Article Date: 5/1/2007

Untitled Document

PEER REVIEWED
Uveitis Diagnosis, Management, and Treatment

O’NEIL M. BISCETTE, MD, MSCmpE • HOWARD F. FINE, MD, MHSc • THOMAS E. FLYNN, MD

Uveitis refers to inflammation of the uveal coat of the eye and is a prevalent cause of visual impairment in most countries. The uvea consists of 3 tissues that are continuous with each other: the iris anteriorly, the choroid posteriorly, and the ciliary body between the iris and choroid. In addition to providing most of the blood supply of the intraocular structures, the uveal coat acts as a conduit for immune cells, particularly lymphocytes, to enter the eye. Consequently, it is directly involved in many intraocular inflammatory processes. The International Uveitis Study Group classifies uveitis in terms of eye(s) involved (ie, unilateral or bilateral), course (ie, acute [lasting less than 12 weeks] or chronic [lasting more than 12 weeks]), and anatomical location in the eye (Table 1).1 Anterior uveitis includes iritis, anterior cyclitis, and iridocyclitis involving the iris and/or pars plicata (anterior ciliary body). Intermediate uveitis includes pars planitis, posterior cyclitis, hyalitis, and basal retinochoroiditis, referring to inflammation of the pars plana (posterior ciliary body) and/or adjacent peripheral retina. Posterior uveitis includes focal, multifocal, or diffuse choroiditis; retinitis; retinochoroiditis; and chorioretinitis; the latter 2 terms indicate which tissue appears primarily involved. Panuveitis refers to inflammation that involves both the anterior and posterior segments. Uveitis is further classified on the presence or absence of granulomatous inflammation, marked by “mutton fat” keratic precipitates (large, greasy-appearing collections of inflammatory cells on the corneal endothelium), iris nodules, and/or choroidal granulomas (Figure 1). Uveitis frequently occurs in the context of systemic inflammatory disease, which may cause additional morbidity. Conversely, uveitis often represents the first manifestation of a systemic disease (Figure 2).2,3 Sixty percent of uveitis is limited to the eyes; in the other 40% of patients, an underlying systemic disease, often of autoimmune origin, can be identified.4 Consequently, management of patients



O’Neil M. Biscette, MD, MSCmpE, is a research fellow at the Edward S. Harkness Eye Institute of the Columbia University College of Physicians & Surgeons in New York. Howard F. Fine, MD, is a fellow in vitreoretinal surgery at the Harkness Institute. Thomas E. Flynn, MD, is associate professor of ophthalmology at the Harkness Institute. Dr. Biscette can be contacted via e-mail at ob2147@columbia.edu. None of the authors have any financial interest in any products mentioned in this article.


with uveitis often requires a multidisciplinary approach. The annual incidence of uveitis is between 17 and 52 per 100,000 people, and the prevalence is 38 to 714 cases per 100,000.5-7 It has been estimated that uveitis accounts for about 10% of the visual handicaps in the western world8 and up to 15% of all cases of total blindness in the United States.9 Legal blindness develops in at least 1 eye in 22% of all uveitis patients and in about 23% of all who require intraocular surgery.9 Visual acuity (VA) loss to worse than 6/18 in at least 1 eye occurs in 35% of patients with uveitis, mainly as a result of persistent macular edema.9 The ocular complications of uveitis are usually directly responsible for the decrease in VA. In 1 study, cystoid macular edema (CME) was the most frequent cause of both irreversible blindness and decrease in VA.10 Other ocular complications of uveitis include cataract, glaucoma, retinal vascular abnormalities, macular lesions,


Figure 1. Keratic precipitates and a small layered hypopyon.

retinal detachment, corneal opacities, optic-nerve atrophy, and phthisis. Uveitis may occur at any age, but it most commonly affects individuals between 20 and 59 years of age.5,8-11 Uveitis in children younger than 16 years old accounts for only 5% to 10% of cases.12 Childhood uveitis is associated with unique diagnostic and management issues, tendency for chronic disease, and high complication rates.13 In 1 study, the most frequent complication was cataract, followed by glaucoma, with 2% suffering bilateral legal blindness and 17% with unilateral legal blindness.14 In this article, we will review the diagnosis of, comanagement of, and current therapy for uveitis. This discussion is limited mainly to noninfectious forms of the disease.


Figure 2. Neuroretinitis in a patient infected with Bartonellae henselae acquired from a kitten.

