Immunomodulatory Therapy for the Treatment of Ocular Inammatory Disease: Evidence-based Medicine Recommendations for Use Eva Christina

Kim, MD C. Stephen Foster, MD

Incidence of Ocular Inammatory Disease

Ocular inammatory disease (OID), with an incidence reported to be as infrequent as 11 to 38 per 100,000 persons per year, is responsible for up to 10% to 15% of all blindness in the United States.14 In addition, 5% to 20% of all patients with OID will become blind and as many as 45% of OID patients will lose 25% of their vision.5,6 Blindness, dened as visual acuity worse than 20/200, is more commonly the result of specic subtypes of severe, untreated OID such as ocular cicatricial pemphigoid, necrotizing scleritis, and Behcet panuveitis.

Current Immunomodulatory Therapies for OID

The current treatment of OID consists of immunomodulatory medications aimed rst at controlling acute inammation, then maintaining long-term remission. Acute attacks are most commonly controlled with corticosteroids. Additional noncorticosteroid immunomodulatory therapies have been shown to be effective either in controlling acute inammation or in the maintenance of long-term remission. Corticosteroids have been relied upon as the mainstay of treatment in OID; however, the well-described morbidity created from its long-term use is problematic. Corticosteroid use is recommended for use in the acute phase of OID with conversion to steroid-sparing immunomodulatory therapy for disease known or proving to be either
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recurrent, chronic, or one with a history of poor outcomes because of corticosteroid monotherapy. The number of options available for the treatment of OID has expanded recently. Immunomodulatory therapies currently used by uveitis specialists/ocular immunologists include antimetabolites, T-cell inhibitors, alkylating agents, and biologic agents. Because of the relatively few numbers of patients with very diverse types of OID, most of the published evidence regarding IMT for the treatment of OID originates from nonrandomized and/or retrospective case series, with a general lack of randomized, controlled, masked clinical trials. Objective data on the efcacy and proper use of many of these therapies is either decient or ambiguous. In an effort to provide comprehensible guidelines for the use of IMT for specic OIDs, this paper will give a synopsis of the currently available IMT used for OID, summarize the current evidence in the literature for use in OIDs, and provide a general recommendation on the use of each drug for specic OIDs.

Grading of Evidence

Recommendations for the use of each IMT will depend on the strength of the recommendations (either supporting or refuting a specic therapy) and on the quality of the evidence (type of scientic evidence or trial). This article will follow a recommendation classication (Table 1) previously reported by an expert panel publication from October 2000 that provided guidelines for the use of immunosuppressive drugs in patients with ocular inammatory disorders.7

Corticosteroids

Corticosteroids may be administered topically, as periocular injections, or systemically (orally or intravenously). In general, topical corticosteroids are useful in the management of anterior uveitis, whereas periocular injections are useful for intermediate uveitis when associated with decreased visual acuity or for the treatment of macular edema associated with posterior uveitis or panuveitis. Many patients, however, may require systemic corticosteroids due to the nature or severity of the OID or because of side effects owing to local corticosteroid administration such as ocular hypertension. However, when systemic corticosteroids are insufcient to control OID, cause intolerable corticosteroid side effects, or are required longterm and at a relatively high dose, which is likely to produce side effects, a corticosteroid-sparing agent is warranted.

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Table 1. Recommendation Classication of the Strength Level and Quality Level of Evidence-based Studies8 Strength Classication A B C D E Quality level 1 2 Evidence Level Strong evidence of efcacy, substantial clinical benet to support recommendation for use; should ALWAYS be offered Moderate to strong evidence of efcacy, only limited clinical benet to support recommendation for use; should generally be offered Insufcient evidence to support recommendation for or against use or evidence of efcacy may not outweigh adverse outcomes; optional use Moderate evidence of lack of efcacy or of adverse outcome supports a recommendation against use; should generally not be offered Strong evidence of lack of efcacy or of adverse outcome supports recommendation against use; should NEVER be offered Evidence type At least one randomized controlled trial At least one well-designed clinical trail without randomization, cohort or case-controlled study, multiple time-series studies, or dramatic results from uncontrolled study Expert opinion

Briey, prednisone is the most commonly used oral corticosteroid, initially dosed at 1 mg/kg/d for no longer than 1 month. Methylprednisolone sodium succinate as a 1-g dose over 30 minutes can be administered intravenously for immediate control of vision-threatening ocular inammation. Immunosuppressive therapy should be considered if a patient on high-dose prednisone worsens, if there is no response after 3 to 4 weeks, or if there is still evidence of inammation after 4 weeks. Also, if chronic suppression of intraocular inammation requires more than 10 mg/d of prednisone, IMT should be considered.7

Antimetabolites

An antimetabolite is dened as a drug, which antagonizes or competes with a metabolite, which is essential for nucleotide synthesis, leading to cell division and proliferation. This section will present the most commonly used antimetabolites in OID: methotrexate, azathioprine, mycophenolate mofetil, and leunomide.

