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Episcleritis and Scleritis: Clinical Features and Treatment Results

DOUGLAS A. JABS, MD, MBA, ABDULBAKI MUDUN, MD, J.P. DUNN, MD, AND MARTA J. MARSH, MS

To evaluate the clinical experience with episcleritis and scleritis at a tertiary care eye center. METHODS: Retrospective chart review. RESULTS: One hundred thirty-four patients with scleral inammation were seen over a 12-year period. Thirty-seven patients had episcleritis, and 97 patients had scleritis. Ocular complications occurred in only 13.5% of patients with episcleritis but in 58.8% of patients with scleritis (P < .0001). No patient with episcleritis had a decrease in visual acuity, whereas 15.9% of patients with scleritis did. Only 16.7% of patients with episcleritis required more than topical corticosteroids for treatment, and these patients required oral nonsteroidal anti-inammatory drugs. Conversely,
See also pp. 492513.

PURPOSE:

Ophthalmol 2000;130:469 476. 2000 by Elsevier Science Inc. All rights reserved.)

CLERAL

INFLAMMATORY

DISEASE

CONSISTS

OF

30.4% of patients with scleritis required nonsteroidal anti-inammatory drugs, 31.9% oral prednisone, and 26.1% systemic immunosuppressive drugs (P < .0001). Necrotizing scleritis and posterior scleritis more often were associated with ocular complications, occurring in 91.7% and 85.7%, respectively, than were diffuse anterior scleritis and nodular anterior scleritis (P .020). Patients with necrotizing scleritis and posterior scleritis were more likely to be treated with oral corticosteroids or immunosuppressive drugs (90% and 100%, respectively) than were patients with diffuse anterior scleritis and nodular anterior scleritis (56.4% and 21.4%, respectively, P .002). CONCLUSIONS: Scleritis is a severe ocular inammation, often associated with ocular complications, and nearly always treated with systemic medications. Nearly 60% of these patients will need oral corticosteroids or immunosuppressive drugs to control the disease. (Am J
Accepted for publication Jul 25, 2000. From the Departments of Ophthalmology and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Requests for reprints to Douglas A. Jabs, MD, MBA, The Wilmer Eye Institute, 550 North Broadway, Suite 700, Baltimore, MD 21205; fax: (410) 955-0629; e-mail: dajabs@jhmi.edu
0002-9394/00/$20.00 PII S0002-9394(00)00710-8

episcleritis, a more supercial inammation, and scleritis, a deeper and more destructive inammation. Previous studies have suggested that scleritis is more often associated with systemic autoimmune diseases.1 6 Ocular complications often occur with scleritis and include keratitis, uveitis, and glaucoma with anterior disease and exudative detachments or other posterior segment complications with posterior scleritis.1 8 The distinction between episcleritis and scleritis has therapeutic import, because episcleritis often may respond to topical anti-inammatory agents, such as topical corticosteroids, whereas scleritis typically requires systemic medications, such as oral nonsteroidal anti-inammatory drugs, oral corticosteroids, or in some cases immunosuppressive drugs. Because episcleritis and scleritis are uncommon disorders, there are a limited number of large series documenting clinical experience with these disorders.15 Therefore, we analyzed our clinical experience with scleral inammation, particularly the level of treatment required to control the disease and the consequences of such treatment.

