There have been many significant advances in our understanding, diagnosis, and treatment of ocular inflammatory disease in recent years. Treatment paradigms for noninfectious uveitis have shifted toward immunomodulatory therapies that have been shown to both improve outcomes and reduce adverse events. The role of pathogenic organisms such as cytomegalovirus (CMV) in uveitic syndromes such as glaucomatocyclitic crisis has also had a significant impact on the way in which these patients are treated and their disease prognosis. In spite of advances such as these, the last 30 years have not seen a significant decrease in the prevalence of blindness in patients with uveitis.1 Therefore, the need for further study in the field, including prospective studies and those involving large cohorts of patients, remains significant. In the 2011–2012 academic year, several important studies have been published that may again challenge our current understanding of ocular inflammatory disease and the way in which it is treated. Studies of the pathogenic mechanisms of recurrent toxoplasmosis and its treatment offer promising results, whereas other studies on alternative diagnostic modalities for ocular sarcoidosis may prove helpful in making a sometimes elusive diagnosis. Of note, the Multicenter Uveitis Steroid Treatment (MUST) study group released several articles, offering insights on areas such as macular edema and hypotony derived from a large, prospective clinical trial.
This review includes a select group of English language articles listed in PubMed and published between July 1, 2011, and June 30, 2012. Particular consideration was given to randomized, controlled clinical trials and analyses of larger cohorts; however, smaller studies and case reports involving new aspects of treatment/diagnosis or expanding the understanding of disease processes were also included.
SYSTEMIC IMMUNOSUPPRESSIVE THERAPY FOR EYE DISEASES STUDY
Treatment of chronic, noninfectious ocular inflammation may involve the use of systemic immunosuppressive medications (IMTs). In fact, early institution of these medications in certain diseases can be essential to good outcomes; however, ophthalmologists may be hesitant to start these medications because of perceived risks including cancer, serious infection, and death. The Systemic Immunosuppressive Therapy for Eye Diseases (SITE) study is a retrospective cohort study involving approximately 8000 patients with noninfectious ocular inflammation from 5 different subspecialty referral centers in the United States. To date, the study has focused on whether immunosuppressive therapy increases mortality in patients with ocular inflammatory disease, its effectiveness in controlling inflammation, its corticosteroid sparing effect, and the incidence of adverse events.
In the initial report from the SITE study,2 the group found no increased risk for overall or cancer-related mortality in patients with ocular inflammation compared to the general US population (total of 936 deaths, 230 attributable to cancer). Similarly, there was no statistically significant difference in the overall or cancer-related mortality between patients treated with immunosuppressive therapy and those who were not. [Overall mortality rate: standardized mortality rate (SMR) = 1.04; 95% confidence interval (CI), 0.93-1.16 for IMT treated; SMR = 1.02; 95% CI, 0.94–1.11. Cancer-related mortality: SMR = 1.03; 95% CI, 0.80–1.31 with IMT; SMR = 1.10; 95% CI, 0.93-1.29.] The authors did note a suggestion of increased cancer-related mortality with both alkylating agents and biologic agents compared with those who did not receive such treatment, although the difference was not statistically significant.
Hypotony in Uveitis
In one analysis of this cohort, Daniel et al3 looked at the prevalence, incidence, and risk factors for low intraocular pressure (<8 mm Hg) and hypotony (<5 mm Hg). Of 6545 patients with uveitis studied, 189 eyes of 161 patients (approximately 2.5%) presented with hypotony at cohort entry. Most of these eyes carried a primary diagnosis of panuveitis (prevalence, 4.8%). Hypotony at presentation was strongly associated with poor visual acuity (84% ≤ 20/200). Patients with hypotony at presentation were also more likely to have had cataract surgery [adjusted odds ratio (aOR), 10.69] or glaucoma surgery (aOR, 2.61) than those without hypotony on entry to cohort. Similar results were seen with pars plana vitrectomy (aOR, 2.76). These eyes also showed more evidence for past and currently active inflammation than eyes without hypotony. Similar associations were found for patients with low intraocular pressure (IOP) at presentation.
The incidence of hypotony was 0.006 per person-year (95% CI, 0.005–0.007). Younger age was a risk factor for developing hypotony with children younger than 18 years [adjusted hazards ratio, (aHR), 2.92] and young adults 18 to 25 years old (aHR, 2.27) more likely to develop hypotony than adults 26 to 35 years old. Interestingly, systemic hypertension carried an increased risk of hypotony (aHR, 2.04). As with the prevalence analysis, panuveitis was associated with an increased risk of hypotony over other types of uveitis (aHR, 1.25). As might be expected, a longer duration of inflammation before study entry (≥5 years) was associated with a 3-fold higher risk of hypotony than newly diagnosed cases (≤6 months). Signs of current inflammatory activity such as vitreous haze/cell, exudative retinal detachment, band keratopathy, and posterior synechiae were associated with an increased risk of developing hypotony. A history of prior cataract surgery carried with it a 7.5-fold higher risk of incident hypotony (aHR, 7.51) even outside the first postoperative month. Importantly, although the relative risk of hypotony was higher for those who underwent cataract surgery, the absolute risk of hypotony was low (1.7%/eye-year). Kaplan-Meier analysis estimated the median recovery time (IOP ≥ 5 mm Hg for at least 30 days) as 0.94 years. By 1 year, approximately 50% could be expected to demonstrate recovery. Grade 2+ or worse anterior chamber cell (88.9% recovered) was a positive predictor of recovery.
Thus, although hypotony was uncommon in this population, it was associated with significant visual morbidity. Younger patients and those with a prior history of intraocular surgery were at a higher risk of hypotony. The authors state that phacoemulsification may be preferable as a method for cataract surgery because the risk of hypotony was lower than for other methods (5-fold risk vs 7.5-fold risk). The findings also support the idea that increased severity and longer duration of inflammation are associated with an increased risk of hypotony. Anterior segment inflammation, similarly, seemed to be a significant cause of hypotony.
Relapse in Anterior Uveitis
In another analysis from the same cohort, Grunwald et al4 analyzed 102 patients seen within 90 days of their first-ever episode of anterior uveitis. The study had a cumulative 165 person-years of follow-up with a median follow-up of 291 days. Most patients were white, female nonsmokers 35 years or older.
At 1.5 years after remission of the initial episode, almost 40% relapsed, with an incident risk of 24% per person-year. Further analysis suggested that the risk may decrease in patients still free of relapse at 2 years. Younger age was associated with a greater risk of relapse, with those 18 to 34 years old having an almost 3-fold higher risk of relapse than patients 35 to 54 years old. Contrary to previous studies, smoking status, human leukocyte antigen-B27 antigen positivity, and presence of spondyloarthropathy were not associated with higher relapse risk. These results were surprising, but the authors acknowledged that they could not rule out more moderate increases in relapse risk. Sarcoidosis was associated with a higher relapse risk, although the results were not statistically significant (although the overall number of patients with systemic disease in the study was low, so the risk may be underestimated). The results suggest close follow-up of patients after their first episode of anterior uveitis is prudent, especially during the first 2 years when risk of relapse was highest.
Effectiveness and Complications of Systemic Corticosteroids
Charkoudian et al5 sought to examine the effectiveness and complication risk of high-dose intravenous (IV) corticosteroids.
One hundred four eyes of 70 patients received IV methylprednisolone (at least 500 mg IV) while their inflammation was active. Approximately one third of patients carried a diagnosis of panuveitis. More than half of the patients achieved complete control (57%), and 82%, near-complete control by 1 month after treatment. White patients (aOR, 2.82) and patients with uveitis (aOR, 3.80) were more likely to have control of inflammation with IV methylprednisolone. Interestingly, the dosage of IV methylprednisolone did not significantly affect the likelihood of control of inflammation. Although this may have been due to selection bias with high dosages being administered to more severe patients, it is also possible that the traditional dosage of 1 g of IV methylprednisolone is not necessary in all cases. Measures of vitreous haze and cell improved less than those of anterior cell (85%) possibly reflecting the increased time necessary for clearance from the vitreous gel compared with the anterior chamber. High-dose IV steroids were less successful in achieving significant improvement with panuveitis than other forms of inflammation (62% vs 100%). Use of immunomodulatory therapy was not associated with a difference in time to complete control of inflammation (P = 0.4) or near-complete control of inflammation (P = 0.94). Reassuringly, no increase in ocular complications, including increased ocular hypertension, was noted 1 month after treatment. A single event of colon perforation was noted; however, other significant adverse effects were not noted. The proportion of patients with visual acuity of 20/40 or greater increased from 35% to 48% 1 month after treatment.
