Immunosuppressive Therapy for Noninfectious Uveitis

RENE A. CERVANTES-CASTAÑEDA, MD • NIDA JAWED • C. STEPHEN FOSTER, MD, FACS, FACR

Ocular inflammatory diseases are defined as acute or chronic inflammation of the ocular tissues and are a significant cause of visual impairment, accounting for up to 10% of blindness in the United States and up to 15% worldwide.¹ Inflammation affecting the uveal tract (iris, ciliary body, and choroid) can be caused by a wide variety of conditions both infectious and autoimmune. In this review, we describe the role and the means of immunosuppressive treatment for noninfectious uveitis.
In the United States, the drugs approved by the Food and Drug Administration (FDA) for ocular inflammatory diseases are corticosteroids.² And even for corticosteroids, only topical administration or sustained release intravitreal implants are FDA-approved for this purpose. All the other uses of corticosteroid treatment for treating uveitis are “off label.”
Chronic administration of systemic corticosteroids is associated with numerous adverse side effects that are unacceptable to both the patient and the physician. This has led to the implementation of immunomodulatory therapy (IMT) by uveitis experts as either a steroid-sparing strategy or first-line treatment or, when indicated, in an effort to minimize secondary side effects and to preserve visual function.
A number of immunosuppressive agents are currently employed for the treatment of uveitis.³ Reports of the use of IMT, although numerous, have come largely from small cohorts, limiting the strength and standardization of their conclusions.
Most immunosuppressive agents have significant potential adverse effects. For this reason, patients on immunosuppressive therapy should be carefully monitored by an expert for the development of intercurrent illnesses or opportunistic infections.
A stepladder algorithm that gives the ophthalmologist the opportunity to reduce the aggressiveness of steroid therapy and also to incorporate newer immunomodulatory agents is represented by the following order:
1. Initial treatment with corticosteroids
2. Systemic nonsteroidal anti-inflammatory drugs (NSAIDs) for selected indications
3. Peripheral retinocryopexy or laser photocoagulation in certain patients with intermediate uveitis or pars planitis
4. Systemic IMT
5. Therapeutic pars plana vitrectomy

CORTICOSTERIODS: INHIBITORS OF INTRACELLULAR SIGNALING
At present, corticosteroids remain the mainstay of management of ocular inflammatory and immune-mediated disease. Corticosteroids act by controlling the rate of protein synthesis. Anti-inflammatory effects of corticosteroids appear to be mediated by suppression of proinflammatory transcription factors, most notably nuclear factor kappa B (NF-κB), and by inhibition of phospholipase A2 production. This in turn inhibits production of arachidonic acid and its metabolites, the prostaglandins and leukotrienes.^4,5 In noninfectious anterior uveitis, topical corticosteroids (eg, prednisolone) are mainly used. Topical application can be as frequent as needed (eg, every 15 minutes in an acute attack of anterior uveitis while awake) but corticosteroids are associated, if used for a long time, with well-known side effects such as cataract and secondary glaucoma.^6,7
Topical corticosteroids do not work for patients with posterior uveitis because of poor penetration; thus oral, periocular, intraocular, or intravenous routes would be more suitable. Prednisone is the preferred oral corticosteroid, and it is typically prescribed at 1 mg/kg/day to 1.5 mg/kg/day and tapered by a decrease of 10 mg/week.
Corticosteroids can also be delivered as periocular or intraocular injections in cases of macular edema or posterior uveitis.^8,9 Other modes of delivery of corticosteroids are intravenous in the form of IV methylprednisolone and Retisert (Bausch & Lomb, Rochester, NY), the latter of which is an intra-vitreal implant that can deliver fluocinolone acetonide to posterior eye tissue for up to 2.5 years.
In a randomized controlled trial (n = 32), Jaffe and associates¹⁰ examined the safety and effectiveness of a fluocinolone acetonide intravitreal implant in the treatment of patients with a history of recurrent noninfectious posterior uveitis. These investigators concluded that the fluocinolone acetonide intravitreal implant effectively controlled intraocular inflammation in the studied population. Secondary glaucoma that required antiglaucoma drops occurred in 51% of implanted eyes. Glaucoma-filtering surgery was done in 6.5% of the implanted eyes, and 9.9% required cataract surgery. The fluocinolone-acetonide–sustained drug-delivery implant seems to be promising in patients with posterior uveitis who do not respond to or are intolerant to conventional treatment. It should be borne in mind that systemic corticosteroids are associated with numerous potential side effects, some of which are guaranteed if used chronically.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
The different subclasses of NSAIDs include phenylacetic acids, indoles, proprionic acids, pyrazolones, arylacetic acids, enolic acids, anthranilates, and the newer, more selective cyclo-oxygenase (COX)-II enzyme inhibitors. NSAIDs are able to reduce inflammation by inhibiting the COX pathway, thereby limiting prostaglandin formation.¹¹
The potential side effects of NSAIDs include, most importantly, gastrointestinal tract ulcerations, which are more likely to occur with the nonselective NSAIDs.¹² Other potential side effects include easy bruising, hypertension, headache, drowsiness, confusion, fluid retention, and allergic reaction.
Patients are monitored every 3 months with assessment for systemic toxicity by liver function test and complete blood count. If there are flare-ups or the patient develops side effects, then we change the NSAID to an alternative one. This is continued for 6 to 12 months or a trial of up to 3 different oral NSAIDs. If, despite this, uveitis recurrence continues, we then consider the case as NSAID failure and move on to IMT.