PATIENTS AND METHODS


THE CHARTS OF 134 PATIENTS WITH SCLERAL INFLAMMA-

tion seen on our service from 1984 through 1996 were reviewed. All of the patients were seen by one of two physicians (D.A.J. and J.P.D.). All patients seen on our service have diagnoses recorded in a computerized database so that the data are retrievable. Data forms were designed to collect the information relevant to this study on these patients, and the data were abstracted from the clinical charts. Information then was entered into a new database for analysis. Patients were diagnosed as having either episcleritis or scleritis on clinical grounds. Episcleritis was dened as edema and injection conned to the episcleral tissue. Episcleritis was classied as either simple, in which case the inammation was sectoral in nature, or nodular.
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Scleritis was dened as edema in the episcleral and scleral tissues with the injection in both the supercial and deep episcleral vessels. Scleritis was classied as anterior, necrotizing, or posterior according to the scheme proposed by Watson and Hayreh.1 Anterior scleritis was further subclassied as diffuse anterior or nodular anterior. Posterior scleritis was diagnosed by a combination of clinical ndings and ultrasonography.5,79 Corneal complications of scleral disease were classied as either interstitial keratitis or marginal corneal ulcer. Interstitial keratitis was dened as inammation associated with corneal edema but an intact epithelium. Marginal corneal ulcer (marginal keratitis, limbal guttering, and peripheral ulcerative keratitis) was diagnosed when there was peripheral corneal inammation with loss of epithelial and stromal tissue. Anterior uveitis was diagnosed based on the presence of cells and are in the anterior chamber, and vitritis was diagnosed on the basis of the presence of cells and debris in the vitreous. An elevated intraocular pressure was dened as greater than 21 mm Hg. Because of the variable length to follow-up of many of these patients, no attempt was made to evaluate the occurrence of disk damage, which would result in a diagnosis of glaucoma. Cystoid macular edema was diagnosed on the basis of clinical grounds and conrmed with uorescein angiography. Cystoid macular edema was considered scleritis related when other conditions that could produce macular edema were absent. A decrease in visual acuity was dened as a decrease in the best-corrected visual acuity of 2 or more Snellen lines from the initial best-corrected visual acuity. An associated systemic disease was diagnosed based on the results of compatible historical, clinical, laboratory, and/or biopsy data, with conrmation of the diagnosis by the appropriate specialist (for example, a rheumatologist, gastroenterologist, or dermatologist). Associated disorders were classied either as infectious or as systemic, presumed autoimmune, rheumatic diseases.13,10 13 Postoperative scleritis was diagnosed by the presence of scleral inammation at the surgical trauma site that occurred after ocular surgery and without the presence of other disease known to be associated with scleritis.14,15 Patients with episcleritis typically did not undergo extensive laboratory evaluations, unless the history dictated appropriate evaluation and/or the disease was persistent despite topical corticosteroid therapy. Patients with scleritis typically underwent a laboratory evaluation that included a chest x-ray, urine analysis, and serum creatinine (to look for evidence of renal dysfunction secondary to vasculitis), an antineutrophil cytoplasmic antibody test, and an FTA-abs (for syphilis). Other tests were obtained as dictated by the history and physical examination. For example, radiographic imaging of the sinuses was obtained only in those patients with sinus symptoms. Antinuclear antibody and rheumatoid factor tests were not obtained routinely but only in those patients where systemic lupus erythematosus or rheumatoid arthritis were likely diagnoses based on the history and physical examination, but 470 AMERICAN JOURNAL
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the diagnosis had not as yet been made. Lyme antibody testing was obtained only in patients with a history of deer exposure in an area where Lyme disease is endemic. For patients requiring treatment, the initial treatment for episcleritis typically consisted of uoromethalone 1% eye drops four times daily. If this treatment failed to control the episcleritis, then more frequent installation was tried, and if uoromethalone was ineffective, prednisolone acetate 1% was used. Occasionally, patients referred from other physicians were treated with prednisolone acetate without rst trying topical uoromethalone. If topical corticosteroids failed, patients with episcleritis were treated with oral nonsteroidal anti-inammatory drugs, most often indomethacin. Patients with anterior scleritis and refractory episcleritis typically were treated initially with indomethacin, 25 mg four times daily. If the scleritis improved, the dose was reduced to 25 mg three times daily until the scleritis was completely quiet, typically at least 1 month in duration. Indomethacin then was discontinued. If indomethacin failed to control the scleritis, then patients were treated with oral corticosteroids. For patients with refractory anterior scleritis, necrotizing scleritis, and posterior scleritis, oral corticosteroids were given as prednisone 1 mg per kg daily. Most often this dose was 60 mg to 80 mg administered as a once-daily dose. For patients who responded to oral corticosteroids, the dose was continued until the scleritis was completely quiet or for a total of 1 month and then tapered. Patients whose eyes were not completely quiet after 1 month of high-dose oral corticosteroids had an immunosuppressive drug added as outlined below. Tapering of the prednisone was individualized. The target schedule was to taper by 10 mg per day increments weekly from 60 mg to 40 mg per day, 5 mg per day increments weekly from 40 mg to 20 mg, and 2.5 mg per day increments weekly thereafter. In some patients with long-standing disease, the rate of taper below 10 mg daily was in 1-mg per day increments. Indications for the use of immunosuppressive drugs were the occurrence of a known systemic autoimmune disease requiring such treatment initially (for example, Wegener granulomatosis), failure of scleritis to respond to oral corticosteroid therapy either by progression while on high-dose oral corticosteroids or the persistence of active disease despite 1 month of high-dose corticosteroids, the occurrence of health-threatening corticosteroid side effects (for example, diabetes, osteoporosis, and so forth), or recurrence of the scleritis with tapering of the prednisone at a dose of prednisone likely to produce severe corticosteroid side effects in the long run. Cyclophosphamide was the most frequently used immunosuppressive drug. Typically, it was started at a dose of 2 mg per kg per day in addition to oral corticosteroid therapy. Complete blood counts and urine analyses were monitored regularly, initially weekly and subsequently less frequently if the dose was stable and well tolerated, but never less frequently than monthly. Drug dosage was adjusted based on clinical OPHTHALMOLOGY OCTOBER 2000