Methotrexate
Mechanism of Action and Metabolism

Methotrexate (Rheumatrex, STADA Pharmaceuticals, Inc, Cranbury, NJ;, Trexall, Barr Pharmaceuticals, Inc, Pomona, NY) is a folic acid

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antagonist that inhibits DNA replication and RNA transcription, thereby inhibiting the proliferation of rapidly dividing immune cells, and having an anti-inammatory effect. This folic acid analog inhibits dihydrofolate reductase, the enzyme that converts dihydrofolate to tetrahydrofolate, which then inhibits thymidylate production, which is essential for DNA replication.9 Methotrexate can be given orally (up to 35% can be metabolized by intestinal ora before absorption), subcutaneously, intramuscularly, and intravenously and is eliminated primarily by the kidney.
Dosage, Adverse Effects, and Monitoring

The treatment of systemic inammatory disease usually entails lowdose methotrexate therapy, usually initiated as an oral dose of 7.5 mg once per week. The dose is often increased to 15 mg/wk over weeks to months, depending on response. Doses greater than 20 mg/wk are usually given subcutaneously or intramuscularly. Folic acid at 1 to 5 mg/d should be given concurrently to maintain adequate folate stores and to reduce toxicity.10 The most common side effects of methotrexate are fatigue, nausea, stomach upset, stomatitis, and anorexia seen in 10% to 25% of patients. The more serious, potential side effects include hepatotoxicity, bone marrow suppression, and interstitial pneumonias, which present as cough or dyspnea. Abnormal liver function tests occur in about 15% of patients whereas only 0.3% of patients develop hepatic cirrhosis.11 Alopecia and rash may occur less commonly. Patients must be counseled that methotrexate is a teratogen and contraindicated in pregnancy. In addition, patients must abstain from alcohol consumption while taking methotrexate. Before starting methotrexate therapy, baseline complete blood count, serum chemistry panel, serum creatinine, liver function tests, hepatitis B surface antigen, and hepatitis C antigen must be obtained. Baseline pregnancy test should be considered. CBC, serum creatinine, and liver function tests should be repeated every 1 to 2 months. 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.
Common Nonophthalmic Use

Methotrexate is effective in the treatment of many systemic inammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis (JIA), psoriatic arthritis, systemic lupus erythematosis, and polymyositis.12,13 There are studies that prove its relative safety when used in children with JIA when properly monitored.14 Methotrexate is

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also an antineoplastic agent approved for treatment of cancers of the breast, head and neck, lung, blood, bone, lymph, and uterus. When methotrexate is used as an antineoplastic agent, the doses are much higher than when it is used to treat systemic and ocular inammatory conditions.
Clinical Evidence for Use in OID

Many uncontrolled case series between 1992 and 2005, consisting of 7 to 160 patients, have used methotrexate to treat various OIDs, including chronic noninfectious uveitis or vitritis or panuveitis, scleritis, retinal vasculitis, orbital myositis, inammatory pseudotumor, JIAassociated uveitis, and sarcoid-associated panuveitis. All studies reported a general decrease in ocular inammation, preserved or improved visual acuity, and decreased corticosteroid use.1420 Samson et al18 published the largest series of 160 patients with chronic noninfectious uveitis treated with methotrexate either as primary therapy or as a corticosteroid-sparing agent. A steroid-sparing response was achieved in 56% of patients, ocular inammation was controlled in 76% of patients, and visual acuity improved or was maintained on 90% of patients. Recommendation: B2 Methotrexate is clearly useful in controlling various types of OID, which are unresponsive to or intolerant of corticosteroid use. Methotrexate may be considered for use alone, with corticosteroids, or with other immunomodulatory therapies, to treat severe OID.

