CLINICAL SCIENCES

Antineutrophil Cytoplasmic Antibody–Associated

Active Scleritis
Lani T. Hoang, MD; Lyndell L. Lim, MBBS, FRANZCO; Brian Vaillant, MD;
Dongseok Choi, PhD; James T. Rosenbaum, MD

Objective: To determine whether antineutrophil cyto- significantly more ocular complications (21 of 14 or 86%
plasmic antibody (ANCA) testing provides prognostic in- vs 20 of 64 or 31%; P ⬍.001), including keratopathy (5
formation in evaluating scleritis. of 14 or 36% vs 6 of 64 or 9%; P=.02), visual acuity of
20/50 or worse (8 of 14 or 57% vs 11 of 64 or 17%;
Methods: Retrospective medical record review of pa- P=.001), and vascular pannus (3 of 14 or 21% vs 1 of 64
tients evaluated at a tertiary care center from January 1, or 2%; P =.02). Aggressive therapy, such as chronic sys-
1995, to June 30, 2006, was performed to compare clini- temic corticosteroids (9 of 14 or 64% vs 9 of 64 or 14%;
cal features, treatments, and associated systemic disease P⬍ .001) and alkylator therapy (8 of 14 or 57% vs 7 of
in patients who test positive for ANCA vs patients whose 64 or 11%; P ⬍ .001), was more likely to be recom-
ANCA tests are negative. mended for patients who tested positive for ANCA.

Results: Among 78 patients identified, 14 tested posi- Conclusions: A substantial subset of patients with scle-
tive for ANCA. Patients with positive ANCA test results ritis are also positive for ANCA. These patients are more
were more likely to have an associated systemic disor- likely to have severe ocular disease and undiagnosed pri-
der (10 of 14 or 71%) than were patients who tested nega- mary vasculitic disease, thereby requiring more aggres-
tive for ANCA (26 of 64 or 41%; P= .04), and the disor- sive therapy. An ANCA test may be useful in the evalu-
der was more likely to have been diagnosed as a result ation and treatment of patients with scleritis.
of scleritis work-up (2 of 10 or 20% vs 19 of 26 or 73%;
P=.007). Patients with positive ANCA test results had Arch Ophthalmol. 2008;126(5):651-655

S
CLERITIS IS A DESTRUCTIVE IN- phosphamide treatment has been shown
flammatory disorder of the to improve survival in patients with WG
outer coating of the eye that and PAN.3,4 Therefore, early diagnosis and
usually manifests as redness initiation of treatment are critical for pa-
and severe ocular pain. The tients with scleritis associated with pri-
inflammation can spread to surrounding mary vasculitic diseases.
structures of the eye, progress to ische- Diagnosing systemic vasculitides may
mia and necrosis, and potentially cause se- be difficult and often relies on a combi-
vere visual loss or blindness.1-3 Nearly half nation of clinical, pathological, and im-
of patients with scleritis have an associ- munological criteria. In clinical settings,
ated immune-mediated condition, such as when patients have active inflammation
rheumatoid arthritis (RA), relapsing poly- and high pretest probability, the detec-
chondritis, inflammatory bowel disease, or tion of antineutrophil cytoplasmic anti-
primary vasculitis.2 bodies (ANCA) serves as a useful clinical
Among patients with an associated dis- marker for vasculitis.5,6 With an indirect
ease, most patients seek treatment for sys- immunofluorescence assay, ANCA stains
temic disease before the onset of scleri- in 2 major patterns. The cytoplasmic pat-
tis.2 However, patients with a primary tern (c-ANCA) detects a neutrophil serine
vasculitic disease, such as Wegener granu- proteinase and exhibits a diffuse staining
Author Affiliations: Oregon lomatosis (WG) or polyarteritis nodosa throughout the cytoplasm. Alternatively,
Health & Science University, (PAN), have a more aggressive form of the perinuclear staining pattern (p-ANCA)
Portland (Drs Hoang, Lim,
Choi, and Rosenbaum), and
scleritis and are more likely to first seek is exhibited when antibodies detect lyso-
Department of Neuro-Oncology, treatment for scleritis.2,3 If left untreated, somal enzymes such as myeloperoxi-
The University of Texas M. D. primary vasculitic disease leads to multi- dase. Typically, c-ANCA has been associ-
Anderson Cancer Center, organ failure and is potentially fatal.3,4 The ated with WG, and p-ANCA has been
