DISEASEOF THE MONTH

ANCA Small-Vessel Vasculitis

RONALD J. FALK* and J. CHARLES JENNETTEt

*Department of Medicine and �Department of Pathology and Laboratory Medicine, University of North

Carolina at Chapel Hill, Chapel Hi!!, North Carolina.

Small-vessel vasculitis (SVV) that is injurious to the kidney

includes immune complex-mediated vasculitis, such as He-

noch-Sch#{246}nlein purpura and cryogbobulinemic vasculitis, and

necrotizing vasculitis associated with anti-neutrophil cytoplas-

mic autoantibodies (ANCA), such as microscopic polyangiitis

and Wegener’s granubomatosis. The most frequent renal lesion

caused by SVV is glomerubonephritis, whereas barge-vessel

vasculitis (LVV) and medium-sized-vessel vasculitis (MVV)

do not cause glomerubonephritis but may cause renal dysfunc-

tion secondary to ischemia.

In 1993, the Chapel Hill Consensus Conference for the

Nomenclature of Systemic Vasculitis ( 1 ) agreed on the names

and definitions of many vasculitides that affect the kidneys

(Table 1 ). These names and definitions are used in this review.

LVV, such as giant-cell arteritis and Takayasu arteritis, rarely

cause clinically significant renal disease (2). When a LVV does

cause renal dysfunction, it is usually in the form of the reno-

vascular hypertension secondary to disease in the main renal

arteries or in the aorta at the ostia of the renal arteries. MVV,

including pobyarteritis nodosa and Kawasaki disease, results in

necrotizing inflammation of arteries without inflammation in

vessels other than arteries, including no glomerulonephritis (2).

MVV may cause aneurysmal dilation, thrombosis, and rupture

of renal arteries, resulting in infarction and hemorrhage (1,2).

Patients with pauci-immune SVV, such as microscopic poly-

angiitis, Wegener’s granubomatosis, and Churg-Strauss syn-

drome, have a high frequency of ANCA (1,2). ANCA react

with cytoplasmic constituents of neutrophils and monocytes

(3,4). Approximately 90% of cytoplasmic-staining ANCA

(C-ANCA) react with a serine proteinase called proteinase 3

(PR3-ANCA). In patients with SVV, approximately 90% of

perinuclear-staining ANCA (P-ANCA) react with myeboper-

oxidase (MPO-ANCA). In ANCA-positive patients who do not

have SVV or gbomerubonephritis, such as patients with ulcer-

ative colitis, primary sclerosing choleangiitis, or Felty’s syn-

drome, many P-ANCA have specificity for antigens other than

MPO, such as lactoferrin and elastase.

PR3-ANCA are most common in patients with Wegener’s

granubomatosis, but are not specific for this disease. Our own

data, as well as that of a recent European vascubitis study group

(E. Christiaan Hagen, personal communication), indicate that

Correspondence to Dr. Ronald J. Falk. UNC School of Medicine, Division of

Nephrology and Hypertension, 349 MacNider Bldg./CB 7155, Chapel Hill, NC27599-7155.

1046-6673/0802-03 14$03.00/0

Journal of the American Society of NephrologyCopyright U 1997 by the American Society of Nephrology

approximately 65% of patients with Wegener’s granubomatosis

have PR3-ANCA and approximately 20% have MPO-ANCA

(Table 2). PR3-ANCA are also found in patients with micro-

scopic polyangiitis and necrotizing gbomerulonephritis without

evidence for systemic SVV, although MPO-ANCA are more

common in these diseases. MPO-ANCA and PR3-ANCA oc-

cur in patients with Churg-Strauss syndrome, but relative fre-

quencies are poorly defined because of the small numbers of

patients who have been studied. Thus, although there are

different frequencies of PR3-ANCA and MPO-ANCA among

different types of SVV, neither ANCA subtype provides a

diagnostic test that allows for the diagnostic differentiation

among different phenotypes of ANCA-SVV. However, in a

patient with signs and symptoms of SVV, ANCA positivity

does confirm the presence of some form of ANCA-associated

SVV, which is often useful for directing management even if

the specific type of ANCA-SVV has not yet been determined.

Pathologic FeaturesThe characteristic acute vascular lesion of ANCA-SVV is

focal fibrinoid necrosis of vessels with associated leukocyte

infiltration, frequently with leukocytoclasia. In a given patient,

this lesion may affect any or all of the following vessels:

arteries, arterioles, venules, and capillaries, especially gbomer-

ular capillaries and pulmonary alveolar capillaries (2,5). The

major clinicopathologic categories of systemic ANCA-vascu-

bitis are microscopic polyangiitis, Wegener’s granubomatosis,

and Churg-Strauss syndrome. Crescentic gbomerubonephritis is

a frequent component of systemic ANCA-vasculitis, and also

occurs as a renal-limited form of ANCA-vasculitis (ANCA-

ON). Microscopic polyangiitis, Wegener’ s granulomatosis,

and Churg-Strauss syndrome all share pathologically identical

necrotizing inflammation in small vessels. Wegener’s granu-

bomatosis is distinguished by the presence of necrotizing gran-

ubomatous inflammation, Churg-Strauss syndrome by the pres-

ence of asthma and eosinophilia, and microscopic pobyangiitis

by the absence of granulomatous inflammation and asthma

(Table 1). Severe necrotizing gbomerulonephritis is a frequent

component of the vascular inflammation in Wegener’s granu-

lomatosis and microscopic polyangiitis, but necrotizing gb-

merulonephritis is less frequent and usually less severe in

Churg-Strauss syndrome.

