Ocular Manifestations of Patients With Antineutrophil Cytoplasmic Antibodies Jose S. Pulido, MD; James A. Goeken, MD; Jeffrey A. Warren M. Sobol, MD; Robert Folberg, MD

Antineutrophil cytoplasmic antibodin patients with systemic vasculitides, especially Wegener's granulomatosis. Antineutrophil cytoplasmic antibodies are helpful laboratory markers for these diseases. We report on the ocular findings of six patients with systemic vasculitis who had antineutrophil cytoplasmic antibodies. Four patients had systemic Wegener's granulomatosis, one had microscopic polyarteritis, and in one a specific histopathologic diagnosis could not be made. Two patients were first evaluated for systemic vasculitis because of \s=b\

ies

are seen

their ocular manifestations. Ocular findings included ptosis, bilateral lacrimal gland masses, proptosis, choroidal folds, episcleritis, phlebitis, retinal and vitreous hemorrhage, keratitis sicca, and bilateral central scotomas. It was difficult to make a systemic diagnosis in all cases. If systemic vasculitis is in the differential diagnosis of a patient with suggestive ocular findings, antineutrophil cytoplasmic antibody testing should be considered. A prospective study of antineutrophil cytoplasmic antibody testing should be considered in patients with ocular findings that suggest the possibility of vasculitis.

(Arch Ophthalmol. 1990;108:845-850)

antibodies (ANCAs) have been shown to be associated with certain systemic

cytoplasmic Antineutrophil ^

vasculitides, especially Wegener's granulomatosis (WG) and microscopic polyarteritis (MPA), two diseases that frequently involve the respiratory Accepted for publication November 21, 1989. From the Departments of Ophthalmology (Drs Pulido, Nerad, Sobol, and Folberg) and Pathology (Drs Goeken and Folberg), The University of Iowa Hospitals and Clinics, Iowa City. Reprint requests to Department of Ophthalmology, The University of Iowa Hospitals and Clinics, Iowa City, IA 52242 (Dr Pulido).

Circulating

Nerad, MD;

tract, skin, eyes, and kidneys.13 Open lung biopsy is said to be the best method to diagnose WG; however, this

has significant morbidity and may still be nondiagnostic until the disease is fully developed systemically." An¬

tineutrophil cytoplasmic antibodies

may also be associated with other

vas-

culitides: Kawasaki's disease, ChurgStrauss syndrome, and idiopathic necrotizing segmentai crescentic glomerulonephritis.58 These diseases are diagnosed by both clinical and histopathologic criteria and in the absence of a laboratory marker, the diagnosis may be difficult because of significant overlap in both the clinical and histo-

pathologic findings.9 Antineutrophil cytoplasmic anti¬

bodies are detectable from the onset of vasculitis in many cases and within a month in most cases. A relatively sim¬ ple ANCA assay may be extremely useful as an early indicator of systemic vasculitis. In patients with ocular find¬ ings and little evidence of systemic disease, ANCA titers may assist the ophthalmologist in deciding if invasive biopsies to establish a diagnosis of vasculitis are indeed warranted. To the best of our knowledge, there are no re¬ ports in ophthalmic literature regard¬ ing positive ANCA titers and systemic vasculitis in patients with ophthalmic signs. We wish to draw attention to the use of ANCA titers and to report on six patients seen in the Department of Ophthalmology at the University of Iowa Hospitals and Clinics, Iowa City, who had ophthalmic signs, systemic vasculitis, and positive ANCA titers. MATERIALS AND METHODS

All patients described were referred to the Department of Ophthalmology, The

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University of Iowa Hospitals and Clinics, for the evaluation of ocular symptoms. An¬ tineutrophil cytoplasmic antibody titers were peformed in the Immunopathology Laboratory.

