Mechanisms of blood-retinal barrier disruption related to intraocular inflammation and malignancy.

Blood-retinal barrier (BRB) disruption is a common accompaniment of intermediate, posterior and panuveitis causing leakage into the retina and macular oedema resulting in vision loss. It is much less common in anterior uveitis or in patients with intraocular lymphoma who may have marked signs of intraocular inflammation. New drugs used for chemotherapy (cytarabine, immune checkpoint inhibitors, BRAF inhibitors, EGFR inhibitors, bispecific anti-EGFR inhibitors, MET receptor inhibitors and Bruton tyrosine kinase inhibitors) can also cause different types of uveitis and BRB disruption. As malignant disease itself can cause uveitis, particularly from breast, lung and gastrointestinal tract cancers, it can be clinically difficult to sort out the cause of BRB disruption. Immunosuppression due to malignant disease and/or chemotherapy can lead to infection which can also cause BRB disruption and intraocular infection. In this paper we address the pathophysiology of BRB disruption related to intraocular inflammation and malignancy, methods for estimating the extent and effect of the disruption and examine why some types of intraocular inflammation and malignancy cause BRB disruption and others do not. Understanding this may help sort and manage these patients, as well as devise future therapeutic approaches.

Can Simvastatin Reduce the Need for Immunomodulatory Drugs to Treat Uveitis?: A Prospective, Randomized, Placebo-Controlled Trial.

Objective: To assess the efficacy of simvastatin 80 mg/day versus placebo in patients with noninfectious nonanterior uveitis receiving prednisolone ≥ 10 mg/day. Design: Randomized, double-masked, controlled trial. Subjects: Adult patients with noninfectious nonanterior uveitis on oral prednisolone dose of ≥ 10 mg/day. Methods: Patients were randomly assigned at a 1:1 ratio to receive either simvastatin 80 mg/day or placebo. A total of 32 patients were enrolled (16 in each arm), all of whom completed the primary end point, and 21 reached the 2-year visit (secondary end points). Main Outcome Measures: The primary end point was mean reduction in the daily prednisolone dose at 12 months follow-up. Secondary end points were mean reduction in prednisolone dose at 24 months, percent of patients with a reduction in second-line immunomodulatory agents, time to disease relapse, and adverse events. Results: Our results show that simvastatin 80 mg/day did not have a significant corticosteroid-sparing effect at 12 months (estimate: 3.62; 95% confidence interval [CI]: -8.15 to 15.38; P = 0.54). There was no significant difference between the groups with regard to prednisolone dose or change in dose at 12 and 24 months. There was no difference between the 2 groups in percent of patients with reduction in second-line agent by 24 months. Among patients who achieved disease quiescence, the median time to first relapse was longer for those receiving simvastatin (38 weeks, 95% CI: 14-54) than placebo (14 weeks, 95% CI: 12-52), although this was not statistically significant. There was no significant difference in adverse events or serious adverse events between the 2 groups. Conclusions: Simvastatin 80 mg/day did not have an effect on the dose reduction of corticosteroids or conventional immunomodulatory drugs at 1 and 2 years. The results suggest that it may extend the time to disease relapse among those who achieve disease quiescence. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Comparison of anatomical and functional outcomes of treating myopic choroidal neovascularization with bevacizumab or ranibizumab.

PURPOSE: To compare results of treatment with bevacizumab and ranibizumab injections in myopic choroidal neovascularization (mCNV). METHODS: Retrospective, observational case series. PARTICIPANTS: patients with mCNV treated with bevacizumab or ranibizumab injections. Best corrected visual acuity (BCVA) and central retinal thickness (CRT) on optical coherence tomography (OCT) scans were collected at baseline, after 3, 6, 12, 24 months and the last visit. MAIN OUTCOME MEASURES: mean change in BCVA and CRT. RESULTS: We included 85 eyes treated with bevacizumab and 125 eyes treated with ranibizumab. There was no difference between the groups regarding BCVA and CRT change. CNV recurrence occurred at the mean time of 66.1 ± 3.7 and 57.3 ± 6.4 months in the bevacizumab- and ranibizumab-treated eyes, respectively (p = 0.006). During the first year 6.9% eyes in the bevacizumab group vs. 27.5% in the ranibizumab group had CNV recurrence (p = 0.001). Risk factors for recurrence of CNV were baseline CNV area (aHR 1.20, 95%CI 1.0-1.32, p = 0.04), subfoveal CNV (aHR 2.13, 95% CI 1.16-3.93, p = 0.01) and ranibizumab treatment (aHR 2.31, 95% CI 1.16-3.93, p = 0.008). CONCLUSION: Eyes treated with bevacizumab and ranibizumab can achieve similar anatomical and functional improvement. CNV recurrence may occur earlier and more frequently during the first year in eyes treated with ranibizumab.

Efficacy of Infliximab in Disease Control of Refractory Orbital Myositis.