In the kidneys of patients with any type of ANCA-SVV,

gbomerular capillaries are affected most often, resulting in

necrotizing glomerubonephritis, usually with crescent forma-

tion (Figure 1 , A and B). Arterioles, arteries, and interstitial

capillaries/venubes (especially medullary vasa recta) may also

be involved (Figure 1 , C and D). Interlobular and arcuate

Large-vessel vasculitis

giant-cell (temporal) arteritis

Takayasu arteritis

Medium-sized vessel vasculitis

polyarteritis nodosa

Kawasaki disease

Small-vessel vasculitis

Wegener’ 5 granulomatosis

Churg-Strauss syndrome

microscopic polyangiitis

Henoch-Sch#{246}nbein purpura

essential cryoglobubinemic vasculitis

cutaneous leukocytoclastic angiitis

ANCA Small-Vessel Vasculitis 315

ANCA-SVV typically has an absence or paucity of immu-

Table 1. Names and definitions of vasculitis adopted by the Chapel Hill Consensus Conference on the Nomenclature of

Systemic Vasculitisa

Granubomatous arteritis of the aorta and its major branches, with a

predilection for the extracranial branches of the carotid artery. Often

involves the temporal artery. Usually occurs in patients older than 50

and is often associated with polymyalgia rheumatica.

Granulomatous inflammation of the aorta and its major branches. Usually

occurs in patients younger than 50.

Necrotizing inflammation of medium-sized or small arteries without

gbomerulonephritis or vasculitis in arterioles, capillaries, or venules.

Arteritis involving large, medium-sized, and small arteries, and associated

with mucocutaneous lymph node syndrome. Coronary arteries are often

involved. Aorta and veins may be involved. Usually occurs in children.

Granulomatous inflammation involving the respiratory tract, and necrotizing

vasculitis affecting small- to medium-sized vessels, e.g., capillaries,

venules, arterioles, and arteries. Necrotizing glomerulonephritis is

common.

Eosinophib-rich and granubomatous inflammation involving the respiratory

tract and necrotizing vasculitis affecting small- to medium-sized vessels,

and associated with asthma and blood eosinophibia.

Necrotizing vascubitis with few or no immune deposits, affecting small

vessels, i.e., capillaries, venubes, or arterioles. Necrotizing arteritis

involving small- and medium-sized arteries may be present. Necrotizing

glomerulonephritis is very common. Pulmonary capi!laritis often occurs.

Vascubitis with immunogbobubin A-dominant immune deposits, affecting

small vessels, i.e. , capillaries, venules, or arterioles. Typically involves

skin, gut, and glomeruli, and is associated with arthralgias or arthritis.

Vasculitis with cryogbobubin immune deposits, affecting small vessels, i.e.,

capillaries, venules, or arterioles, and associated with cryogbobulins in

serum. Skin and glomeruli are often involved.

Isolated cutaneous beukocytoclastic angiitis without systemic vasculitis or

glomerulonephntis.

a The ANCA-associated vasculitides are Wegener’s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. (Modified

from Jennette et al. [I] with permission.).

Table 2. Approximate frequencies of PR3-ANCA (C-ANCA) and MPO-ANCA (P-ANCA) in patients with

glomerulonephritis caused by Wegener’s granubomatosis (WG), microscopic polyangiitis (MPA), and

pauci-immune necrotizing and crescentic gbomerubonephritis without systemic vascubitis (NCON)

ANCA Result WG MPA NCGN

Positive PR3-ANCAIC-ANCA 65 to 75% 35 to 45% 30 to 40%

Positive

Negative

MPO-ANCA/P-ANCA

ANCA

15

10

to 25%

to 20%

45

10

to 55%

to 20%

60 to 70%

10 to 20%

arteries are affected more often than larger arteries, but a few SVV. Necrotizing leukocytoclastic angiitis in medullary vasa

patients with ANCA-SVV will have involvement of interbobar recta may be very severe, and can result in papillary necrosis

and even main renal arteries. The renal necrotizing arteritis of and hemorrhage. The frequency of the medulbary angiitis is

ANCA-SVV is indistinguishable histologically from that of difficulty to know because it is not always sampled in renal

necrotizing MVV, such as polyarteritis nodosa; however, the biopsy cores, which purposefully have more cortex than me-

absence of inflammation in vessels other than arteries (e.g. , dulla.

gbomerubar capillaries) distinguishes the MVV from ANCA-

316 Journal of the American Society of Nephrology

Figure 1. Renal histologic manifestations of ANCA-SVV. (A) Early segmental glomerular fibrinoid necrosis with slight adjacent epithelialproliferation (periodic acid-Schiff stain). (B) Large cellular crescent with focal disruption of Bowman’s capsule at the bottom of the photograph

(periodic acid-Schiff stain). (C) Necrotizing inflammation involving two interlobular arteries (arrow, f,brinoid necrosis; Masson trichrome

stain). (D) Leukocytoclastic angiitis affecting the medullary vasa recta (hematoxylin and eosin stain).

nohistologic staining for immunogbobubins at sites of vasculitis

and gbomerubonephritis. This “pauci-immune” appearance is in

contrast to the characteristic granular immunoglobulin staining

of immune complex-mediated disease and the linear immuno-

globulin staining of anti-gbomerular basement membrane (anti-

GBM) antibody-mediated disease. Although ANCA are much

more common in patients with pauci-immune necrotizing gb-

merulonephritis and vasculitis, patients with anti-GBM gb-

merulonephritis (6) and immune-complex crescentic gbomeru-

bonephritis (7) have a higher frequency of ANCA than healthy

control subjects. Approximately 20% to 30% of patients with

either crescentic immune-complex gbomerubonephritis or anti-

GBM gbomerulonephritis have ANCA. In patients with anti-

GBM disease, the presence of ANCA correlates with the

development of vasculitis that is not seen with anti-GBM

disease alone, such as arteritis, arteriobitis, and venulitis in a

distribution typical for ANCA-vasculitis. In patients with im-

mune-complex gbomerulonephritis, the presence of ANCA cor-

rebates with a greater likelihood of crescent formation and

systemic vasculitis. For example, membranous gbomerulopathy

patients with ANCA often develop crescent formation and

rapidly progressive disease. This suggests that ANCA can

synergize with immune-complex localization to induce more

severe inflammation.