Two different ANCA specificities have been identified thus far. These produce dif¬ ferent patterns of staining of the ethanolfixed neutrophils used as the substrate for this indirect immunofluorescence assay. The perinuclear pattern has been shown to be linked with antimyeloperoxidase, while the cytoplasmic pattern has been report¬ edly linked to antiproteinase 3.610 Both en¬ zymes are found in the primary granule of neutrophils and monocytes.

Antineutrophil cytoplasmic antibody as¬ were considered positive if the titer

says

1:16 or greater. The standard indirect immunofluorescence method for ANCA de¬ tection, adopted at the First International Workshop in ANCA, Copenhagen, Den¬ mark, January 25 and 26, 1988, was employed."12 Immunoblotting was then performed on serum samples of patients with perinuclear staining patterns to con¬ firm specificity for antimyeloperoxidase.6 was

REPORT OF CASES Case 1.—A

15-year-old girl presented to

the ophthalmology service for an evalua¬ tion of upper-lid ptosis (Fig 1). She had in¬ termittent eyelid swelling that had been treated with a topical antibiotic-corticosteroid combination. Her medical history was significant for asthma. Physical exam¬ ination revealed a visual acuity of 20/20 OU. No afferent pupillary defect was noted, and extraocular motility was full. Palpation re¬ vealed fullness of the left lacrimal gland. Hertel's exophthalmometry yielded sym¬ metric findings. Slit-lamp examination re¬ vealed mild corneal marginal thinning bi¬ laterally. The left cornea had a 2-mm pannus superiorly (Fig 2). Fundus examination revealed normal findings. Orbital standardized echography demon¬ strated a large left lacrimal gland; the right lacrimal gland was slightly increased in size. A computed tomographic scan revealed an

enlarged left lacrimal gland. The chest roentgenogram, sinus film, sinus computed tomographic scan, urinalysis results, and

complete blood cell count were all normal.

An incisional biopsy of the left lacrimal gland was performed through a lateral orbitotomy. Pathologic examination showed a necrotizing vasculitis with areas of collagen necrosis surrounded by granulomatous inflammation, consistent with WG (Fig 3). Although a diagnosis of limited WG was considered when the patient was noted to have necrotizing granulomatous involvement of her lacrimal gland, no other clinical signs of WG existed and therefore she was treated only with oral prednisone. The patient was maintained on a taper¬ ing dose of prednisone during a 6-month period. During this time, the lacrimal gland

returned to normal size, and she was even¬ tually weaned from prednisone therapy. Fourteen months later, the patient de¬ veloped a streptococcal pharyngitis fol¬ lowed by hemoptysis, malaise, fever, and a rash. A biopsy specimen of the rash was la¬ beled as a "viral vasculitis" at another hos¬

pital. The patient was transferred to The University of Iowa Hospitals and Clinics

for further evaluation. At the time of ad¬ mission her erythrocyte sedimentation rate (ESR) was 64 mm/h and a urinalysis showed red blood cell casts, white blood cells, and proteinuria (2+). Her white blood cell count was 9.1 X lO'/L, the hematocrit was 0.24, and the hemoglobin level was 77 g/L. A chest roentgenogram showed bilat¬ eral interstitial infiltrates, and an ANCA assay was positive to a 1:320 dilution with a perinuclear pattern (Fig 4). Immunoblotting demonstrated that the ANCA specific¬ ity was to antimyeloperoxidase. These find¬ ings supported the diagnosis of WG. The patient was treated with prednisone and

cyclophosphamide (Cytoxan).

Comment.—Because of her orbital

disease, a diagnosis of limited WG was considered. Limited WG involves only one or two organs.13 One year after her initial presentation, the patient devel¬ oped florid systemic WG, at which time the ANCA titer was greatly elevated. The ANCA titers, along with the or¬ bital biopsy, helped confirm the diag¬ nosis of WG.