Although it might be expected that pulsed IV corticosteroid therapy would have little long-term effect on hyperglycemia, the expectation is altogether different when oral steroids are used over time. When data from patients in the cohort who took oral steroids were analyzed,6 1.21% initiated treatment with hypoglycemic medications during the 12 months after, compared with 0.19% of those who did not take oral steroids (relative risk [RR], 4.39). In fact, the relative risk was higher with higher doses of prednisone: initial dose 40 mg or less daily (RR, 3.23), compared with doses 40 mg or more daily (RR, 5.51). Older patients were more susceptible than younger patients (RR, 1.46/10 years of increasing age), as were African American patients (aRR1.942.946.95). The absolute risk remained low in the cohort (1.8%), which was encouraging. The authors estimated that approximately two thirds of patients who began treatment with hypoglycemic medications were able to stop within a year (Kaplan-Meier estimate, 62.7%). Given the low absolute risk and the risk factors outlined in the article, routine laboratory evaluation of patients on oral corticosteroids may not be necessary except in at-risk individuals.
THE MULTICENTER UVEITIS STEROID TREATMENT TRIAL
Fluocinolone Implant Versus Systemic Immunosuppressive Therapy for Uveitis
The MUST is a randomized, controlled clinical trial designed to evaluate the relative superiority of 2 treatments for uveitis: the fluocinolone acetonide implant (Retisert; Bausch & Lomb, Rochester, NY) and systemic therapy with corticosteroids and/or immunosuppressive therapy. Researchers enrolled 255 patients (479 eyes) with noninfectious intermediate, posterior, or panuveitis from centers in the United States, Australia, and the United Kingdom. Patients were followed up for at least 24 months with the main outcome measures of change in best-corrected visual acuity from baseline and secondary outcomes of uveitis activity, patient-reported quality of life, and adverse effects/complications of therapy.
At 24 months,7 eyes in the implant group showed a greater gain in visual acuity (+6.0 letters vs +3.2 letters), although the difference was not statistically significant. A substantial gain in best-corrected visual acuity (≥15 letters) was noted in 21% of the implant group and 13% in the systemic therapy group. Both groups reported an increase in vision-related quality of life with a greater improvement in the implant group (+11.4 vs +6.8, P = 0.043). The improvement was also more rapid in the implant group with a greater improvement at 6 months, although the effect was equalized between both groups at 24 months. Patients in the implant group had more frequent control of uveitis (88% vs 71% at 24 months, P = 0.001) and more favorable rate of vitreous haze improvement (HR, 1.47; P = 0.014). Likewise, in the immediate term (6 months), the implant group had fewer patients with macular edema, but the difference was not significant at 24 months. There was a 4-fold higher rate of elevated IOP of 10 mm Hg or greater, absolute IOP of 30 mm Hg or greater, and requirement of glaucoma surgery in the implant group. Glaucoma developed in 17% of implanted eyes within 24 months (HR, 4.2; P = 0.001) versus 4% in the systemic treatment group.
The cumulative 24-month risk of developing a cataract was higher in the implant group (91% vs 45%) with a significant portion requiring cataract surgery (80% vs 31%). The risk of other ocular complications, including hypotony, retinal detachment, and infectious endophthalmitis was low and not significantly different between groups.
The systemic group had a greater risk of infections requiring prescription antibiotic therapy (0.60 events/person-year vs 0.36 events/person-year). The rate of hospitalizations was not significantly different, and adverse event reporting did not suggest long-term unfavorable outcomes in these patients.
The data suggest that both treatments are effective for control of inflammation and improvement of vision, although control of inflammation may be more rapid and occur more often in patients treated with the implant. There was a higher rate of ocular complications with significant rate of cataract formation and IOP elevation, whereas systemic therapy carried an increase risk of systemic infection. The authors suggest that choice of therapy would depend on the risks and benefits of each in individual patients.
Although the primary aim of the MUST trial was to compare the effectiveness and adverse events of 2 treatments for uveitis, additional analyses of this cohort have yielded other important information.
Defining a Clinically Significant Change in Retinal Thickness in Uveitic Macular Edema
Macular edema is a common complication of uveitis and a significant cause of visual morbidity. Although studies evaluating uveitic macular edema have benefitted greatly from the advent of optical coherence tomography, outcomes reported have generally been linked to resolution or improvement in macular thickness. Using the MUST cohort, Sugar et al8 aimed to identify a threshold for percent change in retinal thickness that correlates with a clinically significant change in visual acuity. Macular edema was defined as greater than 260 μm thickness of the central retinal subfield by optical coherence tomography (OCT). Based on previously published research, the authors defined a more-than-10-letter change in visual acuity as clinically significant. The authors determined that a 20% improvement in retinal thickness was 77% sensitive and 75% specific for a more-than-10-letter gain in visual acuity. Patients with a 20% or more improvement in retinal thickness had a mean 11-letter improvement in visual acuity (95% CI, 7.7–14.3).
For clinical trials evaluating uveitic macular edema, using a 20% change in retinal thickness provides a clinically significant reference point for outcomes. Given that there were few patients in the study with retinal thickness of greater than 600 μm, the results are only applicable to eyes with less than 600 μm central retinal thickness.
Uveitic Macular Edema and Visual Function
Although the effects of macular edema on visual acuity are well accepted, recent studies have also demonstrated its effect on central visual field as measured by microperimetry. OCT has allowed better qualitative and quantitative assessment of macular edema compared with fluorescein angiography. The presence of macular cysts and macular thickening are readily evident and measured by OCT, but the relationship of the characterization to visual function is not as clear. Are all types of macular edema the same or do some types affect visual function more than others?
In an analysis of 426 eyes of the MUST cohort, Taylor et al9 characterized macular edema as diffuse macular edema, cystoid spaces alone, or cystoid macular edema. Ten percent of eyes had diffuse macular edema (center point thickness > 240 μm without cystoid spaces), 13% had cystoid spaces alone, and 25% had cystoid macular edema (center point thickness > 240 μm and cystoid spaces on OCT). Macular thickening was associated with poorer baseline visual acuity than cystoid changes alone (P < 0.01). Vision was almost 4 times worse in the group with cystoid macular edema (CME) than other groups. They also had double the proportion of patients with visual impairment (≤20/50) and severe visual impairment (≤20/200). Macular thickening of greater than 240 μm was associated with decreased vision (−8.8 letters, P < 0.01), but cystoid spaces alone were not.
Although uveitis itself was associated with decreased visual field sensitivity, eyes with macular thickening had lower sensitivity (P = 0.03). The presence of cysts and/or retinal thickening was associated with greater central visual field impairment (OR, 1.7; P < 0.01).
The authors suggest that macular thickening is a better predictor of decreased visual acuity than presence of macular cysts and therefore may be a better outcome for clinical trials assessing uveitic macular edema and for the clinical management of uveitic macular edema. Moreover, the finding that uveitis and CME can affect central visual field sensitivity should be considered when evaluating patients with abnormal visual fields and ocular hypertension or glaucoma.
Hypotony in Uveitis
Similar to researchers using the SITE cohort, the authors of another study10 sought to evaluate the prevalence of hypotony in patients with severe forms of uveitis.