How “pauci-immune” is the gbomerulonephritis in patients

with ANCA-SVV and ANCA-GN? In a recent evaluation of

21 3 patients with glomerulonephritis and crescent formation

(excluding patients with bupus nephritis and anti-GBM dis-

ease), we concluded that, to be at least 80% predictive of

ANCA disease, “pauci-immune” should be defined as 2+ or

less staining for any immunogbobubin (on a scale of 0 to 4+)

and absence of immune complex-type electron-dense deposits

by electron microscopy (Figure 2) (7).

During the acute phase of disease, ANCA-SVV is charac-

terized by fibrinoid necrosis and neutrophilic infiltration. This

manifests in gbomeruli as segmental necrosis and crescent

formation. If the patient survives, these acute lesions evolve

into chronic sclerotic lesions with predominantly mononuclear

leukocyte infiltrates. For example, acute gbomerular injury

evolves into focal segmental gbomerular scarring or diffuse

#{149}IFAssay

LJELISA

liii

ANCA Small-Vessel Vasculitis 317

100

90

� 80

� 7000.60

(.)

z440

� 30

� 20

a.

0

0 0.5-1+ 1.5-2+ 2.5-3+ 3.5-4+(n=92) (n=72) (n=19) (n=17) (n=13)

Maximum intensity of glomerular staining for any immunoglobulin

Figure 2. The frequency of ANCA positivity by indirect immunoflu-orescence microscopy assay (IF assay) and enzyme immunoassay for

anti-PR3 or anti-MPO (ELISA) in patients with crescentic glomeru-

lonephntis, relative to the intensity of direct immunofluorescence

microscopy gbomerubar staining for immunoglobulin (excluding bupus

nephritis and anti-GBM nephritis patients). Note that the highest

frequency of ANCA is in the patients with the most “pauci-immune”

crescentic glomerulonephritis, but that patients with crescentic im-

mune-complex glomerulonephritis do have a higher frequency of

ANCA than healthy individuals (who have a frequency of <5%).

global gbomerular scarring, depending on the severity of the

acute injury (Figure 3).

The lungs are frequently affected by ANCA-SVV. Acute

pulmonary lesions that occur in all types of ANCA-SVV

include necrotizing inflammation of alveolar capillaries, arte-

rioles, arteries, veins, and venules (8,9). Necrotizing granulo-

matous inflammation occurs in patients with Wegener’s gran-

ulomatosis and Churg-Strauss syndrome, and may involve

vessels and airways. The acute inflammatory pulmonary injury

evolves into more chronic lesions, such as interstitial fibrosis

and bronchiobitis obliterans-organizing pneumonia. No partic-

ular pulmonary lesion is specific for either C-ANCA or

P-ANCA-positive patients; however, necrotizing granuboma-

LIGHT MICROSCOPIC MORPHOLOGY

FOCALSCLEROSING CN � CHRONIC GN

i\ INFOCAL � � NECROSIS AND � CRESCENTIC � END STAGENECROSIS FEW CRESCENTS GN KIDNEY

HEMATURIA and/or ACUTE RAPIDLY SLOWLY

PROTEINURIA NEPHRITIS PROGRESSIVE PROGRESSIVENEPHRITIS NEPHRITIS

CLINICAL PRESENTATiON

Figure 3. The relationship between the severity and stage of patho-

logic injury and the clinical manifestations of ANCA-GN. Note that

there are transitions over time between different pathologic and din-

ical phenotypes.

tous inflammation is more commonly found in C-ANCA pa-

tients.

The tissue distribution of the inflammatory lesions of

ANCA-SVV is extremely varied among patients, resulting in a

wide variety of clinical manifestations. In addition to nephritis

caused by glomerular inflammation and pulmonary hemor-

rhage caused by alveolar capillaries or granulomatous inflam-

mation, patients may have purpura caused by dermab leukocy-

toclastic angiitis, mononeuritis multiplex caused by perineural

and epineural artenolitis and arteritis, myalgias caused by

arteriolitis and arteritis in skeletal muscles, and abdominal pain

caused by venulitis, arteriolitis, and arteritis in abdominal

viscera, such as the gut, liver, pancreas, and spleen.

Clinical FeaturesANCA-SVV is more common in Caucasians than African

Americans, with a ratio of approximately 7.5: 1 . Women and

Men are equally affected, and although patients are usually 55

yr of age or older, patients of any age may develop ANCA-

Svv (10-12). The clinical renal manifestations vary according

to the severity and stage of the underlying renal injury (Figure

3). Hematuria with dysmorphic red blood cells and red blood

cell casts is a frequent clinical feature. Proteinuria tends to be

in the subnephrotic range, with a mean of 2 to 3 g/day,

although some patients have as little proteinuria as 0.5 g/day

and as much as 20 g/day. Although the presentation of ANCA

gbomerulonephritis is frequently that of rapidly progressive

glomerubonephritis, the syndrome of asymptomatic hematuria

with minimal amounts of proteinuria or acute nephritis is

common as well. Unfortunately, at their first presentation,

many patients already require dialysis because of chronic gb-

merubonephritis and severe glomerular sclerosis, and intersti-

tial fibrosis indicative of ESRD. This circumstance is often the

result of a delay in referring the patient to a nephrologist for

management.

Nephrologists are confronted with the diagnostic dilemma of

whether a renal biopsy is essential for the management of

ANCA-GN and ANCA-SVV. The answer to this question is

predicted on several variables, including the features of the

clinical syndrome, the accuracy of the ANCA serologic meth-

odobogy, and most importantly, the form of therapy that will be

used. Some investigators have concluded that PR3-ANCA and

MPO-ANCA assays can have a sensitivity for pauci-immune

necrotizing and crescentic glomerubonephritis ranging between

95% and 100%, with a specificity in excess of 99% (13). If

patients who have strong clinical evidence for ANCA-SVV are

tested with such a high-quality assay system, the positive

predictive value of the ANCA result is greater than 99% (14).