PURPOSE: Orbital myositis is a common cause of orbital inflammation with localized involvement of the extra ocular muscles. This study aimed to assess the value of infliximab in controlling orbital myositis and reducing its relapse rate. METHODS: We conducted a retrospective review of the medical records of all consecutive patients with orbital myositis treated with infliximab between 2007 and 2016. We examined change in corticosteroid and immunomodulatory doses as well as relapse rates following treatment with infliximab. RESULTS: The study included seven patients with an average follow up of 19 ± 13.4 months. The mean dose of systemic corticosteroid was reduced from 28.57 ± 14.35 mg/day at the time of infliximab initiation to 7.00 ± 6.83 mg/day at final follow-up (p = .003). Long-term remission was achieved in 85.7% (n = 6). CONCLUSION: This study supports the role of infliximab in treating refractory orbital myositis and this was associated with clinical improvement, decreasing relapse rate with dose reduction of conventional treatment.

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.

Emerging Antibiotic Resistance Patterns Affect Visual Outcome Treating Acute Endophthalmitis.

Background: Examining the effect of antibiotic resistance, use of intravitreal antibiotics and systemic corticosteroids on visual outcome of eyes with acute endophthalmitis. Methods: We included 226 eyes with acute endophthalmitis, treated using a standardized protocol. Visual outcome up to 12 months was assessed related to biopsy results, antibiotics resistance and treatment regimens. Results: Vitreous biopsies were more likely to be culture-positive (41.1%) than anterior chamber biopsies (21.6%, p < 0.0001). Antibiotic resistance for amikacin was found in 19 eyes (24.7%), vancomycin in 29 eyes (31.5%) and moxiflocacin in 14 eyes (16.1%). At presentation 91.53% of eyes had BCVA < 20/40, reducing by 1 month to 69.94% (p < 0.0001) and remaining stable at 12 months. There was no difference in visual outcome for those receiving early systemic corticosteroids. Endophthalmitis following cataract surgery (OR 1.66, 1.04−2.66 95% CI, p = 0.03) and receiving intravitreal vancomycin (OR 3.15, 1.18−8.42 95% CI, p = 0.02) were associated with a greater chance of final BCVA ≥ 20/40. Conclusion: Using vitreous taps with intravitreal antibiotics, despite an increase in resistance to both vancomycin and moxifloxacin, results in a final BCVA > 20/200 in half of eyes and ≥20/40 in a third. Early treatment with intravitreal antibiotics should not be delayed.

Adhesion Molecule Targeted Therapy for Non-Infectious Uveitis.

Non-infectious uveitis (NIU) is an inflammatory eye disease initiated via CD4+ T-cell activation and transmigration, resulting in focal retinal tissue damage and visual acuity disturbance. Cell adhesion molecules (CAMs) are activated during the inflammatory process to facilitate the leukocyte recruitment cascade. Our review focused on CAM-targeted therapies in experimental autoimmune uveitis (EAU) and NIU. We concluded that CAM-based therapies have demonstrated benefits for controlling EAU severity with decreases in immune cell migration, especially via ICAM-1/LFA-1 and VCAM-1/VLA-4 (integrin) pathways. P-selectin and E-selectin are more involved specifically in uveitis related to vasculitis. These therapies have potential clinical applications for the development of a more personalized and specific treatment. Localized therapies are the future direction to avoid serious systemic side effects.

Intravitreal Antivascular Endothelial Growth Factor Treatment for Inflammatory Choroidal Neovascularization in Noninfectious Uveitis.

PURPOSE: To compare visual outcome and recurrence rates of eyes with noninfectious inflammatory choroidal neovascularization (CNV) treated with or without anti-vascular endothelial growth factor (VEGF) injections and immunosuppression. DESIGN: Retrospective, nonrandomized clinical study. METHODS: Participants: Patients with CNV secondary to noninfectious inflammatory causes who attended uveitis clinics at Moorfields Eye Hospital between January 2000 and April 2016. Data were gathered from the clinical notes of all subjects examined in clinic. MAIN OUTCOME MEASURES: change in best-corrected visual acuity (BCVA), mean time to CNV recurrence, moderate vision loss (≤20/50), and severe vision loss (≤20/200). RESULTS: A total of 166 patients (204 eyes) with noninfectious inflammatory CNV were included in this study with a median follow-up of 6.9 years (interquartile range: 2.9-11.7; 1652 eye-years). The mean BCVA at the time of CNV diagnosis was 0.38 ± 0.05 logarithm of the minimum angle of resolution (logMAR) (Snellen equivalent 20/47) in the eyes that received the first-line anti-VEGF treatment and 0.44 ± 0.03 logMAR (Snellen equivalent 20/55) in the eyes on other treatment modalities (P = .39). Eyes treated first with anti-VEGF (n = 55) received the mean of 4.35 ± 0.53 injections and showed a statistically significant improvement in vision at all time points (P < .001) except for a 5-year visit (P = .25). The rest of the eyes demonstrated no significant change in vision throughout follow-up (all P > .05). At the final visit, the mean BCVA was 0.26 ± 0.11 logMAR (Snellen equivalent 20/36) in the former and 0.35 ± 0.06 logMAR (Snellen equivalent 20/44) in the latter. The mean time to CNV recurrence was 186 ± 15.1 months, and the risk was significantly reduced by treatment with oral corticosteroids (adjusted hazard ratio = 0.32, confidence interval: 0.17-0.59, P < .001) or anti-VEGF injections (adjusted hazard ratio = 0.31, confidence interval: 0.18-0.52, P < .001). CONCLUSIONS: Eyes that developed inflammatory CNV were at risk of vision loss. Those receiving early anti-VEGF injections achieved a better visual outcome and had a reduced risk of CNV recurrence. Oral corticosteroids also had an effect that reduces the risk of recurrence in eyes previously treated.