Of 240 patients, 20 (8.3%) had hypotony (≤7 mm Hg at baseline evaluation or ≤9 mm Hg at baseline with a history of hypotony). Patients with a longer duration of uveitis (≥5 years; OR, 5.0; P < 0.01), patients with a history of ocular surgery (OR, 3.1; P = 0.03), and nonwhite patients (white patients; OR, 0.1; P < 0.01) were more likely to have hypotony. Moreover, patients with a younger age at onset of uveitis also were more likely to have hypotony, although it is unclear if this was colinear with duration of uveitis.
Patients with hypotony were approximately 23 times more likely to have visual impairment of 20/50 or worse (P < 0.01). Patients with pars planitis had greater risk of hypotony (OR18.104.22.168, P = 0.04), as did eyes exhibiting 1+ or greater grade flare in the anterior chamber (OR, 6.1; P < 0.01). Other signs of inflammation, including peripheral anterior synechiae, iris abnormalities, and angle closure were also associated with greater odds of hypotony.
Hypotony can be devastating in these eyes, and the study seems to confirm what was already understood among many uveitis specialists, namely, that hypotony is associated with poorer vision, longer duration of inflammation, and more severe inflammation. The prevalence of hypotony was higher than in the SITE cohort; however, this may be due to the nature of uveitis types included in the MUST cohort (more severe) or the broader definition of hypotony. Given the scarcity of good options for treating hypotony, avoidance through good control of inflammation seems most prudent.
EPIDEMIOLOGY OF UVEITIS
Researchers at the Mayo Clinic analyzed a large database of patients from the Rochester Epidemiology Project that encompasses more than 90% of medical encounters and greater than 96% of hospitalizations over 20 years for local residents of Olmstead County, Minnesota.11 The incidence rate of white dot syndromes was 0.45/100,000 per year (95% CI, 0.19–0.71). The authors found patients with acute posterior multifocal placoid pigment epitheliopathy, multiple evanescent white dot syndrome, multifocal choroiditis with panuveitis, and punctate inner choroidopathy, but no cases of serpiginous choroidopathy, birdshot choroidopathy, or acute zonal occult outer retinopathy. Multiple evanescent white dot syndrome was more common in females, acute posterior multifocal placoid pigment epitheliopathy in males. In addition, half the patients with acute posterior multifocal placoid pigment epitheliopathy and the only patient with punctate inner choroidopathy had psoriasis, suggesting a possible connection between white dot syndromes and systemic disease (although the number of patients in this study was too small for the association to reach statistical significance).
Although uveitis has long been thought to be a disease of working age persons, recent studies have shown that uveitis is a significant problem in elderly patients as well. The clinical characteristics of primary uveitis in the elderly are described in an article from Lyon, France.12 Of 302 patients with newly diagnosed uveitis, 91 (30.1%) patients were older than 60 years, with a mean age of 70 years. Panuveitis occurred most commonly (41.7%), followed by anterior (22.0%), posterior (20.9%), and intermediate (8.8%) uveitis. The most common diagnosis was sarcoidosis (37.4%) and idiopathic uveitis (36.3%). Both panuveitis and sarcoidosis occurred more commonly in elderly patients than in younger patients.
The Aravind Comprehensive Eye Survey Research Group reports the prevalence of uveitis in Tamil Nadu, Southern India.13 Crude and age-adjusted rates of endogenous uveitis were 310/100,000 and 317/100,000. The ratios for ocular inflammation were 450/100,000 and 467/100,000. Interestingly, the prevalence of uveitis in older patients was higher than in younger patients, and more men than women were affected. High rates of vision loss were associated with postsurgical endophthalmitis and posterior uveitis. In the population studied, 0.3% of individuals 40 years and older had had an episode of uveitis.
CHARACTERIZATION OF UVEITIS
Wensing et al14 analyzed the clinical characteristics and visual prognosis of 106 patients with anterior uveitis due to rubella or herpes viruses. Most patients had unilateral disease (80%–97%). Rubella anterior uveitis occurred in younger patients, had a more chronic course, and was more likely to be associated with early cataract formation and diffuse iris atrophy. Moreover, 23% of these eyes were heterochromic. Uveitis associated with herpes simplex virus or varicella zoster virus occurred in older patients, had a more acute course, was more likely associated with focal/sectoral iris atrophy, and more likely to have redness, corneal edema, a history of keratitis and posterior synechiae. Patients with rubella virus and varicella zoster virus were more likely to have vitritis and focal chorioretinal scars than patients with herpes simplex virus. Intraocular pressure greater than 30 mm Hg occurred in 25% to 50% and 18% to 30% developed glaucoma.
Oltra et al15 described the clinical presentation and treatment of 3 patients with uveitis and common variable immunodeficiency. All patients had bilateral chronic anterior uveitis, 2 granulomatous, and 1 nongranulomatous. Two patients needed systemic immunomodulatory therapy for control; the other needed topical steroids only. In 2 patients, sarcoidosis could be considered a codiagnosis because of elevated angiotensin converting enzyme, hilar adenopathy, or systemic granulomas. Given that autoimmune disorders have been reported as the first sign of common variable immunodeficiency, ophthalmologists should elicit a history of recurrent infections to aid in diagnosis.
Chronic inflammatory disease and cytokine abnormalities may have a role in depression. Patients with chronic inflammatory diseases including rheumatoid arthritis and systemic lupus erythematosus have been shown to have higher risks for depression. Is the same true for ocular inflammation? What are the factors that might be associated with depression in these populations? Qian et al16 administered questionnaires to assess levels of depression and visual function to 104 patients with ocular inflammatory diseases. More than a quarter of patients (26.9%) had a positive screen for depression by the Beck Depression Inventory II, higher than the 10% found in the general population. Surprisingly, almost 40% of those who screened positive had not been diagnosed with depression previously. Visual function scores, measured by National Eye Institute-Visual Functioning Questionnaire 25, were significantly lower in those patients who screened positive for depression. Patients in the depressed group were more likely to have chronic inflammation, have bilateral disease, have used corticosteroids, and have a history of using multiple immunosuppressive. Almost half of the depressed patients felt that an ocular inflammatory disease support group would be helpful to them. Patients who self-reported receiving adequate emotional support were 11 times less likely to screen positive for depression. Thus, uveitis may be associated with depression, often unrecognized, and should be screened for in this population.
Sarcoidosis is a multisystem idiopathic inflammatory disorder that may involve the eyes in ways ranging from dry eye to uveitis. Definitive diagnosis is through demonstration of noncaseating epithelioid granulomas in tissue biopsy. In case of ocular involvement without significant systemic signs, definitive diagnosis can be difficult. In fact, a consensus statement from the first International Workshop on Ocular Sarcoidosis developed several categories of diagnosis including definitive, presumed, probable, and possible with varying degrees of histologic evidence, clinical signs, and laboratory investigations. In cases of pulmonary involvement, cytology from bronchoalveolar lavage has been shown to be helpful in the diagnosis: increased CD4 TH1 lymphocytes and a CD4/CD8 ratio of greater than 3.5 can be helpful in cases when histology is absent or unavailable.
In their study, Kojima et al17 examined the vitreous and peripheral blood lymphocyte subsets of patients with ocular sarcoidosis to determine the diagnostic utility of the CD4/CD8 ratio in these patients. Fifty-one eyes of 38 patients with ocular sarcoidosis were diagnosed by laboratory investigations, clinical signs, and histologic evidence by tissue biopsy and classified according to International Workshop on Ocular Sarcoidosis criteria: definite (15 patients), presumed (11 patients), and probable (12 patients). The mean CD4/CD8 ratio in patients with ocular sarcoidosis was 40.7 from vitreous samples and 3.0 from peripheral blood. This was significantly higher than in the nonsarcoid group (vitreous 2.0, P < 0.001; peripheral blood 2.0, P < 0.0163). In patients classified as definite ocular sarcoidosis, the ratio in the vitreous was 70.0, and in the peripheral blood, it was 2.7. Patients with a diagnosis of presumed and probable sarcoidosis had lower ratios for the vitreous than the definite sarcoidosis group, but similar ratios for peripheral blood. In addition, the vitreous CD4/CD8 ratio was significantly higher than the ratio in the peripheral blood in patients with ocular sarcoid (P < 0.001) but not in nonsarcoid patients. All told, a vitreous CD4/CD8 ratio of greater than 3.5 was 100% sensitive and 96.3% specific, higher than that for bronchoalveolar lavage (53% sensitive and 94% specific).