Case 2.—A 72-year-old woman presented to the medical service with multiple cavi-

tary pulmonary nodules. The patient had a history of recurrent sinusitis. Urinalysis results were normal at the time of presen¬

tation, and her ESR was 80 mm/h. An open lung biopsy demonstrated caseating gran¬ ulomas; however, no fungal or acid-fast or¬ ganisms were identified. The patient was given isonicotine hydrazine (INH) and rifampin, although cultures for mycobacteria were negative. Three months later the pa¬ tient complained of ocular irritation and intermittent hyperemia; her local ophthal¬ mologist diagnosed dry eyes, and she was

treated with artificial tears as needed. One year after the patient's initial pre¬ sentation she was readmitted because of low-grade fevers, at which time the ESR was 138 mm/h. Urinalysis showed 10 to 14

white blood cells per high-power field, 5 to cells, and red blood cell casts consistent with a glomerulonephritis; ANCA titer at this time was 1:512, with a

9 red blood

cytoplasmic pattern. The patient was seen in the ophthalmol¬

department because of blurry vision. She had a visual acuity of 20/30 OU with bilateral choroidal folds. Standardized echography revealed thickened choroidal layers bilaterally, which appeared to be infiltrative. Schirmer's testing revealed 7 mm of wetting in the right eye and 14 mm of wetting in the left. A temporal artery bi¬ opsy performed because of her elevated ESR yielded normal findings. A nasal biopsy revealed chronic inflam¬ mation. The previous pulmonary biopsy specimen was reevaluated and thought to be consistent with WG, although granulomatous vasculitis independent of the parenchymal caseous granulomas could not be identified even after recutting of the tissue. In light of the clinical findings, the rééval¬ uation of the lung biopsy specimen, and her ANCA titers, the patient was diagnosed as having WG. Cyclophosphamide and pred¬ nisone therapies were initiated, and the patient has done well for 2 years. ogy

Comment.—This case illustrates the difficulty in establishing a diagnosis of WG

even

with

an

open

lung biopsy. A

histopathologic diagnosis was not made until the patient developed advanced systemic disease and the ini¬ tial pathologic specimen was reexamined; even then, it was only consistent with WG. This patient's ANCA assay was markedly positive at 1:512 dilution at her second admission. Had it been known to be positive at the time of the

initial lung biopsy, a diagnosis of WG could have been made at that time. Ocular findings in this patient included dry eyes and choroidal thickening consistent with uveal involvement by WG. Case 3.—In January 1987, a 55-year-old

noted to have decreased hearing bilaterally and had undergone myringotoman was

mies for relief of otitis performed else¬ where. Two months later he developed arthralgias of his knees, ankles, and wrists that resolved spontaneously. Six months later he noted intermittent bloody drainage from his nose. He presented to his local ophthalmolo¬ gist, who diagnosed scleritis of the left eye in October 1987. The patient was treated with oral corticosteroids. The scleritis con¬ tinued intermittently, and the patient was referred for evaluation. Visual acuity was 20/20 OD and 20/25 OS. Nodular anterior scleritis was noted bilaterally without an¬ terior chamber cell and flare. Applanation tonometry measurements were 36 mm Hg OD and 24 mm Hg OS. Fundus examination revealed peripheral phlebitis and small pe¬ ripheral retinal hemorrhages in the left eye.

Laboratory evaluation showed an ESR of 84 mm/h. Rheumatoid factor was positive at 1:160 dilution, and the angiotensin-con-

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was 9 IU/L. The white blood cell count was 23.2 X lO'/L, and the ANCA titer was positive at 1:256, with a cytoplasmic pattern. The patient was treated with topical i8-blockers, and his oral corticosteroids were continued on a tapering schedule. The patient subsequently had a flare-up of his scleritis accompanied by arthralgia and malaise. The prednisone therapy was re¬ sumed. A chest roentgenogram at this time showed abnormal densities in the right lung. Urinalysis revealed 5 to 7 red blood cells per high-power field and 1+ hematuria by chemistry. An open lung biopsy revealed only emphysematous changes. A tentative systemic diagnosis of MPA was made, but no histologie confirmation was obtained. The patient was unavailable for follow-up.

verting enzyme concentration

Comment—This patient's ocular findings were scleritis and retinal periphlebitis. The patient had evidence of systemic vasculitis as well, mani¬ fested by hematuria, arthralgias, si¬ nusitis, and a positive ANCA titer. A histologie diagnosis of WG or MPA could not be established.

