Abstract
Uveitis, defined as an intraocular inflammatory disease, is one of the main causes of visual impairment in the working-age population. The condition often coexists with other immune-mediated inflammatory diseases (IMID) and greatly contributes to reduced quality of life (QOL) in affected individuals. While visual acuity remains the most commonly used measure of visual function in patients with uveitis, the US National Eye Institute Visual Function Questionnaire is frequently used to assess their health-related QOL. However, despite intuition that coexisting uveitis might exaggerate already impaired QOL in patients with IMID, specific questions related to their visual functioning are rarely included in clinical trials or assessed in daily practice. We provide an overview of the occurrence and significance of uveitis in patients with IMID, its consequences, and the role of tumor necrosis factor-α inhibitors in overall treatment approaches.
Uveitis refers to inflammation of the vascular coat of the eye1. It can affect anterior (iris and ciliary body) or posterior (vitreous, choroid, or retina) segments2. Painful red eye, visual blurring, and photophobia are common presentations of anterior uveitis. In addition, the affected eye may be miotic and have an abnormal pupillary response to light. The redness is concentrated at the limbus and radiates outward (Figure 1). Patients with uveitis report markedly poorer visual functioning and overall health status compared to healthy subjects, which contributes to severely impaired quality of life (QOL)3. Further, severe uveitis often requires systemic treatment with corticosteroids and other antiinflammatory agents, whose side effects might compound the reduction in health-related QOL (HRQOL). Occurring at a younger age (Figure 2) than other common eye-related diseases such as glaucoma, age-related macular degeneration (AMD), and cataracts, uveitis is also associated with high social and economic costs1,4. Thus, in addition to visual function assessment, HRQOL measures should be performed as part of regular followup in these patients to obtain a full understanding of the effects of the disease and its therapies on patient well-being.
PREVALENCE, INCIDENCE, AND CONSEQUENCES
The average annual incidence of uveitis has been reported as approximately 52.4/100,000 person-years5. The total population prevalence of uveitis is 115.3/100,000 persons.
Uveitis is an important cause of visual loss in the developed world, accounting for approximately 10% of the causes of blindness1,6,7. Of 582 patients seen at 2 Dutch referral centers, 203 (35%) exhibited blindness or visual impairment8. Cystoid macular edema was the most common complication implicated in both blindness (29% of cases) and visual impairment (41% of cases). In a more recent study that included 561 consecutive patients with uveitis in the United Kingdom, visual loss was found in almost 20% of patients4. Further, patients over 60 years of age and those with a history of cataract surgery were more likely to lose vision than other patient subgroups. Vision loss was less likely in patients with acute anterior uveitis4. Although the results of the latter study indicated that the proportion of blindness caused by uveitis might be declining, likely due to improvement in diagnosis and treatment, a significant number of patients managed in tertiary-care centers still experience visual loss at some point during the course of the disease7.
CAUSES AND COMORBIDITIES
A variety of conditions can be associated with uveitis, including infections, immune-mediated diseases, and ocular and masquerade syndromes9. Anterior uveitis is also one of the syndromes associated with HLA-B2710. Suspected immune-mediated causes of uveitis include ankylosing spondylitis (AS)11,12, Behçet’s disease (BD)13, inflammatory bowel disease14,15, juvenile idiopathic arthritis16, reactive arthritis11, and psoriatic arthritis12.
It is estimated that 20%–40% of patients with AS experience uveitis at some time during the course of their disease11. The reported prevalence of uveitis in patients with inflammatory bowel disease varies from 2% to 10%14,15. Uveitis occurs in 60%–80% of patients with BD13,17. Severe visual impairment has been reported in up to 38% of a subset of patients with juvenile idiopathic arthritis, with uveitis being one of the main contributors16.
OBJECTIVE MEASURES OF VISUAL FUNCTION AND THEIR LIMITATIONS
Visual acuity (VA) is often the only measure of visual function routinely assessed in patients with uveitis. However, VA alone may not adequately describe visual performance, which can be further influenced by other measures of visual function, including contrast sensitivity, visual field, and color vision18. Measurements of VA are also dependent on time of day, examiner’s experience, lighting, and patient effort. Thus, traditional clinical assessments of vision, such as Snellen VA and the Early Treatment of Diabetic Retinopathy Study chart, may fail to reveal many aspects of visual disability that are identified by patients as important for their daily functioning and overall well-being. To that end, alternative objective measures of visual function are utilized. The Pelli-Robson chart, for example, is often used to determine the contrast required to read large letters of the same size19. Fluorescein angiography, a technique for examining the circulation of the retina using a dye tracing method, allows detection of common complications of uveitis such as cystoid macular edema (Figure 3). This method involves injection of sodium fluorescein into an arm or hand vein. Following this, photographs of the retina are taken to determine circulatory and structural abnormalities. Cystoid macular edema or swelling in the center of the retina can also be detected with optical coherence tomography (Figure 4). This noninvasive imaging technique gives a cross-sectional image of the retina.