TABLE 1. Characteristics of the Patients with Episcleritis and Scleritis


Feature Episcleritis Scleritis P value

Number of patients Demographics Age mean (years) range (years) Gender men (%) women (%) Race white (%) nonwhite (%) Ocular features Bilateral disease (%) Ocular complication (%) Decrease in visual acuity (%) Systemic features Systemic rheumatic disease (%) Rheumatoid arthritis Vasculitis Inammatory bowel disease Systemic lupus erythematosus Relapsing polychondritis Other Infectious disease Herpes zoster ophthalmicus Herpes simplex Lyme disease HIV infection Treatment required* None Topical corticosteroids Oral NSAIDs Oral Prednisone Immunosuppressive drugs Other (e.g., antibiotics, antivirals)

37 45 971 29.7 70.3 83.8 16.2 48.6 13.5 0 29.7 10.8 5.4 8.1 2.7 0.0 2.7 5.4 2.7 0.0 2.7 0.0 16.7 50.0 16.7 0.0 0.0 16.7

97 51 681 28.9 71.1 79.4 20.6 50.5 58.8 15.9 39.2 17.5 7.2 5.2 4.1 3.1 1.0 8.3 5.2 2.1 1.0 2.1 2.9 2.9 30.4 31.9 26.1 5.8 0.120 1.00 0.700

1.00 0.0001 0.110 0.326

0.673

0.001

*Treatment data available on 18 patients with episcleritis and 69 patients with scleritis. NSAIDs nonsteroidal anti-inammatory drugs.

response and tolerance of the medications. The goals of treatment were to achieve complete suppression of the inammation and a white blood count between 3000 and 4000 cells per l. If the leukocyte count decreased below 2500 cells per l, cyclophosphamide therapy was interrupted until the white blood count had increased above 3500 cells per l. The aim of treatment was 1 year of quiescent disease on cyclophosphamide followed by tapering and discontinuation of the medicine. A secondary goal was to keep the entire duration of cyclophosphamide therapy to less than 18 months. Cyclophosphamide was discontinued in patients who developed hematuria or hemorrhagic cystitis. If these patients required continued immunosuppression, chlorambucil was used as an alternative. The initial dose was 0.1 mg per kg daily, and the dose was adjusted using clinical and hematologic guidelines VOL. 130, NO. 4 EPISCLERITIS
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similar to cyclophosphamide. One patient was treated with methotrexate. Clinical characteristics were compared between patients with episcleritis and scleritis, among the different subgroups of scleritis, and between patients with and without associated systemic autoimmune diseases. Distributions of categorical variables were compared using the chi-square test with exact procedures for the calculation of signicance. Continuous variables, such as age, were compared using the t test or analysis of variance methods.

