9 to 78 years)
More commonly seen in Caucasian patients (97%)
Period prevalence of WG (1986-1990) was estimated to
approximate 3 per 100,000 persons
It is likely that the prevalence of WG has been
underestimated
Only since the early 90's has the existence of mild and
more indolent forms of disease has been recognized

WG: Clinical Features

Classic Triad:

Upper airway
Lower respiratory tract
Kidneys

Limited WG

Relatively mild and

indolent without renal
involvement

WG: Upper Airway

Upper airway disease is the most common presenting

feature

Otologic manifestations

70 percent of patients at onset

Develops in more than 90 percent of cases
initial presentation in about 25 percent
60 percent of cases during the course of disease
Serous otitis media is the most common ear problem
encountered (25 to 44%)

Nasal disease

is a prominent presenting feature of WG in about one third of

cases
eventually develops in 64 to 80%

WG: Upper Airway

Sinusitis

Laryngotracheal disease

Initial presentation in about one half to two thirds of patients with

WG
85 percent of cases during the entire course of disease
asymptomatic
subtle hoarseness
stridor and life-threatening upper airway obstruction
The most characteristic lesion is that of subglottic stenosis
(SGS), which occurs in up to 16 percent of patients

In pediatric and adolescent patients SGS is dramatically

increased, reaching an alarming 48 percent prevalence

WG: Pulmonary Manifestations

Pulmonary manifestations occur in

Cough, hemoptysis, and pleuritis are the most common pulmonary

symptoms
~ 1/3 with radiographically demonstrable pulmonary lesions may not
have lower airway symptoms
The most common radiologic findings include

45 percent of cases at presentation

87 percent during the course of disease

pulmonary infiltrates (67%)

nodules (58%)

The pulmonary infiltrates in WG may be quite fleeting, appearing

and resolving in some cases even before the institution of therapy

WG: Pulmonary Manifestations

Persistent diffuse interstitial infiltrates are rare (less than 1%) and
should suggest other diagnoses
Pulmonary nodules in WG are usually multiple, bilateral, and often
cavitate (50%)
CT of the chest may reveal infiltrates and nodules that were
undetected by conventional radiographs in 43 to 63 percent of
cases
Less common pulmonary manifestations of WG include pleural
effusions, diffuse pulmonary hemorrhage, and mediastinal or hilar
lymph node enlargement or mass
Diffuse pulmonary hemorrhage has been reported in up to 8 percent
of cases, and it carries a high fatality rate (50%)

WG: Renal manifestations

Presence or absence of renal disease defines the

subsets of generalized and limited WG
Frequency of renal involvement in WG is difficult to
ascertain

Limited WG may go undiagnosed in patients with mild disease

By excluding such patients, published series may overestimate
the frequency of renal disease in WG

Early renal disease may be clinically silent

Patients who appear to have limited WG at one time may
later develop glomerulonephritis

Monitoring of renal status in all patients is important

WG: Renal manifestations

Renal disease is estimated to occur in

Extrarenal manifestations often precede renal disease

Renal disease may progress to fulminant
glomerulonephritis within days or weeks, resulting in
end-stage renal failure

11 to 18% at presentation
77 to 85% during the course of disease

Untreated, mean survival time for this subset is about 5 months

Initial and recurrent renal damage may lead to chronic

renal insufficiency in up to 42 percent of patients

dialysis (11%)
renal transplantation (5%)

Early Segmental Fibrinoid Necrosis and Infiltration by

Neutrophils in an ANCA Positive Patient with WG

WG: Ocular Manifestations

Reported to occur in 28 to 58 percent of patients with

WG and may be part of the initial presentation in 8 to 16
percent of cases
Any compartment of the eye may be affected

Keratitis, conjunctivitis, scleritis, episcleritis, nasolacrimal duct

obstruction, uveitis, retroorbital pseudotumor with proptosis,
retinal vessel occlusion, and optic neuritis have all been
described