40-year-old man presented polyarthralgias, a perforated nasal septum, sinusitis, otitis media, and a right peripheral seventh-nerve palsy. A biopsy specimen of skin lesions showed necrosis Case 4.—A

with

and inflammation consistent with WG. A biopsy specimen of the sphenoid sinus was initially thought to show chronic inflam¬ mation, but on recutting revealed necrotiz¬ ing granulomatous inflammation consis¬ tent with WG. A diagnosis of WG was made, and the patient was given cyclophosphamide and prednisone. The patient was receiving immunosuppressive therapy for 2 years when he devel¬ oped photophobia of the right eye. Visual acuity was 20/20 OU. Slit-lamp examina¬ tion revealed bilateral episcleritis. The right eye had a mild iritis. The remainder of his eye examination results were normal. After treatment with topical corticosteroid drops, his inflammatory ocular signs re¬ solved. Two years later the patient discontinued his cyclophosphamide and prednisone ther¬ apies. Nine months thereafter he developed glomerulonephritis. His ANCA was posi¬ tive at 1:64 dilution, with a cytoplasmic pattern. Treatment with cyclophosphamide and prednisone was resumed. Comment— This patient had sys¬

temic WG and a positive ANCA titer. Again, the biopsy specimens were not diagnostic, and only after recutting and reexamination of the tissue was a diagnosis made from the biopsy spec¬ imens. Even then it was considered to be consistent with and not diagnostic of WG. His ocular manifestations were episcleritis and iritis. Case 5.—A 49-year-old woman com¬ plained of arthralgias. A diagnosis of He-

noch-Schönlein purpura had been estab¬ lished on the basis of a skin biopsy per¬ formed elsewhere that had disclosed leukocytoclastic vasculitis. Laboratory

Fig 1.—External photograph of case 1 showing violaceous hue, ptosis, and slight fullness of the left upper lid.

Fig 2. Slit-lamp photograph of the left showing a pannus superiorly.

cornea

of

patient

—

Fig 3.—Orbital biopsy from case 1 showing a granulomatous re¬ action to necrotic collagen characteristic of Wegener's granulomatosis (hematoxylin-eosin, original magnification X40).

Fig 4. Note the perinuclear ¡mmunofluorescent staining pattern (arrow) in this ethanol-fixed leukocyte that has been treated with —

the

serum

of

patient 1; positive antineutrophil cytoplasmic anti¬

body titer (original magnification X250).

Fig 5. Photomicrograph of the antineutrophil cytoplasmic anti¬ body immunofluorescence using serum from patient 5. Note the cytoplasmic staining pattern (arrow) (original magnification X312). —

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1

Clinical and Laboratory Findings of ANCA-Positive Patients

Case No./

Sex/Age, 1/F/15

y

Date

Type

of 1st Presentation

of 1st

11/86

Systemic

Diagnosis*

Presentation

WG S, E, L

Eye: ptosis,

proptosis 2/F/72

12/86

Ocular Manifestations Ptosis, bilateral lacrimal gland

Date of Ocular Presentation

Biopsyt Necrotizing granulomatous

11/86

masses,

inflammation of

proptosis

lacrimal

Lung: pulmonary

WG Si, L, , E

Choroidal infiltration

Arthralgla

Systemic

Episcleritis, phlebitis, retinal vitreous, hemorrhage Episcleritis

gland Necrotizing granulomatous inflammation by lung biopsy (reçut) Open lung biopsy specimen normal

nodules

3/M/55

3/87

of knees, ankles, and

vasculitis

wrists 4/M/40

5/82

Perforated nasal

WG S, Si, , E;

