|Year : 1993 | Volume
| Issue : 3 | Page : 107-113
Treatment of uveitis with immunosuppressive agents
Narsing A Rao, Rajeev Buddi
Doheny Eye Institute, University of Southern California School of Medicine, Los Angeles, USA
Narsing A Rao
Department of Ophthalmology, University of Southern California School of Medicine, 1355 San Pablo Street, Los Angeles, California 90033
Source of Support: None, Conflict of Interest: None
The spectrum of uveitis constitutes one of the major causes of blindness. Advances in our understanding of the underlying mechanisms have altered the diagnostic and therapeutic approaches. The most notable development is the increasing usage of several immunosuppressive agents. A systematic approach in making accurate diagnosis is central to employment of specific, more effective treatment. One should be cognizant of the potential benefits and risks of each of these agents before exposing the patients to these very potent drugs.
Keywords: Immunosuppressive agents - Cyclosporine - Corticosteroids - Cytotoxic agents - Cyclophosphamide - Vitreous surgery
|How to cite this article:|
Rao NA, Buddi R. Treatment of uveitis with immunosuppressive agents. Indian J Ophthalmol 1993;41:107-13
Uveitis is one of the major causes of blindness in both developed and developing countries. In about 70% of the cases, the etiology and pathogenesis remain obscure even after exhaustive clinical and laboratory investigations.  In the other 30% of the cases, the intraocular inflammation is caused by trauma or by an infectious agent, the most common of which is Toxoplasma gondii. Most cases of nontraumatic and noninfectious uveitis are believed to represent autoimmunity to ocular tissue components. Regardless of etiology, visual prognosis is worse in those forms of uveitis that present with severe intraocular inflammation, due primarily to retinal and uveal tissue damage in the form of vascular leakage, cystoid macular oedema, secondary glaucoma, cataract, and other alterations mediated by cytokines, proteolytic enzymes and oxygen metabolites and free radicals. ,
sub There is clear experimental evidence to show that retinal and retinal pigment epithelial proteins, including melanin, can function as autoantigens and perpetuate uveitis. ,, Among the various retinal proteins, a soluble protein known as "S" antigen and interphotoreceptor retinoid binding protein (IRBP) have been the most extensively studied in induction of uveitis in various laboratory animals by active immunisation (for example, injection of these antigens into their foot pads) and more recently by passive transfer of antigen specific T-lymphocytes from actively immunised animals.  These retinal antigen-induced intraocular inflammations, and other animal models of uveitis have increased our understanding of the role of autoimmunity in the development of uveitis and have allowed us to study the effects of various immunosuppressive agents in the treatment of autoimmune uveitis. ,
Still more recently, the retinal antigen-induced uveitis models have allowed us to investigate the cellular and molecular mechanisms that are involved in development and in perpetuation of uveitis [Figure - 1]. Based on these experimental animal studies, it appears that the initial events in the induction of uveitis may result from altered tolerance to retinal soluble proteins, probably triggered by an infectious agent.  In most posterior uveitis, this alteration leads to T-lymphocyte mediated autoimmunity directed against retinal/ choroidal proteins. An exciting finding in animal studies is that development of such autoimmunity can be prevented or suppressed by monoclonal antibodies to various T-cell surface molecules  or major histocompatibility complex (MHC class II) antigens.  There is also evidence to suggest that a limited number of T-cells with specific antigen receptors recognise the intraocular antigens such as S-antigen or interphotoreceptor retinoid binding protein (IRBP) which are known to play some role in perpetuation of uveitis.  Elucidation of such antigen specific cellular and molecular changes promise a more specific manipulation of the immune system for treating autoimmune disorders.
Even though these new and exciting treatment possibilities may become available in the near future, for the appropriate management of uveitis today, it is important to recognise and differentiate infectious cases from noninfectious autoimmune uveitis. Management of infectious uveitis is fairly straightforward; these cases are treated with appropriate antimicrobial agents, with or without corticosteroids.The noninfectious and nontraumatic uveitis cases need to be identified prior to administration of anti-inflammatory or immunosuppressive agents such as cyclophosphamide and cyclosporin A, and these are the ones that require a clear understanding of the autoimmune process that can lead to uveitis.
