Judicious Use of Immunomodulatory Agents to Manage Noninfectious Uveitis

Mohamed Ibrahim, MD • Mostafa Hannout, MB BCh • Yasir Sepah, MBBS • Elham Hatef, MD • Jangwon Heo, MD • Jeong Hee Lee, MD • Ovais Shaikh, MD • Roomasa Channa, MD • Afsheen Khwaja, MD • Quan Dong Nguyen, MD, MSc

Uveitis is a leading cause of blindness in the developed world, affecting approximately 0.2% of individuals and accounting for 10% to 20% of cases of legal blindness.^1-2 The etiologies of uveitis and ocular inflammatory diseases are protean; infectious causes and masquerade syndromes (often for an underlying malignancy) need to be considered in appropriate cases. In the United States, many cases of uveitis are judged to be autoimmune in nature.³ Early diagnosis and treatment are important to prevent the vision-threatening complications of uveitis, such as glaucoma, retinopathy and macular edema.⁴

The standard of care for noninfectious uveitis is local, topical and oral corticosteroids (CS). These are currently the only drugs approved by the FDA to treat noninfectious uveitis.^2,5 The primary goal of therapy is to suppress inflammation and achieve remission when the disease exacerbates.^6,7 Although CSs are effective in achieving this primary goal, they often cause significant morbidity and sometimes mortality. All types of CSs, through different modes of deliveries, are associated with adverse effects (AEs) ranging from local effects such as glaucoma, cataract and scleral melting to potentially dangerous complications such as diabetes, congestive heart failure, osteoporosis and Cushing's syndrome. A correlation has been observed between high doses of CS and increased risk of side effects.⁸ The morbidities caused by CSs warranted the development in 2000 by an expert panel of treatment guidelines that were reinforced by the Standardization of Uveitis Nomenclature Working Group in 2005.^9,10 To decrease the risk of serious AEs associated with systemic long-term CS use, current guidelines recommend the addition of immunomodulatory therapeutic (IMT) agents if inflammation cannot be controlled with <10 mg/day of prednisone (or equivalent) within three months.^9,10

However, IMT agents have their own risks, especially if they are not used wisely and properly. IMT can be extremely dangerous and harmful to patients. Therefore, judicious use of IMT requires careful assessment of the patient's health and assessing and understanding the nature of the inflammatory condition at hand, as well as consideration of the condition's severity, careful selection of the IMT agent and treatment regimen and, finally, careful and continuous monitoring of the therapy throughout the entire course, and sometimes after discontinuation, of IMT.

Antimetabolites, calcineurin inhibitors, alkylating agents and, most recently, biologic response modifiers are used as IMT, steroid-sparing agents in noninfectious uveitis. We herein discuss very briefly some of the commonly used IMT agents in the management of uveitis and ocular inflammatory diseases.

ANTIMETABOLITES

Antimetabolites are chemicals that inhibit metabolites, which are parts of normal cellular metabolism. The use of antimetabolites results in interference with normal cell function, especially cell growth and proliferation. Rapidly proliferating cells, eg, T- and B-lymphocytes, are vulnerable to such effect, which accounts for the bioactivity of anti-metabolites in the treatment of immunologic diseases including uveitis.

Methotrexate. Methotrexate is an antifolate agent that competitively inhibits dihydrofolate reductase, thus inhibiting thymidine synthesis, and hence interferes with DNA replication and cellular proliferation.¹⁰ Use of methotrexate in uveitis has been described since 1966.¹¹ Serious AEs include reversible hepatotoxicity with abnormal liver function tests; approximately 0.1% of patients treated with methotrexate develop hepatic cirrhosis. Interstitial hypersensitivity pneumonitis may occur either early or late in treatment.¹² The favorable safety profile of methotrexate, along with the convenience of its weekly administration, have made it a popular steroid-sparing agent in children and adults.

Azathioprine. A purine analog that inhibits DNA replication and RNA transcription, azathioprine suppresses proliferation of T- and B-lymphocytes and reduces mixed lymphocyte reactivity, interleukin-2 synthesis and IgM production.¹⁰ Azathioprine has been shown to be effective in treating sympathetic ophthalmia, Adamantiades-Behçet disease (ABD), Vogt-Koyanagi-Harada (VKH) syndrome, and serpiginous choroidopathy — particularly in combination with steroids or other IMT agents.¹³

Serious AEs of azathioprine include reversible myelo-suppression (25%) and reversible hepatotoxicity with elevated LFTs.¹³ Azathioprine is nonenzymatically converted in vivo to the active metabolites 6-mercaptopurine (90%) and 6-thioinosinic acid (10%).¹⁴ The enzyme thiopurine S-methyltransferase (TPMT) deactivates 6-mercaptopurine. Low activity of TPMT leads to toxicity effects. Therefore, assessment of the serum levels of TPMT at baseline may help to decrease the risk of developing azathioprine toxicity.¹¹ Elevated hepatic enzymes — with AST or ALT more than 1.5x the upper limit of normal values — requires reduction of the dosage. Significant elevations mandate discontinuation of azathioprine.