CALCINEURIN INHIBITORS
Cyclosporine Cyclosporine A (CSA; Neoral, Novartis) is an 11-amino acid cyclic peptide. Its therapeutic effects include the inhibition of lymphocyte proliferation by binding to intracellular immunophilin receptors and blocking calciumdependent intracellular transcriptional signaling of nuclear factor of activated T-cells (NF-AT), all of these affecting the production of interleukin-2 (IL-2).
Cyclosporine A is most often administered orally in a range of 2 to 5 mg/kg/day to treat moderate to severe uveitis. An excellent review published by Hesselink and associates¹³ concludes that cyclosporine is an effective second- line agent. However, despite the use of low-dose regimens, cyclosporine toxicity (ie, renal toxicity, hypertension) remains an important problem.¹³
To keep undesirable side effects under control, monitoring of blood pressure, renal and hematological toxicity, and bone loss in high-risk patients is the preferred standard of care in patients that require the use of CSA.

Tacrolimus
Tacrolimus (Prograf, Astellos) is a macrolide antibiotic shown to have a mechanism of action similar to that of CSA. It also has a similar side-effect profile with significant effects on renal function and blood pressure. Tacrolimus is given orally at 0.15 to 0.3 mg/kg/day. Close monitoring of renal function and blood pressure is essential, as with CSA.
Sloper and colleagues¹⁴ published case reports of 6 patients with posterior uveitis treated with tacrolimus after CSA treatment who had to be stopped due to lack of control or unacceptable adverse effects. The authors concluded that tacrolimus is useful in the treatment of sightthreatening posterior uveitis resistant to CSA therapy.

ANTIMETABOLITES
Methotrexate
There is a growing body of evidence suggesting that the folate antagonist methotrexate (MTX) should be used as a first line corticosteroid-sparing drug or as additional treatment in the wide spectrum of ocular inflammation. Its mechanism of action is exerted by impairing the cellular metabolism of actively proliferating cells. For ocular inflammation, MTX can be given once a week orally, subcutaneously, or intravenously in doses of 7.5 mg to 50 mg. Hepatotoxicity is a potential side effect of MTX use.¹⁵ Thus, monitoring of liver function tests (LFTs) is required.
We reported a cohort of 160 patients with uveitis treated with MTX.¹⁶ It achieved control of ocular inflammation in 72% of the patients. Steroid-sparing effect was obtained in 56% of the patients. Ninety percent improved or maintained visual acuity. Eighteen percent of the patients had to discontinue the drug due to side effects. Potential serious adverse reactions occurred in only 8% of the cases.
Kaplan and colleagues¹⁷ analyzed a cohort of 36 patients with uveitis who were treated with MTX only, most with the diagnosis of idiopathic uveitis or juvenile idiopathic arthritisassociated uveitis (JIAU). Full or partial control of the inflammation was obtained in 76% and the response to MTX therapy was noticed after a mean of 2.4 ± 0.8 months. The authors recommend MTX as a first-line adjunct or steroid-sparing agent for the treatment of patients with noninfectious uveitis.