DIAGNOSIS
As in all medical conditions, the key to diagnosis in uveitis is an accurate and relevant history and physical examination. Depending upon the presentation, specific information can be elicited from the history and physical examination of the eye and body.However, it is often difficult to arrive at a diagnosis on the basis of history and physical alone. Consequently, additional laboratory and other diagnostic investigation often become necessary. The proper diagnosis of the underlying disease process allows the clinician to determine not only the etiology of the inflammation, but also serves to guide the specific treatment. Although great improvements have been made in the diagnostic methods over the past few years, there is no standardized battery of tests that is ordered for all patients with uveitis. Instead, testing should be tailored to individual patients based on their presentation and the differential diagnosis. When the history and physical exam do not clearly indicate a cause, most uveitis specialists recommend a subset of core tests including complete blood count (CBC), erythrocyte sedimentation rate (ESR), angiotensin converting enzyme (ACE), lysozyme, syphilis serologic profile, HLA markers, and chest radiographs. Baseline CBC is usually indicated in patients with uveitis to aid in the diagnosis of common infectious causes of uveitis, as well as rare malignant causes of uveitis such as the acute leukemias,14 to establish a baseline for monitoring the effects of treatments (discussed below). ESR can be useful when giant-cell arteritis is suspected as a potential cause of uveitis, as well as in other inflammatory conditions such as systemic lupus erythematosis and rheumatoid arthritis. ACE and lysozyme are useful in the diagnosis of sarcoidosis, and syphilis serologic profile is also useful if sexual history indicates risk factors. Specific HLA markers can be useful based on family history, signs, and symptoms, as well as geographic location (see below). Depending on risk factors, tests for Lyme disease, Herpes viruses, Bartonella (Figure 2), and skin tests for tuberculosis may be ordered. Some of the most useful diagnostic methods employed in the diagnosis of inflammatory eye diseases will be discussed.
When Should Additional Diagnostic Testing Be Done?
Diagnostic testing in a patient with a single episode of mild unilateral acute anterior uveitis without any accompanying systemic symptoms and signs that behaves in a benign fashion is often avoided. Further investigation should be undertaken if the patient has (1) intermediate, posterior, diffuse, or bilateral inflammation; (2) recurrent, moderate, or severe inflammation, with or without granulomatous features; or (3) systemic symptoms or signs suggesting an underlying medical diagnosis.15
SPECIFIC TESTS
Erythrocyte Sedimentation Rate (ESR)

Both ESR and C-reactive protein (CRP) are acutephase reactants that show good correlation with each other but are very nonspecific in the diagnosis of uveitis.
Angiotensin Converting Enzyme (ACE)

Angiotensin converting enzyme, a relatively nonspecific enzyme, is produced by the capillary endothelial cells in lung and liver tissues and by secretory monocytes. In the setting of uveitis, ACE has increased specificity for granulomatous diseases such as sarcoidosis, leprosy, and histoplasmosis. Levels are elevated in 35% to 80% of patients with sarcoidosis.16 The sensitivity for ACE predicting sarcoidosis in one study was 59%.17
Antinuclear Antibodies (ANA)

Antinuclear antibody elevation is very nonspecific particularly in the elderly. Juvenile idiopathic arthritis ( JIA) is probably the uveitis condition for which ANA testing is most appropriate. The presence of ANA was shown to nearly triple the risk of development of JIA-associated uveitis, which can often be asymptomatic, in children with pauciarticular JIA, who are young, ANA-positive females with fewer than 5 involved joints.18
Antineutrophil Cytoplasmic Antibodies (ANCA)
Antineutrophil cytoplasmic antibody (ANCA) testing is most useful in scleritis or peripheral ulcerative keratitis with uveitis. A positive cytoplasmic ANCA (c-ANCA) is specific for Wegener granulomatosis, which can be a lifethreatening condition. However, both perinuclear ANCA (p-ANCA) and c-ANCA elevations can also occur in inflammatory bowel disease, HIV infection, and in 10% to 20% of patients with chronic idiopathic uveitis.19
Lysozyme
Lysozyme, a hydrolytic enzyme and bacteriolytic glycosidase, has been found in all 3 human neutrophil granules (azurophil, specific, and gelatinase types).20 Serum lysozyme has been shown to be elevated in a number of conditions, including tuberculosis and sarcoidosis, as well as leukemia. Tomita and colleagues17 found serum lysozyme to have a sensitivity of 79.1% for the prediction of sarcoidosis when serum ACE is also elevated and a sensitivity of 72.1% when serum ACE is normal. In that same study, the sensitivity of high-serum ACE for predicting sarcoidosis was 59.0%.
Biopsy
In cases where noninvasive methods fail to clearly elucidate the diagnosis or in situations where specific information regarding tumor genetic makeup or microbiologic identification is required, tissue biopsy can serve as an excellent investigative tool. It can rule out masquerade syndromes such as intraocular lymphoma. Directed biopsy of disSeased tissue such as conjunctival granulomas in sarcoidosis can be successful in elucidating the cause of uveitis in selected circumstances. Mycobacterium leprae has been detected in iris biopsies.21 Sampling of the vitreous, which can be accomplished by needle aspiration or through vitrectomy, combined with other relevant noninvasive diagnostic testing, can significantly increase the chances of identifying the etiology of the disease process through cytopathologic, microbiologic, and molecular analysis of the sample.22 Obtaining a vitreous sample through pars plana vitrectomy (PPV) may have both diagnostic and therapeutic uses.23
Microorganisms