Mycophenolate mofetil. MMF is a prodrug that selectively inhibits the inosine monophosphate dehydrogenase enzyme and thus inhibits the de novo pathway of purine synthesis. MMF prevents the proliferation of B- and T-lymphocytes, suppresses antibody synthesis, interferes with cellular adhesion to the vascular endothelium and decreases recruitment of leukocytes to sites of inflammation.¹⁰ MMF is generally well tolerated; however, uncommon severe toxicities may occur, including leukopenia, opportunistic infections, viral infections (eg, CMV and HSV), hepatotoxicity and lymphoma. The favorable safety profile of MMF, especially the lower risks of myelosuppression and opportunistic infections, has encouraged its use in place of azathioprine in organ transplantation and uveitis.¹⁵ MMF is increasingly used as a steroid-sparing agent in the management of a variety of inflammatory ocular diseases, including VKH, sympathetic ophthalmia, birdshot retinochoroidopathy, ABD, serpiginous choroidopathy and scleritis.

CALCINEURIN INHIBITORS

Activation of the T-cell receptors normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. The activated calcineurin upregulates expression of interleukin 2 (IL-2), which in turn stimulates T-cell growth and differentiation. Blockage of calcineurin results in inhibition of T-lymphocyte proliferation, adhesion and recruitment. Calcineurin inhibitors act by forming a complex through binding to the cytosolic protein immunophilin. Such a complex subsequently inhibits calcineurin. Calcineurin is normally responsible for activation of the transcription factor NF-AT, which in turn increases transcription of IL-2 and other cytokines. IL-2 binds to T-cells and promotes proliferation and further cytokine release. Thus when calcineurin is inhibited, T-cell proliferation and release of proinflammatory cytokines are subsequently blocked.

Cyclosporine A. CsA binds to intracellular immunophilin receptors (cyclophilin), leading to reversible blockage of calcineurin activation. Thus, it inhibits production of IL-2 and related cytokines.¹⁴ CsA has been found in therapeutic levels in the intraocular fluids of uveitis patients.¹⁶ The most significant AEs include reversible nephrotoxicity and hypertension. Less common side effects include gingival hyperplasia, myalgias, hepatotoxicity, tremor and paresthesia.¹⁷

Tacrolimus. A macrolide antibiotic that has been described and used in uveitis since 1991,¹⁴ tacrolimus interferes with proliferation of CD4+ T-lymphocytes in a mechanism similar to CsA through binding to intracellular immunophilin receptors. Tacrolimus, however, is 10 to 30 times more potent than CsA. Such potency is particularly useful when treating sight-threatening uveitis, especially when the uveitis is refractory to CsA or when the AEs of CsA are unacceptable.¹⁴ Tacrolimus has demonstrated long-term efficacy in controlling ABD, intermediate and posterior uveitis, and uveitis refractory to CsA.^18-23 The most important side effects include dose-dependent renal impairment, neurological symptoms, gastrointestinal symptoms, hyperglycemia, dizziness and headache.²⁴

ALKYLATING AGENTS

Alkylating agents are the most potent immunomodulatory agents available. However, they also have the most potential for significant toxicity. Thus, they are usually reserved for severe sight-threatening uveitis.

Alkylating agents are alkylate nucleic acids resulting in DNA-to-DNA and DNA-to-protein cross-linking. DNA cross-linking interferes with DNA replication and RNA transcription, resulting in cell death. These agents are cytotoxic to both resting and dividing lymphocytes, resulting in reduction of T- and B-lymphocytes in peripheral blood and suppression of T-helper cells and cytokines production.¹⁴

Cyclophosphamide. Phosphoramide mustard is the active metabolite of cyclophosphamide (CP). Aldehyde dehydrogenase (ALDH) detoxifies cyclophosphamide through interference with the phosphoramide mustard formation. Highly proliferating cells, such as bone marrow, liver and intestinal epithelium, have a high concentration of ALDH; this confers some level of tolerance to cyclophosphamide against the typical toxic effects of alkylating agents. CP is immunosuppressant and cytotoxic only in high doses.