RESULTS
ONE HUNDRED THIRTY-FOUR PATIENTS WITH SCLERAL IN-

ammation were identied. Ninety-seven of the patients


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had scleritis, and 37 patients had episcleritis. Patients with episcleritis and scleritis are compared in Table 1. There were no differences between patients with episcleritis and scleritis in the demographic characteristics of age, gender, and race. The occurrence of bilateral disease was similar between the two groups. Ocular complications occurred in nearly 60% of patients with scleritis but in only 13.5% of patients with episcleritis (P .0001). No patient with episcleritis had a decrease in visual acuity, whereas nearly 16% of patients with scleritis did. Although there was a suggestion that associated rheumatic diseases were more common in patients with scleritis (39.2%) than in episcleritis (29.7%), the difference was not statistically signicant (P .326). Thirty of the patients (81.1%) with episcleritis had simple episcleritis, and seven (18.9%) had nodular episcleritis. One hundred twenty-six of the patients (94%) with scleral inammation maintained the same type of scleral inammation throughout the course of their disease. Two patients with episcleritis at their initial presentation subsequently evolved into scleritis during the follow-up. Six patients with scleritis progressed to another subtype throughout the course of follow-up. Of the two patients with episcleritis who progressed, one had rheumatoid arthritis. Of the six patients with scleritis whose subtype changed, ve had an associated systemic disease. Of the 18 patients with episcleritis and bilateral disease, 12 presented with bilateral disease and six developed inammation in the second eye during follow-up. The risk of second eye involvement in a patient presenting with unilateral episcleritis was 12% at 1 year. There was no signicant correlation between the development of bilateral disease during follow-up and the subtype of episcleritis, the presence of systemic disease, or the maximum treatment required for control of the disease. Of the 49 patients with bilateral scleritis, 29 had bilateral disease at their initial presentation, and 20 presented with unilateral disease and subsequently developed bilateral disease. The risk of second eye involvement in a patient presenting with unilateral scleritis was 23.5% at 1 year. There was no signicant correlation between the development of second eye disease during follow-up and the subtype of scleritis, presence of systemic disease, or maximum treatment required for control of the disease. The clinical features of the patients with scleritis are outlined in Table 2. Diffuse anterior scleritis was the most common presentation, followed by nodular anterior, necrotizing, and posterior. There was a suggestion that patients with necrotizing scleritis might be older than the other subtypes with a mean age at presentation of 59.6 years compared with 49.7 for diffuse anterior scleritis, 44.8 years for nodular anterior scleritis, and 47.1 years for posterior scleritis (P .06). Ocular complications were signicantly more common with necrotizing or posterior scleritis. Ocular complications were present in approximately 50% of patients with anterior scleritis, but in 91.7% 472 AMERICAN JOURNAL
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of patients with necrotizing scleritis and 85.7% with posterior scleritis (P .020). There was a suggestion that systemic disease was less frequent among patients with posterior scleritis (28.6%) than among the other groups (45.0% to 62.1%), but the difference did not achieve the conventional level of statistical signicance (P .080). Most of the patients (86.5%) with episcleritis had no ocular complications. Five patients had ocular complications: three had mild anterior uveitis, one had uveitis and interstitial keratitis, and one had an elevated intraocular pressure. Corneal complications were the most common ocular complication among patients with anterior or necrotizing scleritis. Marginal keratitis appeared to be more common among patients with necrotizing scleritis (58.3%) than among patients with other forms of anterior scleritis. Anterior uveitis was most common in patients with necrotizing scleritis, occurring in 41.7% of these patients, compared with 29.3% of patients with diffuse anterior scleritis, 14.3% of those with posterior scleritis, and 5% of those with nodular anterior scleritis. An elevated intraocular pressure developed in 9% of patients with scleritis and did not appear to differ substantially by scleritis subtype. Posterior segment complications commonly were observed among patients with posterior scleritis, including vitritis, cystoid macular edema, and exudative retinal detachment. Posterior segment complications appeared to be less common among patients with anterior and necrotizing scleritis. A decrease in visual acuity occurred in 15.9% of patients with scleritis and did not appear to differ substantially by scleritis type. There was no statistically signicant association between vision loss and the presence of corneal complications, cataracts, posterior segment complications, or the maximum treatment required to control the scleritis. However, 27% of patients with an associated systemic disease had loss of visual acuity, whereas only 3% of those without a systemic disease did (P .008). This difference was concentrated in the group with rheumatic disorders, where 36% of patients had a decrease in visual acuity (P .005). Hence, it appears that no single ocular complication was the predominant cause of visual loss. However, it appeared that the presence of an underlying systemic disease might be associated with more severe scleritis, as evidenced by its association with visual loss. Forty-four percent of the patients in this series had an associated systemic disorder. An infectious disease was present in 7.5% of patients, and the most common infection was herpes zoster ophthalmicus. Of interest, two patients with scleritis had early stages of infection with the human immunodeciency virus, had no other infection, and had not yet developed the acquired immune deciency syndrome. Nearly 30% of patients with episcleritis and 39.2% of the patients with scleritis had an associated systemic rheumatic disease. The rheumatic disease most commonly associated with scleral inammation was rheumatoid arthritis, and the second most common was vascuOPHTHALMOLOGY OCTOBER 2000

