Uveitis in Sarcoidosis - Clinical Features and Comparison with Other Non-infectious Uveitis.

PURPOSE: Comparison of sarcoid uveitis with other non-infectious uveitis treatment and visual outcomes. METHODS: Retrospective study of 287 eyes with sarcoid uveitis and 1517 eyes with other non-infectious uveitis (15,029 eye-years follow-up). RESULTS: Sarcoid uveitis patients presented at age 43.1 ± 0.8 years, and 66.2% were female. Panuveitis was the most frequent presentation (48.3%), and 90.1% were bilateral. Moderate visual loss (≤20/50) developed in 19 eyes (6.6%), and severe visual loss (≤20/200) in 13 eyes (4.5%). Sarcoid uveitis had better visual outcomes than other non-infectious uveitis (10-year BCVA anterior uveitis 0.06 vs 0.24 p = .002; posterior disease 0.17 vs 0.38 p = .001). Oral corticosteroid use was more common with sarcoid uveitis (anterior uveitis 45.9% vs 16.4% p < .0005; posterior disease 64.0% vs 61.7% p = .635), but second-line immunosuppression was required less frequently (p = .008). CONCLUSIONS: Compared to other non-infectious uveitis, sarcoid uveitis has better visual acuity outcomes and is less likely to require second-line immunosuppression.

Systemic Associations of Sarcoid Uveitis: Correlation With Uveitis Phenotype and Ethnicity.

PURPOSE: To examine systemic associations of sarcoid uveitis and association with uveitis clinical phenotype and ethnicity. DESIGN: Retrospective cross-sectional study. SUBJECTS: A total of 362 subjects with definite or presumed sarcoid uveitis from Moorfields Eye Hospital, Royal Victorian Eye and Ear, and Auckland District Health Board. METHODS: Data were collected from the review of clinical notes, imaging, and investigations. Sarcoidosis was diagnosed in accordance with the International Workshop on Ocular Sarcoidosis guidelines. MAIN OUTCOME MEASURE: Diagnosis of associated systemic disease secondary to sarcoidosis. RESULTS: A total of 362 subjects with sarcoid uveitis were identified. Median age was 46 years, and 226 (62.4%) were female. Granulomatous anterior uveitis (47.8%), intermediate uveitis with snowballs (46.4%), and multifocal choroiditis (43.1%) were the most frequent clinical presentations, and disease was bilateral in 313 (86.5%). Periphlebitis was observed in 21.0%, and solitary optic nerve or choroidal granuloma in 11.3%. Lung parenchymal disease was diagnosed in 200 subjects (55.2%), cutaneous sarcoid in 98 (27.1%), sarcoid arthritis in 57 (15.7%), liver involvement in 21 (5.8%), neurosarcoid in 49 (13.5%), and cardiac sarcoid in 16 subjects (4.4%). Subjects with cardiac sarcoid were less likely to have granulomatous anterior uveitis (P = .017). Caucasian subjects were older at presentation (48 vs 41 years; P = .009), had less granulomatous anterior uveitis (26.4% vs 51.7%; P < .001), and were less likely to present with cutaneous involvement (23.1% vs 35.4%; P = .040). CONCLUSIONS: Ophthalmologists need to be aware of the systemic associations of sarcoid uveitis, in particular potentially life-threatening complications such as cardiac sarcoidosis. Differences observed in uveitis phenotype and between ethnicities require further investigation.

Functionally distinct IFN-γ+ IL-17A+ Th cells in experimental autoimmune uveitis: T-cell heterogeneity, migration, and steroid response.

Immunopathogenic roles for both Th1 (CD4+ IFN-γ+ ) and Th17 (CD4+ IL-17A+ ) cells have been demonstrated in experimental autoimmune uveitis (EAU). However, the role for Th17/Th1 (CD4+ T cells co-expressing IFN-γ and IL-17A) cells in EAU is not yet understood. Using interphotoreceptor retinoid-binding protein peptide-induced EAU in mice, we found increased levels of Th17/Th1 cells in EAU retinae (mean 9.6 ± 4.2%) and draining LNs (mean 8.4 ± 3.9%; p = 0.01) relative to controls. Topical dexamethasone treatment effectively reduced EAU severity and decreased retinal Th1 cells (p = 0.01), but had no impact on retinal Th17/Th1 or Th17 cells compared to saline controls. Using in vitro migration assays with mouse CNS endothelium, we demonstrated that Th17/Th1 cells were significantly increased within the migrated population relative to controls (mean 15.6 ± 9.5% vs. 1.9 ± 1.5%; p = 0.01). Chemokine receptor profiles of Th17/Th1 cells (CXCR3 and CCR6) did not change throughout the transendothelial migration process and were unaffected by dexamethasone treatment. These findings support a role for Th17/Th1 cells in EAU and their resistance to steroid inhibition suggests the importance of targeting both Th17 and Th17/Th1 cells for improving therapy.