Thus, expert ANCA testing may obviate pathological confir-

mation of ANCA-SVV or ANCA-GN especially in some emer-

gency situations. For instance, in a patient who presents with

pulmonary hemorrhage who requires ventilator support, and

who has red blood cells and red blood cell casts in the urine, a

rapidly rising creatinine concentration, and palpable purpura,

renal biopsy may be unnecessary if the ANCA test is positive.

However, despite the contention by some that ANCA serobog-

ical testing has “come of age,” not all laboratories perform

antigen-specific ANCA assays, and the sensitivity and speci-

318 Journal of the American Society of Nephrology

ficity for PR3-ANCA and MPO-ANCA testing vary among

assay systems. Therefore, clinicians must have knowledge of

the capabilities of the laboratory that is performing their

ANCA testing before they can decide how much weight to give

the test result in their management decisions.

If patients with ANCA-SVV and ANCA-ON could be

treated effectively with innocuous drugs, theoretically, the

clinician could decide to treat the patient empirically without

exhaustive confirmation of the diagnosis. However, because

ANCA-SVV and ANCA-ON are typically treated with potent

anti-inflammatory and immunosuppressive drugs that predis-

pose to life-threatening infections and risk of mutagenesis, it is

our contention that a renal biopsy or other tissue confirmation

is called for whenever possible. An integration of clinical

manifestations, pathologic findings, and serologic data is re-

quired in order to provide optimum information for meaningful

patient-informed consent and for treatment decisions.

In addition to ANCA-SVV, the differential diagnosis for

patients with signs and symptoms of a systemic disease affect-

ing small vessels often includes systemic immune-complex

diseases, such as systemic bupus erythematosus, Henoch-

Sch#{246}nlein purpura, and cryogbobulinemic vasculitis, as well as

the thrombotic microangiopathies and atheroembolization.

Careful clinical, pathologic, and serologic evaluation should

distinguish among these systemic vascubopathies.

Pulmonary-Renal Vasculitic Syndrome

ANCA-SVV has a predilection for the capillary beds of the

respiratory tract (2,9, 15). At least 50% of patients with

ANCA-ON have pulmonary disease spanning the spectrum

from severe life-threatening pulmonary hemorrhage to fleeting

alveolar infiltrates. Among patients with ANCA-ON, 10%

have massive pulmonary hemorrhage, with a mortality rate of

50%. The majority of patients with ANCA-SVV present with

focal or diffuse pulmonary infiltrates with variable amounts

of hemoptysis. In other patients-especialby those with

Wegener’ 5 granubomatosis-pulmonary nodules, cavities, al-

veobar opacities, or diffuse ground-glass opacities are observed

radiographically. Because these parenchymal opacities are ill-

defined at times, routine chest x-rays miss smaller nodular or

cavitary lesions that are best seen on fine-cut computed tomog-

raphy. This form of imaging is a more sensitive approach to

unravel the pulmonary manifestations of ANCA-SVV. Fiber-

optic bronchoscopy with transbronchiab lung biopsy is a useful

procedure in patients in whom a pathological confirmation of

a SVV cannot be made by kidney or upper respiratory tract

biopsy. There may be no renal involvement at the onset of

a SVV. For example, among the first 158 patients studied at

the National Institutes of Health, only 18% of those with

Wegener’s granulomatosis presented with evidence for gbomer-

ubonephritis; however, renal involvement eventually occurred in

77% of patients, usually in the first 2 yr of illness (16).

Upper respiratory tract symptoms of ANCA-SVV include

necrotizing lesions of the nose, sinus, and ear (17). These

lesions are found not only in patients with Wegener’s granu-

lomatosis, but also in patients with microscopic polyangiitis.

Oranubomatous inflammation of the trachea, usually in the

subgbottic region, results in unilateral or bilateral edema, in-

flammation, fibrosis, and tracheal stenosis. The clinical picture

is that of stridor and dyspnea that requires persistent bong-term

immunosuppressive therapy.

The differential diagnoses of pulmonary-renal vascubitic

syndromes other than ANCA-SVV includes anti-OBM disease

(Ooodpasture’s syndrome) and some forms of immune-com-

plex diseases, such as systemic bupus erythematosus. Renal

histology is a definitive means of separating the diagnostic

possibilities. Serological studies-including tests for antinu-

clear antibodies, anti-double-stranded DNA, low serum com-

plement levels, cryogbobulins, hepatitis C antibodies, and anti-

GBM antibodies-are useful for suggesting the appropriate

diagnosis. One should bear in mind that 20% to 30% of

patients with anti-OBM disease also are ANCA-positive and

are at risk for developing any of the manifestations of ANCA-

SVV. Thus, patients with pulmonary-renal vascubitic syndrome

who have anti-OBM antibodies should also be tested for

ANCA, and vice versa.

A difficult differential diagnosis occurs in patients with

ANCA-SVV or ANCA-ON who, during treatment, develop

pulmonary infiltrates with or without hemoptysis. Recurrent

vascubitis must be differentiated from infection, especially fun-

gab or mycobacteria tuberculosis. A high ANCA titer in such a

patient is not definitive evidence for pulmonary vascubitis. A

negative ANCA result makes pulmonary vascubitis less likely.

Bronchoscopy, including bronchial alveolar lavage, may help

differentiate infection from vascubitic alveolar hemorrhage.

Similarly, infections of the upper respiratory tract can mimic

vasculitic lesions in the nose, sinus, and ear. Fiberoptic trans-

lumination of the upper airways with biopsy is useful for

identifying infections and vascular inflammation.