Azathioprine
Azathioprine (AZA) is a prodrug that is metabolized in the liver to its active form, 6-mercaptopurine. The active form interferes with purine metabolism, which is important for DNA and RNA synthesis. AZA is an effective steroid-sparing agent in chronic inflammatory diseases such as JIAU,¹⁵ Vogt-Koyanagi-Harada disease, sympathetic ophthalmia, Adamantiades-Behçet’s disease (ABD), and serpiginous choroidoretinopathy.11 Symptomatic gastrointestinal discomfort (nausea, vomiting, and diarrhea) is the most common side effect, which is the main reason for drug discontinuation.¹⁸ Potential serious side effects are bone marrow suppression with leukopenia and thrombocytopenia, interstitial pneumonitis, hepatocellular necrosis, pancreatitis, stomatitis, alopecia, and, rarely, secondary infections.^19,20Therefore, meticulous blood monitoring of LFTs and complete blood cell counts with differentials should be performed during the treatment period.
Vianna and colleagues published²¹ a case series of 4 patients with serpiginous choroiditis treated with a combination of AZA and corticosteroids. The initial dose of AZA for all patients was 125 mg/day. For the corticosteroids, 2 patients received oral prednisone (1 mg/kg/day) as a single dose in the morning, and the other 2 patients initially received a single dose of 1000 mg of methylprednisolone intravenous, followed by oral prednisone at 1 mg/kg/day dose. The authors reported total control of inflammation within 3 weeks of treatment and suggested that the combination of AZA and corticosteroids is a safe and acceptable option for the treatment of patients with serpiginous choroiditis.

Mycophenolate Mofetil
Mycophenolate mofetil (MM; CellCept, Roche) is a potent, noncompetitive, reversible inhibitor of de novo purine synthesis. It is very effective in rapidly dividing cells such as activated lymphocytes, which, unlike most cell types, cannot use salvage pathways for purine synthesis. MM therefore suppresses antibody production and inhibits lymphocyte recruitment to inflammation sites.²² The typical dose is 1 g bid. Regular blood monitoring (total blood cell count and LFT) is mandatory for all patients on MM.
Choudhary and colleagues²³ reported 10 cases of refractory ocular inflammatory diseases that included 3 patients with scleritis. They concluded from their study that MM was effective in patients who had been unresponsive to other immunomodulators, especially AZA, which suggests that it has potential as a first- or second-line agent and can be considered at doses of even 3 g in such refractory cases.

CYTOTOXIC/DNA CROSS-LINKING AGENTS
Cyclophosphamide
Cyclophosphamide is a cell-cycle–nonspecific alkylating agent that exerts its cytotoxic effect by alkylating nucleophilic groups on DNA bases. Cyclophosphamide is associated with a variety of potential toxic effects, including hemorrhagic cystitis,²⁴ secondary malignancy (bladder cancer), ²⁴ and gonadal dysfunction,²⁵ which is why it is typically reserved for severe cases of uveitis that are sight threatening and refractory to other treatments. Another common side effect is bone-marrow suppression. The cyclophosphamide dose is usually titrated to a target white blood cell count of between 3000 and 5000 cells/μL. All patients receiving cyclophosphamide therapy should drink 2 to 4 L of water per day to encourage good urine flow and dilute its main toxic metabolites, particularly acrolein, which is associated with hemorrhagic cystitis and bladder cancer.
We published the use of intravenous pulses of cyclophosphamide in patients with ocular inflammatory diseases who failed other immunomodulatory therapy regimes.²⁶ We attempted therapy with at least 1 immunomodulatory agent before treatment with pulse IV cyclophosphamide in most of the patients, and we concluded that this regimen can be a highly effective treatment for patients who fail to respond to conventional therapy.