Houston (Dr Vaillant). combination of corticosteroid and cyclo- linked to renal vasculitis and micro-

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 scopic polyarteritis.2-7 However, ANCA testing is not de- by radioimmunoassay for the presence of antibodies to serine
finitive for systemic vasculitis, and there is overlap in clini- proteinase 3 or myeloperoxidase. All tests ordered from Janu-
cal phenotypes among patients with p-ANCA or c-ANCA ary 1, 1995, through June 30, 2006, were performed by ARUP
as well as patients negative for ANCA. Laboratories (Salt Lake City, Utah) using indirect fluorescent
antibody/multianalyte fluorescent detection. Patients with ex-
Although ANCA testing plays a critical role in the
clusively infectious causes of scleritis or episcleritis were not
evaluation of vasculitides, its clinical significance in pa- screened for ANCA and were excluded from the study. Pa-
tients with scleritis has not been clearly established. A tients with inactive scleritis were considered to have low pre-
previous study reviewed the clinical features of and treat- test probability and were also excluded. Patients who had a
ment for scleritis and gave insight into the value of ANCA clearly established connective tissue disorder such as RA and
testing.1 The study found a subset of patients with scle- who had no evidence of a second associated condition were not
ritis who tested positive for c-ANCA but had no evi- screened for ANCA. Other routine tests included urine analy-
dence of an associated systemic disease.1 These patients sis, serum creatinine, and fluorescent treponemal antibody ab-
had difficult-to-control scleritis, suggesting c-ANCA may sorption. Additional tests such as rheumatoid factor, anti-
be an independent prognostic marker. nuclear antibody, erythrocyte sedimentation rate, C-reactive
protein, and chest radiography were performed if deemed ap-
To investigate the prognostic significance of ANCA test-
propriate by a rheumatologist, based on the patient’s history
ing in scleritis, we evaluated patients who tested negative and physical examination.
for ANCA and compared this group with patients who tested Treatment was based on type of scleritis, severity of dis-
positive for p-ANCA or c-ANCA. We also examined ocu- ease, associated medical conditions, and patient preference. Drug
lar complications, treatments, associated diseases, and tim- dosage and tapering were determined by clinical response and
ing of the systemic diagnosis relative to scleritis. tolerance of the medication. For most patients with mild an-
terior scleritis, an oral nonsteroidal anti-inflammatory drug was
the first-line treatment. For complicated, refractory, necrotiz-
METHODS ing, or posterior scleritis, systemic corticosteroid treatment (oral
or intravenous) was initiated. Chronic corticosteroid therapy
Medical records from all patients with scleritis evaluated at the was defined as use for more than 6 months over a 1-year pe-
Inflammatory Eye Disease Clinic, Casey Eye Institute, Oregon riod. Indications for the use of immunosuppressive drugs/
Health & Science University between January 1, 1995, and June steroid-sparing agents included failure of scleritis to respond
30, 2006, were retrospectively reviewed. Patients seen before to corticosteroid therapy, recurrence of scleritis, corticoste-
1995 were excluded because ANCA screening was not rou- roid toxicity, the physician’s judgment that a corticosteroid-
tinely administered. The study protocol was reviewed and ap- sparing drug was indicated, or presence of active associated sys-
proved by the Oregon Health & Science University Institu- temic disease. Corticosteroid-sparing medications included
tional Review Board. antimetabolite therapy (azathioprine, methotrexate sodium, and
Scleritis was diagnosed based on characteristic clinical find- mycophenolate mofetil), alkylator therapy (chlorambucil and
ings of inflammation and edema affecting the scleral tissues, cyclophosphamide), and others (cyclosporine, infliximab, ri-
with involvement of the superficial and deep episcleral vascu- tuximab, and intravenous immunoglobulin).