TABLE 2. Clinical Features of Patients with Scleritis


Diffuse Anterior Nodular Anterior

Feature

Necrotizing

Posterior

P value

Number of patients Demographics Age mean (years) range Gender men (%) women (%) Race white (%) nonwhite (%) Ocular features Bilateral (%) Ocular complication Anterior segment Interstitial keratitis Marginal corneal ulcer Anterior uveitis IOP 21 mm Hg Cataract Posterior segment Vitritis Cystoid macular edema Exudative retinal detachment Decrease in visual acuity Systemic disease Treatment required* None (%) Topical corticosteroids Oral NSAIDs Oral corticosteroids Immunosuppressive drugs Other (e.g., antibiotics, antivirals)

58 49.7 674 29.3 70.7 77.6 22.4 55.2 51.7 20.7 10.3 29.3 12.1 1.7 1.7 0.0 0.0 18.0 62.1 2.6 0.0 33.3 33.3 23.1 7.7

20 43.0 2574 25.0 75.0 85.0 15.0 30.0 50.0 10.0 20.0 5.0 5.0 0.0 0.0 0.0 0.0 7.1 45.0 0.0 14.3 57.1 14.3 7.1 7.1

12 59.6 4381 41.7 58.3 75.0 25.0 50.0 91.7 16.7 58.3 41.7 8.3 16.7 8.3 5.0 0.0 20.0 50.0 10.0 0.0 0.0 20.0 70.0 0.0

7 47.1 2381 14.3 85.7 85.7 14.3 71.4 85.7 0.0 0.0 14.3 14.3 0.0 28.6 28.6 28.6 16.7 28.6 0.0 0.0 0.0 83.3 16.7 0.0 0.060 0.610 0.830

0.160 0.020

0.840 0.080 0.002

*Treatment data available on 69 patients. NSAIDs nonsteroidal anti-inammatory drugs.

