Nonbiologic Immunomodulatory Therapy
Antimetabolites
The antimetabolites include azathioprine, methotrexate, and mycophenolate mofetil. Clinical trials are lacking, but retrospective series report that, compared with the other antimetabolites, azathioprine has a slightly higher incidence of adverse effects and mycophenolate mofetil has a significantly shorter time to treatment success. Antimetabolites are often the first IMTs used when corticosteroid sparing is desired. A head-to-head randomized prospective study of 80 uveitis patients assigned to methotrexate or mycophenolate reported similar efficacy of the 2 medications. While generally effective, ongoing low-dose systemic corticosteroid therapy is often necessary to achieve complete inflammatory control. When initiated, these medications require long-term use, as disease control continues to improve between 6 and 12 months of follow-up.
Azathioprine, a purine nucleoside analogue, interferes with DNA replication and RNA transcription. Azathioprine is administered orally at a dose of up to 2 mg/kg/day in adults. Nausea, vomiting, and upset stomach are the most common adverse effects. Bone marrow suppression is unusual at the doses of azathioprine used to treat uveitis. However, patients taking allopurinol and azathioprine concomitantly are at higher risk for bone marrow suppression. Mild hepatic toxicity can usually be reversed by dose reduction. On average, 25% of patients discontinue therapy due to adverse effects. Complete blood counts and liver function tests must be closely monitored. The variability of clinical response to azathioprine among patients is probably caused by genetic variability in the activity of thiopurine S-methyltransferase (TPMT), an enzyme responsible for the metabolism of 6-mercapto-purine (6-MP). A genotypic test is available that can help determine patient candidacy for azathioprine therapy before treatment and can help clinicians individualize patient doses. Evaluation of TPMT activity has revealed 3 groups of patients:
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low/no TPMT activity (0.3% of patients); azathioprine therapy not recommended
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intermediate TPMT activity (11% of patients); azathioprine therapy at reduced dosage
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normal/high TPMT activity (89% of patients); azathioprine therapy at higher doses than in patients with intermediate TPMT activity
Azathioprine is beneficial in many types of noninfectious ocular inflammatory diseases, including Behçet disease, intermediate uveitis, VKH syndrome, sympathetic ophthalmia, and necrotizing scleritis. Overall, nearly 50% of patients treated with azathioprine achieve inflammatory control and can taper the prednisone dosage to 10 mg/day or less.
Methotrexate is a folic acid analogue and inhibitor of dihydrofolate reductase; it inhibits DNA replication, but its anti-inflammatory effects result from extracellular release of adenosine. Treatment with this medication is unique in that it is given either orally or subcutaneously as a weekly dose of up to 15–25 mg/week in adults. The dosage is variable in children and depends on body surface area. Methotrexate can be given orally, subcutaneously, intramuscularly, or intravenously and is usually well tolerated. It has greater bioavailability when given parenterally. Folate is given concurrently at a dose of 1–2 mg/day to reduce adverse effects. Methotrexate may take up to 6 months to produce its full effect in controlling intraocular inflammation. Gastrointestinal distress and anorexia may occur in 10% of patients. Reversible hepatotoxicity occurs in up to 15% of patients, and cirrhosis occurs in fewer than 0.1% of patients receiving methotrexate long-term. Methotrexate is teratogenic; mixed data exist on safety of male conception while on methotrexate therapy. Complete blood counts and liver function tests should be conducted regularly. Numerous studies have shown methotrexate to be effective in treating various types of uveitis, including juvenile idiopathic arthritis (JIA)–associated anterior uveitis, sarcoidosis, panuveitis, and scleritis. It has been a first-line choice for IMT in children. Uncontrolled clinical trials have shown that it can enable corticosteroid sparing in two-thirds of patients with chronic ocular inflammatory disorders. Intravitreal methotrexate is used for primary intraocular lymphoma; its role in uveitis and macular edema is being investigated.
Mycophenolate mofetil inhibits both inosine monophosphate dehydrogenase and DNA replication. It is given orally at a dosage of 1–1.5 g twice daily in adults. Median time to successful control of ocular inflammation (in combination with less than 10 mg/day of prednisone) is approximately 4 months. Fewer than 20% of patients receiving mycophenolate mofetil have adverse effects—reversible gastrointestinal distress and diarrhea are common—and these can usually be managed by dose reduction. Very few patients find the drug intolerable. Regular laboratory monitoring is required to check for adverse effects. Two large, retrospective studies found mycophenolate mofetil to be an effective corticosteroid-sparing agent in up to 85% of patients with chronic uveitis. It has similar efficacy in children (88%) and can be a safe alternative to methotrexate in patients with pediatric uveitis.
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Doycheva D, Deuter C, Stuebiger N, Biester S, Zierhut M. Mycophenolate mofetil in the treatment of uveitis in children. Br J Ophthalmol. 2007;91(2):180–184.