Renal-Dermal Vasculitic Syndrome

Renal-dermal vasculitic syndromes include Henoch-Sch#{246}n-

lein purpura, cryogbobulinemia vasculitis, systemic bupus ery-

thematosus, and ANCA-SVV (18). Common dermal vasculitic

findings in ANCA-SVV are palpable purpura (usually in the

lower extremities), petechia, ulcers, nodules, ecchymoses, and

bullae. Urticaria is a much more common manifestation of

SVV in the skin than was previously realized. The clinical

syndrome of palpable purpura, nephritis, and ANCA is nearly

diagnostic for ANCA-SVV, although tissue confirmation of

vasculitis is comforting before the institution of toxic immu-

nosuppression treatments. In a patient with renab-dermal vas-

culitic syndrome, biopsy demonstration of immunoglobulin

A-dominant immune deposits in either dermal vessels or gb-

meruli is diagnostic for Henoch-Sch#{246}nlein purpura. A renal

biopsy will include or exclude cryogbobulinemic gbomerubone-

phritis or lupus nephritis. The resolution of the differential

diagnosis in patients with renal-dermal vasculitic syndromes is

very important because the prognosis and appropriate treat-

ments are quiet different among the diagnostic possibilities,

i.e., Henoch-Sch#{246}nbein purpura, cyoglobulinemic vasculitis,

systemic bupus erythematosus, and ANCA-SVV. For example,

a 25-yr-old patient with purpura and nephritis who has He-

noch-Sch#{246}nbein purpura usually does not require aggressive

immunosuppression, whereas a patient with the same clinical

ANCA Small-Vessel Vasculitis 319

a Reprinted from Hogan et a!. (1 1) with permission.

presentation who has ANCA-SVV is at risk for life-threatening

organ injury if not promptly and appropriately treated.

Other Organ System Involvement

The most common neurological manifestation of ANCA-

SVV is peripheral neuropathy, typically manifesting as mono-

neuritis multiplex. Occasionally, patients have central nervous

system inflammation, especially granubomatosis meningial in-

flammation, which may be observed on magnetic resonance

imaging. Patients may develop seizures, which will respond to

immunosuppressive treatment.Gastrointestinal disease, found in one third of patients with

ANCA-SVV, may present with gastric or peptic ulcers de-

tected by endoscopic examination. Vasculitis of the small and

large intestine results in gastrointestinal bleeding, or-if Se-

vere-perforation of the viscus as a consequence of transmurab

infarction.

Iritis, uveitis, and episcieritis result in painful, red eyes.

These lesions are frequently present in a “subclinical” fashion

and require slit-lamp ophthalmologic evaluation for recogni-

tion.

Almost all patients have a prodrome of a “flu-bike illness”

with malaise, myalgias, and arthralgias, which is probably

mediated by the increased systemic levels of cytokines released

from the sites of inflammation. The arthralgias often migrate

from joint to joint.

OutcomeSeveral studies have examined prognostic factors in ANCA-

SVV (11,19). These studies point to the entry-level serum

creatinine value, the presence of pulmonary disease, the sever-

ity of renal disease, and even the initial white blood cell count

as important predictors of outcomes. In our own studies ( 1 1),

the most important determinant of patient survival was the

presence or absence of pulmonary hemorrhage (Table 3). The

presence of any pulmonary symptoms-that is, pulmonary

infiltrates, nodules, or cavities-did not increase the risk of

death. The risk of ESRD was largely attributable to the entry-

level serum creatinine value, even when such variables as the

presence or absence of extrarenal disease and the presence or

absence of pulmonary findings were incorporated into the

model. Crescents and necrosis found on renal biopsy did not

add to the predictive power of the model. Interstitial fibrosis on

renal biopsy was an independent risk factor in individuals with

an entry-level creatinine concentration of <3 mg/dL, whereas

in individuals with serum creatinine concentrations greater

than 4.5 mg/dL, tububointerstitiab injury was present.

TreatmentInduction Therapy

Because renal prognosis appears to be determined by early

treatment, it is reasonable to induce suppression of the vascular

inflammation promptly with aggressive therapy that usually

includes high-dose corticosteroids and cycbophosphamide. Our

approach is to give patients 7 mg/kg per day of methylpred-

nisobone for 3 days, followed by daily oral prednisone.

Whether plasmapheresis and methylprednisobone are equally

good induction therapies, or whether plasmapheresis adds ad-

ditional benefit to methylprednisobone as a means of induction

therapy is currently under study (20). Cycbophosphamide is

administered either intravenously or orally. Intravenous cycbo-

phosphamide is administered on a monthly basis beginning at

a dose of 0.5 g/m2, with adjustment of the dose upward to 1

g/m2 on the basis of 2-wk beukocyte counts ( 10, 12). Oral

cycbophosphamide should begin at a dose of 2 mg/kg per day

(2 1 ). Prednisone is administered at a dose of 1 mg/kg for the

first month, which is tapered to alternate-day therapy in the

second month, with cessation of prednisone therapy at the end

of the third to fourth months. All forms of cycbophosphamide

dosage should be titrated to the beukocyte count. Special atten-

tion to the beukocyte count must be monitored while the patient

is on tapering doses of prednisone, because cycbophosphamide

dosage may need to be adjusted downward as the prednisone

dose is decreased. This induction therapy can be initiated while

clinicians wait for renal biopsy or serologic study results.

The optimal length of cycbophosphamide therapy has not

been determined. It is clear that indefinite treatment with

cycbophosphamide is associated with prohibitable risks, includ-

ing a 15% incidence of transitional cell carcinoma in the

bladder in those patients treated with long-term oral cyclophos-

phamide (22). In patients achieving complete remission within

6 months of therapy, treatment can be stopped under the

provision that there is close patient follow-up. In those mdi-

viduals with persistently active disease at 6 months, it is

Table 3. Predictors of disease-related death in patients with ANCA-positive microscopic polyangiitis (MPA) and ANCA-

positive necrotizing and crescentic gbomerubonephritis (NCGN)�

.Predictor

Relative Risk ofDeath

95% ConfidenceInterval

Value

Pulmonary hemorrhage (present versus absent) 8.64 (3.36 to 22. 19) 0.0002

Any pulmonary symptoms (present versus absent) 2.36 (0.80 to 6.95) 0.16

Disease category (MPA versus NCGN alone) 1 .68 (0.48 to 5.82) 0.61

ANCA pattern (C-ANCA versus P-ANCA) 3.78 (1 .22 to I 1 .70) 0.031

Race (African American versus Caucasian) 2.41 (0.75 to 7.77) 0.34

Treatment (cyclophosphamide versus 0. 18 (0.05 to 0.66) 0.0 12

corticosteroids alone)

320 Journal of the American Society of Nephrology

a Reprinted from Nachman et a!. (12) with permission.

reasonable to continue cyclophosphamide therapy for a full 12

months. Another possible protocol utilizes cycbophosphamide

as the immunosuppressive agent for the first 3 months of

treatment and then azathioprine (2 mg/kg) for the duration of

the therapy (23). Most patients may stop this form of therapy

after a total of 6 to 12 months of treatment.

