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Ocular Characteristics and Disease Associations in Scleritis-Associated Peripheral Keratopathy
Maite Sainz de la Maza, MD, PhD;
C. Stephen Foster, MD;
Nada S. Jabbur, MD;
Stefanos Baltatzis, MD
Arch Ophthalmol. 2002;120:15-19.
ABSTRACT
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Objectives To evaluate ocular characteristics and systemic disease associations
in patients with scleritis-associated peripheral keratopathy and its different
patterns, and to assess any ocular or systemic prognostic significance of
the presence of the types of peripheral keratopathy in patients with scleritis.
Design Review of 125 patients with scleritis alone and 47 patients with scleritis-associated
peripheral keratopathy; review of patients with scleritis and the different
patterns of peripheral keratopathy: peripheral corneal thinning, stromal keratitis,
and peripheral ulcerative keratitis (PUK); review of ocular and systemic outcomes
comparisons between patients with scleritis with and without peripheral keratopathy.
Results Patients with peripheral keratopathy had more necrotizing scleritis
(57%, P<.001), decrease in vision (81%, P<.001), anterior uveitis (62%, P<.002), impending corneal perforation (62%, P<.001), and potentially lethal specific-disease association (87%, P<.001) than did patients with scleritis alone. Patients
with PUK had the worst ocular and systemic outcomes. Of the 24 patients with
PUK, 16 (67%) had necrotizing scleritis (P = .02),
virtually all had a potentially lethal systemic disease (P = .02), and all had impending corneal perforation (P<.001).
Conclusion The detection of peripheral keratopathy, and especially PUK, in a patient
with scleritis indicates a poor ocular and systemic prognosis.
INTRODUCTION
KERATOPATHY associated with scleritis usually occurs directly adjacent
to or in the same quadrant as the active scleritis. It may progress circumferentially,
centrally, or posteriorly (in which case corneal perforation may occur). Early
diagnosis and treatment may improve the ocular prognosis before vision is
affected or perforation is imminent. In a study of enucleated eyes with scleritis
associated with rheumatoid arthritis, Sevel1
found that 36% had peripheral keratopathy, and in different clinical studies,
Watson et al2-3 found that 29%
to 37% of patients with scleritis had peripheral keratitis.
Peripheral keratopathy associated with scleritis may be relatively benign
or serious, and clinical differentiation of the types of keratopathy may be
important if they have different ocular and systemic prognostic significance.
The clinical types of peripheral keratopathy associated with scleritis include
peripheral corneal thinning (intact epithelium and no inflammatory cells in
the stroma), stromal keratitis (intact epithelium but with inflammatory cells
in the stroma and without stromal ulceration), and peripheral ulcerative keratitis
(PUK) (epithelial defect, inflammatory cells in the stroma, and stromal ulceration).
This study evaluated the ocular characteristics and systemic disease associations
of patients with all 3 patterns of scleritis-associated peripheral keratopathy.
SUBJECTS AND METHODS
We reviewed the records of 172 consecutive patients (231 eyes) with
scleritis seen in the Ocular Immunology and Uveitis Service of the Massachusetts
Eye and Ear Infirmary, Harvard Medical School, Boston, during an 11-year period
and divided them into 2 categories: those with and those without peripheral
keratopathy. Patients with scleritis-associated peripheral keratopathy were
further divided into subgroups depending on the pattern: peripheral corneal
thinning, stromal keratitis, and PUK. The 3 patterns of scleritis-associated
peripheral keratopathy were defined as follows:
- In peripheral corneal thinning, the periphery of
the cornea (within 2-3 mm of the limbal margin) becomes grayish and about
one-third thinner in 1 or more areas. The epithelium remains intact throughout
the thinning process.
- In stromal keratitis, isolated or multiple white
or gray nummular opacities composed of leukocytes appear within the corneal
stroma, and, unless successfully treated, expand slowly toward the periphery
and/or center of the cornea. The epithelium is intact.
- Finally, PUK is a peripheral corneal ulcer with
epithelial defects, stromal infiltration, and stromal degradation. The ulcer
has a well-defined border on its limbal and corneal edges.
Patient data, including age, sex, type of peripheral keratopathy, type
of scleritis, bilaterality of peripheral keratopathy, and previous ocular
surgery, were analyzed. Scleritis was characterized as anterior or posterior,
according to the classification of Watson and Hayreh2;
anterior scleritis included the diffuse, nodular, necrotizing, and scleromalacia
perforans types. For the purpose of this study, scleritis-associated peripheral
keratopathy after ocular surgery was defined as scleral inflammation and peripheral
keratopathy appearing in the exact area of the previous surgical procedure.