Azathioprine
Mechanism of Action and Metabolism

Azathioprine (Imuran, Prometheus Laboratories, Inc, San Diego, CA) is a precursor to 6-mercaptopurine, a purine analog competitive inhibitor of de novo purine synthesis, blocking DNA replication and RNA synthesis, thereby inhibiting the proliferation of actively dividing immune cells. Azathioprine decreases circulating lymphocytes, suppresses lymphocyte proliferation, and inhibits antibody production.21 It is used widely as an immunosuppressive agent in kidney transplantation and for the treatment of autoimmune disorders including rheumatoid arthritis and systemic lupus erythematosis. Azathioprine is absorbed orally, with bioavailability ranging between 27% and 83%.22 Xanthine oxidase and thiopurine methyltransferase are enzymes that create relatively inactive compounds, whereas other enzymes are responsible for creating cytotoxic and immunosuppressive

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compounds. Because azathioprine metabolism is dependent upon xanthine oxidase, allopurinol may increase its efcacy and its toxicity, and should therefore not be coadministered.23
Dosage, Adverse Effects, and Monitoring

Azathioprine is administered orally at a dose of 1 to 3 mg/kg/d. Dosing is adjusted according to response, although a dose of 2 mg/kg/d is often effective. The most common side effects of azathioprine are gastrointestinal, including nausea, vomiting, and diarrhea. In fact, approximately 15% to 30% of patients discontinue azathioprine because of gastrointestinal side effects. Elevated liver enzymes occur in only 2% of patients. Myelosuppression is a potentially serious and relatively common side effect that is dose-related and reversible.24 Increased risk of malignancy has been reported in renal transplant patients treated with azathioprine; however, it is not clear whether this applies to patients with systemic inammatory diseases.25 While on azathioprine therapy, a complete blood count with platelets and liver enzymes should be performed every 4 to 6 weeks. If there is evidence of hepatotoxicity (elevation of 1.5 times the upper limit of normal), dosage should be reduced by 50 mg/d with a reevaluation of liver enzymes after 2 weeks.
Common Nonophthalmic Use

Azathioprine is most commonly used in the setting of renal transplantation, especially in combination with prednisone and cyclosporin A (CSA). Azathioprine is also approved for use in rheumatoid arthritis and has shown efcacy in the treatment of psoriatic arthritis, Reiter syndrome, ulcerative colitis, and systemic lupus erythematosis.2628
Clinical Evidence for Use in OID

With regard to OID, azathioprine has been most thoroughly studied in Behcet disease. A 2-year randomized, placebo-controlled, doublemasked trial of azathioprine at 2.5 mg/kg/d was conducted in 73 Turkish men with Behcet disease. Azathioprine was effective in decreasing the occurrence of eye disease in those without prior ocular involvement and decreasing the occurrence of second eye disease in those with unilateral disease in a statistically signicant manner. In addition, there was a statistically signicant reduction in the number of episodes of hypopyon uveitis in patients with eye disease.29 Azathioprine proved to be effective in disease control after 8 years of follow-up.30,31 Several uncontrolled

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case series from the 1960s to the 1970s suggested that azathioprine was effective for the treatment of severe chronic uveitis when used in combination with corticosteroids.3234 Success has also been found with case series studying azathioprine treatment, usually in combination with prednisone or CSA, in treating serpiginous choroiditis, multifocal choroiditis and panuveitis, and tubulointerstitial nephritis.3538 Recommendation: B1 Azathioprine has been shown to be superior to placebo in controlling many types of OID, especially in patients with ocular inammation due to Behcet disease and in patients with ocular inammation that has failed monotherapy with systemic corticosteroids. Azathioprine can be considered in certain OIDs in combination with lowdose corticosteroids or CSA.

Mycophenolate Mofetil
Mechanism of Action and Metabolism

Mycophenolate mofetil (CellCept Roche Pharmaceuticals, Inc, Nutley, NJ) inhibits T and B cells by inhibiting inosine monophosphate dehydrogenase, an enzyme critical in de novo purine synthesis. Lymphocytes are critically dependent on de novo purine synthesis; therefore, mycophenolate mofetil has a relatively selective inhibition of T and B cell proliferation without causing as much myelotoxicity. In addition, it suppresses antibody synthesis, interferes with cellular adhesion to vascular endothelium, and decreases recruitment of leukocytes to sites of inammation. Mycophenolate mofetil has high oral bioavailability and should be taken without food. Mycophenolic acid, the highly protein-bound metabolite, is excreted into the urine, although dose adjustments are not usually required in patients with kidney disease.
Dosage, Adverse Effects, and Monitoring

When used to treat OID, mycophenolate mofetil is administered orally at 1 g twice daily. Gastrointestinal side effects, including nausea, vomiting, and diarrhea, have been reported in up to 31% of patients receiving mycophenolate mofetil for the prevention of organ transplant rejection. Other reported adverse effects in allograft patients receiving doses higher than those used in uveitis included opportunistic infections in up to 46% (cytomegalovirus and herpes simplex infections) leukopenia in 19%, lymphoma in 1%, and nonmelanoma skin cancers in 9%.39,40 Complete blood count 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.