Further evidence of the utility of diagnostic vitrectomy in cases of ocular sarcoidosis was found in a report of vitreous biopsies from 2 patients with uveitis.18 Matsuoka et al18 describe 2 patients, a 56-year-old man with bilateral iridocyclitis, vitreous opacities, and optic neuritis and a 77-year-old man with bilateral vitreous opacities and optic neuritis, with strongly suggestive ocular findings and no systemic sarcoid findings. In each, epithelioid and multinucleated giant cells without necrosis were found on vitreous biopsy. In both patients, a diagnosis of sarcoidosis was made and treatment with corticosteroids resulted in improvement of visual acuity to 20/20.
Similarly, Kinoshita et al19 examined the vitreous removed by pars plana vitrectomy from 7 patients with vitreous inflammation in whom sarcoidosis was in the differential diagnosis. In all cases, lymphocytes and epithelioid cells with an absence of necrosis in the background were noted. In 85.7%, multinucleated giant cells were found. Taken together, the studies show the value of cytologic analysis of the vitreous specimens in establishing the diagnosis in patients suspected of having ocular sarcoidosis.
Toxoplasma gondii, an obligate intracellular parasite, is a leading cause of uveitis in many parts of the world and can be a significant cause of ocular morbidity. Characterized by a retinochoroiditis, ocular toxoplasmosis may occur long after initial infection with reactivation of ocular lesions not uncommon. Recurrence of ocular lesions typically occurs at the border of old lesions and is thought to be due to the rupture of cysts releasing tachyzoites into the surrounding tissues, inducing necrosis and inflammation. Still, some have observed new lesions arising some distance from older lesions: at odds with local tissue cyst rupture theory of recurrence. In 2 studies of Brazilian patients with ocular toxoplasmosis, analysis of blood samples suggested the presence of free tachyzoites (parasitemia) in the blood of acute and chronically infected patients.
Silveira et al20 confirmed the presence of T. gondii in the blood of both acutely infected individuals (as diagnosed by serologies) and chronically infected individuals with recurrent choroiditis using light microscopy, direct immunofluorescence, and polymerase chain reaction (PCR). Patients in their study with +IgG antibodies and inactive scars, +IgG without scars, and IgG− and IgM− controls did not have evidence of tachyzoites in the peripheral blood.
A second study by Mattos et al21 of 184 immunocompetent patients (49 with ocular toxoplasmosis by clinical factors and 135 with other ocular conditions) analyzing samples by conventional PCR, real-time PCR, indirect immunofluorescence, avidity test, and epithelial specific antigen-ELISA also showed a difference in PCR positivity between patients with ocular signs of toxoplasmosis and those without. Almost 41% of patients with ocular toxoplasmosis by clinical examination had +PCR for T. gondii, whereas none of those with other ocular disease did, including those with asymptomatic toxoplasmosis. Almost one fourth of patients with ocular toxoplasmosis showed high titers of anti-epithelial specific antigen antibodies, found in patients actively infected with toxoplasmosis.
Both studies suggest that parasitemia may be associated with ongoing disease.
Parasitemia would help to explain 2 findings: the presence of new lesions distant from old lesions and the effect of trimethoprim/sulfamethoxazole (which is not effective against the local encysted form) in preventing recurrent disease.
Although excellent systemic treatments for toxoplasma retinochoroiditis exist, there are instances in which a localized therapy may be more desirable. Pregnant patients, for example, may be excluded from treatment because of potential effects on the fetus. Indeed, adverse effects of the traditional medication regimen itself (pyrimethamine, sulfadiazine, systemic corticosteroids), including leucopenia and thrombocytopenia, can pose significant risks to the patient. In addition, several reports of successful outcomes with local intravitreal administration of clindamycin have previously been published, but to date, it is unclear if local treatment is equivalent to conventional therapy. Soheilian et al22 randomized 68 patients with active ocular toxoplasmosis to either intravitreal clindamycin with dexamethasone (IVCD: 1 mg clindamycin/400 μg dexamethasone) or classic therapy (CT) with pyrimethamine, sulfadiazine, and systemic corticosteroids. Patients in the included study had more significant inflammation with moderate to severe decreased vision in the affected eye and a location of a lesion near the optic nerve or macula but not within the central 500 μm of the macula. Patients injected with IVCD were retreated every 2 weeks up to 3 injections, guided by response to therapy, with a mean of 1.6 injections. Patients in the CT group received standard treatment for 6 weeks.
Both treatments resulted in statistically significant decrease in the size of the retinochoroidal lesions (approximately 60%), improvement in visual acuity, and decrease in inflammation, although the difference between the 2 was not significant. Recurrence rates were also similar (approximately 6%) within 2 years. Subgroup analysis of patients with antitoxoplasma IgM antibodies versus those who were IgM− found IgM+ patients to have a greater reduction in lesion size with CT, whereas IgM− patients responded more favorably to IVCD. Given the small number of patients with +IgM in this study, it is difficult to draw firm conclusions from this. The authors suggest that acutely infected (IgM+) patients have a systemic illness that would respond more favorably to CT; however, the theory would be at odds with the findings of parasitemia in chronically infected patients in the studies mentioned previously.
The use of local steroid injection for scleritis has been controversial largely because of threat of scleral melt or necrosis. A multicenter study23 evaluated the long-term outcome and adverse effects of subconjunctival triamcinolone acetonide injection in eyes with nonnecrotizing, noninfectious scleritis. The retrospective study of 68 eyes (53 patients) found that 97% of eyes had improved signs and symptoms after just 1 injection, with 90% experiencing complete resolution after a single injection. Half of the patients were still inflammation free at 4 years. In addition, half of the patients noted to have adverse effects from systemic medications were no longer taking them at the last follow-up visit. Most of the patients still taking systemic medications after injection needed them for associated systemic disease. Elevated IOP occurred in 20% of patients, but none required intervention. Most importantly, there were no cases of scleral necrosis or melt.
An analysis of 585 patients with scleritis and episcleritis from 2 tertiary referral centers revealed a higher number of ocular complications in patients with scleritis, including decreased vision, anterior uveitis, peripheral ulcerative keratitis, and ocular hypertension (P < 0.0001).24 A systemic disease association was observed in 35.8% of patients with scleritis, lower than that noted in previous studies. Moreover, scleritis preceded systemic disease in 38.7% of the patients. More than a quarter of patients with episcleritis (27.1%) also had a systemic disease association. Necrotizing scleritis was associated with a greater likelihood of systemic disease association and ocular complication than other types of scleritis (P < 0.0001).
Avadhani et al25 report a 78-year-old man who developed anterior uveitis shortly after using topical podophyllum for facial warts. The inflammation resolved with discontinuation of podophyllum and use of topical corticosteroids, but a flare of inflammation occurred 2 months later with rechallenge of podophyllum. The authors note that podophyllum is associated with acute inflammatory reactions elsewhere in the body. This case scored highly using formalized criteria to evaluate a causal relationship, indicating possible causation.
The advent of biologic agents such as the tumor necrosis factor α (TNF-α) inhibitors has significantly expanded the range of treatments for uveitis. Although a therapeutic benefit has been demonstrated, the drugs have also been found to worsen inflammation in some cases. Indeed, considerable attention has been paid to the association between etanercept and uveitis.