Serum Angiotensin-Converting Enzyme Has a High Negative Predictive Value in the Investigation for Systemic Sarcoidosis.

PURPOSE: To examine whether measurement of serum angiotensin-converting enzyme (ACE) is useful in diagnosing sarcoidosis in undifferentiated uveitis. DESIGN: Evaluation of a diagnostic test. METHODS: Data collection was performed from 1035 consecutive subjects presenting with uveitis to Moorfields Eye Hospital undergoing measurement of serum ACE as part of baseline investigations for underlying systemic disease. The main outcome measures were sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of elevated serum ACE. RESULTS: Mean age of the sample was 41.7 years and 56.1% of subjects were female. Sarcoidosis was the underlying cause for the uveitis in 110 subjects (10.6%) and was more common in adults, female subjects, black subjects, and subjects with intermediate uveitis or panuveitis. ACE was elevated in 196 subjects (18.9%) and elevated levels were observed in 85 subjects eventually diagnosed with underlying sarcoidosis (true positive 77.3%) and in 111 subjects with an alternate diagnosis (false positive 12.0%). In adult subjects, sensitivity of serum ACE was 78.1%, specificity 90.0%, and PPV 43.6%, but the NPV was 97.0%. The test performed well, with area under curve (AUC) 0.897 (95% confidence interval [CI] 0.854-0.941). Serum ACE performed less well in distinguishing sarcoid uveitis in pediatric subjects, with sensitivity 60.0%, specificity 78.5%, and PPV 10.0%, but again NPV was high at 96.9% and AUC was 0.828 (95% CI 0.571-1.000). CONCLUSIONS: Serum ACE had a very high negative predictive value for sarcoid uveitis, eliminating the need for further screening tests in subjects with normal serum ACE, unless clinical suspicion was high.

Risk Factors for Developing Choroidal Neovascular Membrane and Visual Loss in Punctate Inner Choroidopathy.

PURPOSE: To examine a large cohort of subjects with punctate inner choroidopathy (PIC) looking at risk factors for development of choroidal neovascular membrane (CNVM) and visual loss. DESIGN: Retrospective case series. PARTICIPANTS: A total of 203 participants (318 eyes) with PIC seen at Moorfields Eye Hospital between 1996 and 2016. METHODS: Information was gathered from the clinical notes of all subjects identified with PIC. MAIN OUTCOME MEASURES: Development of CNVM, moderate visual loss (MVL) (≤20/50), and severe visual loss (SVL) (≤20/200). RESULTS: Participants were predominantly young (median age at presentation, 32.9 years; interquartile range [IQR], 26.1-42.2), myopic (91.5%), female (87.2%), and white (75.9%). Disease was bilateral at presentation in 115 participants (56.7%), and CNVM was present at presentation in 152 eyes (47.8%). Median follow-up was 8.4 years. New CNVM occurred in 58 eyes (33.5% of affected eyes and 4.3% of initially unaffected eyes). An increased risk of developing CNVM was associated with the presence of a CNVM in the fellow eye (P < 0.0005; hazard ratio [HR], 2.73), and previous oral corticosteroid treatment was associated with halving of the risk of developing CNVM (P = 0.035; HR, 0.45). No difference was observed in visual outcome with oral corticosteroids, but subjects treated with anti-VEGF had better visual outcomes (12-month median visual acuity, logarithm of the minimum angle of resolution [logMAR] 0.00 with anti-VEGF and 0.20 without; P = 0.018). Median best-corrected visual acuity (BCVA) was 20/30 at presentation (IQR, 0.00-0.50) and remained at 20/30 throughout all follow-up periods. Moderate visual loss occurred in 40 eyes (12.6%), with an incidence of 0.01 per eye-year, and SVL occurred in 49 eyes (15.4%), with an incidence of 0.01 per eye-year. Female participants were half as likely as male participants to develop MVL (P = 0.030; HR, 0.448), and participants with CNVM had a higher risk of MVL (P = 0.003; HR, 21.074). CONCLUSIONS: Visual loss is common in subjects with PIC, predominantly secondary to late development of CNVM. Treatment with oral corticosteroids may help to reduce the risk of CNVM development, and anti-VEGF therapy for CNVM was associated with better clinical outcomes.

Predictors of Long-Term Visual Outcome in Intermediate Uveitis.