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Common Nonophthalmic Use

Mycophenolate mofetil, when added to oral corticosteroids and CSA, has been shown to signicantly reduce cardiac and renal allograft rejection.39 In randomized, controlled comparisons to azathioprine, mycophenolate mofetil when added to oral corticosteroids and CSA, was associated with a reduced rate of early graft failure. However, signicant long-term (3 y) differences were not detected.40
Clinical Evidence for Use in OID

There have been only 4 published studies reporting the use of mycophenolate mofetil in patients with OID.4144 All studies conclude that it is effective in the treatment of patients with steroid-dependent or steroid-resistant chronic OID when used in combination with other therapies such as oral corticosteroid or CSA. In the largest study of 54 patients, Baltatzis et al43 reported control of ocular inammation with mycophenolate mofetil monotherapy in 65% of patients and a steroidsparing effect in 54% of patients. Visual acuity was maintained or improved in 94% of patients. Side effects leading to discontinuation occurred in 18% of patients. The efcacy of mycophenolate mofetil in comparison with other drugs such as azathioprine cannot be determined by existing data. In a study of 8 patients with scleritis, mycophenolate mofetil was found to be a useful steroid-sparing agent in 3 of 4 patients with previously controlled scleritis, but not an effective agent for control of 4 patients with active scleritis.45 Recommendation: B2 Mycophenolate mofetil may be considered for use with patients who have failed combination treatment with other immunosuppressive drugs such as azathioprine, methotrexate, or CSA and/or are intolerant of chronic corticosteroid therapy. It may not be useful in the treatment of active scleritis.

Leunomide
Mechanism of Action and Metabolism

Leunomide (Arava, Aventis Pharmaceuticals, Inc, Bridgewater, NJ) is a prodrug that, when activated to its active derivative, inhibits activated T-cell proliferation through de novo pyrimidine synthesis inhibition. Other mechanisms of action include inhibition of leukocyte adhesion to vascular endothelium and alterations in levels of transforming growth factor-b and interleukin (IL)-2.46
Dosage, Adverse Effects, and Monitoring

Leunomide therapy is oral and is usually started with a loading dose of 100 mg/d for 3 days then followed by 20 mg/d of maintenance

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therapy. Common side effects of leunomide include diarrhea, stomach upset or pain, rash, and reversible alopecia. Serious side effects of leunomide include reversible hepatotoxicity and leukopenia.46
Common Nonophthalmic Use

Leunomide is used to treat active rheumatoid arthritis and to retard structural damage to joints as manifested on radiologic lms as joint space narrowing and erosion.
Clinical Evidence for Use in OID

To date, there are no published studies describing the use of leunomide in OID in humans. However, a study of leunomides ability to improve ocular disease processes was investigated in a model of autoimmune eye disease, experimental autoimmune uveitis, in Lewis rats. Leunomide, administered orally or topically each day, suppressed the signs and symptoms of ocular disease and retinal necrosis and reduced the S-antigen antibody levels associated with EUA in a dosedependent manner.47 These results suggest that leunomide may be useful for treating autoimmune diseases of the eye. Recommendation: C There is insufcient evidence for or against the use of Leunomide in OID and to date, there have been no human studies involving leunomide and OID.

T-Cell Inhibitors/ Calcineurin Inhibitors

T-cell inhibitors were originally developed for use in organ transplantation. This class of drugs inhibits replication and activation of T-cell lymphocytes by inhibiting a phosphatase known as calcineurin, which dephosphorylates nuclear factor of activated T cells, which is a transcription factor regulating IL-2 production.48 This section will review the use of CSA in OID. FK506/tacrolimus will not be discussed.
Mechanism of Action and Metabolism

CSA is an 11-amino acid cyclic peptide formed naturally by the fungus Beauvaria nivea, which binds cyclophilin, and then calcineurin, which disrupts the transcription of genes preferentially for T lymphocyte activation and cytokine production. CSA is available in 2 oral preparations, a gelatin capsule (Sandimmune, Novartis Pharmaceuticals Corporation, East Hanover, NJ) and a more commonly prescribed microemulsion (Neoral, Novartis Pharmaceuticals Corporation, East Hanover, NJ). It is metabolized in the liver via the cytochrome P-450 enzyme system and excreted into bile. CSA has