The identification of microorganisms can play a key role in determining the cause of uveitis especially when infection is suspected. Methods of identification include culture and sensitivity, identification of organisms on darkfield microscopy, direct detection of antigens in clinical specimens, demonstration of rising immunoglobulin M (IgM) antibodies in body fluids, and the detection of specific nucleic acid sequences either by amplification or probes. Depending on the risk factors particular attention should be paid to syphilis, herpes viruses, tuberculosis, and Lyme disease.
Syphilis Testing
Diagnosis of infection with Treponema pallidum, the causative agent in syphilis, is based upon clinical presentation and supported by serologic testing. Direct microscopic identification of T pallidum is possible using techniques such as darkfield microscopy, silver staining, and immunofluorescence staining. Serologic diagnosis is normally based upon the results of both nontreponemal tests such as the Veneral Disease Research Laboratory (VDRL) or rapid plasma regain (RPR) and treponemal tests such as the fluorescent treponemal antibody absorption (FTA-ABS) or microhemagglutination assay-treponemal pallidum (MHA-TP). The nontreponemal tests derive their name from the fact that the detected antibodies are directed against mammalian membrane phospholipids such as cardiolipin. These anticardiolipin antibodies may not be detectable in as many as 30% of treated and untreated people during the late latent or tertiary stages of infection. 24,25 These antibodies may be seen in patients with diseases unrelated to syphilis (eg, collagen vascular disease). Therefore it is necessary to use specific treponemal antibody assays in all cases of suspected disease with a negative RPR or VDRL test. Positive nontreponemal tests indicate active disease and exposure to the bacteria and are best used to diagnose a primary infection, monitor disease activity, or monitor response to therapy based on titer. Both the VDRL and RPR test results return to normal with effective therapy. The fluorescent treponemal antibody absorption test (FTA-ABS) or the more specific MHA-TP test is more reliable to prove past infection and may remain positive for life. A 5% to 17% rate of transient or persistent seroreversion has been demonstrated in some studies.26 Patients with uveitis and positive serologic results should undergo spinal fluid examination to rule out asymptomatic neurosyphilis.Traditionally, the VDRL has been used to detect neurosyphilis; however, the serum VDRL may be low or negative, while serum FTA-ABS and CSF serologic tests are positive. In latent syphilis, VDRL and FTA-ABS results are positive, while CSF results are negative.27 Enzyme immunoassay and polymerase chain reaction are being used with increasing frequency in the diagnosis of syphilis because of the high sensitivity and specificity in the former and when test samples are minute in the latter.28-30
Polymerase Chain Reaction
Polymerase chain reaction (PCR) is a powerful molecular technique for evaluating very small amounts of DNA and RNA. It is a simple, rapid, sensitive, and specific tool for the diagnosis of infection, autoimmunity, and masquerade syndromes in the eye. PCR can be helpful as an adjunct to evaluate biopsy specimens in the diagnosis of cases that have failed to be identified by conventional methods.31
HLA Associations
All animals with leukocytes express a family of cell surface glycoproteins called major histocompatibility complex (MHC) proteins. In humans the MHC proteins are called human leukocyte antigen (HLA) molecules. HLA genes are located on the short arm of chromosome 6. Some uveitis syndromes are associated with the possession of certain HLA types (Table 2).32 Despite the fact that numerous studies have revealed an association between various HLA antigens and uveitis syndromes, the mechanism underlying the development of these syndromes remains unknown.With further investigation we may be able to characterize genetic susceptibilities for individual uveitis syndromes and, from this, gain insights into the molecular mechanisms of their pathogenesis.



Other Laboratory Diagnostic Tests

There are numerous other diagnostic laboratory tests that can in specific situations be useful in elucidating the cause of uveitis. Examples include sacroiliac joint radiographs in patients with the HLA B-27 gene, endoscopy of the GI tract when inflammatory bowel disease is suspected, and lumbar puncture and analysis of cerebrospinal fluid when associated neurologic disease is present.
Ocular Imaging Techniques

Imaging techniques such as chest radiograph and computed tomography (CT) scan of the chest for sarcoidosis or tuberculosis are well established. CT scan of the orbits or B-scan ultrasonography can assist in the diagnosis of posterior scleritis, orbital myositis, and orbital inflammatory disease. Magnetic resonance imaging (MRI) of the brain may


Figure 3. Cytomegalovirus retinitis. Note the full thickness retinal necrosis with advancing granular border and retinal hemorrhage. Fundus photography can be important in tracking disease progression.

reveal demyelination, indicating inflammatory activity that can be caused by various entities such as multiple sclerosis and Lyme disease, both of which can be associated with pars planitis, suggest orbital malignancy or neurosarcoidosis when used in conjunction with ocular imaging techniques. These provide useful information in the diagnosis and management of uveitis, as well as the diagnosis and management of the disease process itself. In this paper, we will concentrate on ocular imaging techniques.
▪ Color fundus photography. Color fundus photography is useful in documenting the presence of posterior-segment pathology. Color photography can often highlight subtle clinical findings, and it is especially useful for establishing a baseline and detecting disease progression over time (Figure 3).
▪ Fluorescein angiography. Fluorescein angiography (FA) is useful in evaluating changes such as breakdown in the blood-retinal barrier, which can lead to CME and papillitis. FA is also useful in detecting vascular occlusion from vasculitis, which can be the result of the numerous causes of posterior uveitis and choroiditis,33-35 as well as complications such as retinal or choroidal neovascularization (CNV).
▪ Indocyanine green angiography. Indocyanine green (ICG) angiography is used mainly as an adjunct to FA to help evaluate the choroidal vasculature. The most useful information is obtained in the later phases of the ICG study.36 Herbort and colleagues37 developed in 1997 a standardized protocol for administration and interpretation of posterior uveitis using ICG. Several conditions, such as birdshot retinochoroiditis, are much more prominent with ICG angiography.
▪ Autofluorescence.Autofluorescence (AF) imaging highlights the presence of lipofuscin in the retinal pigment epithelium (RPE). Since many posterior uveitic conditions, particularly the white spot syndromes, affect the outer retina-RPE-choriocapillaries complex, AF can be a particu-


Figure 4. Multiple chorioretinal spots from infection with West Nile Virus are subtle on color photography but prominent on autofluorescence imaging.