Ocular manifestations, including permanent loss of best-corrected visual
acuity, anterior uveitis, and impending corneal perforation, were analyzed.
Decrease in visual acuity was defined as loss of vision of 2 or more Snellen
lines at the end of the follow-up period or visual acuity of 20/80 or worse
at presentation related to the inflammatory disease process. Anterior uveitis
was diagnosed based on the detection of inflammatory cells in the anterior
chamber with or without synechiae or keratic precipitates. Impending corneal
perforation was defined as progressive destruction of the peripheral cornea,
leaving only some layers of deep stroma and/or Descemet membrane.
We studied specific disease association as a result of compatible history,
review of systems, laboratory, and biopsy data. For the purpose of this study
we grouped interrelated disorders under the term spondyloarthropathies; those disorders include ankylosing spondylitis, Reiter syndrome,
psoriatic arthritis, and arthritis and inflammatory bowel disease (Crohn disease
and ulcerative colitis).
Data were analyzed with a customized database software program, and
comparisons were made between patients with scleritis-associated peripheral
keratopathy and patients with scleritis alone. A multifactorial analysis of
variance was performed for all variables except age (Mann-Whitney test). Relative
risk analysis between patients with scleritis with and without peripheral
keratopathy was conducted for all variables except age. Comparisons were also
made among scleritis patients with different patterns of peripheral keratopathy
(peripheral corneal thinning, stromal keratitis, and PUK). Statistical analysis
was performed with the  2 test for 3 variables; specific analysis
between groups of 2 patterns was conducted with the 2 test
for 2 variables with a Bonferroni adjustment.
RESULTS
A total of 47 patients (27.3%; 65 eyes) with scleritis had an associated
peripheral keratopathy; 12 patients (16 eyes) had peripheral corneal thinning,
11 patients (15 eyes) had stromal keratitis, and 24 patients (34 eyes) had
PUK.
Patients with scleritis-associated keratopathy (47 patients, 65 eyes)
were compared with patients with scleritis alone (125 patients, 166 eyes)
(Table 1). Eleven patients (18
eyes) with keratopathy had diffuse scleritis, 9 patients (11 eyes) had nodular
scleritis, 26 patients (35 eyes) had necrotizing scleritis, and 1 patient
(1 eye) had both anterior (diffuse) and posterior scleritis. Comparisons of
types of scleritis between patients with and without peripheral keratopathy
showed that diffuse scleritis was significantly more frequent in patients
without peripheral keratopathy (P<.001), and necrotizing
scleritis was significantly more frequent in patients with peripheral keratopathy
(P<.001). Nodular scleritis did not differ significantly
when compared in patients with scleritis with and without peripheral keratopathy.
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Table 1. Comparisons Between Patients With Scleritis-Associated Peripheral
Keratopathy and Scleritis Alone*
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Patients with scleritis-associated keratopathy (mean age, 62.53 years;
range, 15-85 years) were older than patients without peripheral keratopathy
(mean age, 48.47 years; range, 11-87 years) (P<.001).
Twenty-seven patients (57.4%) with keratopathy were women, and 20 (42.6%)
were men. The predominance of women did not differ significantly when patients
with scleritis with and without keratopathy were compared. Scleritis was bilateral
in 18 patients (38.3%) with peripheral keratopathy and in 41 patients (32.8%)
without peripheral keratopathy. This difference was not statistically significant.
Previous ocular surgery was detected in 18 patients (38.3%) with scleritis-associated
peripheral keratopathy and in 10 patients with scleritis alone (8%) (P <.001). The mean interval between ocular surgery and
onset of scleritis was 6.62 months (range, 1-14 months) and 11.2 months (range,
1-28 months), respectively. Previous ocular surgical procedures included cataract
extractions in all patients with peripheral keratopathy and in all but 2 patients
with scleritis alone; those 2 patients developed scleritis following strabismus
and retinal detachment procedures, respectively.
In patients with peripheral keratopathy, 38 (80.9%) had decrease in
vision, 29 (61.7%) had anterior uveitis, and 29 (61.7%) had impending corneal
perforation. Comparisons of these conditions between patients with keratopathy
and those with scleritis alone showed that decrease in vision, anterior uveitis,
and impending corneal perforation were found more frequently in patients with
peripheral keratopathy (P<.001, P = .002, and P<.001, respectively).