Most ocular findings are nonspecific

proptosis is a diagnostically helpful finding

poor prognostic sign for vision

WG: Cutaneous Manifestations

Reported in 40 to 50 percent of patients with WG and

may be part of the initial presentation in 13 to 25 percent
of cases
The cutaneous manifestations of WG have included

ulcers, palpable purpura, subcutaneous nodules, papules, and

vesicles

Cutaneous lesions tend to parallel disease activity in

other organs
The presence of active skin lesions is a reliable clinical
marker for active systemic disease

WG: Joint Disease

Arthritis is observed in up to 28 percent of patients

several patterns can be observed, including monoarticular

disease, migratory oligoarthritis, and symmetric or asymmetric
polyarthritis of small and large joints.

Symmetric polyarthritis of small and large joints may be

mistaken for RA
A positive test for rheumatoid factor (RF) may be
observed in as many as 50 to 60 percent of cases
In contrast to RA, the symmetric polyarthritis of WG is
generally nonerosive and nondeforming

WG: Neurologic

Rarely a presenting feature of WG, may develop during the course

of disease in 22-50%

Peripheral neuropathy is the most common single neurologic

manifestation (10 to 16%)

Mononeuritis multiplex (12 to 15%)

Distal and symmetric polyneuropathy (2%)

Cranial neuropathy occurs in 6 to 9%

Cerebrovascular events (4%)

Multiple neurologic complications may occur in up to 11 percent of

patients

cerebral or brain stem infarction, subdural hematoma, and subarachnoid

hemorrhage

Diffuse meningeal and periventricular white matter disease has

been reported

WG: Other Manifestations

Gastrointestinal:

Genitourinary

Abdominal pain, diarrhea, and bleeding are the most frequently

reported symptoms
Relate to the presence of ulcerations in the bowel
Perforation may occur
Case-reports of bladder wall, prostate involvement
Hemorrhagic cystitis complication of cyclophosphamide

Cardiac

Pericarditis
Myocarditis
Arteritis

WG: Diagnosis

Non-specific abnormalities

Organ specific

Leucocytosis, thrombocytosis, high ESR, anemia

Urinalysis, sediment, creatinine

The sensitivity of PR3-ANCA is about 90 percent in active WG and

40 percent when disease is in remission
The specificity of PR3-ANCA in the diagnosis of WG exceeds 95
percent
In general, the presence of high-titer ANCA by IFA combined with
confirmatory antigen-specific assay for either PR3 or MPO in the
setting of a high index of suspicion for vasculitis (i.e., high pretest
probability) is sufficient for diagnosis, even in the absence of tissue
confirmation

Positive Predictive Value of ANCA

Positive Predictive Value

100

2 1
3
4
1. Documented WG
2. Pulmonary-Renal Syndrome
3. Systemic Necrotizing Vasculitis
4. Rapidly Progressive GN
5. GN
6. Hospitalized Patient

5
50

50

100

Disease Prevalence

Jennette. Amer J Kidney Dis 18:164, 1991

Diagnostic Yield of Biopsy in WG

Inflammatory lesions in WG

Necrosis
Granulomatous changes
Vasculitis

Diagnostic yield of a biopsy

Nasal, paranasal sinus biopsies

Small amount of tissue available in may make it difficult to identify all of the
pathologic features
Complete diagnostic triad is only seen in 3 to 16%

Lung

Transbronchial biopsies are rarely diagnostic (less than 7%)

Open lung biopsies reveal various combinations of vasculitis, granulomas,
and necrosis in 90%

Kidney

Focal and segmental GN

True vasculitis of medium-sized renal arteries is only occasionally noted (3 to
15%), and granulomatous changes are equally rare (3%)
The results of kidney biopsies usually not diagnostic of WG

Wegeners granulomatosis:
lung (photomicrographs)

WG: Principles of Treatment

General:

Rapid diagnosis, assessment of extent of disease activity

Untreated high mortality

Pharmacotherapy

Induction of remission
Prevention of relapse
Management of drug-toxicity

WG: Induction of Remission

Glucocorticoids (GC)

Pulse therapy for life threatening disease

1g Solu-Medrol daily for 3 days

High dose steroid treatment 1mg/Kg daily

Taper after 1 month

For classic WG (with renal involvement)

Begin concurrent daily oral cyclophosphamide (CTX)

2mg/Kg/day
Pulse cyclophosphamide has been studied but not currently
recommended
Consider methotrexate for less severe or limited disease

WG: NIH experience

Hoffman GS, et al: Ann Intern Med 116(6):488498, 1992.

158 patients with WG followed at the NIH for up to 24

years (mean follow-up period of 8 years)

84% received "standard" therapy with daily CTX and GC

Marked improvement in 91%
Complete remission in 75%
Disease relapse was seen in 50%
permanent morbidity from disease occurring in 86%

chronic renal insufficiency (42%)

hearing loss (35%)
nasal deformities (28%)
tracheal stenosis (13%)
visual loss (8%)

Permanent morbidity as a result of treatment with GC and CTX

occurred in 42%
46% experienced serious infectious episodes

Summary of Cyclophosphamide

Cyclophosphamide induces remission, but

Relapses are common, and
Cyclophosphamide causes toxicity

WG: Efforts to find less toxic alternatives to

cyclophosphamide

NIH open label study (Sneller MC, et al Arthritis Rheum

38(5):608613, 1995)

open-label study of weekly low-dose MTX plus GC in 42 patients

with biopsy-proven WG
Patients with life-threatening disease excluded
serum creatinine above 2.5 mg/dl or acute pulmonary hemorrhage

50 percent had active glomerulonephritis

remission in 71% after a median of 4.2 months
relapses occurred in 36% after a median of 29 months
Toxicity: PCP in 4 with 2 deaths

WG: Efforts to find less toxic alternatives to

cyclophosphamide

EUVAS trial of MTX vs CYC (de Groot, et al Arthritis

Rheum; 52:24619, 2005) in ANCA associated vasculitis

94% had WG
Patients with life-threatening disease excluded
serum creatinine above 2.5 mg/dl or acute pulmonary hemorrhage

30% had active glomerulonephritis

At 6 months, the remission rate with MTX (89.8%) was not
inferior to CYC (93.5%)
Relapse rates at 18 months were 69.5% in the MTX group and
46.5% in the CYC group

Summary of Methotrexate as an alternative

to Cyclophosphamide for induction

MTX, given at a dosage of 2025 mg per week in

combination with glucocorticoids, has emerged as the
standard remission induction regimen for WG in patients
whose disease is classified as limited, early systemic,
or nonlife or organ threatening.
However relapse remains a problem

WG: Maintaining remission

Options

Methotrexate to maintain remission

Continue cyclophosphamide for 12 months after remission is

achieved
Switch to methotrexate or azathioprine as soon as remission is
achieved (usually 3-6 months)
De Groot, et al. Arthritis Rheum 1996; 39:2052
Langford, et al. Arthritis Rheum 1999; 42:2666

Azathioprine to maintain remission

Jayne et al.. N Engl J Med 2003; 349:36

WG: New agents

Etanercept

WGET trial (N Engl J Med 2005;352:351-61)

Failed to show that etanercept was effective in maintaining
remission (no difference when compared with control groups)
6 solid tumors versus none in controls

Rituximab

11 refractory patients all responded with remission and decrease

in ANCA titers (8/11 became ANCA negative)
Arthritis Rheum. 2005 Jan;52(1):262-8

Microscopic Polyangiitis (MPA)

MPA was first recognized as a distinct entity by Davson

and colleagues in 1948

described as a subgroup of polyarteritis nodosa, distinguished

by the presence of segmental necrotizing glomerulonephritis.