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Gangaputra S, Newcomb CW, Liesegang TL, et al; Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Methotrexate for ocular inflammatory diseases. Ophthalmology. 2009;116(11):2188–2198.
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Malik AR, Pavesio C. The use of low dose methotrexate in children with chronic anterior and intermediate uveitis. Br J Ophthalmol. 2005;89(7):806–808.
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Pasadhika S, Kempen JH, Newcomb CW, et al. Azathioprine for ocular inflammatory diseases. Am J Ophthalmol. 2009;148(4):500–509.
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Rathinam SR, Babu M, Thundikandy R, et al. A randomized clinical trial comparing methotrexate and mycophenolate mofetil for noninfectious uveitis. Ophthalmology. 2014;121(10):1863–1870.
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Siepmann K, Huber M, Stübiger N, Deuter C, Zierhut M. Mycophenolate mofetil is a highly effective and safe immunosuppressive agent for the treatment of uveitis: a retrospective analysis of 106 patients. Graefes Arch Clin Exp Ophthalmol. 2006;244(7):788–794.
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Teoh SC, Hogan AC, Dick AD, Lee RW. Mycophenolate mofetil for the treatment of uveitis. Am J Ophthalmol. 2008;146(5):752–760.
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Thorne JE, Jabs DA, Qazi FA, Nguyen QD, Kempen JH, Dunn JP. Mycophenolate mofetil therapy for inflammatory eye disease. Ophthalmology. 2005;112(8):1472–1477.
T-cell inhibitors
Cyclosporine, a macrolide product of the fungus Beauveria nivea, and tacrolimus, a product of Streptomyces tsukubaensis, are calcineurin inhibitors that eliminate T-cell receptor signal transduction and downregulate interleukin-2 (IL-2) gene transcription and receptor expression of CD4+ T lymphocytes.
Cyclosporine is available in 2 oral preparations. One is a microemulsion (Neoral, Novartis) and has better bioavailability than the standard formulation (Sandimmune, Novartis). These 2 formulations are not bioequivalent. The microemulsion is initiated at 2 mg/kg/day, and the standard formulation at 2.5 mg/kg/day in adults. Dosing is adjusted based on trough levels, toxicity, and clinical response to 1–5 mg/kg/day. The most common adverse effects with cyclosporine are systemic hypertension and nephrotoxicity. Additional adverse effects include paresthesia, gastrointestinal upset, fatigue, hypertrichosis, and gingival hyperplasia. Blood pressure, serum creatinine levels, and complete blood counts must be assessed regularly. If serum creatinine levels rise by 30%, dose adjustment is required; sustained elevation requires medication cessation. Cyclosporine was shown to be effective in a randomized, controlled clinical trial for the treatment of Behçet uveitis, with control of inflammation in 50% of patients. However, the dose used in this study was 10 mg/kg/day—substantially higher than current dosing (5 mg/kg/day)—and led to substantial nephrotoxicity. Even at standard dosages, toxicity necessitating cessation of therapy is more common in patients over the age of 55 years. Overall, cyclosporine is modestly effective in controlling ocular inflammation (33.4% and 51.9% of patients by 6 and 12 months, respectively). As with antimetabolites, the need for ongoing low-dose systemic corticosteroid therapy is often necessary to achieve complete inflammatory control.
Tacrolimus is given orally at 0.10–0.15 mg/kg/day in adults. Because of its lower dose and increased potency, its main adverse effect, nephrotoxicity, is less common than with cyclosporine. Serum creatinine level and complete blood counts are monitored regularly. The dose is escalated until a therapeutic trough blood level is reached. A prospective trial of cyclosporine and tacrolimus suggested equal efficacy in controlling chronic posterior and intermediate uveitis, with tacrolimus demonstrating greater safety (lower risk of hypertension and hyperlipidemia). Long-term tolerability and efficacy are excellent as well, with an 85% chance of reducing prednisone dosage to less than 10 mg/day. A randomized uveitis trial of tacrolimus monotherapy versus tacrolimus plus prednisone showed no difference, confirming that steroid discontinuation can be achieved in many cases.
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Hogan AC, McAvoy CE, Dick AD, Lee RW. Long-term efficacy and tolerance of tacrolimus for the treatment of uveitis. Ophthalmology. 2007;114(5):1000–1006.
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Kaçmaz RO, Kempen JH, Newcomb C, et al. Cyclosporine for ocular inflammatory diseases. Ophthalmology. 2010;117(3):576–584.
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Lee RW, Greenwood R, Taylor H, et al. A randomized trial of tacrolimus versus tacrolimus and prednisone for the maintenance of disease remission in noninfectious uveitis. Ophthalmology. 2012;119(6):1223–1230.