larly useful noninvasive diagnostic tool (Figure 4). For instance, the numerous dots and spots of MEWDS are much easier to appreciate with fundus AF.38
▪ B-scan ultrasonography. B-scan ultrasonography has been most useful in the evaluation of intraocular disorders associated with opacified media. Opacified media can be caused by intraocular inflammation and its complications, as well as other conditions, including but not limited to corneal opacification, anterior chamber hyphema or hypopyon, posterior synechiae with miosis, cataract, vitreous hemorrhage, and retinal detachment. Ultrasound can also be used to evaluate inflammatory infiltration of the choroid, as occurs in chronic uveitis including Vogt-Koyanagi-Harada (VKH) syndrome, sympathetic ophthalmia, and combined scleral and choroidal thickening from scleritis.39 In these situations, ultrasound becomes useful in evaluating patients prior to instituting therapy or planning surgery. In the presence of clear media, high-frequency ultrasound or ultrasound biomicroscopy (UBM) can be of additional use, particularly for examination of the region of the ciliary body and pars plana, which are often involved in patients with intermediate uveitis and can be difficult to visualize clinically (Figure 5).40 UBM may also identify occult foreign bodies in cases of chronic uveitis occurring after trauma.
▪ Optical coherence tomography. Optical coherence tomography (OCT) is currently one of the most important imaging techniques used in the study of uveitis. It enables imaging of the optic nerve head, nerve fiber layer, retina, choroid, and the vitreoretinal interface in a noncontact and noninvasive manner. It can be repeated as often as necessary since there are no serious side effects in OCT testing. OCT can be used to quantify macular thickening and thus is an excellent way of diagnosing CME and monitoring the effectiveness of treatment (Figure 6).41,42 OCT can detect vitreoretinal interface disorders such as epiretinal membranes, macular holes, and vitreomacular traction, which can assist in management.43-45 OCT is also valuable in the study of the different types of retinal detachment and the role, location, and density of an associated exudate. The most important limitation of OCT is its reliance on relatively clear media for useful images. A second factor limiting OCT’s utility is the need for patient cooperation with fixation and control of eye movements. These limitations may prove difficult for photophobic subjects.


Figure 5. Inflammatory ciliary body effusion and detachment detected on ultrasound biomicroscopy (UBM) in a patient with sarcoidosis with hypotony. S=sclera, K=cornea, CB=ciliary body, I=iris.

MANAGEMENT
The current treatment of uveitis consists of immunomodulatory medications aimed at first controlling acute inflammation and then maintaining long-term remission. Despite considerable progress, we continue to have significant challenges in the safe and effective management of uveitis. Additionally, uveitis frequently occurs in the context of systemic inflammatory disease, which may cause additional morbidity.2,3 Therefore, management of uveitis requires close collaboration between the ophthalmologist and primary care provider — and possibly uveitis specialist and/or rheumatologist. Management of a patient with uveitis involves the diagnosis of the particular uveitis subtype, evaluation of the level of intraocular inflammation, and the institution of appropriate therapy. For mild anterior uveitis, local therapy is typically appropriate, including topical corticosteroids and cycloplegia, periocular corticosteroid injections, and recently, long-term intraocular corticosteroid implants. For more severe cases of uveitis, especially posterior uveitis or panuveitis, systemic therapy is often warranted. Corticosteroids represent the mainstay of medical therapy of patients with uveitis due to their effectiveness at controlling inflammation in both the short and long terms. There are myriad side effects of corticosteroids, however, both ocular and systemic. Ocular sequelae include acceleration of cataract formation and glaucoma. Systemic side effects include weight gain, gastric ulceration, osteoporosis, fluid retention, hypertension, diabetes mellitus, and mental status changes, to name a few.


Figure 6. Optical coherence tomogram through fovea in patient with cystoid macular edema.

Use of medications requires the physician to follow the response to treatment and monitor the patient for drugrelated side effects, both in the eyes and systemically. Surgery may be planned to augment medical treatment or visually rehabilitate the eyes. However, steroid-sparing therapy or additional immunosuppressive therapy often must be prescribed because of the severity and duration of disease and the inevitable presence of corticosteroid side effects. Classes of noncorticosteroid immunosuppressive agents include antimetabolites, cyclosporines, alkylating agents, T-cell inhibitors, biologic agents, and intravenous immunoglobulin (IVIg). A panel of 12 US physicians with expertise in ophthalmology, rheumatology, pediatrics, and the care of inflammatory diseases recently reviewed published data and developed recommendations regarding the role of systemic immunosuppressive agents in the management of inflammatory eye diseases. The report is a valuable resource46 to assist in deciding to employ these medications.
CORTICOSTEROIDS

Corticosteroids have been used effectively in the treatment of inflammatory disease of a noninfectious cause. Because of their immediate efficacy, topical corticosteroids are useful in the management of anterior uveitis, whereas periocular and intravitreal steroid injections can be used for intermediate and posterior uveitis and CME. Some patients may require systemic corticosteroids that can be administered orally or intravenously. Patients may have adverse effects from locally administered corticosteroids, making the use of systemic corticosteroids or other agents necessary.When systemic corticosteroids are insufficient to control the disease because of adverse corticosteroid side effects or are required for long-term use (more than 3 months) and at a high dose (more than 10 mg/day of prednisone), a corticosteroid-sparing agent should be considered.47
Topical Corticosteroids

Topical corticosteroid eye drops in combination with cycloplegic agents are the first line of treatment for anterior uveitis. Depending on the severity of the inflammatory reaction, these agents are used as frequently as every halfhour initially, and anterior uveitis is often readily controlled without the need for additional immunosurpression. In chronic cases — for example, patients with JIA-associated uveitis — topical corticosteroids cause cataract and elevate intraocular pressure (IOP), requiring additional immunosuppression to control intraocular inflammation after the initiation of therapy.48
Periocular Corticosteroids