PURPOSE: To describe factors that predict visual loss and complications in intermediate uveitis. DESIGN: Cross-sectional study. PARTICIPANTS: Subjects with intermediate uveitis were identified from a database of 1254 uveitis patients seen in the clinic of a single consultant (S.L.L.) between 2011 and 2013. METHODS: Information was gathered from the clinical notes of all subjects examined in clinic. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), moderate visual loss (MVL; ≤20/50), severe visual loss (SVL; ≤20/200). RESULTS: Three hundred and five subjects (550 eyes) were included in the study, comprising 24.3% of subjects seen in clinic. Mean (± standard deviation) age at diagnosis was 40.9±16.9 years, and 64.6% of subjects were female. Median follow-up was 8.2 years (mean, 9.7 years, 5452 eye-years). Systemic diagnosis was made in 36.1% of patients, with sarcoidosis (22.6%) and multiple sclerosis (4.6%) the most frequent systemic associations. Median BCVA was 20/30 (mean logarithm of the minimum angle of resolution [logMAR] 0.26±0.38, n = 550 eyes) at presentation, 20/30 (mean logMAR 0.22±0.42, n = 430) at 5 years, and 20/30 (mean logMAR 0.23±0.46, n = 260) at 10 years. Macular edema was observed in 224 eyes (40.7%) and was associated with idiopathic disease (P = 0.001) and diabetes (P = 0.001). Topical therapy was used in 82.7%, and 34.2% received local injections of corticosteroids. A total of 50.5% required oral steroids and 13.8% required second-line immunosuppression. Subjects with a diagnosis of sarcoidosis were less likely to require a second-line agent (4.3% vs. 16.2%, P = 0.011). On multivariate analysis, visual acuity at referral, retinal pigment epithelial atrophy, and macular scarring were associated with increased risk of MVL; and visual acuity at referral, local therapy, macular scarring, retinal detachment, and hypotony and phthisis were associated with increased risk of SVL. CONCLUSIONS: Intermediate uveitis has a long disease course with frequent complications and often requires systemic treatment. Despite this, most subjects are still able to achieve good long-term visual outcomes.

Corticosteroid intravitreal implants vs. ranibizumab for the treatment of vitreoretinal disease.

PURPOSE OF REVIEW: Three long-acting corticosteroid implants are now available for the treatment of retinal disease, offering control of macular edema and inflammation for between 6 months and up to 3 years. This review evaluates their efficacy and side-effect profile in comparison with the antivascular endothelial growth factor agent ranibizumab in diabetic macular edema, retinal vein occlusion, pseudophakic macular edema, and uveitis. RECENT FINDINGS: Trials of ranibizumab in diabetic macular edema have demonstrated excellent efficacy without serious safety concerns to date. Fluocinolone acetonide implants can be considered, but have a high risk of cataract and sequelae from intraocular pressure rise. In retinal vein occlusion, both ranibizumab and Ozurdex have been shown to be effective, although their relative efficacy has not been determined in head-to-head clinical trials. In pseudophakic and uveitic macular edema, steroid implants are probably the first choice therapy, although there is evidence that ranibizumab is effective. For choroidal neovascularization secondary to inflammatory disease, ranibizumab is indicated, whereas Retisert has been shown to reduce the risk of uveitis relapse. SUMMARY: In diabetic macular edema, ranibizumab has shown greater efficacy with fewer side-effects than steroid implants. Both ranibizumab and steroid implants can be considered in retinal vein occlusion, but trials are awaited to determine their relative efficacy.

Valacyclovir in the treatment of acute retinal necrosis.

BACKGROUND: To report the outcome of oral valacyclovir as the sole antiviral therapy for patients with acute retinal necrosis (ARN). METHODS: This study reports a retrospective, interventional case series of nine consecutive patients with ten eyes with newly diagnosed ARN treated with oral valacyclovir as the sole antiviral agent. Eight patients received oral valacyclovir 2 g tid (Valtrex, GlaxoSmithKline) and one patient with impaired renal function received oral 1 g tid. The main outcome measures were response to treatment, time to initial response to treatment, time to complete resolution of retinitis, best corrected visual acuity (BCVA) at final follow-up, retinal detachment and development of recurrent or second eye disease. RESULTS: Retinitis resolved in ten of ten (100%) affected eyes. The median time to initial detectable response was seven days and the median time to complete resolution was 21 days. A final BCVA of 20/40 or better was achieved in 6/10 (60%) of eyes. 3/10 eyes (30%) developed a retinal detachment. No patients developed either disease reactivation or second eye involvement over the course of the study (mean follow up 31 weeks, range 7 to 104 weeks). CONCLUSIONS: Treatment with oral valacyclovir as the sole antiviral therapy resulted in complete resolution of retinitis. Final BCVA and retinal detachment rate were comparable with previously reported outcomes for intravenous acyclovir.

Clinical and molecular features associated with cystic visceral lesions in von hippel-lindau disease.