Intravenous and oral cyclophosphamide appear to have

equal efficacy in inducing remission. Whether oral cycbophos-

phamide treatment results in a decrease in the relapse rate when

compared with intravenous cycbophosphamide remains an is-

sue for study. Intravenous cyclophosphamide allows for a

smaller total dose of cyclophosphamide than the oral regimen.

As a consequence, there is a threefold decrease in both minor

and major infections. The most bothersome feature of cyclo-

phosphamide therapy, however, is the long-term mutagenic

risk, especially the risk of induction of transitional cell carci-

noma of the bladder (22). Gonadal toxicity in women over the

age of 35 yr results in premature menopause.

Because cycbophosphamide is toxic, the question arises

whether prednisone is an adequate treatment option; however,

the requirement of cycbophosphamide as a necessary adjunct to

prednisone has been appreciated for years (21). In our own

studies, we have determined that treatment with prednisone

alone resulted in a three-fold increased risk of relapse when

compared with treatment with cyclophosphamide (12). Thus,

patients with ANCA-SVV who are not dialysis-dependent

should be treated with combination therapy including cycbo-

phosphamide.

Alternative Treatment Strategies

DeRemee and colleagues suggested that local-regional dis-

ease of the upper respiratory tract should be treated first with

trimethoprin-sulfamethoxazole and then with corticosteroid

therapy in the event of unsuccessful antibiotic therapy (24).

The rationale for this approach is based largely on empirical

data, but is supported by the fact that chronic nasal carriage of

Staphylococcus aureus is a risk factor for relapse in Wegener’s

granubomatosis (25). In 1985, DeRemee et a!. described their

results in treating patients with Wegener’s granubomatosis

(24). One hundred new patients with Wegener’s granubomato-

sis were treated with trimethoprin-sulfamethoxazole. Eleven of

these patients improved, four of them without concurrent or

previous immunosuppressive treatment. Most recently, Rein-

hold-Keller et a!. (26) studied 19 patients with Wegener’s

granulomatosis restricted to the upper and lower airways, and

found similar results. A prospective placebo-controlled trial

with tnmethoprin-sulfamethoxazole (960 mg twice daily) was

performed in 81 patients with Wegener’s granulomatosis (27).

In 19% of these patients, therapy was stopped because of side

effects. A statistically significant reduction in the number of

relapses was observed in the groups assigned to trimethoprin-

sulfamethoxazole, although the decrease in relapse rate was

limited to relapse in the upper respiratory tract, and not to

relapse in the lower respiratory tract or the kidney.

Conflicting data are beginning to emerge, however, in that a

randomized trial comparing methotrexate and trimethoprin-

sulfamethoxazole for maintenance of remission in 65 patients

with Wegener’s granulomatosis was recently completed (25).

In this study, generalized Wegener’s granubomatosis was

brought into remission by treatment with cyciophosphamide

and prednisone. The maintenance of remission was much more

effective with methotrexate therapy than with either tri-

methoprin-sulfamethoxazole or prednisone. In fact, tri-

methoprin-sulfamethoxazole and prednisone together seemed

to increase the chance of relapse. Thus, the use of trimethoprin-

sulfamethoxazole in patients with Wegener’ s granubomatosis is

still controversial.

Methotrexate may be a useful form of therapy for SVV,

especially in individuals with normal or near-normal renal

function, and in patients with vasculitis predominantly con-

fined to the kidneys (29). Methotrexate should not be used if

the patient’s serum creatinine concentration is greater than 2

mg/dL. Pooled intravenous y-gbobulin has been tried anecdot-

ally, not only for induction therapy but also for individuals

resistant to cyclophosphamide and azathioprine therapy. The

long-term role of these agents in the treatment of ANCA-SVV

awaits further investigation.

Remission and Relapse

The terms “remission” and “relapse” for ANCA-SVV pa-

tients are defined in Table 4 (1 1). ANCA-SVV and ANCA-ON

patients treated with either intravenous or oral cycbophospha-

mide have a long-term remission rate of between 60% and

85%. Relapse occurs in up to 40% of patients within a mean of

18 months after therapy has stopped. Relapse typically occurs

in the same organ system initially affected by the disease,

Table 4. Criteria for evaluating treatment responses in

patients with ANCA-SVV and ANCA�GNa

S Remission. Stabilization or improvement of renal function

(as measured by serum creatinine concentration), resolution

of hematuria, and resolution of extrarenal manifestations of

systemic vasculitis. Persistence of proteinuria was not con-

sidered indicative of persistence of disease activity.

. Remission by therapy. The achievement of remission

while still receiving immunosuppressive medication or cor-

ticosteroids given at a dose greater than 7.5 mg per day of

prednisone or its equivalent.

S Treatment resistance. (1) Progressive decline in renal

function with the persistence of an active urine sediment or

(2) persistence of new appearance of any extrarenal mani-

festation of vasculitis despite immunosuppressive therapy.

. Relapse. Occurrence of at least one of the following: (1)

rapid rise in serum creatinine concentration, accompanied

by an active urine sediment; (2) a renal biopsy demonstrat-

ing active necrosis or crescent formation; (3) hemoptysis,

pulmonary hemorrhage, or new or expanding nodules with-

out evidence for infection; (4) active vasculitis of the respi-

ratory or gastrointestinal tracts as demonstrated by endos-

copy with biopsy; (5) iritis or uveitis; (6) new mononeuritis

multiplex; or (7) necrotizing vasculitis identified by biopsy

in any tissue.