Many clinicians titrate CP dose to obtain a leukocyte count of 3,000-4,000 cells/mL, after discontinuation of oral corticosteroid therapy; it is thought that this level of immunosuppression is associated with better long-term inflammatory control and ability to achieve disease remission.²⁵

A common serious AE of cyclophosphamide is hemorrhagic cystitis, which can be avoided through adequate fluid intake (> 2L/day). One of CP's metabolites, acrolein, is thought to be responsible for the urologic toxicity. The use of 2-mercaptoethane sulfonate may detoxify acrolein.¹⁰ Increased risk of bladder cancer, myelosuppression, sterility and opportunistic infections are also serious AEs of CP.

Chlorambucil. A nitrogen mustard, chlorambucil is an alkylating agent that is mainly used in treatment of chronic lymphocytic leukemia (CLL). It is also used in treating other malignancies, including various types of non-Hodgkin's lymphoma and Waldenström macroglobulinemia. Chlorambucil is also used in management of auto-immune and inflammatory conditions, such as nephrotic syndrome, and hematological conditions, such as polycythemia vera. Although well tolerated, chlorambucil has largely been replaced by fludarabine in treatment of young patients with CLL.

Chlorambucil has been used in selected cases of uveitis and ocular inflammatory diseases, although its effectiveness may be less predictable than cyclophosphamide. Anemia and thrombocytopenia are common with chlorambucil. Also, in addition to serious AEs similar to those associated with cyclophosphamide, chlorambucil can cause peripheral neuropathy, seizures (in children with nephrotic syndrome), hallucinations and hepatotoxicity.

BIOLOGIC RESPONSE MODIFIERS

Biologics are medicinal products created through biological processes. Those in use for management of noninfectious uveitis either target regulating cytokines that mediate the immune response (cytokine blockers) or target cellular receptors of specific immune cells (receptor blockers).

Cytokine Blockers

Most cytokine blockers used in uveitis target tumor necrosis factor (TNF)-α, a proinflammatory cytokine. However, recent studies have demonstrated a potential role of interferon-α 2-α. TNF-α is produced in response to inflammation, infection, and other environmental stresses. Most cells express TNFR1 (tumor necrosis factor receptor 1), which is believed to be the major mediator of the cytotoxicity of TNF-α.²⁶ TNF-α holds a very important role in the inflammatory cascade, which accounts for the powerful effect of TNF-α blockers in controlling the inflammatory process. The role of T-cell activation and TNF-α production in uveitis in humans has also been demonstrated.^27,28

Infliximab. A chimeric monoclonal antibody (mAb) composed of human-murine sequences, infliximab has been used successfully in children with noninfectious uveitis, leading to maintenance of visual acuity, improved control of ocular inflammation and reduced reliance on corticosteroids.²⁹ There are also excellent results reported in adults with ABD and other causes of posterior uveitis and scleritis.³⁰ In Japan, recent studies have supported the use of infliximab as first-line therapy for ABD. Serious AEs include myelosuppression, demyelinating neurological disorders (eg, multiple sclerosis), infectious diseases, activation of latent infections (TB and HBV), malignancies and immunological disorders, such as drug-induced SLE and immune hypersensitivity reactions.

Adalimumab is a fully human mAb that targets TNF-α. Being fully humanized and having a subcutaneous route of administration are clear advantages of adalimumab when compared to infliximab. Several reports have demonstrated a successful use of adalimumab in management of ABD, severe forms of VKH syndrome, JRA-associated uveitis and idiopathic pediatric uveitis.^31-35 The most common side effect associated with adalimumab is injection-site reaction (10%). It is relatively safe and tolerable with rare serious AEs, including serious infections, lymphoma, tuberculosis, herpetic keratitis, opportunistic infections, demyelinating diseases, drug-induced SLE, elevated hepatic enzymes and congestive heart failure.⁶

Etanercept is a genetically engineered fusion protein of TNF receptor p75. There have been few case series reporting successful use of etanercept in uveitis.³⁶ Other trials reported no difference in inflammatory indices between groups treated with etanercept and placebo in patients with juvenile idiopathic arthritis (JIA)-associated uveitis.³⁷ In other trials, etanercept did not appear to protect against the onset,³⁸ nor relapses, of uveitis.³⁹ When compared with infliximab in the treatment of uveitis, etanercept has repeatedly been found to be inferior.⁴⁰ Given its low efficacy, etanercept is not currently being used often in management of uveitis and ocular inflammatory disease.

