Uveitis is a potentially blinding condition. Ocular inflammatory diseases, including uveitis, can generally be categorized etiologically into infectious and non-infectious. Infectious uveitis can often be eradicated with proper anti-infectious treatment such as anti-bacterial, anti-fungal, or anti-parasitic agents. Despite a wide range of (off-label) local and systemic therapies used to treat non-infectious uveitis, insufficient control of inflammatory episodes may lead to cumulative damage and, potentially, irreversible vision loss. Ophthalmologists, both comprehensive and subspecialists, should be aware of the body of evidence supporting the theory of cumulative damage in chronic noninfectious posterior segment uveitis; they should also be familiar with current management practices for ocular inflammatory diseases. Practitioners should then draw on their understanding of cumulative damage when weighing the benefits and limitations of the various treatment options.
Incidence and Prevalence of Uveitis
Uveitis accounts for 10% to 15% of all cases of total blindness in the United States, using the World Health Organization definition of less than 20/400 in the better eye (Br J Ophthalmol. 1996;80(9):844-848). It is considered to be the fourth most common cause of blindness in individuals 20 to 60 years of age in developed countries (Br J Ophthalmol. 2004;88(9):1159-1162). The incidence of chronic noninfectious posterior segment uveitis is 14 to 17 per 100,000 (Curr Eye Res. 1992;11(suppl):1-9.)
The prevalence of uveitis varies worldwide, from 38 to 730 per 100,000 (Br J Ophthalmol. 2004;88(9):1159-1162). In the United States, the prevalence has been estimated at 200 per 100,000 (Arch Ophthalmol. 1962;68:502-514.) The frequency of visual loss due to uveitis requiring treatment beyond topical corticosteroids varies by type (intermediate uveitis, posterior uveitis, or panuveitis), ranging from 28% to 59%. In posterior uveitis, 46% of the patients develop visual impairment (<20/40); 28% of patients with posterior uveitis develop macular edema, which is the most common cause of vision loss (Br J Ophthalmol. 1996;80(4):332-336).
Consequences of Recurrent or Chronic Inflammation
In most forms of uveitis, visual morbidity does not result from a single episode but rather from recurrent or chronic episodes of inflammation that cause cumulative damage (Br J Ophthalmol. 2004;88(9):1159-1162). Visual outcomes may be influenced by delays in presenting to a subspecialist, total duration of the disease, location of the uveitis (anterior, posterior, or panuveitis), and, most important, the number of inflammatory episodes (Ophthalmology. 1996;103(11):1846-1853.
Cumulative damage in uveitis results from repeated inflammatory attacks on tissues and may be greater than the sum of the individual insults. Over time, the damage may lead to irreversible consequences. An acute inflammatory episode may be controlled by medication. However, during each recurrence of inflammation, the patient may slowly lose vision and may not regain visual acuity.
Patients with chronic disease who are treated with periocular injections of corticosteroids typically experience small flares of uveitis, leading to incremental declines over a period of several years and, ultimately, to a loss of vision.2,7
The ophthalmologist's goals in managing patients with chronic noninfectious posterior segment uveitis are to suppress and control inflammation; to alleviate symptoms; and to prevent cumulative damage and complications such as macular edema, glaucoma, hypotony, and retinal detachment.
There are no guidelines or published literature describing how many episodes of inflammation must occur or how long each episode must last before cumulative damage is apparent. The number and duration of episodes vary among ocular disease types. Therefore, it is the role of the physician to determine when the disease should be considered chronic and long-term therapy is required.
Chronic Inflammation
Chronic inflammation can occur in a number of ways. The disease may be refractory to the point that there is no adequate treatment for it; the patient may receive inappropriate or insufficient treatment; or the treating physician may be willing to allow a small amount of persistent inflammation that may lead to cumulative damage. Some physicians may feel that incremental damage is acceptable, even though visual function may be lost. However, it is crucial to recognize that in posterior uveitis with chronic inflammation, patients may eventually experience complications, such as choroidal neovascularization or macular edema that can result in permanent damage and loss of visual acuity.
Uveitis requires careful management to minimize loss of vision. Insufficient or inappropriate treatment that allows frequent recurrences of disease or "low grade" chronic inflammation to occur may lead to cumulative damage. To prevent such damage from occurring, the aim should be the eradication of all inflammation.
Available Treatment Options
Corticosteroids
Treatment for chronic posterior segment uveitis often includes periocular injections of steroids, usually of triamcinolone acetonide (Kenalog), in the sub-Tenon space. The possible side effects of periocular injections include elevated intraocular pressure (IOP), optic nerve damage, visual field defects, and cataract formation. More severe side effects, such as perforation of the globe and infection, are less common (Philadelphia, PA: WB Saunders; 2002:142-157).