lar plexus.8 Posterior scleritis was confirmed by B-scan ultra- Clinical characteristics, treatments, and associated medi-
sonography, computed tomography, and/or magnetic reso- cal conditions were compared between patients positive for
nance imaging of the orbits.7,8 Scleritis was classified as diffuse ANCA and patients negative for ANCA and between patients
anterior, nodular, necrotizing, scleromalacia perforans, or pos- positive for c-ANCA and p-ANCA. Distributions of categori-
terior based on the system devised by Watson and Hayreh.8 cal variables were compared using the Fisher exact test with
Patient data, including age, sex, eye involvement, and fol- exact procedures for the calculation of significance. Continu-
low-up period, were recorded. Ocular complications included ous variables were compared using the 2-tailed t test. Nominal
visual impairment, scleral thinning, corneal involvement, uve- P values were used for all comparisons, and P⬍.05 was con-
itis, elevated intraocular pressure, and posterior segment in- sidered statistically significant.
volvement. Visual impairment was categorized as visual acu-
ity of 20/50 or worse and visual acuity of 20/200 or worse. Scleral
thinning was defined as degeneration of the sclera leading to RESULTS
loss of scleral rigidity.7 Corneal involvement included any signs
of corneal infiltrates, corneal thinning, stromal keratitis, and
corneal ulceration.7 Uveitis was classified according to the guide-
Of 101 patients with scleritis, 78 met the inclusion cri-
lines from the Standardization of Uveitis Nomenclature Work- teria, and 23 were excluded because they had inactive
ing Group.9 Elevated intraocular pressure was defined as greater disease, episcleritis exclusively, or infectious scleritis. Of
than 21 mm Hg. Cystoid macular edema was defined by clini- the 78 patients included, 14 patients (18%) tested posi-
cal and angiographic criteria. Posterior segment involvement tive for ANCA, and 64 were considered ANCA negative,
included any findings of optic nerve edema, serous retinal de- including 52 patients with a negative ANCA test result
tachment, or choroidal folds.7 Because the percentages of com- and 12 patients with clearly established RA without evi-
plications found are potentially affected by the duration of follow- dence of a second immune-mediated disorder. Demo-
up, we further analyzed the rate at which these outcomes graphic characteristics and scleritis classifications were
occurred.10 not significantly different between the 2 study groups
Associated systemic disease was diagnosed based on com-
patible medical history, physical findings, imaging, laboratory
(Table 1). Most patients in both subgroups were women
results, and confirmation by an appropriate specialist. All pa- aged 40 to 50 years. The mean follow-up for ANCA-
tients were evaluated by a rheumatologist. At the initial evalu- positive patients (22 months; range, 0-86 months) was
ation of scleritis, nearly all patients were routinely screened for longer than that for ANCA-negative patients (9 months;
ANCA immunofluorescence to determine the presence of range, 0-63 months), but this difference was not statis-
c-ANCA or p-ANCA. Results of the screening were confirmed tically significant (P=.09). Anterior diffuse scleritis was

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 Table 1. Clinical Comparisons for Patients With Positive Table 2. Onset of Scleritis Complications
vs Negative ANCA Test Results
Complication Developed
Negative Positive P During Follow-up, %
Characteristic for ANCA a for ANCA a Value b
Negative Positive
Demographic characteristic Complication for ANCA for ANCA
No. of patients 64 14
Mean age at diagnosis, y 48 55 .12 Visual acuity ⱕ20/50 32 8
Women 45 (70) 10 (70) ⬎.99 Visual acuity ⱕ20/200 4 8
Mean duration of follow-up 9 (0-63) 22 (0-86) .09 Scleral thinning 28 17
(range), mo Keratopathy 16 17
Bilateral eye involvement 25 (39) 9 (64) .14 Vascular pannus 4 8
Scleritis type Uveitis 12 4
Diffuse anterior 35 (55) 10 (71) .37 Elevated intraocular pressure 0 0
Nodular anterior 22 (34) 2 (14) .21 Cystoid macular edema 0 0
Scleromalacia perforans 2 (3) 0 ⬎.99 Posterior complication 4 4
Necrotizing 1 (2) 0 ⬎.99
Posterior 4 (6) 2 (14) .29 Abbreviation: ANCA, antineutrophil cytoplasmic antibodies.