The Chapel Hill International Consensus Criteria defined

MPA as

a necrotizing vasculitis (with few or no deposits) affecting small

vessels (i.e., capillaries, venules, or arterioles)
It was noted that MPA is frequently associated with necrotizing
glomerulonephritis and pulmonary capillaritis

MPA: Clinical Features

Clinical Feature

Percentage

Constitutional symptoms

76-79

Fever

50-72

Renal Disease

100

Arthralgia

28-65

Purpura

40-44

Pulmonary Disease

50

Neurologic Disease

28

ENT

32

MPA: Renal Disease

100 % occurrence reflects ascertainment bias

The renal lesion of MPA is that of necrotizing
glomerulonephritis
It is indistinguishable from the renal lesion of WG

MPA: Pulmonary Disease

Lung involvement is common in MPA and is present in more than

half of reported cases in most series
Diffuse alveolar hemorrhage (DAH) is the most serious form of lung
involvement and has been reported in 12 to 29 percent of patients in
several series
The clinical manifestations range from mild dyspnea and anemia
without any hemoptysis to massive hemorrhage and bleeding with
profound hypoxia with acute onset in most patients
The radiographic features of DAH are nonspecific, demonstrating
patchy or diffuse alveolar infiltration
The characteristic histopathology of MPA is that of pulmonary
capillaritis

MPA: Diagnosis

Problems in diagnosis

Variable clinical presentation

Histologic findings not specific
Imperfect association with p-ANCA (anti-MPO)
c-ANCA (anti-PR3) can be positive in MPA
Differentiation from WG may at times be difficult
granulomas are not always found in WG
Prominent involvement of the upper respiratory tract or the presence
of PR3-ANCA should seriously raise the possibility of WG

Churg Strauss Syndrome (CSS)

The syndrome defined by Churg and Strauss in 1951 has

undergone several redefinitions but is still characterized by
three histopathologic features:

necrotizing vasculitis
infiltration by eosinophils
extravascular granulomas

The 1994, Chapel Hill classification defined the disease as

an eosinophil-rich and granulomatous inflammation involving the

respiratory tract
necrotizing vasculitis involving the medium-sized vessels
associated with asthma and eosinophilia

Churg-Strauss syndrome:
bowel (photomicrograph)

CSS: Clinical Features

CSS is characterized by three distinct phases

Prodrome, dominated by allergic features, is common in patients

ultimately diagnosed with CSS
Allergic rhinitis and asthma may often precede diagnosis of
vasculitis by 3 to 7 years
Systemic vasculitis

CSS: Organ Involvement

Pulmonary Disease

Nervous System Involvement

Peripheral neurologic involvement often dominates the clinical picture

and has been reported in the majority of patients

Renal Disease

Pulmonary infiltrates
Pleural effusions (often eosinophilic)
Pulmonary hemorrhage

Kidney involvement is less common in CSS than MPA or WG

Skin involvement

has often led to confusion, for the term Churg-Strauss granuloma may
be seen in other disorders
Palpable purpura has been observed in nearly 50 percent of CSS
patients

Diagnostic Approach to Small Vessel Vasculitis

Vasculitis suspected (lung-renal
syndrome, purpura, neuropathy)

Not ANCA associated

ANCA associated
Granulomatous

IgA deposit

Yes

No

Yes

No

Asthma/eosinophilia

MPA

HSP

Cryoglobulins

Yes

No

CSS

WG

Yes
Cryoglobulinemia

No
Other

Summary

ANCA-associated vasculitides are still rare but lifethreatening disorders

ANCA testing is yet to fully standardized
ANCA-associated vasculitides may present with lungrenal syndromes often with neurologic, ocular or
cutaneous manifestations
MPA and WG may be hard to separate when the clinical
presentation is incomplete
CSS appears to be a more distinctive disorder
The treatment approach is similar and largely successful
Relapse and long-term morbidity are still serious issues