Two case reports highlight the development of sarcoid uveitis associated with TNF-α inhibitor treatment. In the first report, Fonollosa et al26 present a 30-year-old woman treated with etanercept for psoriatic arthritis who developed bilateral anterior and intermediate uveitis with snowball opacities in the vitreous and periphlebitis. Systemic symptoms included headache, fever, and fatigue. Investigators found an elevated ACE and hilar and mediastinal lymphadenopathy (biopsy of which showed noncaseating granulomas). Other etiologies were ruled out. With discontinuation of etanercept and institution of steroids, the uveitis resolved. The authors also reviewed the literature and found 6 similar cases of sarcoid uveitis associated with TNF-α inhibitor use, most of which were etanercept associated. All types of uveitis have been reported, occurring up to 6 years after initiation of therapy, and most improved with discontinuation of therapy. In another report, Seve et al27 describe a 61-year-old woman with rheumatoid arthritis treated with adalimumab who developed bilateral granulomatous panuveitis. Once again, elevated ACE and a positive biopsy of a skin nodule indicated sarcoidosis. With cessation of adalimumab and institution of corticosteroids, the skin nodule and uveitis resolved.
Similar findings have been described for nonocular sarcoid associated with TNF-α inhibitors. The mechanism may be related to interferon levels that vary with TNF-α levels or perhaps to increased presence of organisms that may cause noncaseating granulomas. Etanercept may differentially inhibit circulating and tissue-based TNF-α leading to local cytokine imbalance resulting in granulomas.28
In an effort to assess toxic effects of benzalkonium chloride (BAK) on the anterior chamber, researchers at Ghent University Hospital29 randomized 28 patients with untreated ocular hypertension to receive BAK-preserved timolol in one eye and nonpreserved timolol in the contralateral eye. Although both groups showed increased anterior chamber inflammation, measured by laser flare photometry, inflammation was significantly higher in the BAK-timolol treated eyes at 1 month posttreatment. The study suggests that BAK itself may be a source of intraocular inflammation; however, further studies would be needed to ascertain the relevance in clinical practice.
In a retrospective review of 40 case reports of uveitis associated with fluoroquinolone therapy, Hinkle et al30 noted a median time from initiation of therapy to onset of adverse drug reaction of 13 days (range, 0–20 days). Five cases reviewed had positive dechallenge reports, that is, the adverse event disappeared once the drug was stopped. Median dosage was within manufacturers recommendations for each fluoroquinolone. The authors suggest that fluoroquinolone-associated uveitis be considered in the workup of patients with uveitis, especially in cases of bilateral uveitis with iris transillumination defects and pigment dispersion.
UVEITIC MACULAR EDEMA
Intravitreal and Periocular Treatment for Uveitic Macular Edema
Rahimi et al31 randomized 60 eyes of 55 patients with uveitic cystoid macular edema to receive either 4 mg of intravitreal triamcinolone acetonide (IVTA) or 1.25 mg of bevacizumab (IVB) intravitreally. Best visual acuity was achieved at 6 months post treatment in both groups. Ninety-six percent of eyes that received IVTA injection and 83% of eyes that received IVB had improvement in visual acuity at 6 months. Both groups showed a reduction in mean macular thickness with slightly more reduction in the IVTA group (P < 0.001).
In a retrospective analysis of 31 eyes of 31 patients with noninfectious uveitis and macular edema researchers from Seoul, South Korea compared eyes that received IVB, IVTA, and posterior sub-Tenon triamcinolone acetonide.32 All patients were followed up for at least 14 weeks (mean, 22.3 weeks). In all groups, visual acuity and central foveal thickness showed the most improvement at 4 weeks and deteriorated until 12 weeks, although the visual acuity was still improved over baseline (P < 0.001). Eyes treated with triamcinolone acetonide showed greater reduction in central foveal thickness (from mean (SD) 594 (151) μm to 230 (99) μm) than those treated with bevacizumab. As would be expected, the mean increase in IOP was greater in eyes receiving triamcinolone than in those receiving bevacizumab (P = 0.007). Among eyes treated with bevacizumab, those with Behcet uveitis had a better improvement in visual acuity than those with other types of uveitis (P = 0.045). The median estimated period of effect was longest in the IVTA group (30 weeks vs 16 weeks with IVB and 12 weeks with posterior sub-Tenon triamcinolone acetonide).
Acharya et al33 reported on the possible bilateral effect of unilateral intravitreal injections of ranibizumab. Of 3 patients, 2 had improved visual acuity with decreased macular edema in both eyes. The authors speculate that ranibizumab may have had limited effect in the third patient because of the presence of epiretinal membrane.
Nonsteroidal anti-inflammatory drugs have also been part of the arsenal used to treat uveitis and CME, but modes of administration have largely been confined to oral routes, which may have systemic adverse effects, and topical administration, which may be ineffective for more severe CME. Kim et al34 at Vanderbilt University conducted a prospective phase I trial to evaluate the safety of 4 mg of intravitreal ketorolac in patients with chronic uveitis and macular edema refractory to previous treatment and in those intolerant to corticosteroids. Ten patients were evaluated with electroretinogram, fluorescein angiography, spectral domain optical coherence tomography, Goldman visual field, and ophthalmic examination over 90 days. No frank toxic effects were noted based on visual field, electroretinogram, and ophthalmic examination. Interestingly, both patients with chronic uveitis had complete quiescence of their inflammation within 7 days after injection. Of the remaining 8 patients who had CME, 50% had improvement in CME by OCT and fluorescein angiogram.
The mainstay of treatment for uveitic CME has been corticosteroids, often locally injected corticosteroids.35 Researchers at Johns Hopkins University sought to study the effectiveness and rate of adverse effects of periocular corticosteroid injections for uveitic CME. In their study of 156 eyes of 126 patients, just more than half of those treated had resolution of CME at 1 (53%) and 3 (57%) months after a single injection. In eyes requiring more than 1 injection because of persistent CME, 81% had resolution 1 month after the second injection and 48% at 3 months. Median time to resolution was 7.8 weeks after the first injection and 14.4 weeks after the second injection. Median time to recurrence was 20.2 weeks after initial resolution (53% of patients at 1 year). Rates of IOP elevation 22 mm Hg or greater and 30 mm Hg or greater were 0.35 per eye-year and 0.14 per eye-year, respectively. The rate of newly diagnosed cataract was 0.13/eye-year.
Systemic Therapy for Uveitic Macular Edema
Previous research has shown the efficacy of interferon α-2a in the treatment of refractory uveitic macular edema. Butler et al36 report the results of 4 patients with refractory uveitic macular edema treated with the closely related interferon α-2b (6 million units subcutaneously every day). All patients had long-standing bilateral CME (mean duration, 31.3 months) and had failed treatment with multiple therapies ranging from corticosteroids to immunosuppressive agents. All patients experienced improvement in CME (reduction in mean thickness from 563 to 267 μm at last visit, P = 0.002) and visual acuity (logMAR +0.81 at baseline to +0.45 at final visit, P = 0.0004). Adverse effects from the treatment affected all 4 patients and included malaise, arthralgias, nausea, fatigue, and weight loss; however, no adverse effects were severe enough to discontinue therapy. The mechanism by which interferon affects CME is unclear, but a possible explanation includes stabilization of the blood-retinal barrier.
Finally, to assess the effectiveness of mycophenolate mofetil (MMF) in uveitic cystoid macular edema, Doycheva et al37 analyzed patients with noninfectious uveitis and CME treated with MMF and followed up for at least 5 years. In patients with CME onset before MMF initiation (24 patients, predominantly with intermediate uveitis), 50% experienced resolution of CME without recurrence. Four additional patients (17%) had resolution initially but developed recurrent CME with flare of inflammation. Eight patients (33%) had no or incomplete resolution. In patients with new-onset CME, 50% occurred on the full dose of MMF, and 50%, during a reduction in dosage. Half of these patients experienced a flare of their inflammation at the same time as recurrence of CME. Good visual acuity at cohort entry was associated with better final visual acuity. Mycophenolate mofetil–related adverse effects occurred in 45% of patients (rate of 0.11/person-year).