litis. Other associated disorders included inammatory bowel disease, systemic lupus erythematosus, and relapsing polychondritis. The vasculides in patients with scleritis and episcleritis included Wegener granulomatosis, polyarteritis nodosa, giant cell arteritis, and Takayasu arteritis. Five patients had postoperative scleritis. All of these patients had unilateral scleral necrosis. Previous surgical procedures included cataract surgery, pterygium surgery, pars plana vitrectomy, and suture removal after cataract surgery. Although all of these patients were treated with systemic anti-inammatory agents, the role of these agents in controlling postoperative scleritis was unclear. One postcataract surgery patient appeared to improve only after removal of surgical sutures, and one patient who underwent pterygium surgery with mitomycin C appeared to do equally well both with and without anti-inammatory drug therapy. Discontinuation of anti-inammatory drug therVOL. 130, NO. 4 EPISCLERITIS
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apy in this patient was associated with subsequent stabilization and ultimate healing of the lesion. Data on treatment and the response to treatment were available on 18 patients with episcleritis and 69 patients with scleritis. There was a signicant difference in the level of treatment required to control the different types of scleral inammation. Among patients with episcleritis, 16.7% required no treatment and spontaneously remitted, 50% responded to topical corticosteroids, and only 16.7% required oral nonsteroidal anti-inammatory drugs. No patient required oral corticosteroids or immunosuppressive drugs. Conversely, 30% of the patients with scleritis required oral nonsteroidal anti-inammatory drugs, 31.9% oral corticosteroids, and 26.1% immunosuppressive drugs. There was a signicant difference among the scleritis subtypes in the treatment required. Nodular anterior scleritis and diffuse anterior scleritis were more likely to
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respond to oral nonsteroidal anti-inammatory drugs. Nodular anterior scleritis most often responded to oral nonsteroidal anti-inammatory drugs (57.1%) and least often required immunosuppressive drugs (7.1%). Thirtythree percent of patients with diffuse anterior scleritis responded to oral nonsteroidal anti-inammatory drugs. Necrotizing scleritis most often required systemic immunosuppressive drugs (70%). Posterior scleritis was treated most often with oral corticosteroids (83.3%) and occasionally with immunosuppressive drugs (16.7%). Three patients with scleritis were started on indomethacin 25 mg three times daily rather than the protocol outlined in the Patients and Methods section. Two of these patients responded, representing 4.9% of all patients treated with indomethacin and 9.1% of all patients who responded to indomethacin therapy. Twenty-two percent of the patients treated with indomethacin for scleritis responded to a dose of 25 mg four times daily, representing 40.9% of indomethacin responders. Finally, 26.8% of the patients treated with indomethacin for scleritis responded to a dose of 50 mg three times daily, representing 50% of the patients who responded to indomethacin. Hence, among patients with scleritis treated with indomethacin, approximately 50% of responders responded to lower doses (100 mg daily or less) and 50% required the higher dose (150 mg daily). The median duration of indomethacin therapy was 7.5 weeks. Among those patients treated for scleritis with prednisone, the median maximum dose was 60 mg daily and the median duration of therapy was 44 weeks, with a range of 2 to 502 weeks. Because this analysis included those patients who did not respond to prednisone alone and were advanced to immunosuppressive drug therapy, we analyzed the subgroups of patients treated with prednisone but not cyclophosphamide, which should represent prednisone responders. Among this group the median duration of prednisone therapy was 30 weeks, with a range of 2 to 502 weeks. The median initial dose of cyclophosphamide was 150 mg, with a range of 100 to 150 mg daily. The median maximum cyclophosphamide dose was 150 mg daily, with a range of 100 to 250 mg daily. The median duration of cyclophosphamide therapy was 48.5 weeks, with a range of 12 to 235 weeks. Hence, not all patients were able to achieve the goal of duration of cyclophosphamide therapy for 1 year after quiescence of disease, but among patients treated with cyclophosphamide therapy, prolonged administration was required. Because some of these patients had underlying systemic disorders, such as vasculitis, which mandated treatment with prednisone or cyclophosphamide, treatment of these disorders would have lengthened the duration of cyclophosphamide therapy in some patients. Selected complications of the medications required for the treatment of scleritis are outlined in Table 3. Over 70% of patients treated with indomethacin tolerated the medication without problems. The most common compli474 AMERICAN JOURNAL
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TABLE 3. Treatment Complications


Number of patients Percent of patients

Drug

Complication

Indomethacin

45

Prednisone

41

Cyclophosphamide

16

Gastrointestinal upset Headache Oral ulcer Hyperglycemia Osteoporosis Psychiatric Myopathy Leukopenia 2,500 cells/L Microscopic hematuria Gross hematuria Cytomegalovirus pneumonitis Cardiomyopathy