HRQOL MEASURES USED IN UVEITIS
The National Eye Institute Visual Function Questionnaire (NEI VFQ) and its short-form version, NEI VFQ-25, are intended to measure vision-specific QOL in individuals with visual impairments20,21. The instrument consists of the following vision-related subscales: overall vision, difficulties with near-vision activities, limitation in social functioning, dependency on others, mental health problems, driving difficulties, limitation with peripheral and color vision, and ocular pain. The tool was originally developed for use in patients with 5 specific eye diseases: age-related macular degeneration, diabetic retinopathy, cytomegalovirus retinopathy, glaucoma, and cataracts. Schiffman, et al22 applied the NEI VFQ-25 along with the Medical Outcomes Study Short-Form 36 to measure HRQOL in 76 patients with uveitis. The overall NEI VFQ and both physical and mental component summary scores were significantly lower among patients with uveitis compared to the general US population. As the 2 instruments used in this study provided complementary information on patient function, the authors suggest that both should be used in patients with uveitis to measure the effect of the disease and its therapy on QOL. It is also important to note that some disease-specific HRQOL instruments, such as that used in BD, include vision-related questions23. On the other hand, questionnaires used to assess HRQOL in patients with AS (i.e., Evaluation of Ankylosing Spondylitis Quality of Life) generally do not include specific questions related to visual function24.
EFFICACY OF ANTI-TUMOR NECROSIS FACTOR AGENTS IN THE OVERALL MANAGEMENT OF IMID-RELATED UVEITIS
Tumor necrosis factor (TNF) inhibitors are often used to treat IMID that are associated with episodes of uveitis, e.g., AS25. Some evidence suggests that inhibition of TNF reduces recurrence of uveitis in this patient population25,26,27. In a metaanalysis that included 4 placebo-controlled trials (2 with infliximab and 2 with etanercept) and 3 open-label studies, reduction in uveitis was slightly more marked among patients treated with infliximab26; however, the difference was not significant. Similarly, infliximab appears to be more effective than etanercept in treating uveitis associated with JIA28. In a multicenter, open-label study that involved 1250 patients with active AS, adalimumab treatment reduced the rate of uveitis by 51%. The reduction was even more pronounced in patients with a history of uveitis (58%; Table 1)28. However, none of the studies with anti-TNF inhibitors included specific questions related to visual outcomes and their influence on HRQOL.
CONCLUSION
As a common IMID-related comorbidity, uveitis presents a significant burden to patients and society. However, its influence on HRQOL in this patient population has yet to be fully appreciated. One reason is that objective measurements of visual acuity do not completely assess visual function. Further, specific tools that assess visual function and QOL are underutilized in patients with IMID. In order to comprehensively assess HRQOL in these individuals, generic, disease, and vision-specific QOL measures should be used. The TNF inhibitors adalimumab and infliximab have been proven effective in decreasing the incidence of IMID-related uveitis, particularly that related to AS. However, the effect of TNF inhibition on visual function in these patients remains to be confirmed.
Footnotes
-
Supported by an unrestricted grant provided by Abbott Canada. Dr. Rosenbaum has received research grants for clinical trials from Abbott, Centocor, Bausch and Lomb, Eyegate, Celgene, Lux, and Genentech; and has been a consultant for Abbott, Amgen, Lux, ESBA Tech, Xoma, Glaxo, and Pfizer. Dr. Russell has received consultant fees from Amgen/Wyeth, Schering-Plough, UCB, and Abbott Canada, and speaking fees from Roche and BMS. Dr. Guenther has acted as consultant for Abbott Laboratories, Amgen Canada, Galderma Canada, LEO Pharma, Janssen, Schering-Plough Canada, and Wyeth, received investigator-initiated study support from Astellas Pharma Canada, and contract research support from Abbott Laboratories, Amgen Canada, Astellas Pharma Canada, Celgene Corporation, Centocor Ortho Biotech, EMD Serono Canada, Galderma Canada, Isotechnika, Janssen-Ortho, LEO Pharma, Novartis Pharmaceuticals Canada, Pfizer, Schering-Plough Canada, and Stiefel Laboratories.