Many factors must be taken into consideration when deciding when and how to treat noninfectious uveitis patients. A solid understanding of the natural history of a particular uveitis entity is mandatory to avoid exposing the patient to unnecessary, excessive, or inappropriate treatment. A well- documented 'treatment response' history should be considered when developing a fresh treatment strategy. Although symptoms can be useful parameters for judging treatment efficacy, in some instances, for example floaters, they need not be pursued to extinction. The presence of inflammation alone is not always an indication for treatment. For example, a patient who has intermediate uveitis (pars planitis) with moderate vitreous cells but with a visual acuity of 20/25 does not require treatment. Likewise, a patient who has Fuchs' heterochromic iridocyclitis should not be given intensive topical corticosteroid treatment, as this will merely hasten the development of cataract. On the other hand, a patient who has juvenile rheumatoid arthritis and chronic flare alone does not need corticosteroid medications, but may require chronic mydriatic therapy to prevent the development of posterior synechiae. In all instances, a risk-benefit analysis should be made, and therapy should be instituted only when the benefits of such therapy outweigh the potential complications.
| Cycloplegic agents|| |
Mydriatic/cycloplegic agents are used primarily to relieve the ciliary spasm and pain that often accompanies iridocyclitis, and to prevent the development of posterior synechiae. In general, the intermediate acting agents such as homatropine are preferred in most cases of anterior uveitis. The stronger, longer-acting agents may be indicated to help break synechiae that have already formed, while shorter-acting agents may be preferred in instances where there is a high likelihood of posterior synechia formation (for example, severe iritis with intense flare), as these agents tend to keep the pupil relatively mobile.
| Corticosteroids|| |
Corticosteroids are the mainstay of anti-inflammatory therapy for most types of uveitis, and effectively suppress the inflammatory response regardless of its cause. The anti-inflammatory effects are initiated when the corticosteroid molecule enters the target cell and combines with the appropriate receptor within the cytoplasm. This steroid- receptor complex is then transported to the cell nucleus where it influences DNA transcription, resulting in changes in messenger RNA production, protein synthesis, and cell function. 
Corticosteroids are available as topical, periocular, and systemic preparations.
For most cases of anterior uveitis, corticosteroids need be administered only topically, sometimes as frequently as every hour if necessary. Only in particularly severe cases may periocular or systemic corticosteroids be indicated.. However, topical corticosteroids penetrate the posterior segment poorly, and thus are not usually indicated in the treatment of intermediate or posterior uveitis. In these instances, periocular injections should be given if possible, particularly in unilateral cases. The preferred method of delivery in most cases is by injection into the posterior sub-Tenon's space, through one of the temporal quadrants. This can be easily accomplished using only topical anaesthesia, such as 4% lignocaine, proparacaine or tetracaine [Table - 1].
It is in cases of bilateral uveitis or in patients who have severe unilateral inflammation and who are intolerant of, or unresponsive to, periocular injections that systemic corticosteroids are employed. The principles involved in the management of uveitis by oral corticosteroids are summarised in [Table - 2]. An oral dose of 40 to 100 mg of prednisone per day is used initially, in most cases, then is tapered gradually as the inflammation subsides. It is preferred that the prednisone be reduced about 5 mg every week. Once a dose of 10 to 20 mg per day is reached, the dose can be doubled and given on alternate days, as this may reduce the systemic side effects of chronic corticosteroid use. However, some patients may experience an exacerbation of symptoms on alternate day therapy and may need to remain on daily doses until the medicine is discontinued. When using either topically or systemically administered corticosteroids, it generally is preferred to begin with a higher or more frequent dose (for example,one drop every one to two hours, or 40 to 100 mg of prednisone per day) and taper the medication as the inflammation subsides, rather than starting with a low dose and having to increase it to control the inflammation . 
It is important that the physician be familiar with the ocular and systemic complications of these medications, regardless of the route of administration; these include elevated intraocular pressure in predisposed patients, predisposition to infections, posterior subcapsular cataract formation, gastric ulceration, hypertension, osteoporosis, diabetes, and mental changes such as euphoria, psychosis, and others. Note that while the periocular route decreases the incidence and severity of these systemic effects, it does not eliminate the risk completely. In general, the development of these side effects is related to the dose of medication and to the duration of treatment. Patients also need to be made aware of the possible side effects prior to beginning therapy, and they should be monitored closely while receiving corticosteroids.
| IMMUNOSUPPRESSIVE (Cytotoxic Agents)|| |
In general, use of immunosuppressive agents [Table - 3] is reserved for severe, sight-threatening cases of uveitis that are poorly responsive to corticosteroids, or for use in patients who develop intolerable side effects from corticosteroids. As opposed to the more "cytostatic" effects of corticosteroids, the cytotoxic agents are believed to exert their beneficial effects in uveitis by actually killing the rapidly dividing clones of lymphocytes that are responsible for the inflammation.
The following indications generally apply to the use of immunosuppressive agents in the treatment of uveitis: (1) vision-threatening nature of the intraocular inflammation; (2) reversibility of the disease process; and (3) no response to corticosteroid treatment or corticosteroid treatment contraindicated because of a systemic problem.
Prior to initiation of therapy with any cytotoxic agent; it is important to consider these guidelines: (1) absence of infection; (2) absence of hematologic contraindications; (3) meticulous follow-up by ophthalmologist or internist or a medical oncologist, if necessary; (4) objective evaluation of the disease process; and (5) informed consent.