An associated disease was found in 41 patients (87.2%) with peripheral
keratopathy and in 57 patients (45.6%) with scleritis alone (P<.001). Specific associated diseases in patients with scleritis
with and without peripheral keratopathy included connective tissue or vasculitic
diseases in 34 patients (72.3%) and 52 patients (41.6%), respectively, and
infectious diseases in 7 patients (14.9%) and 5 patients (4%), respectively
(Table 2). Rheumatoid arthritis,
Wegener granulomatosis, and infectious diseases were found more frequently
in patients with peripheral keratopathy than in patients with scleritis without
peripheral keratopathy (P<.001, P<.001, and P = .01, respectively).
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Table 2. Scleritis-Associated Peripheral Keratopathy and Specific Disease
Associations*
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Relative risk analyses showed that, compared with patients with scleritis
alone, patients with peripheral keratopathy were 5.3 times more likely to
have necrotizing disease and 4.8 times more likely to have had previous ocular
surgery. The relative risks for complications in patients with peripheral
keratopathy were 3.9 for decrease in best-corrected visual acuity, 1.7 for
anterior uveitis, and 1.9 for associated diseases (Table 3). Furthermore, patients with peripheral keratopathy were
3.4 times more likely to also have Wegener granulomatosis and 3.7 times more
likely to have an infectious disease.
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Table 3. Relative Risk Analysis for Different Conditions in Patients
With Scleritis-Associated Peripheral Keratopathy*
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Comparisons among the different patterns of peripheral keratopathy with
respect to types of scleritis and previous ocular surgery (Table 4 and Table 5)
showed that PUK was more frequently associated with necrotizing scleritis
(16 patients, 66.7%) and previous ocular surgery (14 patients, 58.3%) than
stromal keratitis (2 patients, 18.2%, and 1 patient, 9.1%, respectively) (P = .02 and P = .03, respectively).
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Table 4. Patterns of Scleritis-Associated Peripheral Keratopathy*
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Table 5. Comparisons Between Different Patterns of Scleritis-Associated
Peripheral Keratopathy*
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Comparisons among the different patterns of peripheral keratopathy with
respect to ocular manifestations (Table
4 and Table 5) did not
show statistically significant differences for decrease in vision and anterior
uveitis. However, PUK was more frequently associated with impending corneal
perforation (24 patients, 100%) than peripheral corneal thinning (3 patients,
25%) or stromal keratitis (2 patients, 18%) (P<.001
and P<.001, respectively).
Comparisons among different patterns of peripheral keratopathy with
respect to specific disease associations (Table 4 and Table 5) showed that PUK was more frequently correlated with an associated disease
(24 patients, 100%) than was stromal keratitis (7 patients, 63.4%) (P = .02). Different patterns of peripheral keratopathy
did not differ significantly with respect to specific associated diseases
(Table 6).
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Table 6. Patterns of Scleritis-Associated Peripheral Keratopathy and
Specific Disease Associations*
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COMMENT
The results of this study provide insight into the severity of scleritis-associated
peripheral keratopathy and its different patterns. The detection of peripheral
keratopathy in a patient with scleritis should be regarded as a grave ocular
sign because scleritis patients with peripheral keratopathy more often had
necrotizing scleritis, decrease in vision, anterior uveitis, and impending
corneal perforation. In addition, it is interesting to compare scleritis-associated
peripheral keratopathy at different tertiary referral centers. Our proportion
of scleritis patients with peripheral keratopathy (65 of 231 eyes, 28%) is
similar to the proportion reported in a large retrospective study performed
in 1976 by Watson and Hayreh2 at Moorfields
Eye Hospital, London, England (88 of 301 eyes, 29%). However, the peripheral
keratopathy population from our service showed a higher proportion of eyes
with necrotizing scleritis (35 of 48 eyes, 73%) and a lower proportion of
eyes with diffuse scleritis (18 of 197 eyes, 17%) and nodular scleritis (11
of 50 eyes, 22%) than the population reported by Watson and Hayreh (necrotizing
scleritis, 59% of eyes; diffuse scleritis, 23%; and nodular scleritis, 26%).
The detection of peripheral keratopathy in a patient with scleritis
is also a warning sign of increased likelihood of an associated disease. In
this study, scleritis patients with peripheral keratopathy more often had
an associated disease than patients with scleritis alone (87% vs 46%). Rheumatoid
arthritis, Wegener granulomatosis, and infectious diseases were the most common
associated diseases.