Although there is no systemic therapy currently approved by the Food and Drug Administration for chronic noninfectious posterior uveitis, often the initial treatment is systemic corticosteroids. These agents are effective at reducing inflammation regardless of the etiology, including transient improvements in some cases of malignancy and infection. However, the nearly universal side effects associated with the chronic use of these drugs are protean and may be serious; they include adrenal suppression, risk of myopathy and myalgias, osteoporosis, and avascular necrosis.
In children, the use of systemic corticosteroids is limited by the risk of growth retardation. Some side effects, such as Cushingoid changes and dermatologic conditions (eg, striae and acne), are considered minor but can have a pronounced negative effect on quality of life. Other side effects include mood lability, increased cholesterol, glucose, and blood pressure, and cardiovascular events.
Immunomodulatory Therapy
If corticosteroid treatment is not tolerated or is not effective in controlling uveitis, immunomodulatory therapy (IMT) may be used alone or in combination with corticosteroids to reduce inflammation. Agents used as part of IMT have the benefit of being corticosteroid-sparing . The efficacy of antimetabolites or T-cell inhibitors in the treatment of uveitis varies. They may provide long-term control of the inflammation; however, they do have many side effects, including hepatic and hematologic toxicities and gastrointestinal disturbances. Because of these side effects, these therapies may provide only transient immunosuppression[P1] , as inflammation and further cumulative damage may recur once treatment is stopped or titrated to lower levels.
Alkylating agents such as cyclophosphamide and chlorambucil can induce longer periods of drug-free remission and provide very effective control of inflammation. However, these agents are also associated with serious side effects, including increased risk of cancer, hematologic toxicities, teratogenicity, and sterility. These side effects often limit the duration of therapy.
All of the systemic immunosuppressive agents have potential for teratogenicity, and patients of child-bearing age must be instructed to use appropriate and effective methods of contraception.
Cytokine inhibition
A newer approach to the treatment of uveitis is cytokine inhibition. Cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin 2, have been implicated in the pathogenesis of inflammatory disease. Selective inhibition of specific cytokines is expected to provide focused inhibition of the immune system. The various cytokine inhibitors exhibit multiple mechanisms of action. Cytokines may be bound by a soluble receptor, making them transiently unavailable. Antibodies against selected cytokines can permanently remove the cytokine from circulation. Alternatively, antibodies against the cytokine receptor can prevent circulating cytokines from binding to the receptor, inhibiting the inflammatory response.
Several cytokine inhibitors are used in the treatment of chronic noninfectious posterior uveitis; often these are used in cases that have been resistant to other treatments. Their efficacy and ability to provide long-term control of inflammation in uveitis have been demonstrated in a number of small studies.
Adverse Effects of Systemic Therapies
When considering treatment options, it is important to recognize that systemic therapies may be associated with severe side effects. Systemic therapy has a place in the armamentarium of treatment options and is one of the primary therapeutic approaches. However, because it can be challenging to completely control inflammation with acceptable dose level of systemic therapy, patients face the risk of recurring inflammation and cumulative damage because of the need for titration or for discontinuation due to side effects.
Sustained-Release Devices and Patient Compliance
During the past two decades, significant progress has been made toward delivering pharmacologic agents in a constant, long-term approach. The availability of the ganciclovir device (Vitrasert) has saved the vision for many patients who have suffered from cytomegalovirus retinitis. The 0.59-mg fluocinolone acetonide device (Retisert), available since 2005, has become the first drug or device approved by the FDA for the treatment of noninfectious uveitis.
The constant delivery of medication in a sustained device such as the RetisertTM has been shown to decrease the recurrence of inflammation, the need for adjunctive therapy, as well as the necessity for systemic therapy when compared to eyes that have not received the implant.9,10 Thus, sustained-release devices, with proper therapeutic agents, are likely to help physicians and patients achieve the goal of no tolerance for any degree of inflammation and to decrease or prevent risk of cumulative damage.