Heinz et al38 performed a retrospective analysis of 24 patients with juvenile uveitic glaucoma who underwent either trabeculectomy or modified deep sclerectomy (deep sclerectomy plus circumscribed goniotomy). Both techniques achieved lower IOPs from baseline; however, those in the trabeculectomy group had a higher chance of postoperative success and lower IOPs. Of note, 4 patients (50%) of the patients included in the modified deep sclerectomy group needed additional surgery compared with only 1 patient in the trabeculectomy group (P = 0.023). Patients in the trabeculectomy group had a higher proportion of patients who experienced choroidal detachment and shallow anterior chamber postoperatively.
Another retrospective study39 of 26 eyes of patients with uveitic glaucoma and deep sclerectomy augmented with subconjunctival mitomycin c application before scleral flap dissection resulted in lower IOPs at 1-, 2-, and 3-year postoperative time points. Preoperative IOP was [mean (SD)] 33 (12) mm Hg and was 13 (4) mm Hg, 13 (4) mm Hg, and 14 (4) mm Hg at 1, 2, and 3 years after surgery. The probability of IOP of 18 mm Hg without medications was 84% at 3 years.
DIAGNOSTICS IN UVEITIS
Polymerase Chain Reaction
Eales disease has traditionally been thought to be idiopathic in origin, although several studies have shown a strong association with tuberculosis (TB). Singh et al40 showed that a significant portion (57.14%) of vitreous humor specimens from patients with findings consistent with Eales disease that were real time-PCR positive for the MPB64 gene of Mycobacterium tuberculosis with a load ranging from 1.52X104 to 1.01X106. The authors put forward that a significant proportion of patients diagnosed with Eales disease may in fact have TB-associated ocular inflammation. It should be noted that the study was carried out in an area endemic for TB possibly skewing the results; however, patients with Eales disease are also found in higher numbers in those areas.
Similarly, Cornut et al41 used rt-PCR for the polymerase I gene of Treponema pallidum to examine the aqueous humor of 5 patients suspected of having ocular syphilis. Polymerase chain reaction results were positive for 3 patients with panuveitis and negative for 2 patients: one with optic neuritis and another with posterior placoid chorioretinitis. The 2 negative cases may be due to a lack of direct intraocular infection or may represent autoimmune reactions. Rt-PCR may be valuable in the diagnosis of ocular syphilis, especially in cases with a known history of treated infection where results of serologic testing could be confusing.
QuantiFERON-TB Gold (QFT-G; Cellestis Limited, Carnegie, Victoria, Australia) is an interferon-γ (IFNγ) release assay for the detection of TB infection that has advantages over traditional Mantoux skin testing. Gineys et al42 prospectively examined 96 patients presenting with ocular infection with the QuantiFERON-TB Gold test, treating positive patients with 6 months of anti-TB treatment. In QTB Gold–positive patients with successful treatment (decrease in inflammation to grade 0 or 2-step decrease in inflammation and systemic steroid tapered to ≤10 mg/d), the median QTB Gold level (7.67 IU/mL) was significantly higher than the median value for patients who failed treatment (1.22 IU/mL, P = 0.026). The higher median value was greater than the manufacturer’s suggested cutoff implying that a higher value would be useful in predicting a patient’s chance of successful treatment.
Abbasian et al43 evaluated the serum of 15 patients with idiopathic ocular inflammation and a family history of inflammatory bowel disease for immunologic markers predicting bowel disease (Prometheus IBD serology 7; Prometheus Laboratories, San Diego Cal) and for single-nucleotide polymorphisms of the NOD2 gene (associated with Crohn disease). Patients with a family history of inflammatory bowel disease were more likely to have elevated perinuclear antinutrophilic cytoplasmic antibody levels (53% vs 20%; P = 0.04; OR, 6.0) as well as immunologic markers predictive of ulcerative colitis (27% of patients). Patients in this cohort with intraocular inflammation had similar carrier rates for NOD2 single-nucleotide polymorphisms.
Cytokine analysis of ocular fluids may provide another method by which to distinguish different uveitic entities. Ang et al44 performed a cytokine and chemokine analysis on aqueous humor samples of patients with TB-associated uveitis and idiopathic uveitis. Patients with TB-associated uveitis had higher levels of interleukin (IL) 6, IL-8, monokine induced by IFNγ, and IFNγ-induced protein 10 relative to controls. This profile was not typical for that expected in active infection (increased IL-12, TNF-α, and IFNγ). Patients with idiopathic uveitis had higher levels of IL-6, monocyte chemotactic protein 1, IL-8, IL-9, and lower levels of IL-2 and TNF-α than controls. The different cytokine profile for patients with TB-associated uveitis may be more suggestive of autoimmune ocular inflammation triggered by TB than active infection.
Nagat et al45 used multiplex ELISA analysis to identify 17 cytokines whose levels in the vitreous were higher in patients with sarcoid uveitis than nonsarcoid controls (platelet derived growth factor-BB, IL-1 ra, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-12, granulocyte colony stimulating factor, IFNγ, interferon-γ-induced protein 10, MCP-1α, macrophage inflammatory protein-1β, regulated on activation, normal T cell expressed and secreted, TNF-α, and vascular endothelial growth factor). Evaluation of serum levels of cytokines was similar in both groups with the exception of decreased IL-15 and increased IP-10 in ocular sarcoidosis patients. Elevation of some of the cytokines also appeared to be associated with thinner macular thickness after vitrectomy.
MEDICAL THERAPY FOR UVEITIS
Most new therapies introduced for uveitis in recent years have focused on sustained release intravitreal drug delivery systems (Ozurdex; Alcon, Ft Worth, Tex; and Retisert; Bausch & Lomb, Rochester, NY) or adoption of systemic therapies such as biologic agents for use in ocular diseases. Few topical therapies have been introduced in recent years. Difluprednate (Durezol; Alcon), a prodrug of difluprednisolone butyrate, is approved for use in the United States to control pain and inflammation postoperatively but has also found usefulness in the treatment of anterior uveitis. In particular, there is interest in using it to treat children, who may be more susceptible to adverse effects of systemic or injectable therapies.
In a retrospective case series of patients with pediatric uveitis treated with difluprednate, Slabaugh et al46 evaluated its efficacy and estimated adverse effects including IOP elevation and cataract development. Twenty-six eyes of 14 patients younger than 18 years with noninfectious uveitis and 6 months or more follow up were included. Diagnoses included juvenile idiopathic arthritis-associated anterior uveitis, idiopathic chronic anterior and intermediate uveitis, and tubulointerstitial nephritis with uveitis syndrome. Patients were treated for a mean of 27 weeks (range, 4–63 weeks) with frequency of administration ranging from every 2 hours to 4 times daily. For eyes that discontinued difluprednate, median follow up was 42 weeks.
Most patients achieved improvement in disease activity at 6 months (≥2-step decrease in inflammation or decrease in activity to grade 0 cell) with more than half achieving quiescence. Cystoid macular edema, noted in 35% of patients at the initial visit, improved in nearly 80% [mean (SD) macular thickness improvement from 492 (134) μm to 299 (48)]. The result suggests increased penetrance or efficacy than prednisolone acetate as all patients had been using topical prednisolone acetate before being switched to difluprednate with no effect on CME.
Fifty-percent of patients in the study experienced a clinically significant rise in IOP of 10 mm Hg or greater from baseline and 24 mm Hg or greater, whereas 14% required glaucoma surgery. Eight eyes of 5 patients progressed from clear lenses to visually significant posterior subcapsular cataracts during therapy with difluprednate. There was a statistically significant difference in cumulative drop load for patients who developed clinically significant increased IOP [after mean (SD) 161 (68) drops] versus those who did not [mean (SD), 467 (237), p+0.001], possibly suggesting that other factors may be at play in terms of risk for IOP rise.