ANCA Small-Vessel Vasculitis 321

although new organ system involvement occurs as well. Re-

lapses in the kidney are heralded by the recurrence of micro-

scopic hematuria, red blood cell casts, and worsening renal

function. Fluctuations in the amount of proteinuria are not

good indicators of active disease, and may be related to gb-

merular sclerosis. Relapse in the lungs tends to occur in the

same locus as the site of original injury. Many patients’ re-

lapses are heralded by a recurrence in a migratory polyar-

thropathy.

How to best diagnose and treat relapse is a matter of sub-

stantial investigation. Table 4 provides some clinical indicators

that relapse is occurring. There is no consensus on the value of

ANCA titers for monitoring remission. Full-blown vasculitic

relapse should be treated with a repeat course of prednisone

and cycbophosphamide. In general, these patients require main-

tenance on long-term immunosuppression with cyclophospha-

mide, azathioprine, or methotrexate. Less ominous relapse of

the upper respiratory tract may be treated with prednisone

alone or perhaps with trimethoprin-sulfamethoxazole.

Serial ANCA Testing

The value of ANCA titers for disease monitoring has been

the subject of several investigations. ANCA titers rise during

relapse in 23% to 77% of patients (30,31). ANCA titers may

increase without overt clinical relapse, and in some patients,

persistently high ANCA titers are found during clinical remis-

sion. In addition, some patients have a clinical relapse that is

not associated with any rise in ANCA titers. At the very least,

however, a rise in ANCA titer should raise the possibility of a

relapse. The disappearance of ANCA is at least suggestive of

remission. Many serologic tests, including ANCA titers, may

have greater importance in some patients than in others. For

instance, in some patients, the ANCA titers may closely follow

the clinical disease course, whereas in other patients, ANCA

titers may not correlate well at all with clinical events. Perhaps

serial monitoring of different ANCA isotypes or affinities will

prove to be a useful approach in the future. As of now, ANCA

titers should not be used as a determinant for beginning or

altering immunosuppressive therapy.

Treatment of Dialysis-Dependent Patients

At least 20% of patients with ANCA-SVV and ANCA-ON

will require dialysis at the time of diagnosis. Half of these

patients may come off dialysis within 8 to 12 wk of therapy.

Which patient will remain on long-term dialysis or will have a

dialysis-free response is not clear at the initiation of dialysis.

The dialysis-free interval may last from as little as a few weeks

to 3 to 4 yr. The degree of immunosuppression warranted

during the first 12 wk of dialysis depends on the risk-to-benefit

ratio. It is our practice to treat dialysis-dependent patients for at

beast 8 to 12 wk with pulse methylprednisolone and oral

prednisone. If patients’ renal functions improve, we continue

corticosteroid treatment and institute cyclophosphamide ther-

apy. Whether plasmapheresis is a more effective way of in-

ducing dialysis-free intervals than methylprednisobone is not

yet known.

Transplantation

ANCA-ON and ANCA-SVV rarely recur after renal trans-

plantation. Recurrence is not confined to the transplanted kid-

ney, but may also recur in nonrenal sites, such as the upper and

lower respiratory tracts. The question of whether ANCA titers

need to normalize before renal transplantation has not been

resolved. In those patients who are in clinical remission with a

negative ANCA titer, transplantation should proceed. Delay of

transplantation may be warranted in patients who have had a

persistently negative ANCA titer, but who then develop a

marked rise in titer. In patients who have persistently high

ANCA titers but no clinical evidence for SVV, it is reasonable

to proceed with renal transplantation.

References1. Jennette IC, Falk Ri, Andrassy K. Bacon PA, Churg J, Gross

WL, Hagen EC, Hoffman GS, Hunder GG, Kallenberg CG,McCluskey RT, Sinico RA, Rees Al, van Es LA, Waldherr R,

Wiik A: Nomenclature of systemic vasculitides: Proposal of an

international consensus conference. Arthritis Rheum 37: 187-

192, 1994.

2. Jennette JC, Falk Ri: The pathology of vasculitis involving the

kidney. Am J Kidney Dis 24: 130-141, 1994.

3. Falk RI, Jennette JC: Anti-neutrophil cytoplasmic autoantibodies

with specificity for myeloperoxidase in patients with systemic

vasculitis and idiopathic necrotizing and crescentic glomerulo-

nephntis. N Engl J Med 318: 1651-1657, 1988.

4. Hagen EC, Ballieux Be, van Es LA, Daha MR, van der Woude

FJ: Antineutrophil cytoplasmic autoantibodies: A review of the

antigens involved, the assays, and the clinical and possible patho-

genetic consequences. Blood 81: 1996-2002, 1993.

5. Jennette IC, Wilkman AS, Falk RI: Anti-neutrophil cytoplasmic

autoantibody-associated glomerulonephritis and vasculitis. Am J

Pathol 135: 921-930, 1989.

6. Jennette JC, Wilkman AS, Tuttle RH, Falk Ri: How pauci-immune is ANCA-associated crescentic gbomerulonephritis(CGN)? [Abstract] J Am Soc Nephrol 7: 1735, 1996.

7. Short AK, Esnault VL, Lockwood CM: Anti-neutrophil cytoplas-

mic antibodies and anti-glomerular basement membrane antibod-

ies: Two coexisting distinct autoreactivities detectable in patients

with rapidly progressive glomerulonephritis. Am J Kidney Dis

26: 439-445, 1995.

8. Fienberg R, Mark El, Goodman M, McCluskey RT, Niles IL:

Correlation of antineutrophil cytoplasmic antibodies with the

extrarenal histopathology of Wegener’s (pathergic) granulomatosis

and related forms of vasculitis. Hu,n Pathol 24: 160-168, 1993.

9. Gaudin PB, Askin FB, Falk Ri, Jennette JC: The pathologicspectrum of pulmonary lesions in patients with anti-neutrophil

cytoplasmic antibodies specific for anti-proteinase 3 and anti-

myeloperoxidase. Am J C/in Pathol 104: 7-16, 1995.