Skin: necrotizing

11/84

arthralgias

septum,

inflammation: sphenoid sinus: necrotizing granulomatous

polyarthralgias, chronic sinusitis, 7th-nerve palsy

inflammation 5/F/49

2/87

Lung and skin

WG L, K, E, S;

purpura,

arthralgias

Keratoconjunctivitis

(reçut) Renal: NSCGN;

3/87

sicca

skin:

hematuria, abdominal 6/F/54

5/88

leukocytoclastic

pain,

arthralgias Rash, fever

vasculitis

MPA

vs

incomplete

WG

Central scotomas, 2° bioccipital infarcts

Renal: NSCGN,

6/88

nongranulomatous necrotizing arteritis: skin: nondiagnostic K, kidney; S, skin; Si, sinusitis; and MPA, microscopic polyarteritis. L, K, E, S

*WG indicates Wegener's granulomatosls; L, lung; E, eye; tNSCGN indicates necrotizing segmental crescentic glomerulonephritis. tANCA indicates antineutrophil cytoplasmic antibodies; disease staging: 1 indicates §AntiMPO+ denotes specificity for antimyeloperoxidase by immunoblotting.

evaluation showed a creatinine level of 570 µ /L, an ESR of 125 mm/h, a white blood cell count of 15.5 X 10VL, and bilateral in¬ terstitial pulmonary infiltrates on chest roentgenogram. A renal biopsy revealed necrotizing crescentic glomerulonephritis without IgA deposits. The patient was rediagnosed as having WG and was treated with cyclophosphamide and prednisone. An ANCA assay was performed several months after initiation of therapy. This as¬ say was positive at 1:16 dilution, with a cy¬

toplasmic pattern (Fig 5).

One month after her initial presentation the patient complained of ocular irritation and decreased vision. Visual acuity mea¬ sured 20/20 OU. Anterior and posterior segment examinations yielded normal re¬ sults. Basal tear secretion measured 2 mm of wetting at 5 minutes. The patient was treated with artificial tears.

Cyclophosphamide therapy was tapered during a 4-month period. The patient was readmitted with florid systemic WG and

her ANCA results were abnormal at 1:5120 dilution. Cyclophosphamide therapy was resumed.

Comment.—Patients with positive ANCA titers have been noted to have dry eyes (24% of cases14)· This patient

underwent a skin biopsy elsewhere and was diagnosed as having HenochSchònlein purpura, again illustrating the difficulty in establishing a histo-

active

disease; 2, inactive disease;

logic diagnosis of WG.

Case 6.—A 54-year-old woman presented

because of malaise, fatigue, fever, chills, anorexia, and a petechial rash. Her medical history was significant for mitral valve prolapse and multiple sinus surgeries for "chronic sinusitis." Laboratory evaluation showed an ESR of 111 mm/h, a white blood cell count of 25.0 X 10VL, a serum creatinine level of 800 µ /L, and a serum urea nitrogen level of 38.9 mmol/L of urea. Uri¬ nalysis showed proteinuria (1+) and 2+ hematuria. The ANCA assay was positive at 1:64 dilution, with a perinuclear pattern.

Antimyeloperoxidase specificity was con¬ immunoblotting. A skin biopsy was performed at the University of Iowa Hospitals and Clinics and thought to be nondiagnostic. No antiglomerular base¬ firmed by

ment membrane antibodies were seen. A

kidney biopsy specimen showed a fibrinoid necrotizing arteritis and segmental necro¬ tizing and crescentic glomerulonephritis. A diagnosis of incomplete WG vs MPA was made. The patient was treated with cyclo¬ phosphamide and prednisone and placed on renal dialysis. One month later the patient developed seizures and left upper-extremity paresis. Visual acuity at that time was 20/200 OU,

and visual fields demonstrated bilateral central scotomas. The remainder of her eye examination results were normal. A com¬ puted tomographic scan showed bioccipital infarcts, right frontoparietal infarcts, and

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a,

systemic disease; and b, limited disease.

thalamic infarcì. The patient subse¬ An autopsy was not per¬ formed. a

quently died.