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been found in the intraocular uid of patients only with intraocular inammation.49
Dosage, Adverse Effects, and Monitoring

An initial dose ranging from 2 to 5 mg/kg/d divided into 2 doses is usually used for OID, which is modied according to response and side effects. Doses employed in organ transplantation are often higher than 10 mg/kg/d. Renal toxicity is the most common adverse effect, especially with doses higher than 10 mg/kg/d, which is often reversible with cessation. Hypertension is also very common. Other side effects include stomach upset, hypertrichosis, gingival hyperplasia, myalgias, tremor, paresthesia, hypomagnesemia, hyperkalemia, and elevated uric acid levels.50 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.
Common Nonophthalmic Use

CSA is approved for use in the prevention and treatment of graft rejection and in the treatment of severe, active, recalcitrant rheumatoid arthritis and psoriasis.51,52
Clinical Evidence for Use in OID

There are numerous case series reporting the efcacy of CSA in treating noninfectious OID.5360 Although earlier studies employed doses around 10 mg/kg/d for uveitis patients, studies in the past decade have widely reported the improved safety prole and effectiveness of low-dose therapy. There have been 3 randomized, controlled studies regarding CSA and chronic uveitis.6163 One concluded that the combination of CSA plus corticosteroid was superior to low-dose prednisone alone and to placebo alone.60 Another randomized study compared CSA alone with prednisolone alone and found a 46% improvement in both groups. Patients who failed either treatment alone were given both CSA and prednisolone, often with improvement.61 The strongest evidence supporting the efcacy of CSA in OID is in the treatment of ocular Behcet disease. Most reports are of uncontrolled case series using a combination of low-dose CSA and corticosteroids;6470 however, there are 2 randomized controlled trials, both at doses of 10 mg/kg/d. The rst trial reported high-dose CSA to be superior to corticosteroids or chlorambucil.71 Another double-masked study of 96 patients found CSA to be more effective than colchicine in controlling both ocular and systemic symptoms of Behcet disease.72

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CSA has also been shown to be useful in the treatment of birdshot retinochoroidopathy, serpiginous choroiditis, sympathetic ophthalmia, scleritis, and multifocal choroiditis and panuveitis. 3537,7377 Of note, a study of 104 patients with ocular cicatricial pemphigoid found CSA to be an ineffective therapy in patients already being treated with other immunomodulatory therapies.78,79 Recommendation: B1 Low-dose CSA may be considered rst line immunomodulatory therapy either with or without low-dose corticosteroids in patients with Behcet disease and a variety of OIDs. CSA should not be used as an adjunct to treat ocular cicatrical pemphigoid.

Alkylating/Cytotoxic Agents

Alkylating agents, which include cyclophosphamide and chlorambucil, were developed for the treatment of cancers. They are widely used in the treatment of rheumatologic diseases. Alkylating agents work by alkylating DNA, which results in cross-linking of DNA, inhibition of DNA synthesis, and cell death.

Cyclophosphamide
Mechanism of Action and Metabolism

Cyclophosphamide (Cytoxan, Bristol-Meyers Squibb Company, Princeton, NJ) is an alkylating agent derived from mustard gas that inhibits T-cell and B-cell proliferation by targeting a nitrogen atom of guanine to cause guanine-thymidine cross-links in DNA. It is cytotoxic to both resting and dividing lymphocytes. 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.80 Cyclophosphamide is absorbed well through the gut; however, it can be given intravenously, giving similar plasma concentrations of active metabolites formed by the liver. Inactive metabolites are excreted by the kidney, one of which, acrolein, is presumed to be the cause of bladder toxicity.81 Reduction of doses is required in patients with renal dysfunction.
Dosage, Adverse Effects, and Monitoring

Cyclophosphamide seems to be most effective when used orally on a daily basis, at 1 to 3 mg/kg/d. However, recent reports have found safety and success with pulse intravenous cyclophosphamide.82