The immunosuppressive agents that have been used in treatment of uveitis include cyclophosphamide, chlorambucil, azathioprine and methotrexate. 
Cyclophosphamide treatment is begun at about I to 2mg/kg/day, while chlorambucil is begun at 2 mg/ day and slowly increased to a dose of 8 to 12 mg/ day. The patient's blood count must be monitored closely, the goal being a reduction in white blood cell count to no lower then 3000 cells/mm 3. The dose is tapered as the inflammation subsides, or if the white cell or platelet count falls too drastically. Azathioprine and methotrexate are examples of antimetabolites. Azathioprine is given usually in a dose of 50 to 150 mg/day,while methotrexate can be given as a weekly oral or intramuscular dose of 7.5 to 25 mg. The latter agent is used much less commonly than are the others because of its extreme toxicity. In a recent study, however, methotrexate at the low dose of 12.5 mg/week was shown to be effective therapy for corticosteroid resistant uveitis,  but further studies are required to confirm the beneficial effects of such therapy.
Needless to say, the side effects and potential complications of any of these agents are many and at times fatal. The most feared complications include the future development of malignancies, such as leukemia, lymphoma, or soft tissue tumours, as well as teratogenesis (for example, chromosomal damage, azoospermia), which makes their use in younger patients particularly troublesome. Whenever these agents are used, the patient should be advised fully of the potential complications, including development of opportunistic bacterial [Figure - 2], fungal and viral infections, and consideration should be given to obtaining informed consent prior to beginning therapy. All patients should be monitored closely by an internist who is experienced with these medications, and treatment should be discontinued at the first sign of major toxicity or should no benefit be obtained with therapeutic levels of the drug.
Because cytotoxic agents have such serious side effects, their use in the treatment of uveitis is restricted to severe and chronic cases that do not respond to other therapy. The International Uveitis Study Group made an attempt to categorise the indications for immunosuppressive agents into "absolute", "relative", and "questionable" [Table - 4]. There are uveitis entities that do warrant cytotoxic agents for suppression of the intraocular inflammation. These entities include Behcets disease and rheumatoid necrotizing sclerouveitis. Even though these intraocular inflammatory disorders may initially respond well to corticosteroids, the long-term prognosis and morbidity, are unacceptable. Initial treatment of these entities with cytotoxic agents has been shown to improve the long-term prognosis and to lessen the visual morbidity. In addition to these two entities, there is an absolute indication for cytotoxic agents in patients with the Vogt-KoyanagiHarada syndrome and in patients with serpiginous choroidopathy. Relative indications for the cytotoxic agents include those conditions that require corticosteroids as the initial agents of choice. If these agents fail to control the inflammation, then cytotoxic agents might be tried. The clinical entities in this relative indication category include intermediate uveitis (pars planitis), retinal vasculitis, and chronic iridocyclitits. With some of these conditions, however, particularly in children it is not clear whether cytotoxic agents should be employed; an example would be a child with intermediate uveitis. Due to the long-term serious side effects, use of cytotoxic agents should generally be avoided in children. In these patients, the newer immunosuppressive agents such as cyclosporine and related drugs may be helpful. A recent multi-centre controlled clinical trial has shown low-dose weekly methotrexate treatment with low-dose steroids and other anti-inflammatory agents to be effective in cases of juvenile rheumatoid arthritis (JRA), with minimal side effects in the short term (six months).  Similar results have been reported with JRA associated uveitis. 
| Cyclosporine|| |
Cyclosporine (cyclosporin A) is a naturally occurring compound produced by soil fungi. It has a much more specific effect on immune function than do either corticosteroids or cytotoxic agents. While the exact mechanism of action of cyclosporine remains controversial, the primary effects appear to be related to inhibition of T-cell activation and recruitment, most likely through its suppressive effect on interleukin-1 function and indirect inhibition of interlukin-2(IL-2) production, which are necessary for activation of T- lymphocytes.
Cyclosporine has been found to suppress retinal S-antigen induced experimental autoimmune uveitis (EAU) in rats,  and clinically has been shown to be effective in treating various types of uveitis, such as Behcets syndrome and Vogt-Koyanagi-Harada syndrome. , Therapy is begun usually at a dose of 5 mg/ kg/day, and may be combined with prednisone 20 to 40 mg for a more potent anti-inflammatory effect. It should be noted that cyclosporine is not cytolytic (for example, it does not kill the lymphocytes responsible for the inflammation); thus, the beneficial effects usually disappear when the medication is discontinued, making long-term treatment necessary in many patients.