Interferon α-2a is an immunomodulating cytokine with antiviral, antiproliferative and antiangiogenic properties. It has been commonly used in the treatment of hepatitis C, myeloproliferative diseases and lymphomas.⁴¹ Several studies have reported successful short- and long-term use, as well as steroid-sparing effect, of interferon α-2a in ocular ABD^42-46 and chronic posterior uveitis refractory to conventional treatment.^1,41,47 Other case series have reported promising results in MS-related intermediate uveitis and in serpiginous choroiditis.⁴⁸

Systemic AEs are flu-like symptoms, mild leukopenia and alopecia. Less common but serious side effects include CNS effects (depression, confusion, seizures and psychosis), autoantibodies (antithyroid), thrombocytopenia, hypotension and elevated liver enzymes.

Cell Receptor Blockers

Specific cell receptors are being targeted through specially designed recombinant mAb. Interleukin receptors are the main targets for these mAb in noninfectious uveitis.

Daclizumab is a recombinant mAb composed of human-murine IgG-1 sequences that targets interleukin-2 (IL-2) receptors of activated T- and B-lymphocytes,^49,50 consequently inhibiting the IL-2 signaling pathway. One trial found no benefits of daclizumab in treating posterior inflammation associated with ABD.⁵¹ Another found that daclizumab allowed control of inflammation with low-dose corticosteroids or other immunosuppressive agents in intermediate and posterior uveitis.¹⁷ Serious side effects reported with daclizumab use were rare; however, it has been discontinued in the United States. According to the manufacturer, this decision was based on the availability of alternative treatments and the diminishing market demand.⁵²

Anakinra. A recombinant human mAb targeting the interleukin 1 (IL-1) receptors, anakinra downregulates the IL-1-mediated immune response through competitive inhibition of IL-1 receptors of T- and B-lymphocytes and NK cells. Teoh et al. reported a successful use of anakinra in a four-year-old boy with posterior uveitis associated with CINCA (chronic infantile neurological, cutaneous, and articular) syndrome. Similarly, Dinarello et al. reported another successful use in 75-year-old female with ABD refractory to other treatments including infliximab.^53,54

Rare, serious AEs have been reported in association with anakinra, including bacterial cellulitis, neutropenia, serious infections and malignancies (melanoma, lymphoma and breast cancer).

AGENTS IN DEVELOPMENT FOR UVEITIS AND OCULAR INFLAMMATORY DISEASES

Voclosporin. This novel calcineurin inhibitor is more similar to CsA than to a single functional group. Voclosporin is currently being developed with indications for prevention of organ graft rejection and treatment of auto-immune diseases, such as psoriasis. It has also been evaluated in phase 3 studies for use in noninfectious uveitis and has been found to be four times more potent than CsA in in vitro and in vivo studies. The adverse events of voclosporin have been found to be much less than those of CsA. Results from early studies suggest that voclosporin has a more favorable safety profile as lower therapeutic doses can be used, and it has a higher bioavailability than CsA. Additional phase 3 studies of voclosporin in active, noninfectious, intermediate, posterior, or panuveitis are being conducted for approval by the FDA.

AIN457. The cytokine interleukin 17 (IL-17) is a protein produced by inflammatory cells that initiates, maintains, or augments the inflammatory response in certain conditions. The levels of IL-6, IL-17 and IL-18 are elevated in serum of patients with ABD. IL-17 mRNA levels in peripheral blood mononuclear cells are also elevated in some patients with uveitis. Thus far, IL-17 appears to play a role in the development or maintenance of uveitis.

Therapy with AIN457, an anti-IL-17 antibody given either systemically or via intravitreal injections, reduces inflammation in mouse models of uveitis. Studies of subcutaneous injections with AIN457 are currently being conducted in patients with uveitis who require steroid-sparing therapy, and this may provide information about the potential of this drug in the management of uveitis and ocular inflammatory diseases.

Sirolimus, also known as rapamycin, was isolated in the 1970s from Streptomyces hygroscopicus in soil samples from Easter Island. Sirolimus is the active pharmaceutical ingredient in two products approved by the FDA, specifically Rapamune, an immunosuppressive agent used in renal transplant patients, and the Cypher Sirolimus-eluting Coronary Stent, approved for improving coronary luminal diameter in patients with symptomatic ischemic disease.

The mechanism of action of sirolimus in immunosuppression has been described extensively in the literature. Sirolimus blocks T-lymphocyte activation and smooth muscle and endothelial cell proliferation that occurs in response to antigenic and cytokine (IL-2, IL-4 and IL-15) stimulation, employing either Ca2+ dependent or Ca2+-independent pathways. Sirolimus arrests cell cycle progression by direct interaction with two intracellular proteins and the mammalian target of rapamycin (mTOR), a multifunctional serine-threonine kinase.