Chlorambucil
Chlorambucil (Leukeran, GlaxoSmithKline) is an alkylating agent with mechanism of action similar to that of cyclophosphamide; it has inhibitory effects on both humoral and cellular immunity. It has been used successfully in the treatment of ocular inflammatory diseases such as necrotizing scleritis,²⁷ serpiginous choroiditis,²⁸ sympathetic ophthalmia,^29,30 and ABD.³¹
The initial dose of chlorambucil is 0.1 mg/kg. This is adjusted weekly according to the white blood cell count, with a target white cell count between 3000 and 4500 cells/μL. Once the appropriate dose is achieved for a specific patient, following up with blood monitoring every 4 weeks is mandatory.
Our experience with chlorambucil was reported in 2002.³²We reviewed a cohort of 28 patients with chronic noninfectious uveitis treated with chlorambucil.We concluded that chlorambucil can be considered an effective drug for controlling ocular inflammation in patients with uveitis that is refractory to other less potentially toxic treatment. We further emphasized that, because of the potential for significant drug-related side effects, it should not be used as a first-line agent, especially in young patients with non-life–threatening diseases.

BIOLOGIC DRUGS
Infliximab
Infliximab (Remicade, Schering-Plough) is a monoclonal antibody that binds both circulating and membranebound tumor necrosis factor (TNF)-α. It must be administered intravenously at a dose of 5 to 10 mg/kg in patients with uveitis. The main potential side effects associated with infliximab include anaphylaxis during the infusion, upper respiratory tract infection, urinary tract infection, pneumonia, sepsis, and reactivation of tuberculosis. ^33,34 Drug-induced lupus is also a well-known potential adverse event and can be present in up to 42% of the patients at the 10th week.³⁵ It can be prevented by adding methotrexate to the patients’ recipe during the treatment with infliximab. Infliximab has been demonstrated to be effective in treating rheumatoid arthritis^36,37 and for the systemic manifestations of other inflammatory diseases related to uveitis, including ankylosing spondylitis (AS), Crohn’s disease,⁴⁰ ABD,^41,42 and sarcoidosis.⁴³ Liver function studies and a complete blood cell count with differential should be monitored every 6 weeks.
Benitez-del-Castillo and colleagues⁴⁴ reported 7 patients (12 eyes) with posterior noninfectious uveitis refractory to conventional immunomodulatory therapy who received infliximab in addition to their current immunomodulator regime and who were followed for 3 years. Patients received 5 mg/kg of infliximab.They concluded that 50% of the patients had a significant improvement after the first 3 infusions and all but 1 maintained or improved their acuities.

Adalimumab
Adalimumab (Humira, Abbott) is an anti-TNF-α antibody that affects both soluble and TNF-α bound to receptors like infliximab. It is administered subcutaneously at 40 mg every other week. The most frequent adverse effect is a self-limiting injection site reaction
Biester and colleagues⁴⁵ published 18 pediatric cases with uveitis treated with adalimumab. Seventeen of these patients had JIAU. All patients failed first- and second-line immunomodulatory therapy. Sixteen of 18 patients responded to adalimumab, 1 patient had a mild effect, and 1 patient did not show any effect; none showed any side effects to the medication.

CONCLUSION
While steroids remain the primary initial treatment for patients with uveitis, the serious adverse effects associated with their chronic use make them an unacceptable treatment strategy in chronic cases. Hence the current trend toward treatment of noninfectious uveitis incorporates the use of immunomodulatory agents. Immunomodulators have the ability of inducing durable remission, eventually enabling many patients to remain in remission and off all medications. Selecting an immunomodulatory agent for a particular case is a difficult task. It will depend on the cause and clinical behavior of each case, the presence or absence of an underlying systemic disease, the patient’s general health, and the patient’s response to such immunomodulatory therapy. The advent of biologic agents may provide added benefit with reasonable safety profiles in selected cases of uveitis resistant to conventional immunomodulatory therapy.

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Rene A. Cervantes-Castañeda, MD, is a fellow in the Ocular Immunology and Uveitis Foundation at the Massachusetts Eye Research and Surgery and Institute (MERSI) in Cambridge, Mass. Nida Jawed is a final year medical student at the Aga Khan University in Karachi, Pakistan. C. Stephen Foster, MD, FACS, FACR, is clinical professor of ophthalmology at the Harvard Medical School in Boston, founder and president of MERSI, and founder and CEO of the Ocular Immunology and Uveitis Foundation. None of the authors have any financial interest in any products mentioned in this article.