22.2 4.4 2.2 9.8 4.9 7.3 2.4 37.5 18.8 12.5 6.2 6.2

cation was gastrointestinal upset, occurring in nearly one in ve. Headache and oral ulcers were uncommon. Only two of the patients treated with indomethacin (4.1%) could not tolerate the side effects and discontinued the drug. Although Cushingoid habitus was a common occurrence in patients treated with high-dose oral corticosteroids, this problem resolved with tapering and discontinuation of prednisone. A common serious complication of oral corticosteroid therapy was hyperglycemia, which occurred in 10% of the patients. Pre-existing diabetes was present in six patients (4.5% of the entire population). Three of the four patients who developed hyperglycemia while on corticosteroids required treatment with hypoglycemic agents. Osteoporosis developed in two patients on prednisone (4.9%) and corticosteroid myopathy in one patient (2.4%). Although many patients complained of mild mood disturbances while on high-dose oral corticosteroids, particularly sleeplessness and anxiety, more severe psychiatric disturbances (corticosteroid psychosis) occurred in 7.3%. Cyclophosphamide was used in 16 patients. Six patients (37.5%) developed reversible leukopenia with a white count less than 2,500 cells per l. Microscopic hematuria and/or gross hematuria was the second most common complication. Hematuria also was reversible in all patients with discontinuation of therapy and has been without long-term sequelae. In patients without underlying systemic necrotizing vasculitis, treatment typically was discontinued after the onset of hematuria. One patient requiring long-term cyclophosphamide therapy developed a cardiomyopathy, which may have represented cyclophosphamide toxicity. Two patients were treated with chloramOPHTHALMOLOGY OCTOBER 2000

bucil, and one developed reversible leukopenia. Infectious complications of immunosuppressive drug therapy included cytomegalovirus pneumonitis in one patient treated with cyclophosphamide and Pneumocystis carinii pneumonia in one patient treated with chlorambucil.

DISCUSSION
AS WITH ALL RETROSPECTIVE ANALYSES, OUR DATA MUST

be interpreted with caution. Our institution is a tertiary care referral center and is likely to see more severe disease than is a general practice. This bias may be present in our data on episcleritis, where the frequency of associated systemic diseases in our study was higher than that reported in previous series, because other series have reported that episcleritis typically is a disorder limited to the eye and most often unassociated with a systemic disease.13 Similarly, our treatment data, particularly the duration of therapy and the need for immunosuppressive drugs, could be biased to more severe disease and more aggressive therapy. However, because episcleritis and scleritis are uncommon disorders, there is value in the reporting of a large clinical experience. Previous series have reported that approximately 40% to 50% of patients with scleritis will have an associated systemic disorder. As in our series, infections account for less than 10% of these, and rheumatic diseases account for the rest.13 As with other series, the most commonly associated systemic disease was rheumatoid arthritis with vasculitis (particularly Wegener granulomatosis), with inammatory bowel disease, systemic lupus erythematosus, and relapsing polychondritis occurring less frequently. The distinction between episcleritis and scleritis is important, because it predicts the probability of ocular complications and guides therapy. In our series ocular complications were uncommon in patients with episcleritis. No patient with episcleritis lost visual acuity, and no patient required oral systemic corticosteroids or immunosuppressive drug therapy. Previous series1 have suggested that episcleritis often is a spontaneously remitting disorder that does not require treatment. A minority of our patients (16.7%) with episcleritis did not require treatment. This experience may represent referral bias, because it is likely that patients with more severe and or persistent disease were referred to us. Some authors1,4 have used topical nonsteroidal anti-inammatory agents for the treatment of episcleritis. The agents used in the British series are unavailable in the United States; therefore, we typically started treatment with uoromethalone, a topical corticosteroid with limited intraocular penetration. The majority of our patients with episcleritis who required treatment responded to such treatment. A small percentage of patients (16.7%) required oral nonsteroidal anti-inammatory drugs. Scleritis is a more severe and destructive ocular process. VOL. 130, NO. 4 EPISCLERITIS
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Nearly 60% of patients developed an ocular complication, and 15.9% had a decrease in visual acuity. Nearly 90% of patients required systemic medications. Oral urbiprofen has been used in some countries for the treatment of scleritis,4 but it is unavailable in the United States. The risk of aplastic anemia from phenylbutazone and oxyphenbutazone has limited their use in the United States. Therefore, our initial nonsteroidal anti-inammatory drug was indomethacin, and if patients failed indomethacin, we typically switched them to oral corticosteroids. Our clinical impression has been that other available nonsteroidal anti-inammatory drugs are less effective than indomethacin for the treatment of scleritis; therefore, we have few formal data on their use. Approximately 30% of patients with scleritis responded to nonsteroidal anti-inammatory drugs, and nodular anterior scleritis appeared to be most likely to respond, because more than 50% of the patients with nodular anterior scleritis were controlled with oral nonsteroidal anti-inammatory drugs. Conversely, necrotizing scleritis and posterior scleritis typically required more aggressive medical management. The one patient with follow-up who had necrotizing scleritis but did not require treatment had surgically induced scleral necrosis. The majority of patients with necrotizing scleritis required immunosuppressive drug therapy. All of the patients with posterior scleritis responded to systemic corticosteroids, but one patient required long-term immunosuppression because of relapses with tapering of the oral corticosteroid. Caution must be exercised in interpreting these data. Based on the experiences of previous authors,1 6 we did not routinely use indomethacin for necrotizing scleritis or posterior scleritis. As a result, some patients with posterior scleritis might respond to nonsteroidal anti-inammatory drugs and not require systemic corticosteroids. Rosenbaum and Robertson9 reported a small case series of patients with posterior scleritis who responded to oral indomethacin therapy. However, our patients with posterior scleritis did well on systemic corticosteroid therapy, with most patients responding promptly and not requiring more aggressive treatment. One of our patients with posterior scleritis was treated with indomethacin and had no response to this therapy. The duration of treatment required appears to depend on the severity of the disease, at least as measured by the required therapy. The median duration of indomethacin therapy was only 7.5 weeks, whereas the median duration of prednisone therapy was 44 weeks. The median duration of prednisone therapy among those patients who were not treated with cyclophosphamide was somewhat shorter, 30 weeks, but still of extended duration. The median duration of cyclophosphamide therapy was nearly 1 year. These data suggest that for patients who require more than indomethacin to control their scleritis, long-term therapy on the order of 6 to12 months is likely to be required. The complications of treatment with systemic medications, particularly immunosuppressive drugs, were not inAND