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Murphy CC, Greiner K, Plskova J, et al. Cyclosporine vs tacrolimus therapy for posterior and intermediate uveitis. Arch Ophthalmol. 2005;123(5):634–641.
Alkylating agents
Alkylating agents include cyclophosphamide and chlorambucil. These drugs are generally used only if other immunomodulators fail to control uveitis, and their use may now be partially supplanted by the targeted efficacy and preferred safety profile of the biologic agents. The most worrisome adverse effect of alkylating agents is an increased risk of malignancy. Use of alkylating agents for a limited duration may be justifiable for severe, vision- or life-threatening recalcitrant disease, but otherwise cancer risk may be a relevant constraint on use of this approach. Patients with polycythemia rubra vera treated with chlorambucil had a 13.5-fold-greater risk of leukemia. Patients with granulomatosis with polyangiitis treated with cyclophosphamide had a 2.4-fold-increased risk of cancer and a 33-fold-increased risk of bladder cancer. With the doses and durations used for the treatment of uveitis, the risk is probably lower. Nonetheless, these drugs should be used with great caution and only by clinicians experienced in the management of their dosing and potential toxicity. Patients may wish to consider sperm or embryo banking before beginning cyclophosphamide or chlorambucil therapy because of the high rate of sterility if the cumulative dose exceeds certain limits. Alkylating agents may be used as first-line therapy for necrotizing scleritis associated with systemic vasculitides, such as granulomatosis with polyangiitis or relapsing polychondritis. These drugs have been found beneficial as well in patients with intermediate uveitis, VKH syndrome, sympathetic ophthalmia, and Behçet disease.
Cyclophosphamide is an alkylating agent whose active metabolites alkylate purines in DNA and RNA, resulting in impaired DNA replication and cell death. It is probably more effective in controlling ocular inflammation when given orally at a dose of 2 mg/kg/day in adults than when administered as intermittent intravenous pulses. The dose is adjusted to maintain leukocyte counts between 3000 and 4000 cells/μL after the patient has been tapered off corticosteroids. Myelosuppression and hemorrhagic cystitis are the most common adverse effects. Hemorrhagic cystitis is more common when cyclophosphamide is administered orally, but fluid intake of more than 2 L/day reduces the risk. Complete blood counts and urinalysis are monitored weekly to monthly. Microscopic hematuria is a warning for the patient to increase hydration, and gross hematuria is an indication to discontinue therapy. If the leukocyte count falls below 2500 cells/μL, cyclophosphamide should be discontinued until the cell count recovers. Other toxicities include teratogenicity, sterility, and reversible alopecia. Opportunistic infections such as Pneumocystis jirovecii pneumonia occur more commonly in patients receiving cyclophosphamide; trimethoprim–sulfamethoxazole prophylaxis is recommended for these patients. Inflammation control is achieved in three-fourths of patients within 12 months; disease remission occurs in two-thirds of patients within 2 years; and one-third of patients discontinue therapy within 1 year because of reversible adverse effects.
Chlorambucil is a very long-acting alkylating agent that also interferes with DNA replication. It is absorbed well when administered orally. The drug is traditionally given as a single daily dose of 0.1–0.2 mg/kg in adults. It may also be administered as short-term, high-dose therapy. Because chlorambucil is myelosuppressive, complete blood counts should be monitored closely. Like cyclophosphamide, it is associated with increased hematologic malignancy risk. It is also teratogenic and causes sterility. Uncontrolled case series suggest that chlorambucil is effective, providing long-term, drug-free remissions in 66%–75% of patients with recalcitrant sympathetic ophthalmia, Behçet disease, and other vision-threatening uveitic syndromes.
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Faurschou M, Sorensen IJ, Mellemkjaer L, et al. Malignancies in Wegener’s granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. J Rheumatol. 2008;35(1):100–105.
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Patel SS, Dodds EM, Echandi LV, et al. Long-term, drug-free remission of sympathetic ophthalmia with high-dose, short-term chlorambucil therapy. Ophthalmology. 2014;121(2):596–602.
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Pujari SS, Kempen JH, Newcomb CW, et al. Cyclophosphamide for ocular inflammatory diseases. Ophthalmology. 2010;117(2):356–365.
Biologic agents
Inflammation is driven by a complex series of cell–cell and cell–cytokine interactions. Inhibitors of various cytokines and inflammatory mechanisms have been labeled biologic agents or, occasionally, biologic response modifiers. They play an important role in the treatment of uveitis, as these drugs result in targeted immunomodulation, thereby theoretically reducing the short-term systemic adverse effects that are common with the previously discussed non-biologic immunomodulatory drugs. Biologic agents are considerably more expensive and may carry higher long-term risks of serious infections or secondary malignancies than anti-metabolites and T-cell inhibitors. Therefore, biologic agents are reserved for specific conditions, such as Behçet disease or situations in which nonbiologic-IMT agents have failed.
Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.