Scleritis complications
Ocular complications 20 (31) 12 (86) ⬍.001
Visual acuity ⱕ20/50 11 (17) 8 (57) .001
Visual acuity ⱕ20/200 5 (8) 3 (21) .39
curred more frequently in ANCA-positive patients than
Scleral thinning 17 (27) 6 (43) .33 in ANCA-negative patients (visual acuity ⱕ20/50, P=.001;
Keratopathy 6 (9) 5 (36) .02 visual acuity ⱕ20/200, P=.39) (Table 1). Keratopathy was
Vascular pannus 1 (2) 3 (21) .02 3 times more common in patients positive for ANCA than
Uveitis 4 (6) 3 (21) .11 it was in patients negative for ANCA (P=.02). Vascular
Elevated intraocular pressure 3 (5) 2 (7) .22 pannus also was seen more often in patients positive for
Cystoid macular edema 1 (2) 0 ⬎.99
ANCA (P=.02). In addition, more patients positive for
Posterior complication 2 (3) 1 (7) .45
Treatment ANCA had scleral thinning, uveitis, elevated intraocu-
Any systemic drug 63 (98) 14 (100) ⬎.99 lar pressure, and posterior segment complications, but
NSAID only 12 (19) 0 ⬎.99 the number of patients involved was too small for sta-
Corticosteroid, PO or IV 49 (77) 14 (100) .059 tistical analysis.
Chronic PO corticosteroids c 9 (14) 9 (64) ⬍.001 Outcomes are frequently affected by the duration of
Any steroid-sparing drug 31 (48) 13 (93) .002
follow-up.10 As noted above, the duration of follow-up
Antimetabolite d 29 (45) 9 (64) .25
Alkylator e 7 (11) 8 (57) ⬍.001
differed slightly between groups. To analyze the effect
Other f 9 (14) 2 (14) ⬎.99 of duration of follow-up, we calculated the rate of de-
Medical history velopment of specific outcomes in terms of patient years.
Any associated systemic disease 26 (41) 10 (71) .04 These rates did not differ significantly between patients
Diagnosed before scleritis 19/26 (73) 2/10 (20) .007 positive for ANCA and patients negative for ANCA
Any primary vasculitic disease 5 (8) 10 (71) ⬍.001 (Table 2).
Wegener granulomatosis 1 (1) 7 (50) ⬍.001
Generalized 0 3 (21) .004
Most patients were treated with a systemic medica-
Limited 1 (1) 4 (29) .003 tion, including nonsteroidal anti-inflammatory drugs
Polyarteritis nodosa 0 2 (14) .03 (Table 1). Most required systemic corticosteroids, but far
Rheumatoid arthritis 17 (26) 0 ⬍.001 more patients positive for ANCA were treated with long-
Psoriasis 2 (3) 0 ⬎.99 term corticosteroid therapy (P ⬍ .001). A steroid-
Cogan syndrome 2 (3) 1 (7) .45 sparing agent was also used with significantly greater fre-
Relapsing polychondritis 2 (3) 0 ⬎.99
quency among patients positive for ANCA (P=.002). This
Unidentified vasculitis 2 (3) 0 ⬎.99
difference is most striking when comparing the use of
Abbreviations: ANCA, antineutrophil cytoplasmic antibodies; alkylator therapy, 57% (8 of 14) of patients positive for
IV, intravenous; NSAID, nonsteroidal anti-inflammatory drug; PO, oral. ANCA required alkylator therapy compared with 11% (7
a Data are presented as number (percentage) unless otherwise indicated.
b P value derived from Fisher exact test, except for P values for mean age
of 64) of patients negative for ANCA (P ⬍.001).
at diagnosis and mean duration of follow-up which were derived from t test.