Comment.—This patient had bilat¬ eral central scotomas caused by smallvessel vasculitis in her occipital lobes. The ANCA assay was helpful in this case in establishing the diagnosis of a systemic vasculitis. Distinguishing MPA from WG is difficult, as illus¬ trated in this case. COMMENT

These six cases illustrate the use of the ANCA assay in helping to diagnose systemic vasculitides. Four of these six patients had WG. The other two had a systemic vasculitis that was difficult to further subclassify, one of whom was diagnosed as having MPA and the

other, although diagnosed clinically as having some type of vasculitis, never had a specific tissue diagnosis of which type. Patient 1 originally presented

with ocular manifestations and pa¬ tient 3 was first referred to The Uni¬ versity of Iowa because of his ocular disease (Table). In all six cases a diagnosis could not be made from just the original histopathologic findings. Patient 1 was di¬ agnosed as having WG only after she

ing ANCAs, while only

4 of 32 who in remission or had inactive dis¬ ease tested positive. Cases 2 and 5 illustrate this, with the titers chang¬ ing with treatment. Following the re¬ port of ANCA by van der Woude et al (which the authors called anticytoplasmic antibody or ACPA), several additional reports were published in support of the sensitivity of the test for WG, but some patients having MPA or were

ANCA Titer

(Disease Stage at Time of

Titer) [Date]* (1,a) [12/88]

1:320

Staining Pattern! Perinuclear AntiMPO+

(1,a) [12/87], 1:160 (2,a) [3/89]

Cytoplasmic

(2,b) [5/88]

Cytoplasmic

(2,a) [12/87]

Cytoplasmic

1:512

1:256

1:64

idiopathic necrotizing segmental crescentic glomerulonephritis, and rarely other vasculitides such as ChurgStrauss syndrome,2·3·68 were also found to have positive titers. Savage et al5 found that combining a radioimmunoassay with indirect immunofluores¬ cence gave a sensitivity of 96% and a

specificity of 96% for diagnosing WG MPA. A prospective study3 found a sensitivity for active WG of 100% and a specificity of 88%, while findings for active MPA were a sensitivity of 80% and a specificity of 88%. Because of the rapid growth in knowledge about ANCAs and the de¬ or

(2,a) 16/87]),

1:16

1:5120

Cytoplasmic (1,a)

[4/89] (1,a) [5/88]

1:64

Perinuclear AntiMPO+

had ANCA testing and presented with systemic disease. In patient 2, an open lung biopsy specimen had to be reçut and reexamined, and in case 4 a sphe¬ noid sinus biopsy specimen also had to be reçut and reexamined in light of other systemic findings. Patient 3 had an open lung biopsy specimen from

which

a

histopathologic diagnosis

could not be made. Patient 5 was treated elsewhere after being diag¬ nosed as having Henoch-Schonlein purpura because of systemic and skin biopsy findings. In case 6 it was diffi¬ cult to diagnose whether the patient had WG or MPA from just the kidney biopsy specimen and a skin biopsy specimen was considered nondiagnostic. The ANCA testing in these pa¬ tients was helpful in conjunction with the clinical findings in establishing a diagnosis of a systemic vasculitis and in following their response to therapy. In 1985 van der Woude et al1 de¬ scribed 41 patients with WG who were tested for antibodies reacting with the cytoplasm of ethanol-fixed granulocytes and monocytes. The authors were encouraged to do this after they found one patient with active WG who ini¬ tially had high ANCA titers that de¬ creased in parallel with the disease activity. They found that 25 of 27 patients with active WG had circulât-