Sometimes an increase in disease activity warrants an increase in medication beyond the use of topical medication. Periocular steroids represent a good alternative to systemic medications and have been used in the treatment of CME and posterior uveitis.49-52 The traditional medicines and routes of administration are triamcinolone acetonide (Kenalog, Bristol-Myers Squibb) 40 mg/mL52 in the posterior subtenon space in the superotemporal quadrant and methylprednisolone acetate 40 mg/mL53 in the orbital floor.54-56 It has been suggested that triamcinolone acetonide administered in the posterior subtenon space is more efficacious.57 Known complications of the procedure include increase in IOP in steroid-responsive patients, inadvertent intraocular penetration with the needle, scleral melting when used in some scleritis patients, worsening of undiagnosed intraocular infections (eg, toxoplasma), and ptosis when triamcinolone acetonide is given in the posterior subtenon space.58
Intravitreal Corticosteroids

Intravitreal triamcinolone acetonide (IVTA) injections have been gaining popularity since their first use in humans in the late 1990s. The use of IVTA is currently referred to as “off-label” because the medication has not been approved by the Food and Drug Administration (FDA) for intraocular administration. Despite the widespread use of triamcinolone acetonide in and around the eye for decades, the manufacturer of the drug, at the urging of the FDA, mailed a “Dear Healthcare Provider” letter to ophthalmologists in November 2006, reminding them that Kenalog has not been approved for intraocular administration.59 It is probably too early to determine the complete impact of this letter; however, the Ophthalmic Mutual Insurance Company’s (OMIC) legal/risk-management department conducted its own analysis of the impact of the letter, consulting with attorneys and FDA officials, and concluded, “It is our opinion that it remains legal for ophthalmologists to administer Kenalog (triamcinolone acetonide) by the routes mentioned in the letter, despite the manufacturer’s warning, as part of ‘the practice of medicine.’”57 IVTA injections have been used to treat various ocular diseases such as uveitis, age related macular degeneration (AMD), and CME from various causes.54-56,60-63 Intravitreal administration of small amounts of corticosteroids provides high intraocular levels with limited systemic side effects.64 The use of IVTA injections in noninfectious uveitis is limited because of its temporary effect, especially on chronic uveitis, which requires sustained therapeutic levels of corticosteroids.65 However, IVTA injections can become useful as additional medication in acute exacerbations or as initial therapy to quickly control inflammation or treat macular edema. Some of the adverse effects of IVTA include endophthalmitis,66,67 elevated IOP,68-71 and cataract.72 The National Eye Institute (NEI) is currently conducting 3 randomized clinical trials on the use of IVTA in various macular diseases.73
Systemic Corticosteroids
In a study on prognosticators for visual outcomes in sarcoid uveitis, Dana and colleagues82 demonstrated that, in patients treated with topical corticosteroids, transseptal corticosteroids, systemic corticosteroids, topical nonsteroidal anti-inflammatory medications (NSAIDs), and systemic NSAIDs, systemic corticosteroid treatment was associated with better VA outcomes, suggesting that systemic therapy has an important role to play in the management of patients with chronic uveitis.74 The most common type of oral corticosteroid used is prednisone at a typical initial dose of 1 mg/kg/day for high-dose administration in the adult patient, which is then gradually tapered. If high-dose immediate-acting steroid therapy is needed in order to save vision, methylprednisolone sodium succinate (Solu-Medrol, Pfizer) can be given intravenously. The usual regimen consists of 1-g pulses per day given on 3 consecutive days and is followed by oral corticosteroid therapy.75 Long-term monthly pulses have been employed for serious autoimmune diseases such as lupus nephritis and may prove useful in a very limited group of severely affected uveitis patients. While on corticosteroid therapy, patients should be monitored closely for response to steroid treatment and for adverse effects from the medication. If the inflammatory reaction is not completely quiet after 4 weeks of treatment with high-dose steroid therapy, the physician should consider adding additional local or systemic immunosuppressive therapy. After a satisfactory suppression of inflammation, systemic corticosteroids should be tapered and discontinued if possible. If the inflammation recurs during the tapering schedule, resume a higher dosage until the disease is again quiet and taper back to just above the threshold at which the disease reactivated. If chronic suppression of disease requires more than 5 to 10 mg/day of prednisone or its equivalent, a steroid-sparing immunosuppressive drug should be instituted.47 Long-term steroid therapy, whether administered systemically or locally, can result in considerable adverse effects on the eye, including cataract formation and increased IOP.76-78 Patients can also have delayed wound healing, secondary infection, and reactivation of latent herpes simplex infections.79-82 A skin test for prior exposure to tuberculosis should be considered before starting systemic steroid or any other immunosuppressive medication. Additional systemic side effects include osteoporosis, endocrinologic abnormalities including hyperglycemia, cardiovascular abnormalities, aseptic necrosis of bone, psychosis, pancreatitis and myopathy.83-91 Therefore, patients should be counseled and monitored continuously when on chronic steroid therapy. Alternatives to steroid therapy should be considered early and discussed fully with patients when a course of treatment is begun.
Immunosuppressive Drugs

In patients with diseases poorly responsive to corticosteroids, chronic or relapsing disease requiring a dose of prednisone of more than 10 mg/day, or intolerable corticosteroid side effects, corticosteroid therapy is often replaced or supplemented with immunosuppressive therapy. There are also cases in which early and aggressive immunosuppressive drug therapy can play a key role in preventing irreversible vision loss.92 Current immunosuppressive medication classes, along with their dosages, efficacy, side-effect profiles and the conditions in which they have been used, are discussed below.
ANTIMETABOLITES