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The most common side effect is a dose-related, reversible myelosuppression. However, clinicians monitor the degree of leukopenia as a marker for immunosuppressive effect. Leukocyte counts of less than 2500 to 3500 cells/mL warrant discontinuation. Another common and serious side effect is opportunistic infections, especially with oral regimens.83 Many clinicians advocate prophylactic treatment for Pneumocystis carinii. Patients can be at risk for hemorrhagic cystitis and bladder cancer without proper hydration or if with preexisting bladder motility problems. Patients should be instructed not to smoke, to drink 2 to 4 liters of water per day, and may be given 2-mercaptoethane sulfonate, a compound which binds acrolein, to reduce bladder toxicity.84 Cyclophosphamide is a teratogen and also suppresses ovarian and gonadal function; thus, patients should be counseled appropriately.85 Other side effects include alopecia, stomach upset, and malignancies. A complete blood count with platelets and urinalysis should be obtained weekly initially then every 4 weeks when stable. Dosage should be reduced by 25 to 50 mg/d if mild bone marrow suppression is noted.7 Therapy should be interrupted if hematuria occurs or if severe myelosuppression occurs. With severe myelosuppression, cyclophosphamide may be resumed at a lower dose once cell counts have recovered.
Common Nonophthalmic Use

Cyclophosphamide is most commonly used as an antineoplastic agent. It is also used in systemic inammatory diseases such as systemic lupus erythematosis and Wegener granulomatosis.86,87 It has been used in patients with rheumatoid arthritis with secondary vasculitis as well.
Clinical Evidence for Use in OID

There has been only 1 randomized, controlled clinical trial studying cyclophosphamide use in ocular disease, which reported that cyclophosphamide with corticosteroids is more effective in disease control than corticosteroids alone, for cicatrical pemphigoid with eye involvement.88 The remaining studies have been uncontrolled case series. A recent study concluded that pulse IV cyclophosphamide is an effective therapy in patients with severe or recalcitrant ocular inammation. Control of inammation was achieved in 68% of patients, with 55% achieving quiescence and with some degree of steroid-sparing effect in all patients who were previously taking corticosteroids.82 Two uncontrolled studies have found similar results reporting that either monotherapy with pulse intravenous cyclophosphamide or combination therapy between cyclophosphamide and colchicines was inferior to therapy involving CSA.67,89 Foster et al36 reported success

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in tapering steroids and inducing drug-free remission in 4 patients with serpiginous choroiditis on cyclophosphamide. Cyclophosphamide combined with corticosteroids has led to long-term remission in patients with Wegener granulomatosis, many of whom had ocular inammation such as scleritis,80 and in select patients with ocular cicatricial pemphigoid.78,79 Common side effects included leukopenia and hemorrhagic cystitis. Recommendation: C2 In combination with corticosteroids or other immunomodulatory therapies, cyclophosphamide seems to be effective in ocular cicatricial pemphigoid and ocular inammation related to Wegener granulomatosis. Owing to its toxicity, only select cases of chronic uveitis and serpiginous choroiditis should be considered for its use.

Chlorambucil
Mechanism of Action and Metabolism

Chlorambucil (Leukeran, GlaxoSmithKline, Research Triangle Park, NC) is an alkylating agent that cross-links DNA similar to cyclophosphamide, by substituting an alkyl group for hydrogen ions in organic compounds, leading to faulty DNA replication, transcription, and nucleic acid function.90 Chlorambucil is given orally with a wide range of bioavailability, with food increasing bioavailability. It is metabolized to an active metabolite in the liver, and inactive metabolites are excreted in the urine.
Dosage, Adverse Effects, and Monitoring

In the treatment of uveitis, chlorambucil is typically given at a dose of 0.1 to 0.2 mg/kg/d as a single dose, which is continued for 1 year after disease quiescence. Tapering of corticosteroids may begin once the eye is quiet. Short-term high-dose therapy for 3 to 6 months also exists. Reversible myelosuppression is the most common side effect of chlorambucil. Rarely, bone marrow aplasia may occur.91 As with cyclophosphamide, opportunistic infections may occur. Permanent sterility in men and amenorrhea in women often occur. Chlorambucil is a teratogen. A complete blood count should be monitored weekly initially, then monthly once counts are stable.
Common Nonophthalmic Use

Chlorambucil is an antineoplastic agent used to treat leukemias such as chronic lymphocytic leukemia, lymphomas, and other cancers.92 Other than its use in Behcet disease, it is less frequently used in nonmalignant diseases as compared with cyclophosphamide.

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Clinical Evidence for Use in OID

There have been numerous small, uncontrolled case series reporting the effectiveness of chlorambucil for various sight-threatening OIDs including chronic, treatment-resistant uveitis,93,94 Behcet disease,9397 sympathetic ophthalmia,93,98,99 and serpiginous choroiditis,36 with the suggestion of long-term, disease-free remissions after 6 to 24 months of therapy. Most patients required coadministration with corticosteroids initially, with tapering and discontinuation over 4 months. Recommendation: C2 Chlorambucil may be a useful second line agent in severe, sight-threatening, treatment-resistant ocular inammation, especially in Behcet disease. As with cyclophosphamide, its use is limited by its potential for serious toxicity.