sire to standardize the assay to allow international comparison of results, the first International Workshop on ANCAs was held in 1988.11·12 Results initially reported at this workshop by Falk and Jennette6 led to the conclu¬ sion that there were a minimum of two autoantibody specificities involved in ANCA assays. The initial pattern rec¬

ognized was finely granular cytoplas¬ mic staining with some perinuclear

accentuation. This pattern has been found in most patients with WG, and was named C-ANCA at the Second In¬ ternational Workshop on ANCAs held April 28 and 29,1989 (Fig 5). The sec¬ ond pattern was perinuclear/nuclear staining of neutrophils only and was found to be due to antimyeloperoxi¬ dase (Fig 4). This staining pattern is a laboratory artifact produced when the neutrophils are fixed with ethanol, al¬ lowing the basic myeloperoxidase mol¬ ecule to escape from the primary gran¬ ules and bind to acidic nucleic acid. The

myeloperoxidase specificity (called P-ANCA at the Second International

Workshop on ANCA, Leiden, the Neth¬ erlands) has been noted predomi¬ nantly in patients with MPA or idio¬ pathic necrotizing segmental crescentic glomerulonephritis; however, occasionally patients with WG have this antibody, such as patient 1 in this report.

It has been questioned whether ANCA titers are positive in limited WG. Gans et al10 and Hoare and Rhys Evans15 found that limited WG had positive ANCA titers. Specks et al8 found that the sensitivity was depen-

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dent

on

the extent and

activity of the

disease, with limited active WG having positive titers in 69% of the patients

and limited inactive disease having positive titers in 35%; systemic active WG had positive titers in 84% of patients, while generalized inactive WG had positive titers in 37% .8 The median titers were 1:16 in limited dis¬ ease and 1:32 in generalized disease. Others have found that the ANCA ti¬ ter could be low in limited WG and that on progressing to the systemic disease, the ANCA titers then become positive; with subsequent remission, the ANCA titers would revert to negative.16 More information needs to be obtained from more centers regarding the titer positivity in limited WG and in other vasculitides. Wegener's granulomatosis is diag¬ nosed from both clinical and histopathologic findings.4·17·18 It is a necro¬ tizing granulomatous inflammation with small-vessel vasculitis primarily affecting the respiratory tract, along with a focal necrotizing glomerulone¬ phritis. Microscopic polyarteritis is a nongranulomatous small-vessel vas¬ culitis that also has focal segmental glomerulonephritis.19 Because there have been no systemic markers, these diseases are difficult to diagnose, and the separation between WG, MPA, and other vasculitides is not always clearcut.20 Parlevliet et al9 noted that in only 2 of 11 patients with clinical criteria suggestive of WG could a sound histo¬ logie diagnosis be made. However, ANCA titer was positive in 10 of 11 cases. In patients without the classic features, treatment and diagnosis may be delayed, for instance in case 1, and this could affect the ultimate progno¬ sis. In these cases ANCA assays might be helpful. Whether ANCAs, besides being a marker, have a pathogenetic function in vasculitis is not yet known, but some evidence suggests that they do.6·21 These diseases have overlapped manifestations, and the common de¬ nominator may be ANCAs. The ocular manifestations of sys¬ temic vasculitides, especially WG, are numerous and include dry eyes and as seen in case 5.14 Other eye findings include conjunctivitis, episcleritis, scleritis, peripheral corneal ulcér¬ ations, uveitis, retinal vasculitis, choriocapillaris, orbital mass, orbital cellulitis, and nasolacrimal duct ob¬ struction.417·22·23 Ocular findings have been detected in 21% to 58% of pa¬ tients with WG; episcleritis was seen in 24% of patients with MPA,20 while another series had a 5% incidence of ocular findings in cases of MPA.19 Although all our patients had sys-