Patients positive for ANCA also had systemic disease
c Chronic corticosteroids defined as treatment lasting more than 6 mo over significantly more often than patients negative for ANCA
1-y period. (P=.04); in particular, ANCA-positive scleritis was as-
d Includes azathioprine, methotrexate sodium, and mycophenolate mofetil.
e Includes chlorambucil and cyclophosphamide. sociated with a primary systemic vasculitis (P ⬍ .001)
f Includes cyclosporine, infliximab, and rituximab. (Table 1). The most common primary systemic vasculi-
tis associated with ANCA was WG, which was seen in 7
patients (50%), followed by PAN, which was seen in 2
patients (14%). Among patients with WG positive for
the most common type in both groups. Bilateral eye in- ANCA, 3 had generalized WG and 4 had limited WG.
volvement was present in approximately half the patients. Limited WG was also diagnosed in 1 patient with a nega-
Patients who tested positive for ANCA experienced tive ANCA test.
more complications than patients who tested negative for Scleritis was more likely to be the presenting feature
ANCA (86% vs 31%; P ⬍.001). Visual impairment oc- of an associated systemic disease in patients positive for

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 ocular pressure. Visual impairment was present in all pa-
Table 3. Comparison of Patients With c-ANCA tients positive for c-ANCA and 5 of 7 patients positive
and p-ANCA Scleritis for p-ANCA. Nearly all patients in each subgroup re-
quired a steroid-sparing agent in addition to an oral cor-
Characteristic c-ANCA a p-ANCA a
ticosteroid. The use of alkylators and antimetabolites was
Total 7 7 similar in both subgroups. Association with a primary
Demographic characteristic vasculitis was also similar in both groups. Among pa-
Mean age at diagnosis, y 46 64
Women 5 5
tients positive for c-ANCA, 5 had WG, and 1 had Cogan
Mean duration of follow-up, mo 14 28 syndrome. Among patients positive for p-ANCA, 2 had
Bilateral eye involvement 4 5 WG and 2 had PAN.
Scleritis type
Diffuse anterior 3 7
Nodular anterior 2 0 COMMENT
Scleromalacia perforans 0 0
Necrotizing 0 0
Posterior 2 0 We examined the prognostic value of ANCA testing in
Scleritis complications scleritis. Our results indicated that ANCA testing iden-
Ocular complications 7 5 tifies a subset of patients with scleritis who are more likely
Visual impairment 7 5 to have severe ocular disease, require multiple immuno-
Scleral thinning 4 2 suppressive therapies, and have an underlying vasculi-
Keratopathy 1 4
tis diagnosed as a result of their scleritis. We also inves-
Vascular pannus 2 1
Uveitis 3 0
tigated the difference between p-ANCA scleritis and
Elevated intraocular pressure 1 1 c-ANCA scleritis. Patients positive for p-ANCA had dif-
Posterior complication 1 0 fuse anterior-type scleritis, whereas patients positive for
Treatment c-ANCA had heterogeneous types of scleritis; other-
Oral corticosteroids 7 7 wise, there was no striking distinction between c-ANCA
Antimetabolite 5 4 and p-ANCA scleritis. Because there was a small num-
Alkylator 4 4
Other 2 0
ber of patients in both subgroups, statistical analysis
Medical history was limited, and larger studies are required for future
Any associated systemic disease 6 4 investigations.
Wegner granulomatosis 5 2 Most patients with scleritis positive for ANCA pre-
Generalized 2 1 sented de novo without any history of an immune-
Limited 3 1 mediated condition. With further work-up, most of these
Polyarteritis nodosa 0 2
patients were found to have an underlying primary vas-
Cogan syndrome 1 0
culitic disease, most commonly WG. This correlates with
Abbreviations: c-ANCA, cytoplasmic pattern antineutrophil cytoplasmic the results found in a previous study, which showed that
antibodies; p-ANCA, perinuclear pattern antineutrophil cytoplasmic patients with a primary vasculitis are more likely to be
antibodies.
a Data are presented as number of patients unless otherwise indicated.
identified as a consequence of their scleritis.2 Because of
the potential for life-threatening complications, all pa-
tients with scleritis should have an ANCA test per-
formed, and those who test positive should be thor-
ANCA. Of 26 patients negative for ANCA with an asso- oughly evaluated for an underlying systemic vasculitis.