Several distinctive patterns of peripheral keratopathy are found in
patients with scleritis: peripheral corneal thinning, stromal keratitis, and
PUK. In our experience, all 3 patterns may cause decrease in vision and may
be associated with anterior uveitis. Studies with anterior segment fluorescein
angiography showed that corneal thinning, stromal keratitis, and PUK in patients
with scleritis had varying degrees of vaso-occlusive changes in the arterial,
venous, or capillary circulations of the episcleral and conjunctival vasculature.4-6 In some instances, this
vascular shutdown may lead to catabolic resorption of the stromal tissue.5 The larger the area of vaso-occlusion, the greater
the degree of corneal and scleral destruction.6
Therefore, the vaso-occlusive changes of peripheral corneal thinning or stromal
keratitis are less extensive than the ones present in PUK. Furthermore, the
area of vaso-occlusion is larger if areas of peripheral corneal thinning or
stromal keratitis undergo impending corneal perforation. In our experience,
impending corneal perforation was present in patients with all 3 patterns
of peripheral keratopathy, but it was found most frequently in patients with
PUK.
Histopathologic studies on conjunctival, episcleral, and scleral biopsies
from patients with PUK and necrotizing scleritis showed that most had an inflammatory
microangiopathy of the episcleral and conjunctival vasculature.7
All patients with PUK had an associated disease, including systemic vasculitis
diseases and infectious diseases. The inflammatory microangiopathy in scleritis
patients with PUK may be caused by the extension of a systemic vasculitis
process, a bacterial or viral invasion, or a local immune response to these
organisms.7-8
Inflammatory microangiopathy of the episcleral and conjunctival vasculature
may be triggered by trauma such as ocular surgery in predisposed patients
with systemic vasculitic disease.9 This may
result in scleral and/or corneal destruction. In this study, the pattern of
peripheral keratopathy most frequently found after ocular surgery such as
cataract extraction was PUK. All patients with PUK had an underlying vasculitic
disease. Immune complex–mediated vasculitic damage following the surgical
trauma may underlie the pathogenesis.9-10
The findings presented here are clinically relevant and provide important
advice for practicing ophthalmologists:
- Look for corneal involvement in every follow-up
visit of a patient with scleritis. Scleritis patients with peripheral keratopathy
must be followed especially closely because they are more likely to have necrotizing
scleritis, decrease in vision, anterior uveitis, and impending corneal perforation
than patients with scleritis alone.
- Search for an underlying disease in all scleritis
patients. Scleritis patients with peripheral keratopathy are especially likely
to have an associated disease, the most common being rheumatoid arthritis,
Wegener granulomatosis, and infectious diseases.
- Distinguish the different patterns of scleritis-associated
peripheral keratopathy. Although scleritis patients with any type of peripheral
keratopathy may have ocular complications, such as decrease in vision, anterior
uveitis, and impending corneal perforation, scleritis patients with PUK have
the worst ocular prognosis because they have the highest risk of developing
impending corneal perforation. Furthermore, scleritis patients with PUK more
frequently have potentially lethal underlying diseases.
- Be aware that surgical trauma may trigger inflammatory
microangiopathy (episcleral and conjunctival vasculature) in a predisposed
patient with a systemic vasculitic disease, resulting in scleritis-associated
peripheral keratopathy. Investigate such patients aggressively to identify
this potentially lethal disease while it is still amenable to successful treatment.
AUTHOR INFORMATION
Accepted for publication September 5, 2001.
Supported in part by grant FU 90/37276861 from the Fulbright Program,
Bethesda, Md.
Presented in part as an invited paper at the World Congress on the Cornea
IV, Orlando, Fla, April 1996.
We thank Llorenç Quinto for his extensive statistical assistance.
Corresponding author: C. Stephen Foster, MD, Massachusetts Eye and
Ear Infirmary, Harvard Medical School, 243 Charles St, Boston, MA 02114 (e-mail: fosters{at}uveitis.org).
From the Ocular Immunology and Uveitis Service and the Hilles Immunology
Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston
(Drs Sainz de la Maza, Foster, and Jabbur); and the Department of Ophthalmology,
University of Athens, Greece (Dr Baltatzis). Dr Sainz de la Maza is now with
the Hospital Clinico y Provincial, Barcelona, Spain.
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7. Tauber J, Sainz de la Maza M, Hoang-Xuan T, Foster CS. An analysis of therapeutic decision-making regarding immunosuppressive
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