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substantial. Indomethacin was relatively well tolerated, although approximately 20% of patients developed some degree of gastrointestinal upset, sometimes requiring treatment with either an H2 blocker or a proton pump inhibitor. Only two patients required discontinuation of indomethacin for side effects. The most common serious complication of prednisone therapy was hyperglycemia, which occurred in 10% of patients. Because of the longterm adverse effects of diabetes on health, every effort was made to minimize such treatment in these patients. In addition, 5% of our patients had pre-existing diabetes, and corticosteroids would be expected to exacerbate their disease. Slightly over 25% of our patients with scleritis required immunosuppressive therapy. The complications of therapy with the alkylating agent cyclophosphamide and chlorambucil were substantial but reversible. The occurrence of leukopenia requiring interruption of therapy attests both to the difculty in achieving the target leukocyte range of 3,000 to 4,000 cells per /l without overshooting and to the need for aggressive treatment to control the eye disease. We were concerned about bladder toxicity from cyclophosphamide and monitored for it carefully. The encountered toxicity was reversible; however, because of the concerns about the potential association of hemorrhagic cystitis with subsequent bladder problems, including bladder cancer, our approach was to discontinue cyclophosphamide after the occurrence of hematuria. If necessary, chlorambucil or another agent was substituted. Eleven percent of our patients treated with alkylating agents developed an opportunistic infection. Our experiences in treating patients with cyclophosphamide for scleritis and for mucous membrane pemphigoid has led us to consider the use of primary prophylaxis for P. carinii pneumonia in patients treated with alkylating agents. This experience has been seen by others treating Wegener granulomatosis with oral daily cyclophosphamide, and they have made similar recommendations.16 In conclusion, our data suggest that episcleritis is most often a mild ocular disorder, unassociated with ocular complications, and that it responds to topical medications. Although occasional cases may progress to scleritis, most cases of episcleritis remain as episcleritis. Conversely, scleritis is a more severe ocular disease often associated with ocular complications and requiring oral medications. Nearly 67% of patients with scleritis will require more than nonsteroidal anti-inammatory therapy, and slightly over 25% will need immunosuppressive drugs. Although scleritis can be controlled by these medications, there is the potential for side effects, which require both close moni-

toring and cooperation among physicians caring for these patients, including ophthalmologists, internists, and rheumatologists.

REFERENCES
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