Methotrexate
Methotrexate is a folic acid analog that inhibits dihydrofolate reductase, an action that inhibits the production of thymidylate, which is essential for DNA replication. Therefore, methotrexate inhibits rapidly dividing cells, such as leukocytes, producing an anti-inflammatory or immunosuppressive effect.93 Methotrexate can be given orally, subcutaneously, intramuscularly, or intravenously. It is typically administered at a dose ranging from 7.5 to 25 mg once per week in a single or divided dose. Folic acid at 1 to 5 mg/day or folinic acid should be given concurrently to maintain adequate folate stores and to reduce toxicity. The full effect from methotrexate therapy takes 6 to 8 weeks to occur.94 Methotrexate has been used to treat a variety of ocular inflammatory conditions in both children and adults, including vasculitis, panuveitis, intermediate uveitis, vitritis, scleritis, orbital pseudotumor, myositis, and sarcoid-associated panuveitis. In general, preserved or improved VA, decreased corticosteroid use, and decreased ocular inflammation were reported.95-98 Common side effects of methotrexate are fatigue, nausea, stomach upset, stomatitis, and anorexia and are seen in 10% to 25% of patients.48 The more serious potential side effects include hepatotoxicity (abnormal liver function tests occur in about 15% of patients, whereas only 0.3% of patients develop hepatic cirrhosis), bone marrow suppression (<5%), and interstitial pneumonias (rare and idiosyncratic).99-101 Methotrexate is a teratogen and contraindicated in pregnancy; contraception should be discussed before prescribing this (or any other) immunosuppressive medication. Baseline labs that should be ordered before methotrexate therapy is initiated include CBC, serum chemistry panel, serum creatinine, liver function tests, hepatitis B surface antigen, hepatitis C antigen, and pregnancy test. CBC, serum creatinine, and liver function tests should be repeated every 1 to 2 months. The concurrent use of methotrexate with alcohol is discouraged, and use with statins and other hepatoxic drugs requires close attention. If liver enzymes double on 2 separate occasions, the methotrexate dose should be reduced. If liver enzymes remain elevated after dose reduction, methotrexate should be discontinued.48
Azathioprine
Azathioprine is a purine nucleoside analog that interferes with purine synthesis and thus with DNA and RNA replication and transcription. Azathioprine decreases circulating lymphocytes, suppresses lymphocyte proliferation, and inhibits antibody production.102-104 Azathioprine has been shown to be effective in the treatment of Behçet disease as solo therapy105 or in combination with prednisone or cyclosporin in treating serpiginous choroiditis, multifocal choroiditis and panuveitis, and tubulointerstitial nephritis.106-108 Azathioprine is administered orally at a dose of 1 to 3 mg/kg/day. Dosing is adjusted according to response. Adverse effects of azathioprine include gastrointestinal (GI) upset, hepatotoxicity, and bone marrow suppression.109-111 Patients should be monitored for bone marrow suppression with complete blood and platelet counts every 4 to 6 weeks, as well as with liver function tests. If mild abnormalities are noted, the dose should be decreased by about 30% to 50%; if major abnormalities are noted, the medication should be temporarily halted and the patient followed closely (every 2 weeks) to verify recovery. The medication then may be restarted at lower dosages.112
Mycophenolate mofetil
Mycophenolate mofetil (CellCept, Roche) inhibits the enzyme inosine monophosphate dehydrogenase involved in guanosine nucleotide synthesis and thus interferes with nucleic acid synthesis. It has relatively selective inhibition of T- and B-cell proliferation without causing as much myelotoxicity.113 When used to treat uveitis, mycophenolate mofetil is usually given orally, 1 to 1.5 g twice daily. It is best absorbed on an empty stomach and is metabolized to its active acid form, mycophenolic acid. It is excreted by the kidneys.Mycophenolate mofetil has been shown to be effective in the treatment of patients with steroid-dependent or steroid-resistant chronic uveitis when used in combination with other therapies, such as oral corticosteroid or cyclosporine A.114-117 Adverse side effects at the higher dosage levels required for the prevention of organ transplant rejection include GI side effects, opportunistic infections, leucopenia, lymphoma, hepatotoxicity, and nonmelanoma skin cancers.118,119 CBC should be monitored every week for 4 weeks, every 2 weeks for 2 months, and then every month thereafter. Liver enzymes should be monitored every 3 months.48
T-CELL INHIBITORS/CALCINEURIN INHIBITORS

Cyclosporine
Cyclosporine, an 11-amino acid cyclic peptide, is a natural product of fungi that binds cyclophilin and then calcineurin, preferentially affecting immunocompetent T-lymphocytes, as well as their ability to produce lymphokines, such as interleukin-2.120 In the treatment of uveitis, an initial dose is 2 to 5 mg/kg/day divided into 2 doses, which is adjusted according to response and side effects. By comparison, organ-transplant doses usually begin at 10 mg/kg/day. Cyclosporine has been reported to be effective either as monotherapy or in combination with corticosteroids or antimetabolites. The effect of the combination therapy was shown to be superior to either individual therapy.121-124 Adverse effects include renal toxicity, especially with doses higher than 10 mg/kg/day or very prolonged duration of administration. This is often reversible with cessation. Other side effects include hypertension, stomach upset, hypertrichosis, gingival hyperplasia, myalgias, tremor, paresthesia, hypomagnesemia, hyperkalemia, and elevated uric acid levels.125 Serum creatinine and blood pressure should be checked every 2 weeks, then monthly if proving to be stable. Electrolytes and uric acid levels should also be monitored periodically. Cyclosporine levels are sometimes monitored in the blood to assess toxicity or “therapeutic range” based on transplant requirements; the use of these levels in uveitis is not well established.
FK506/Tacrolimus