Intravenous Immunoglobulin

Intravenous Immunoglobulin (IVIg) was developed to treat or prevent infections in immunodecient persons but has become useful in the treatment of immune-mediated diseases such as Gullain-Barre syndrome, Kawasaki disease, and dermatomyositis.100102 IVIg is not associated with immunosuppression, unlike most therapies for autoimmune disorders. The mechanism by which IVIg alters immunemediated disease is poorly understood but thought to involve inhibition of cytokines and suppression of B-cell responses.100 There have been very few published studies reporting the use of IVIg in OID with encouraging results. A study by LeHoang et al103 of 18 patients with active birdshot chorioretinopathy receiving IVIg as sole therapy over 6 months showed either maintenance or improvement in visual acuity in 33 of 36 eyes. Similar encouraging results were seen in studies using IVIg in patients with chronic, refractory uveitis, and Behcet disease. 104,105

Recommendation: C2 Owing to the small number of studies conducted, there is insufcient evidence for or against the use of IVIg in uveitis, although the studies that exist are encouraging.

Biologic Agents

Biologics are drugs directed against specic cytokines or their receptors, created by molecular biologic techniques. Use of biologics to treat ocular inammation is considered off-label. Although studies have been promising, randomized, controlled trials have yet to be performed

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and biologic therapy is costly. This section will discuss tumor necrosis factor-a (TNF-a) antagonists (iniximab and etanercept), interferon-a (IFN-a), IL-2 receptor antagonist (daclizumab), and IL-1 receptor antagonist (anakinra).

IFN-a

IFN-a is an endogenous cytokine produced in response to viral infection and tumors, and is an immune regulator. It is currently approved for use in the treatment of various hematologic malignancies and chronic viral infections.106 It is administered as a subcutaneous injection 3 times weekly. Side effects include ulike symptoms, bone marrow suppression, injection site inammation, anorexia, nausea, diarrhea, and clinical depression. Cotton-wool spots and retinal hemorrhages have been reported after onset of therapy. IFN-a has shown some promise in improving both ocular and extraocular manifestations of Behcet disease. In a double-masked, placebo-controlled trial of 50 patients with Behcet disease, Alpsoy et al107 reported signicant decrease in pain and duration of oral and genital ulcerations. Five of the 6 patients in the treatment group who had ocular symptoms reported improvement but this was not statistically signicant when compared with the placebo group. In an open 4-center trial of 50 patients with ocular manifestations of Behcet disease, Kotter et al108,109 reported a signicant improvement in ocular inammation in 92% of patients, with only 36% of patients reporting improvement in oral aphthous ulcers. Recommendation: B2 IFN-a may be considered for patients with Behcet disease who have failed combination treatment with more traditional immunosuppressive medications. (Owing of the small number of patients with ocular manifestations of Behcet disease in the existing randomized controlled trial of IFN-a, the quality level remains at 2.)

Iniximab

Iniximab (Remicade, Centocor, Inc, Malvern, PA) is a mousehuman chimeric immunoglobulin G1 monoclonal antibody to soluble and membrane-bound TNF-a, which is an inammatory mediator, produced by macrophages and activated T cells. It has been approved for use in rheumatoid arthritis, Crohn disease, and ankylosing spondylitis. It is administered intravenously every 2 to 6 weeks at a dose ranging from 5 to 10 mg/kg. Side effects include infusion hypersensitivity reactions, upper respiratory tract infections, cellulitis, and possible

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reactivation of tuberculosis; thus tuberculosis infection should be ruled out before initiating treatment. Iniximab is contraindicated in patients with heart failure. A complete blood count and liver function tests should be periodically monitored. Since 2001, there have been over 20 published reports of iniximab with various OIDs including HLA-B27 anterior uveitis, Behcet panuveitis, chronic, recalcitrant uveitis and scleritis, and sarcoid-related uveitis.110123 Most studies involved patients with severe or treatmentresistant ocular inammation with encouraging responses to iniximab therapy. Ohno et al119 studied the effect of multiple4 iniximab infusions on frequency of ocular attacks in patients with Behcet disease. Doses at 5 or 10 mg/kg signicantly and dramatically decreased the frequency of attacks for all patients treated. One of the patients receiving 10 mg/kg developed reactivation of tuberculosis.119 Similar encouraging results have been reported in case series of patients with Behcet disease and other posterior inammatory diseases.