10. Falk RI, Hogan 5, Carey TS, Jennette IC: Clinical course of

anti-neutrophil cytoplasmic autoantibody-associated glomerulo-nephritis and systemic vasculitis: The Glomerular Disease Col-

laborative Network. Ann Intern Med I 13: 656-663, 1990.

1 1 . Hogan SL, Nachman PH, Wilkman AS, Jennette IC, Falk RJ, andthe Glomerular Disease Collaborative Network: Prognostic

markers in patients with ANCA-associated microscopic polyan-

giitis and glomerulonephritis. JAm Soc Nephrol 7: 23-32, 1996.

12. Nachman PH, Hogan SL, Jennette IC, Falk Ri: Treatment re-

sponse and relapse in ANCA-associated microscopic polyangiitis

and glomerulonephritis. J Am Soc Nephrol 7: 23-32, 1996.

322 Journal of the American Society of Nephrology

13. Niles IL, Pan G, Collins AB, Shannon T, Skates S, Fienberg R,

Arnaout MA, McCluskey RT : Value of antigen-specific radio-immunoassays for measuring anti-neutrophil cytoplasmic anti-

bodies (ANCA) in the differential diagnosis of rapidly progres-

sive glomerulonephritis. J Am Soc Nephrol 2: 27-36, 191.

14. Niles IL: A renal biopsy is essential for the management ofANCA-positive patients with gbomerulonephritis: The Contr

View. Sarcoidosis Vascu/itis and D�ffuse Lung Diseases 13:

232-234, 1995.

15. Bosch X, Lopez-Soto A, Mirapiex E: Antineutrophil cytoplasmic

autoantibody-associated alveolar capillaritis in patients present-

ing with pulmonary hemorrhage. Arch Patho/ Lab Med 118:517-518, 1994.

16. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS,Travis WD, Rottem M, Fauci AS: Wegener’s granulomatosis:

An analysis of 158 patients. Ann Intern Med 1 16: 488-498,

1992.

17. Andrassy K, Rasmussen N: Treatment of granulomatous disorders

of the nose and paranasal sinuses. Rhinology 27: 221-230, 1989.

18. Jennette IC, Milling DM, Falk RJ: Vasculitis affecting the skin:A review [Editorial]. Arch Dermatol 130: 899-906, 1994.

19. Savage CO, Winearls CG, Evans DI, Rees Al, Lockwood CM:Microscopic polyarteritis: Presentation, pathology and prognosis.

Q J Med 56: 467-483, 1985.

20. Pusey CD, Rees Al, Evans DI, Peters DK, Lockwood CM:

Plasma exchange in focal necrotizing gbomerubonephritis without

anti-GBM antibodies. Kidney Int 40: 757-763, 1991.2 1 . Fauci AS, Katz P, Haynes BF, Wolff SM: Cycbophosphamide

therapy of severe systemic necrotizing vasculitis. N EngI J Med

301: 235-238, 1979.

22. Tarlar-Williams C, Hijazi Y, Walther M, Linehan WM, Hallahan

CW, Lubensky I, Kerr GS, Hoffman GS, Fauci AS, Sneller MC:

Cyclophosphamide-induced cystitis and bladder cancer in pa-

tients with Wegener’s granulomatosis. Ann Intern Med 124:

477-484, 1996.

23. Gaskin 0, Savage CO, Ryan II, Jones S, Rees AJ, Lockwood

CM, Pusey CD: Anti-neutrophil cytoplasmic antibodies and dis-

ease activity during long-term follow-up of 70 patients with

systemic vasculitis. Nephro/ Dia/ Transp/ant 6: 689-694, 1991.

24. DeRemee RA, McDonald TI, Weiland LH: Wegener’s granulo-

matosis: Observations on treatment with antimicrobial agents.

Mayo C/in Proc 60: 27-32, 1985.

25. Stegemann CA, Cohen-Tervaert 1W, Sluiter WI, Manson WL, de

long PE, Kallenberg CGM: Association of chronic nasal carriage

of Staphylococcus aureus and higher relapse rates in Wegener’ s

granulomatosis. Ann Intern Med 120: 12-17, 1994.

26. Reinhold-Keller E, Dc Groot K, Rudert H, N#{246}lleB, Heller M,

Gross WL: Response to trimethoprin-sulfamethoxazole in We-

gener’s granulomatosis depends on the phase of disease. Q J Med

89: 15-23, 1996.

27. Stegman CA, Cohen Tervaert 1W, de long PE, Kallenberg CGM:

Trimethoprin-sulfamethoxazole for the prevention of relapses of

Wegener’s granubomatosis. N Engl J Med 335: 16-20, 1996.

28. De Groot K, Reinhold-Keller E, Tatsis E, Paulsen I, Heller M,

N#{246}lleB, Gross WL: Maintenance of remission therapy in 65

patients with generalized Wegener’s granubomatosis: Methotrex-

ate versus trimethoprin-sulfamethoxazole [Abstract]. Sarcoidosis

Vascu/itis and Diffuse Lung Diseases 13: 276, 1996.

29. Hoffman GS, Leavitt RY, Kerr GS, Fauci AS: The treatment of

Wegener’ S granulomatosis with glucocorticoids and methotrex-

ate.Arthritis Rheum 35: 1322-1329, 1992.

30. Cohen Tervaert 1W, Stegeman CA, Kallenberg CGM: Serial

ANCA testing is useful in monitoring disease activity of patents

with ANCA-associated vasculitides. Sarcoidosis Vascu/itis and

Diffuse Lung Disease 13: 241-245, 1996.

3 1 . DeOliveira J, Gaskin G, Dash A, Rees AJ, Pusey CD: Relation-

ship between disease activity and anti-neutrophil cytoplasmic

antibody concentration in long-term management of systemic

vascubitis. Am J Kidney Dis 25: 380-389, 1995.