Tacrolimus (Prograf, Astellas) is a macrolide antibiotic that interacts with and inhibits calcineurin, thus inhibiting both T-lymphocyte signal transduction and interleukein (IL)-2 transcription.126 When used for the treatment of uveitis, tacrolimus is usually administered orally. However, it is also available as an intravenous formulation. The initial oral uveitis dose is 0.05 mg/kg/day, while an initial oral dose of 0.10 to 0.15 mg/kg/day is recommended for adult liver transplant patients. Successful treatment of uveitis with tacrolimus has been reported. Efficacy was also reported in patients that failed cyclosporine treatment.127-130 Common side effects, which are often reversible with reduced dosing, include renal impairment, neurologic symptoms, GI symptoms, and hyperglycemia. Additional reported adverse events include hypomagnesemia, tremor, headache, trouble sleeping, paresthesias, and hypertension.129 Cytomegalovirus (CMV) retinitis is a known complication of tacrolimus used in transplant regimens; the infection often abates when the level of immunosuppression is decreased. Baseline and weekly laboratory assessment should include liver enzymes, bilirubin, blood urea nitrogen, creatinine, electrolytes, cholesterol and triglyc-erides, glucose, and CBC. After a stable dose has been established, the frequency may be reduced to monthly. Blood pressure should also be monitored at every visit.
ALKYLATING/CYTOTOXIC AGENTS
Cyclophosphamide
Cyclophosphamide is an alkylating agent derived from mustard gas that inhibits T-cell and B-cell proliferation. The drug has been shown to suppress humoral and cellular immune responses and therefore decreases the numbers of B- and T-cells, decreases antibody production, and suppresses delayed-type hypersensitivity to antigens in rheumatologic patients.131 The oral dose of cyclophosphamide is 1 to 3 mg/kg/day, which can be adjusted depending on response and toxicity. Cyclophosphamide may also be employed intravenously on a monthly dosing schedule. The daily dosage typically is decreased by 25 to 50 mg for toxicity. Foster and colleagues132 reported that cyclophosphamide with corticosteroids is more effective in disease control than corticosteroids alone for cicatrical pemphigoid with eye involvement. Efficacy has also been reported in other uncontrolled case series.133,134 Side effects of cyclophosphamide include bone marrow suppression, which is dose dependent, reversible, and more common in older individuals; and hemorrhagic cystitis, which is uncommon and seen primarily in individuals with bladder stasis or those unable to take adequate fluids. Other toxicities include teratogenicity (cyclophosphamide is contraindicated in pregnancy), ovarian suppression, testicular atrophy, and azospermia. Baseline and weekly laboratory assessment should include a CBC, platelet count, and urinalysis. After stable dosing is established, the frequency of testing should be decreased to at least every 4 weeks. If mild bone marrow suppression is seen, the dosage should be lowered by 25 to 50 mg/day and the laboratory tests repeated in 2 weeks. If more severe bone marrow suppression is seen (eg, leukocytes less than 2500 cells per mL), therapy is interrupted until the counts have recovered, and then therapy is resumed at a lower dose. If hematuria occurs, cyclophosphamide should be discontinued. If hematuria persists after 3 to 4 weeks, a urologist should be consulted.135
Chlorambucil
Chlorambucil (Leukeran, GlaxoSmithKline) is an alkylating agent that interferes with DNA replication, DNA transcription, and nucleic acid function.136 Chlorambucil is typically given at a dose of 0.1 to 0.2 mg/kg/day as a single dose, which is continued for 1 year after disease quiescence.137 Short-term high-dose therapy for 3 to 6 months can also be administered. Efficacy of chlorambucil in the treatment of various subtypes of uveitis has been reported. Most patients required coadministration with corticosteroids initially, with tapering and eventual discontinuation.138-143 Side effects of chlorambucil include reversible myelosuppression, bone marrow aplasia, permanent sterility in men, and amenorrhea in women.144,145 Baseline and weekly CBC should be monitored initially. Once a stable dose has been achieved, the frequency of monitoring may be reduced to monthly.
Intravenous Immunoglobulin

The mechanism of action of intravenous immunoglobulin (IVIg) is not well understood. Several small studies have reported on the use of IVIg in the treatment of uveitis with encouraging results.146-148
BIOLOGIC AGENTS
Biologic agents are drugs created by molecular biologic techniques directed against specific cytokines or cell-surface markers, including their receptors.149
Infliximab
The efficacy of infliximab (Remicade, Centocor), a tumor necrosis factor (TNF)-alpha antagonist mousehuman chimeric antibody, has been demonstrated in the treatment of several uveitis subtypes, including but not limited to Behççet disease. Most studies involved patients with severe or treatment-resistant ocular inflammation with encouraging responses to infliximab therapy.150-154 Infliximab is administered intravenously at 1 to 2 month intervals at doses of 3 to 10 mg/kg, with the dose and frequency depending on clinical response. The level of immunosuppression obtained with these agents can be profound. The use of TNF-alpha inhibitors with lupus and demyelinating disease is contraindicated. Pre-existing infections, such as tuberculosis or unsuspected fungal infections, must be rigorously screened — severe reactivation of infections and even fatalities have occurred with this class of medication. The drug is given concomitantly with methotrexate or another immunosuppressive drug to limit development of host antibodies to the agent.
Adalimumab

Adalimumab (Humira, Abbott) is a human antibody developed to TNF-alpha that may avoid some of the issues associated with long-term use of chimeric antibodies. The agent is administered every 1 to 2 weeks subcutaneously, with or without an adjunct immunosuppressive agent. The use of adalimumab for serious uveitis in children has been recently reported by our group155 and a second study156 has replicated this finding.
Etanercept