Two other articles also point to the effectiveness of difluprednate in pediatric uveitis and the potential for serious adverse effects. Kurz et al47 document a 9-year-old boy with pars planitis successfully treated with difluprednate. The clinical course was complicated by increased IOP approximately 6 months posttreatment, with IOP rising to 38 mm Hg, despite maximal medical therapy. The IOP did return to normal 10 days after discontinuing the drops. Additional complications included the rapid development of a cataract within 3 weeks. In a retrospective study48 of 27 patients treated with difluprednate, including 5 children, 80% of the children developed an IOP rise of 15 mm Hg or greater from baseline and 40% a rise of 20 mm Hg or greater. In 60% of the children, a peak IOP rise 30 mm Hg or greater occurred. Intraocular pressure elevation was noted in patients without a history of steroid response, suggesting elevations in pressure secondary to difluprednate might not be predictable based on past experience. The authors also noted that most patients in the study had mild to moderate amounts of inflammation, and concluded that the elevation in IOP was unlikely to be due to a gain in ciliary body secretion with reduced inflammation.
Common to all 3 articles was the unpredictability in IOP rise, including IOP elevation in those not previously noted to have steroid response and significant IOP rises at different time points during treatment (often suddenly and without warning). These findings suggest that difluprednate drops may be an effective tool in combating intraocular inflammation, and possibly uveitic cystoid macular edema but that close monitoring of IOP was important, especially for pediatric patients.
In a report of 2 cases from France, Muselier et al49 detailed the treatment of 2 patients with uveitis refractory to multiple immunosuppressives with tocilizumab, an anti–IL-6 receptor monoclonal antibody. Interleukin-6 promotes the differentiation of TH17 cells and is itself an important mediator of inflammation. The first patient, diagnosed with birdshot retinochoroidopathy, had persistent CME despite treatment with other immunosuppressive agents and responded favorably with improved visual acuity and decreased macular edema (17% reduction OD and 41% reduction OS). The second patient, diagnosed with idiopathic panuveitis, also has persistent CME and inflammation despite multiple immunosuppressive regimens. She also responded to tocilizumab with improvement in both visual acuity and macular edema. The authors suggest that further study of the drug is warranted in the case of uveitis.
Turkcuoglu et al50 examined the effect of MMF on the frequency of attacks in 8 patients with recurrent punctate inner choroidopathy. Episodes of activity were defined as recurrent inflammation or choroidal neovascularization. They found that the use of MMF decreased the mean frequency of attacks from [mean (SD)] 1.09 (0.75) to 0.23 (0.32) (P = 0.036). Moreover, the authors noted fundus autofluorescence findings in 6 of the 8 patients. Hyperfluorescent halos surrounding the lesions were noted in 4 patients and thought to correlate with active disease (a decrease in hyperfluorescence was noted after treatment in 1 patient and was persistent in another with recurrent disease). The authors suggest that hyperfluorescent halo may be due to retinal pigment epithelium changes (size, number, fluorophore content) occurring with inflammation whereas a decrease in hyperfluorescence could reflect a decrease in inflammation or a loss due to chronic or end-stage disease.
Doycheva et al51 report the long-term results of MMF treatment for ocular mucous membrane pemphigoid in patients with at least 4 years of follow-up. Control of inflammation was achieved in 58% of eyes (11 eyes of 6 patients, 0.11/person-year) with the remainder of eyes having mild inflammation (2 eyes of 4 patients, 0.07/person-year). Mycophenolate mofetil prevented progression of conjunctival cicatrization in 9 (47%) of 19 eyes and restricted progression to mild worsening in 42%. Progression to stage IV was noted in 1 patient. Adverse effects occurred in 7 patients (0.12/person-year). Most patients had stage IIIb or worse. The rate of discontinuation of MMF was 0.02 per person-year, compared with previous reports of 0.20 per person-year for cyclophosphamide in other studies.
Kolomeyer et al52 conducted a retrospective chart review of 22 patients with nonnecrotizing noninfectious scleritis treated with MMF for at least 6 months. Ninety-one percent of the patients failed treatment with another immunomodulatory agent. Patients were followed up for a mean (SD) of 32.1 (1.9) months and had an average duration of 13.9 months for before treatment. Patients were treated with a mean (SD) maintenance dosage of 2.0 (0.75) g. The authors defined inflammation control as resolution of all signs and symptoms of scleral inflammation for 2 months or more. Corticosteroid sparing was defined as a 50% decrease in oral steroid dose or final dose of less than 10 mg daily. Inflammatory control was noted in 91% to 100% of patients taking MMF for 6, 12, 18 and 24 months. Criteria for corticosteroid sparing were met in 100% of patients at all time points. The average time to control of inflammation was 2.8 months (2-8 months). Sixty-four percent of patients experienced some medication-related adverse effect, but only 18% discontinued MMF.
Tumor Necrosis Factor–α Inhibitors
In a study of patients with noninfectious uveitis treated with infliximab and adalimumab, Martel et al53 evaluated control of inflammation (≤grade 0.5+ anterior chamber cell, vitreous haze, anterior vitreous cell and absence of retinal, choroidal, scleral inflammation or retinal vasculitis sustained for at least 4 weeks) and corticosteroid sparing effect (≤10 mg of prednisone daily, ≤4 drops of prednisolone daily and no corticosteroid injections within 3 months). A total of 41 patients who required biologic therapy largely, for ocular inflammation were evaluated, 31 treated with infliximab and 12 treated with adalimumab with some crossover between the 2 groups. In the infliximab group, 33.3% achieved sustained control of inflammation at 3 months, 60.7% at 6 months and 60.9% at 12 months after treatment. Patients treated with adalimumab achieved sustained control of inflammation in 37.5% at 3 months, 62.5% at 6 months, and 57.1% at 12 months. Median time to sustained control with steroid-sparing success was 98 days for infliximab and 169 days for adalimumab. There was a low rate of discontinuation in the infliximab group due to adverse events (0.11/person-year) with most adverse events occurring 1 year after the initiation of treatment. No patients discontinued adalimumab due to adverse reactions. The rates of control of inflammation with corticosteroid sparing were higher at 6 months than those reported for other immunomodulatory therapies reported in the SITE cohort (20%-40%). As most patients in the study were using an antimetabolite concurrently, the results of the study reflect treatment with combination therapy.
To evaluate the utility of adalimumab in treating uveitis, Diaz-Llopis et al54 prospectively enrolled 131 patients with uveitis refractory to prednisone and at least 1 IMT to receive subcutaneous injection of 40 mg of adalimumab every 2 weeks for 6 months. They found a statistically significant decrease in measures of inflammation and macular thickness (P < 0.001) at 6 months. Corticosteroid sparing was similarly demonstrated by a significant reduction in mean steroid dose from 0.74 to 0.20 mg/kg/d at 6 months (P < 0.001). Eighty-five percent of patients were able to decrease their immunosuppressive load by at least 50% and 70% of patients with CME at baseline had complete resolution at 6 months.
Valganciclovir and Cytomegalovirus-Associated Anterior Segment Inflammation
Cytomegalovirus is increasingly being recognized as a cause of ocular inflammation in immunocompetent patients. Although effective treatments for CMV exist, the efficacy of these treatments and duration of therapy needed for control of anterior segment inflammation are not well known. In a study of 13 eyes of 11 patients treated for anterior segment inflammation caused by CMV (CMV PCR+), all eyes achieved quiescence of inflammation within 3 weeks of treatment.55 Patients underwent induction dosing with 900 mg of valganciclovir twice daily for at least 2 weeks followed by a reduction to 450 mg twice daily maintenance dosing. Mean visual acuity improved between baseline and last follow-up visit (P = 0.048). Cytomegalovirus, like other herpes viruses, is often associated with elevated IOP and glaucoma. There was a significant decrease in both the mean IOP (P = 0.021) and number of glaucoma medications (P = 0.004) with treatment. More importantly, 5 patients (38.5%) had recurrence of inflammation when valganciclovir was stopped, with a median time to recurrence of 2 months. No adverse effects of valganciclovir were noted. The study indicates that although oral valganciclovir may be effective, some patients with CMV–associated anterior segment inflammation may be dependent upon the drug for control of their disease.