Sustained-release devices may also improve patient compliance relative to systemic therapy, as patients may be less compliant with systemic drugs when they have to experience the adverse side effects. Nevertheless, although compliance is less of a concern with a sustained-release device than with systemic medications, it remains a significant factor in managing patients with uveitis. Patients still need to be monitored closely for intraocular pressure. Therefore, a patient who is not compliant with follow-up visits is not a good candidate for a steroid-release device (Retina. October 2006:(suppl):1-16). In such cases, one could be simply exchanging one type of blinding condition (uveitis) for another (untreated glaucoma); the ophthalmologist may be able to maintain the inflammation in quiescence, but the patient may suffer from glaucomatous optic neuropathy (Retina. October 2006:(suppl):1-16). Thus, it is critical that the ophthalmologist has a direct, honest, and comprehensive discussion with the patient, emphasizing the need to prevent cumulative damage as well as the potential risks and benefits for each therapeutic option.
In choosing a therapy, the physician needs to be vigilant about the risk of cumulative damage that may result from recurrent inflammation after a treatment approach, such as corticosteroid injections with or without systemic therapy. One also needs to recognize that cumulative damage could occur in patients treated with oral corticosteroids, often because the tolerable dose of corticosteroids is too low to attain adequate inflammatory control. The 0.59-mg fluocinolone acetonide device is estimated to last approximately 30 months. The patient may not have achieved disease quiescence at 30 months. In all instances, physicians should constantly bear in mind the goal of avoiding cumulative damage and should provide additional treatments, such as implanting a second sustained-release device, in order to achieve this goal.
The Last Words
The management of chronic uveitis is challenging because of its protean etiologies as well as its manifestations both ocular and systemic. We know that chronic inflammation, regardless of grade, can lead to cumulative damage that eventually causes significant visual loss. It would be beneficial to patients with chronic uveitis for ophthalmologists to recognize recurrent inflammation before cumulative damage occurs so that appropriate therapy, systemic medications or use of sustained-release devices can be initiated in a timely manner. Being aware of the detrimental effects of cumulative damage and the principle of "zero tolerance to any degree of inflammation" will enable the ophthalmologist to help preserve the vision of many patients with uveitis.
References
1. Suttorp-Schulten MS, Rothova A. The possible impact of uveitis in blindness: a literature survey. Br J Ophthalmol. 1996;80(9):844-848.
2. Durrani OM, Tehrani NN, Marr JE, Moradi P, et al. Degree, duration, and causes of visual loss in uveitis. Br J Ophthalmol. 2004;88(9):1159-1162.
3. Baarsma GS. The epidemiology and genetics of endogenous uveitis: a review. Curr Eye Res. 1992;11(suppl):1-9.
4. Darrell RW, Wagener HP, Kurland LT. Epidemiology of uveitis: incidence and prevalence in a small urban community. Arch Ophthalmol. 1962;68:502-514.
5. Rothova A, Suttorp-van Schulten MSA, Treffers WF, Kijlstra A. Causes and frequency of blindness in patients with intraocular inflammatory disease. Br J Ophthalmol. 1996;80(4):332-336.
6. Dana MR, Merayo-Lloves J, Schaumberg DA, Foster CS. Prognosticators for visual outcome in sarcoid uveitis. Ophthalmology. 1996;103(11):1846-1853.
7. Jabs DA. Treatment of ocular inflammation [editorial]. Ocul Immunol Inflamm. 2004;12(3):163-168.
8. Vitale AT, Foster CS. Corticosteroids. In: Foster CS, Vitale AT, eds. Diagnosis and Treatment of Uveitis. Philadelphia, PA: WB Saunders; 2002:142-157.
9. Jaffe GJ, Martin D, Callanan D, Pearson PA, et al, for the Fluocinolone Acetonide Uveitis Study Group. Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: thirty-four-week results of a multicenter randomized clinical study. Ophthalmology. 2006;113(6):1020-1027.
10. Jaffe GJ, Martin D, Callanan D, Levy B, Comstock T, for the Fluocinolone Acetonide Study Group. Fluocinolone acetonide intravitreal implant for the treatment of uveitis affecting the posterior segment: 3-year results of a randomized, dose-masked, multi-center clinical trial. Paper presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology; April 30-May 4, 2006; Fort Lauderdale, FL.
11. Nguyen QD, Callanan D, Dugel P, Godfrey DG, et al. Treating chronic noninfectious posterior segment uveitis: the impact of cumulative damage. Proceedings of an expert panel roundtable discussion. Retina. October 2006:(suppl):1-16.
Author Disclosure
Dr. Nguyen is a member of the Uveitis Advisory Board for Bausch & Lomb, Inc. Arrangements for his participation on the Advisory Board were approved by the Office of Policy Coordination at Johns Hopkins University. The views expressed by Dr. Nguyen in this article do not constitute or imply endorsement by the Johns Hopkins University, the Johns Hopkins Hospital, or the Johns Hopkins Health System.