Studies of the use of etanercept (Enbrel, Wyeth), another TNF-alpha antagonist, in the treatment of uveitis have been less encouraging than with infliximab157-159 or adalimumab. A number of patients in various studies pre-sented with uveitis occurring while on etanercept that responded readily to another TNF-alpha inhibitor or other immunosuppressive agent.157
INTERLEUKIN-2 RECEPTOR ANTAGONISTS
Daclizumab

In a small uncontrolled case series, daclizumab (Zenapax, Roche), a monoclonal antibody to the interleukin- 2 receptor (anti-Tac), facilitated the reduction in immunosuppressive therapy for patients with uveitis.160 It has been further postulated as a therapy for resistant multiple sclerosis (MS), which allows effective treatment of MSrelated uveitis resistant to other medications. It is given monthly intravenously at 1 mg/kg with or without adjunctive immunosuppression. Results of therapy are encouraging but effectiveness may be limited by side-effects such as medication allergy.
Interferon-alpha
Interferon (IFN) alpha, an endogenous cytokine, has shown some promise in improving both ocular and extraocular manifestations of Behçet disease.161-163
SURGICAL TREATMENT

In order to overcome some of the problems inherent with the traditional delivery methods, attention is increasingly turned to intraocular drug-delivery systems. Additionally, there are cases in which medication alone is simply not sufficient to control or halt the complications of intraocular inflammation. For those patients, PPV has been an effective adjunct to medical therapy in the treatment of intraocular inflammation.
Intraocular Drug Delivery
▪ Implantable devices. Implantable devices consist of biodegradable and nonbiodegradable devices. The biodegradable systems are more suitable for short-term therapy and do not have to be removed from the eye, whereas nonbiodegradable systems are used in the management of chronic diseases. Biodegradable devices can be implanted in the anterior chamber, the peribulbar or intrascleral space, or in the vitreous cavity. A rabbit model of CMV retinitis was effectively treated with a ganciclovir sustained-release scleral plug that was inserted through a 1-mm sclerotomy.164 Okabe and colleagues165 also demonstrated delivery of betamethasone phosphate into the vitreous and choroid at concentrations that suppressed inflammatory reactions for more than 8 weeks. The intravitreal ganciclovir implant (Vitrasert, Bausch & Lomb, Rochester, NY), a nonbiodegradable drug-delivery device, has been used with success to deliver prolonged levels of ganciclovir intravitreally for the treatment of CMV retinitis in patients with AIDS.166-168 Reports on the long-term follow- up results of the nonbiodegradable fluocinolone acetonide implant (Retisert, B&L) to treat posterior uveitis indicate that the implant seems to be promising in patients with posterior uveitis who do not respond to or are intolerant to conventional treatment.169 Additionally, the fluocinoline implant significantly reduced uveitis recurrences, improved VA, and decreased the need for adjunctive therapy in the studied patient population. The most common side effects included increased IOP and cataract progression.170 These devices are relatively large and require a 4- to 5-mm sclerotomy at the pars plana for implantation. They must also be removed or reimplanted if additional treatment is required, during a second surgery. Complications in the posterior segment, including vitreous hemorrhage, rhegmatogenous retinal detachment, endophthalmitis, and CME with epiretinal membrane, can develop after implantation.171
PARS PLANA VITRECTOMY
Since the introduction of PPV, there have been numerous reports describing the use of vitrectomy in the management of uveitis and its complications.172-175 The reports provide suggestive evidence that PPV is beneficial in improving visual and disease outcomes in patients with uveitis. Additionally, owing to the technical development of PPV, the indications for PPV in the management of uveitis continue to increase.177,178 In a prospective, interventional, randomized, controlled pilot study, 23 eyes of 23 patients were evaluated for the effect of PPV on CME associated with chronic uveitis. That study showed a significant beneficial effect on visual function in one-third of the patients. A large-scale study to define the role of vitrectomy in uveitis is still pending.
FUTURE DIRECTIONS
Currently there are many uveitis therapies under clinical investigation. Some of these studies are listed in Table 3,37 which can be viewed online at www.retinalphysician.com/ uveitis-table/. The results of these studies should contribute to our understanding of the efficacy and side-effect profiles of those treatments. Novel treatments under development include oil-in-water-type lipid emulsions for drugs that are poorly water soluble. Difluprednate (DFBA) is a waterinsoluble synthetic glucocorticoid that has been formulated as a 0.05% lipid emulsion.When compared with the DFBA 0.05% ophthalmic suspension, the DFBA lipid emulsion showed a 5.7-fold higher concentration of the active metabolite of DFBA in aqueous humor.179 A phase 3 study to assess the efficacy and safety of 0.05% DFBA ophthalmic emulsion in patients with endogenous anterior uveitis in comparison with 0.1% betamethasone sodium phosphate ophthalmic solution (BP) was completed in November 2003, but the results have not yet been published. The drug is currently under further development. There are several revolutions in medicine today that are bound to make marked improvements in uveitis diagnosis and treatment. Advances in structural and functional imaging are having an impact on the early detection and diagnosis of disease activity. Novel drug-delivery systems hold the promise to provide sustained local therapy while minimizing toxicity. Increased understanding of which genes, microbes, and/or environmental triggers are involved in the pathogenesis of various disease states will afford new diagnostic tests and chip away at the large proportion of uveitis cases that are deemed “idiopathic,” or that are diagnosed by clinical pattern recognition rather than objective laboratory testing. Finally, a better molecular understanding of the pathogenesis of disease will also lead to novel, more specific therapies with less ocular and systemic side effects.

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Retinal Physician, Issue: May 2007