Recommendation: B2 Iniximab should be considered in patients with ocular Behcet disease who are resistant to or intolerant of conventional immunomodulatory treatment, such as azathioprine, chlorambucil, or cyclophosphamide, and CSA. In fact, some experts feel it should be rst line treatment for ocular Behcet disease.123 Iniximab may also be considered in select cases of chronic, recalcitrant OID.

Etanercept

Etanercept (Enbrel, Immunex Corporation, Thousand Oaks, CA) is a fusion protein consisting of the extracellular portion of the human p75 TNF-a receptor linked to the Fc portion of the human IgG1. It specically binds extracellular TNF-a inhibiting signaling. It has been approved for use in rheumatoid arthritis, polyarticular JIA, psoriatic arthritis, and ankylosing spondylitis. Etanercept is administered subcutaneously at 25 mg 2 to 3 times per week. Side effects are similar to iniximab and include injection site reactions and infections, although tuberculosis reactivation is rare. Complete blood count and liver function tests should be periodically monitored. Studies of etanercept and uveitis have been less encouraging than with iniximab. Smith et al124 found that only 6 of 16 patients with uveitis or scleritis showed ocular improvement. Notably, 12 of 12 patients with active arthritis reported improvement. Five patients developed their rst episode of ocular inammation while in the trial.124 In a later randomized, placebo-controlled, double-masked study of 10

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children, Smith et al125 found no apparent difference in the anterior segment inammation between patients treated with etanercept and placebo. Finally, in a randomized, controlled, double-masked trial of 20 patients with chronic or recurrent noninfectious uveitis controlled with low-dose methotrexate, etanercept had no signicant efcacy over placebo in preventing relapses of uveitis in patients being tapered from methotrexate.126 Recommendation: C1 Etanercept seems to be no better than placebo in the treatment of chronic OID. The use of etanercept for ocular inammation is optional and not encouraged.

Daclizumab

Daclizumab (Zenapax, Roche Pharmaceuticals, Inc, Nutley, NJ) is a humanized immunoglobulin G monoclonal antibody that binds CD25 of human IL-2 receptor, which is expressed on activated T lymphocytes, thus selectively inhibiting activated T cells. It is approved for the prophylaxis of acute allograft rejection in kidney transplant patients with off-label use in other organ transplants and psoriasis. There are no randomized, controlled trials studying daclizumab and ocular inammation to date. However, in a long-term, phase I/II singlearmed interventional study by Nussenblatt et al,127 7 out of 10 patients were tapered from all other immunosuppressive medications and maintained exclusively on daclizumab for 4 years. None of the patients were permanently withdrawn from the study because of adverse side effects.127 A study by Papaliodis et al128 found less encouraging results, although the study population consisted of patients who had previously failed standard treatment modalities. Recommendation: B2 Daclizumab seems to be useful as an option, possibly as monotherapy, for chronic uveitis if a patient is intolerant to but not refractory to more standard immunomodulatory therapy.

Anakinra (a-IL-1)

Anakinra (Kineret, Amgen Inc, Thousand Oaks, CA) is a recombinant form of human IL-1 receptor antagonist. It competitively binds to the IL-1 receptor, blocking native pro-inammatory signaling.129 Anakinra has been shown to be effective in the treatment of rheumatoid arthritis in several randomized, controlled, double-masked clinical trials. It is given as a subcutaneous injection of 100 mg/d, with injection site reactions being common. The risk of serious infections was small but

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signicant (2.1% vs. 0.4% in placebo).130 There are no human studies for the use of Anakinra for ocular inammation to date.

Recommendation: C There is insufcient evidence for or against the use of anakinra in OID and to date, there have been no human studies involving anakinra and OID.

Concluding Statement

Corticosteroids remain the primary initial treatment for patients with OID, but chronic use is associated with unacceptable and unavoidable side effects in addition to poor outcome when used as monotherapy for select OIDs including Behcet disease, serpiginous choroiditis, birdshot retinochoroidopathy, and JIA. The addition of immunomodulatory therapy in some patients introduces not only a steroid-sparing effect but also potential long-term remission. The choice of therapy can be complex and depends on the cause and severity of ocular inammation, the status of systemic inammation, and on the patients past history with or without response to various immunomodulatory medications. With immunomodulatory therapy come a host of potential side effects that require close monitoring and individualized dosing. If used properly, the introduction of immunomodulatory medications may lead to safe and long-term suppression of ocular inammation. Biologic agents seem to provide possible benet for patients with disease unresponsive to conventional immunomodulatory therapy.

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