The inhibition of mTOR blocks IL-2-mediated signal transduction pathways that prevent cell cycle progression from G1 to S phase in T-cells, endothelial cells, osteosarcoma cells, myogenic cell lines and smooth muscle cells. In addition, sirolimus inhibits the production of antibodies. Sirolimus has also been shown to downregulate the expression of many genes related to inflammation, such as interleukin-8 and inducible nitric oxide synthase.

Sirolimus, administered systemically, has been used in selected cases of refractory posterior and panuveitis. Currently, local administration of sirolimus, either as subconjunctival or intravitreal injection, is being investigated as potential therapeutic options for noninfectious uveitis requiring IMT or steroid-sparing therapy. Such formulary may be very welcome if efficacy can be demonstrated and systemic adverse events can be eliminated or diminished significantly.

PRECAUTIONS WHEN EMPLOYING IMT

The expected insufficiency of CSs in controlling sight-threatening conditions (eg, ABD, sympathetic ophthalmia, VKH and necrotizing sclerouveitis) are clear indications for its early use of IMT. However, even in those cases where the success of CS therapy is expected, early use of IMT may be indicated either to improve the long-term prognosis or to avoid or reduce the long-term morbidities associated with CS. Intolerable side effects from CSs and chronic/relapsing diseases requiring long-term CS in doses > 10 mg per day are relative indications of IMT.

However, although the use of IMT is clearly indicated in many cases of noninfectious uveitis, for both safety and efficacy outcomes, before initiating IMT a clinician should rule out the presence of concurrent active or latent infections or hepatic and hematologic contraindications, and the physician should be aware of concomitant use of other IMT and interacting drugs. In addition, the treating physician should bring all patients up to date with their vaccinations, discuss with patients the risks associated with pregnancy and breast-feeding, and discuss family planning if alkylating agents are to be used.

Laboratory investigations should include complete blood count with differential and platelets, liver function tests, renal function tests, blood glucose level, lipids profile and electrolytes profile. Other specific measures should also be taken with certain agents, such as chest X-ray with anti-metabolites, TPMT levels with azathioprine, hepatitis Bs-Ag and hepatitis C-Ab with mycophenolate mofetil, and urinalysis with alkylating agents. Remind patients regularly to alert their primary care physician of their IMT agents and to report to their ocular immunologists/uveitis specialists any change in their concomitant medications to avoid potential toxicities that may result from drug interactions.

During therapy, close monitoring of the inflammatory indices and drug toxicity parameters should guide the dosage or possible discontinuation of the IMT agent. Remissions encourage reduction of dose mild or moderate toxicity may require reduction of dose and/or addition of other agents; and severe toxicities warrant discontinuation of the therapeutic agent. Laboratory investigations, such as CBC with differential and platelets, renal function tests, liver function tests, blood sugar, lipids profile and electrolyte profile, should be performed routinely every six to eight weeks to monitor potential IMT toxicities. Blood pressure should be monitored at every clinic visit, which should be every six to eight weeks, especially with calcineurin inhibitors; urinalysis every six to eight weeks with alkylating agents; chest X-ray every six months with antimetabolites; and plasma levels of cyclosporine every six months.

In addition to all the above-mentioned routine investigations, a major part of IMT monitoring requires the cooperation of patients in reporting any symptoms/signs that may suggest an IMT toxicity, especially infections, hematuria, delayed wound healing, cardiological manifestations such as congestive heart failure and arrhythmias, neurological manifestations such as seizures, paresthesia, myalgia and muscular weakness, and psychological symptoms such as hallucinations, insomnia, depression and suicidal/homicidal thoughts.

CONCLUSION

Clinician scientists caring for patients with uveitis and ocular inflammatory diseases should employ a no-tolerance policy toward any degree of inflammation. Recently, a survey study of ophthalmologists and rheumatologists in the United States who routinely manage patients with uveitis revealed very worrisome results: 75% of those surveyed were not familiar with or did not adhere to currently recommended guidelines for management of uveitis. High doses of corticosteroids (>10 mg of prednisone or equivalent) are still being used to maintain control of disease, and there is a low level of awareness of recommended guidelines to treat noninfectious uveitis.⁵⁵ When IMT is employed properly and monitored appropriately, the potential adverse events are manageable and may be acceptable when benefits to patients can be demonstrated.¹⁴ The findings from the survey clearly underscore the need to educate the medical community and to reinforce treatment guidelines to improve the care of patients with uveitis. RP

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