Denniston et al56 investigated immune regulation in the inflamed eye by isolating dendritic cells from the aqueous humor and peripheral blood of patients with active uveitis and studying the effect of uveitic aqueous humor supernatant on isolated dendritic cells. Dendritic cells are an important part of the adaptive immune response. Is uveitis due to a failure of immune privilege or due to dysregulation of immune regulatory mechanisms? Isolated dendritic cells had high levels of major histocompatibility complex class I and II expression but decreased expression of CD86, a coreceptor needed for activation of naive T cells. Indeed, T cell responses were diminished with inflammatory aqueous humor. Although IFN-γ levels were elevated in uveitic aqueous humor versus noninflammatory aqueous humor, the overall effect was suppression of dendritic cell function. Immune privilege was maintained during inflammation with increased dendritic cell regulatory effects different from pathways found in noninflamed aqueous (cortisol/transforming growth factor β2 pathways).
To help elucidate the mechanism by which IL-6 blockade may inhibit the development of experimental autoimmune uveoretinitis (EAU), researchers induced EAU in IL-6–deficient mice and analyzed T-helper cell differentiation and tissue cytokines.57 Inflammation was absent in IL-6 knockout mice and both TH17 and interphotoreceptor retinoid binding protein (IRBP)-specific TH1 cell populations were decreased relative to wild-type, IL-17 knockout, and IFN-γ knockout mice. Depletion of T regulatory (Treg) cells in IL-6 knockout mice induced EAU. The authors conclude that IL-6 deficiency in EAU inhibits TH17, inhibits interphotoreceptor retinoid binding protein (IRBP)-specific TH1 response, and promotes IRBP-specific Treg cell populations.
The pattern recognition receptor toll-like receptor (TLR) 4 recognizes bacterial endotoxin and signals through myeloid differentiation primary response protein 88 (MyD88) and TIR-domain-containing adapter-inducing interferon-β (TRIF) pathways as part of the innate immune response. It is thought that these pathways are important in the endotoxin-induced uveitis (EIU) mouse model. Kezic et al58 found that MyD88 −/− mice had a decreased cellular response to lipopolysaccharide with decreased production of MyD88-related cytokines. Mice deficient in TRIF had reduced production of TRIF-related cytokines but no change in cellular response to lipopolysaccharide. In addition, they found that wild type→TLR4 −/− chimeric mice were resistant to EIU suggesting non–bone marrow–derived cells in the eye were more important to the development of EIU than bone marrow–derived cells.
Forkhead box p 3 (Foxp3) is expressed on Treg cells and is necessary for Treg cell development and function. Sugita et al59 examined CD4+ T cells from the peripheral blood of patients with Behcet disease treated with colchicine, cyclosporine, and/or infliximab. Patients with active uveitis had a lower percentage of Foxp3+ T cells—significantly lower than patients with inactive or remitted uveitis. Patients treated with infliximab had higher percentages of Foxp3+ cells in their blood. In addition, patients with high numbers of Foxp3+ cells while being treated with infliximab did not have any episodes of acute uveitis, as opposed to those who had low numbers. In vitro exposure of T cells to infliximab caused increased expression of Foxp3, increased production of TGFβ, and suppressed bystander T cells.
Zhang et al60 studied the effect of intraperitoneal rapamycin on the immune response in EAU. Low-dose rapamycin was found to exacerbate EAU in a mouse model, but high doses attenuated the inflammatory response.
In a study of paired aqueous humor and serum samples of 16 patients with birdshot chorioretinopathy (BSCR), Kuiper et al61 found elevated levels of IL-2, IL-17, IL-1β, IL-6, and TNF-α relative to age-matched controls. Levels of IL-1β, IL-17, and TNF-α were higher in the aqueous humor than serum in patients with BSCR. The findings support BSCR as a T cell–mediated disease and the use of anti–IL-2 (daclizumab) and anti–TNF-α therapy in t1reating BSCR patients.
In a study of Behcet disease, Sugita et al62 set out to determine if TNF-α inhibition with infliximab could hinder TH17 cell differentiation. Aqueous and vitreous humor samples from patients with Behcet disease treated with infliximab showed no inflammatory cytokines, whereas samples from infliximab naive patients with active uveitis showed elevated levels of IFNγ, IL-2, TNF-α, IL-6, and IL-17. Similarly, CD4+ T cells from patients with Behcet disease produced large amounts of TNF-α and IL-17 when activated, whereas those exposed to infliximab did not. CD4+ T cells from patients with Behcet disease treated with infliximab also expressed lower levels of retinoid acid receptor–related orphan receptor gamma positive (RORγ+, a transcription factor needed for TH17 cell differentiation) than those not treated with infliximab. Infliximab, anti–TNF-α therapy, suppresses TH17 cell differentiation in patients with Behcet disease.
Using transgenic mice, Wang et al63 showed that the presence of T cells expressing IL-21 and IL-2 into the retina was associated with the development of EAU. Mice deficient in IL-21 were more resistant than wild-type mice to developing EAU. When T cells from IL-21–deficient mice were used for adoptive cell transfer, they induced less severe EAU, suggesting a central role for IL-21 in the development of EAU. Interleukin-21 may offer another potential target for drug therapy in the treatment of uveitis.
Ke et al64 explored the role of IL-22 in experimental autoimmune uveitis by administering IL-22 to EAU-susceptible mice. The severity of EAU reduced with IL-22 and fewer IFNγ+, IL-17+ effector T cells and greater numbers of Foxp3+ regulatory T cells were produced. Further analysis demonstrated that IL-22 acted upon CD11b+ antigen presenting cells. CD11b+ antigen presenting cells treated with IL-22 in vitro resulted in increased IL-10 and TGFβ production and caused IRBP-specific T cells to gain immunosuppressive activity and lose uveitogenic activity.
Using a mouse model of chronic uveitis, Oh et al65 demonstrated that IRBP-specific autoreactive memory T cells relocated to the bone marrow in between episodes of inflammation. These cells can persist in the bone marrow for extended periods of time and can become uveitogenic T cells once exposed to IRBP antigen/antigen presenting cells. Adoptive transfer experiments were able to induce EAU in naive recipients of bone marrow cells from EAU mice. Furthermore, IRBP-specific memory T cells from CD4-STAT3 knockout mice were not able to extravasate into the bone marrow, suggesting that STAT3-dependent mechanisms (including osteopontin expression and α4β1 integrin activation) are important to the development of uveitis and may be potential targets for therapy.
The same group also found a subtype of TH17 cells that constitutively produced low-levels of IL-2 during priming than TH1 cells, conferring protection against activation-induced cell death.66 This subtype increased in the peripheral blood and retina of mice with EAU. Removal of IL-2 via IL-2–neutralizing antibodies resulted in the TH17 cells having a similar susceptibility to apoptosis as TH1 cells. The results offer further insights into the possible role of TH17 cells in chronic uveitis and provides support for the use of anti-IL2 therapies such as daclizumab in the treatment of chronic uveitis.
Toll-like receptors are critical to innate immunity mechanisms in humans. Toll-like receptor 4, activated by LPS, is central to the development of uveitis in the mouse model EIU. Other pattern recognition receptors have also been implemented in the development of uveitis including TLR2 and NOD2. Researchers from the Casey Eye Institute67 in Portland, Oregon, were able to demonstrate that stimulation of other TLRs also caused increased proinflammatory cytokine production and increased chemotaxis of leukocytes into the iris tissue. There was a relative difference in the response between different TLR agonists, suggesting additional areas of interest for future investigations.
The studies covered in this review offer much promise for our future understanding, diagnosis, and treatment of ocular inflammatory disease. Although some researchers this year have confirmed the effectiveness of current therapies for uveitis including many of the newer biologic agents and sustained-release drug implants, others have taken up the task of elucidating the mechanisms whereby ocular inflammation occurs such as T cell activation and cytokine effects. The continued progress in these areas is welcome news for patients and the physicians who care for them.
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