ciated disease, 19 (73%) presented with a known his- In this respect, we use the ANCA test in evaluating pa-
tory of the concurrent systemic disease. In contrast, 2 of tients with scleritis far differently than the rheumatoid
10 patients positive for ANCA with an underlying dis- factor or antinuclear antibody tests. We do not rou-
ease (20%) also had a pre-existing systemic diagnosis tinely screen patients with scleritis and a rheumatoid fac-
(P=.007). tor or antinuclear antibody because (1) scleritis is rarely
Within the ANCA-positive group, 7 (50%) were posi- the presenting manifestation for either RA or systemic
tive for c-ANCA, and 7 (50%) for p-ANCA (Table 3). lupus erythematosus; and (2) the specificities of rheu-
Patients positive for p-ANCA were significantly older at matoid factor and antinuclear antibody are such that a
initial treatment for scleritis than were patients positive diagnosis of either RA or systemic lupus erythematosus
for c-ANCA (mean age, 64 years [range, 49-84 years] vs cannot be established by laboratory values in the ab-
46 years [range, 30-61 years]; P = .01). All patients posi- sence of a compatible clinical presentation. In contrast,
tive for p-ANCA had anterior diffuse scleritis; con- a positive ANCA value can identify a population that is
versely, patients positive for c-ANCA had an assortment at increased risk for developing a systemic vasculitis,
of scleritis types, including 3 with diffuse, 2 with nodu- which has a substantially worse prognosis than other
lar, and 2 with posterior scleritis. Scleritis type corre- causes of scleritis. We do not recommend repeating the
lated with complications in both subgroups. In patients ANCA test once it is found to be negative unless the pa-
positive for p-ANCA, 2 had scleral thinning, and 4 had tient has developed additional evidence of systemic dis-
corneal complications; in comparison, 4 patients posi- ease, such as glomerulonephritis.11
tive for c-ANCA had scleral thinning, 3 had uveitis, 2 had Significantly more patients positive for ANCA had long-
corneal complications, 2 had vascular pannus, 1 had pos- term prescriptions for systemic corticosteroids and al-
terior segment complications, and 1 had elevated intra- kylator therapy than patients negative for ANCA. The

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 more aggressive treatment required for ANCA-positive would be helpful in distinguishing any differences be-
scleritis is confounded by the associated immune con- tween patients with scleritis and positive p-ANCA test
dition in most patients positive for ANCA. As was shown results vs c-ANCA test results.
in previous studies, patients with scleritis and a primary
systemic vasculitis, such as WG or PAN, often require Submitted for Publication: June 1, 2007; final revision
systemic corticosteroids combined with alkylator therapy received November 12, 2007; accepted November 19,
for control of their eye disease.4 There may also be a bias 2007.
to initiate more aggressive treatment because of the poor Correspondence: Lani T. Hoang, MD, Casey Eye Insti-
prognosis of patients with primary vasculitic diseases. tute, Oregon Health & Science University, 2934 NW
Patients positive for ANCA are at increased risk for de- Telshire Terr, Beaverton, OR 97006.
veloping visual impairment, keratopathy, and vascular pan- Author Contributions: Drs Hoang, Choi, and Rosenbaum
nus. Corneal changes from corneal infiltrates, thinning, or had full access to all the data in the study and take re-
ulceration were the most common threat to vision. Al- sponsibility for the integrity of the data and the accu-
though patients with ANCA-positive scleritis had signifi- racy of the data analysis.
cantly more ocular complications, a referral bias may ex- Financial Disclosure: None reported.
ist because our clinic is part of a tertiary care medical center Funding/Support: This study was supported in part by
and is likely to see more severe cases of scleritis. grant 5-P30-EY010572 from the National Institute of
As with all retrospective studies, our data must be in- Health, a Research to Prevent Blindness Senior Scien-
terpreted with caution. We found a significant subset of tific Investigator Award, and the Stan and Madelle Rosen-
patients with scleritis who were positive for ANCA. Al- feld Family Trust (Dr Rosenbaum).
though ANCA test results may serve the physician as ad- Role of the Sponsor: The sponsors had no role in the de-
junct evidence for the diagnosis of vasculitis, these re- sign and conduct of the study; in the collection, analy-
sults must be viewed in the context of the patient’s clinical sis, and interpretation of the data; or in the preparation,
picture and disease activity. Testing for ANCA is most review, or approval of the manuscript.
valuable in settings where there is a high pretest prob-
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