The major side effects of cyclosporine are nephrotoxicity and hypertension, which occur in up to 75% and 25% of patients, respectively. The renal impairment is often reversible if the dose is decreased, but irreversible tubular damage has occurred in patients on prolonged therapy. Other side effects include paraesthesia, gastrointestinal upset, fatigue, hypertri-chosis, gingival hyperplasia, elevated sedimentation rate, and a normochromic, normocytic anaemia. Obviously, patients receiving cyclosporine sould be followed closely by an internist to monitor their renal function as well as blood pressure and hematologic status. It is recommended that the dosage be reduced should serum creatinine increase by more than 20-30% above the pretreatment baseline value.
Studies are currently being done with other types of cyclosporine, for example, cyclosporin G,  which appears to be less nephrotoxic than is cyclosporin A. At present, cyclosporine should be considered in cases of severe bilateral posterior uveitis that is poorly responsive to more conventional therapy. While probably not carcinogenic, in contrast to the cytotoxic agents, the teratogenic effects of cyclosporine are unknown. Its use in pregnancy should thus be avoided unless absolutely necessary, and then should be used only after consultation with the patient's obstetrician or internist, or both.
Similar to cyclosporine, a potent new immunosuppressive agent, FK506, has been introduced in the management of severe uveitis.  This agent has been tried in a very limited number of patients with uveitis, and further studies are required to evaluate the indications and contraindications of its use, and the use of other such potent immunosuppressive agent.
| Nsaid|| |
Nonsteroidal anti-inflammatory drugs exert their effects by interfering with prostaglandin synthesis. While these drugs appear to have some role in the treatment of aphakic cystoid macular oedema and certain types of scleritis, they generally have been found to be of little value in the treatment of most uveitis entities. However, experimental studies do suggest that, specific lipoxygenase inhibitors may be useful in granulomatous uveitis  The lipoxygenase inhibitors are not yet available for clinical use, but once such agents become available, they may be found to be effective in the management of granulomatous uveitis.
| Vitreous surgery|| |
There have been cases in which core vitrectomy in uveitis has altered the course of the disease. This beneficial effect was seen in some patients with intermediate uveitis and in others with chronic uveitis associated with vitritis. Vitreous surgery is usually reserved for cases that fail to respond to systemic corticosteroids. For example, we employ the following stepladder approach in the management of intermediate uveitis [Figure - 3]. These patients are treated initially with sub-Tenon's deposteroid injections for at least four to six injections weekly or bimonthly. If there is no response to this therapy, we recommend systemic oral corticosteroids in the dose range of 40 to 60 mg /day. This therapy is then continued for at least six to 12 weeks. If there is no response at the end of 12 weeks, the patient undergoes either pars plana vitrectomy or cryotherapy of the pars plana, as described by Aaberg and associates  There are potential complications with both of these procedures, and these should be discussed with the patient prior to surgical intervention. Following vitrectomy, some patients show improvement in the intraocular inflammation. Others may not show improvement from the surgical procedure, but may respond well to sub-Tenon's injections of steroids or to oral prednisone therapy to which they were refractory prior to pars plana vitrectomy. There is a third group of patients who do not show any beneficial effects from the surgery or from surgery plus steroid therapy, and it is these patients who are usually managed by cytotoxic/immunosuppressive agents.
| Treatment strategies|| |
Prior to consideration of any therapy for uveitis, it is essential to exclude infectious etiology and masquerade syndromes that may clinically simulate uveitis, such as necrotic tumours, retinoblastoma, leukemia, and juvenile xanthogranuloma in children, and lymphoma and other malignancies in adults. Once the infectious process and neoplastic possibilities are excluded, the noninfectious uveitis should be classified as anterior, intermediate, posterior, or panuveitis, based on slit lamp and ophthalmoscopic findings.
For most cases of anterior uveitis, frequent topical corticosteroids combined with cycloplegic agents should be sufficient; in severe cases, periocular' injections or a short course of systemic steroids may be necessary. For intermediate or posterior uveitis, periocular injections are the preferred route; systemic steroids are used in bilateral cases or if the patient is intolerant of periocular injections. Cyclosporine or cytotoxic agents should be used only as a last resort in severe sightthreatening cases of uveitis unresponsive to more conventional therapy. In all instances, treatment is continued only for as long as it takes to bring the inflammation under control. However, care must be taken not to taper the medication too rapidly, as this may result in a recurrence of the inflammation. Some patients with chronic uveitis respond well to pars plana vitrectomy, and this procedure should be considered prior to initiation of immunosuppressive or cytotoxic agents, particularly in patients with intermediate uveitis. Dietary supplementation with antioxidants such as vitamin E  may help to reduce the severity of uveitis and may protect the retina from peroxidative damage. Such treatment can be part of the anti-inflammatory therapy, and can be used in conjunction with either corticosteroids or immunosuppressive agents.
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[Figure - 1], [Figure - 2], [Figure - 3]
[Table - 1], [Table - 2], [Table - 3], [Table - 4]