BACKGROUND: Von Hippel-Lindau (VHL) is an uncommon oncogenic disorder which occurs as a result of genetic mutations on chromosome 3p. Retinal capillary haemangiomas and CNS haemangioblastomas have been well-characterised in genotypic-phenotypic analyses, but cystic visceral lesions are less common and have been less frequently studied. The aim of this study was to perform genotypic and phenotypic analysis of a cohort of VHL patients that developed cystic visceral lesions to determine whether their genotype differs from that seen in other manifestations of VHL and whether the ocular manifestations differ. METHODS: This study reports a prospective case series of twenty-one patients identified from the Hammersmith Hospital Genetics Service database as having VHL mutations. Patients underwent regular ocular and systemic screening as well as genotypic analysis. The main outcome measures were the development of VHL lesions, either ocular or systemic. RESULTS: Cystic visceral lesions were detected in six of the 21 patients from the clinic (29%). These included renal cysts in four patients, pancreatic cysts in three patients, and an epididymal cystadenoma in one patient. Renal cysts were not associated with any specific genotype. Pancreatic cysts appeared to occur in association with VHL gene deletions and all developed CNS haemangioblastomas. Only one patient developed ocular manifestations, which occurred in this patient in the form of two retinal capillary haemangiomas. CONCLUSIONS: VHL gene deletions appeared to be associated with pancreatic cysts and the development of CNS haemangioblastomas. Ocular manifestations are uncommon in this group of patients.

Rituximab in refractory ophthalmic Wegener's granulomatosis: PR3 titers may predict relapse, but repeat treatment can be effective.

OBJECTIVE: To report the long-term outcome of the treatment of refractory ophthalmic Wegener's granulomatosis (WG) with rituximab (RIT), including rates of relapse, predictors of relapse, and results of repeat treatment. DESIGN: Retrospective case series. PARTICIPANTS: We included 20 consecutive patients with refractory ophthalmic WG treated with RIT. INTERVENTION: Intravenous RIT infusion, 2 doses of 1 g given 2 weeks apart. MAIN OUTCOME MEASURES: Regular clinical, serologic, and immunologic examinations for disease activity and extent, and for treatment-related side effects. RESULTS: All 20 patients entered remission, the median time to remission being 2 months (range, 1-6). Seven patients (35%) relapsed at a median of 13 months (range, 9-18). Five of these patients took a second course of RIT, and all achieved remission without further relapse. In the 16 patients with positive anti-proteinase-3 (PR3) titers at baseline, rising anti-PR3 titer was a statistically significant predictor of relapse. There were 4 severe adverse events during the study, of which one was directly attributed to treatment with RIT. CONCLUSIONS: In this series of 20 patients with refractory ophthalmic WG, RIT was effective in inducing remission. Relapse occurred in one third of patients within 18 months and seemed to be predictable by rising anti-PR3 titers, but retreatment with RIT was effective in this group. In patients with ophthalmic WG, RIT may be capable of inducing extended remission, in contrast with other biologic and conventional treatments in common use. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Intraocular methotrexate in the treatment of uveitis and uveitic cystoid macular edema.

OBJECTIVE: A pilot study to evaluate the use of intravitreal methotrexate (MTX) for the treatment of uveitis and uveitic cystoid macular edema (CME). DESIGN: Prospective, consecutive, interventional case series. PARTICIPANTS: Fifteen eyes of 15 patients with a unilateral exacerbation of noninfectious intermediate, posterior uveitis, or panuveitis and/or CME such that visual acuity (VA) was 20/40 or worse, together with a history of increased intraocular pressure (IOP) in response to corticosteroid administration. INTERVENTION: Intravitreal injection of 400 microg in 0.1 ml MTX. MAIN OUTCOME MEASURES: The primary outcome measure was VA (using the Early Treatment Diabetic Retinopathy Study chart). Other outcome measures included ocular inflammation scores, time to relapse, levels of systemic corticosteroid and immunosuppressive therapy, and ocular coherence tomography. Potential complications of intravitreal MTX injection, including cataract progression, vitreous hemorrhage, retinal detachment, and corneal epitheliopathy, were assessed. RESULTS: VA improved at all time points and was statistically significant at the 3- and 6-month follow-up examinations. The mean visual improvement was 4 lines at 3 months and 4.5 lines at 6 months, with no statistical difference between the best VA obtained after MTX injection and after previous corticosteroid treatment, including intravitreal triamcinolone acetate injection. Five patients relapsed after a median of 4 months; a similar improvement was seen after re-injection. Ocular inflammation scores improved at all time points, and systemic immunosuppressive medication was reduced in 3 of 7 patients taking this at the start of the trial. CONCLUSIONS: In patients with uveitis and uveitic CME, intravitreal MTX can improve VA and reduce CME and, in some patients, allows the reduction of immunosuppressive therapy. Relapse occurs at a median of 4 months in some patients, but reinjection has similar efficacy.