temic

findings by the time ANCA as¬ performed, two patients originally presented with only ocular findings. It would be interesting to says

were

know in the future whether ANCA ti¬ ters can be positive in limited ocular disease. Ophthalmologists should con¬ sider the use of an ANCA assay in pa¬ tients with eye symptoms of possible vasculitis, especially in the presence of scleritis. If scleritis is present, it is very important to rule out a systemic vasculitis; if it is not present, careful follow-up should be maintained to watch for the possibility of subsequent development of a systemic vasculitis. A prospective study of the use of ANCA assays in patients with scleritis should be performed to learn more about the clinical usefulness of ANCA testing in these patients. This study was supported in part by an unre¬ stricted grant from Research to Prevent Blind¬ ness, Ine, New York, NY. Dr Folberg is the recip¬ ient of a Senior Scientific Investigator Award from Research to Prevent Blindness, Inc. The authors have no proprietary interest in the development or marketing of any drug or sero¬ logie test mentioned. References der Woude FJ, Rasmussen N, Lobatto S, et al. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of dis1.

van

activiity in Wegener's granulomatosis. Lan1985;1:425-429. 2. Feehally J, Wheeler DC, Walls J, Jones S, Lockwood CM, Savage COS. A case of microscopic polyarteritis associated with antineutrophil cytoplasmic antibodies. Clin Nephrol. 1987;27:214\x=req-\ ease

ANCA. Acta Pathol Microbiol Immunol Scand

cet.

Suppl. 1989;97(suppl 6):12-14. 12. Rasmussen N, Wiik A, Hoier-Madsen M, Borregaard N, van der Woude F. Anti-neutrophil cytoplasm antibodies. Lancet. 1988;1:706. 13. DeRemee RA, McDonald TJ, Harrison EG, Coles DT. Wegener's granulomatosis: anatomic correlates, a proposed classification. Mayo Clin

215. 3. Venning MC, Arfeen S, Bird AG. Antibodies to neutrophil cytoplasmic antigen in systemic vasculitis. Lancet. 1987;2:850. 4. Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med. 1983;98:76-85. 5. Savage COS, Winearls CG, Jones S, Marshall

PD, Lockwood CM. Prospective study of radioim-

munoassay for antibodies against neutrophil cytoplasm in diagnosis of systemic vasculitis. Lancet. 1987;1:1389-1393. 6. Falk RJ, Jenette JC.

Anti-neutrophil cytoplasmic autoantibodies with specificity for myin with eloperoxidase patients systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med. 1988;318:1651-1657. 7. Wathen CW, Harrison DJ. Circulating antineutrophil antibodies in systemic vasculitis. Lancet. 1987;1:1037. 8. Specks U,

Wheatley CL, McDonald TJ, Rohrbach MS, DeRemee RA. Anticytoplasmic granulomatosis. Mayo Clin Proc. 1989;64:28-36. 9. Parlevliet KJ, Henzen-Logmans SC, Oe PL, Bronsveld W, Balm AJM, Donker AJM. Antibodies to components of neutrophil cytoplasm: a new diagnostic tool in patients with Wegener's granulomatosis and systemic vasculitis. Q J Med. 1988;249:55-63. 10. Gans ROB, Goldschmeding R, Donker AJM,

Neutrophil cytoplasmic autoantibodies and Wegener's granulomatosis. Lancet. 1989;1:269\x=req-\ et al.

270. 11. Wiik A. Delineation of a standard procedure for indirect immunofluorescence detection of

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In Other AMA Journals AJDC

Gonococcal Conjunctivitis in Prepubertal Children Lisa S. Lewis; Tracy A. Glauser; Mark D. Joffe (AJDC. 1990;144:546-548).

Limiting Treatment for Extremely Premature, Low-Birth-Weight Infants (500 to 750 g) Ernie W. D. Young, David K. Stevenson (AJDC. 1990;144:549-552).

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