CD4+ T-Cell Plasticity in Non-Infectious Retinal Inflammatory Disease.

Non-infectious uveitis (NIU) is a potentially sight-threatening disease. Effector CD4+ T cells, especially interferon-γ-(IFNγ) producing Th1 cells and interleukin-17-(IL-17) producing Th17 cells, are the major immunopathogenic cells, as demonstrated by adoptive transfer of disease in a model of experimental autoimmune uveitis (EAU). CD4+FoxP3+CD25+ regulatory T cells (Tregs) were known to suppress function of effector CD4+ T cells and contribute to resolution of disease. It has been recently reported that some CD4+ T-cell subsets demonstrate shared phenotypes with another CD4+ T-cell subset, offering the potential for dual function. For example, Th17/Th1 (co-expressing IFNγ and IL-17) cells and Th17/Treg (co-expressing IL-17 and FoxP3) cells have been identified in NIU and EAU. In this review, we have investigated the evidence as to whether these 'plastic CD4+ T cells' are functionally active in uveitis. We conclude that Th17/Th1 cells are generated locally, are resistant to the immunosuppressive effects of steroids, and contribute to early development of EAU. Th17/Treg cells produce IL-17, not IL-10, and act similar to Th17 cells. These cells were considered pathogenic in uveitis. Future studies are needed to better clarify their function, and in the future, these cell subsets may in need to be taken into consideration for designing treatment strategies for disease.

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.

Small-molecule antagonist of VLA-4 (GW559090) attenuated neuro-inflammation by targeting Th17 cell trafficking across the blood-retinal barrier in experimental autoimmune uveitis.

BACKGROUND: The integrin VLA-4 (α4ß1) plays an important role in leukocyte trafficking. This study investigated the efficacy of a novel topical α4ß1 integrin inhibitor (GW559090, GW) in a mouse model for non-infectious posterior uveitis (experimental autoimmune uveitis; EAU) and its effect on intraocular leukocyte subsets. METHODS: Mice (female; B10.RIII or C57Bl/6; aged 6-8 weeks) were immunized with specific interphotoreceptor retinoid-binding protein (IRBP) peptides to induce EAU. Topically administered GW (3, 10, and 30 mg/ml) were given twice daily either therapeutically once disease was evident, or prophylactically, and compared with vehicle-treated (Veh) and 0.1% dexamethasone-treated (Dex) controls. Mice were sacrificed at peak disease. The retinal T cell subsets were investigated by immunohistochemistry and immunofluorescence staining. The immune cells within the retina, blood, and draining lymph nodes (dLNs) were phenotyped by flow cytometry. The effect of GW559090 on non-adherent, adherent, and migrated CD4+ T cell subsets across a central nervous system (CNS) endothelium was further assayed in vitro and quantitated by flow cytometry. RESULTS: There was a significant reduction in clinical and histological scores in GW10- and Dex-treated groups as compared to controls either administered therapeutically or prophylactically. There were fewer CD45+ leukocytes infiltrating the retinae and vitreous fluids in the treated GW10 group (P < 0.05). Immunofluorescence staining and flow cytometry data identified decreased levels of retinal Th17 cells (P ≤ 0.001) in the GW10-treated eyes, leaving systemic T cell subsets unaffected. In addition, fewer Ly6C+ inflammatory monocyte/macrophages (P = 0.002) and dendritic cells (P = 0.017) crossed the BRB following GW10 treatment. In vitro migration assays confirmed that Th17 cells were selectively suppressed by GW559090 in adhering to endothelial monolayers. CONCLUSIONS: This α4ß1 integrin inhibitor may exert a modulatory effect in EAU progression by selectively blocking Th17 cell migration across the blood-retinal barrier without affecting systemic CD4+ T cell subsets. Local α4ß1 integrin-directed inhibition could be clinically relevant in treating a Th17-dominant form of uveitis.

The prognostic value of total macular external limiting membrane and ellipsoid zone damage for clinical outcome in treatment-resistant neovascular age-related macular degeneration.

PURPOSE: To examine the prognostic value of the extent of damage to the ellipsoid zone (EZ) and external limiting membrane (ELM) in response to the treatment of age-related macular degeneration (AMD) eyes switched from ranibizumab to aflibercept. METHODS: This is a retrospective study of patients with neovascular AMD resistant to ranibizumab defined as having persistent intra- or subretinal fluid on OCT scans despite at least 6-month treatment and switched to aflibercept. Clinical data was collected and quantitative measurements of the area of EZ and ELM damage were obtained, on en-face optical coherence tomography images, at the time of switch to aflibercept (baseline) and up to 6 months of follow-up. RESULTS: The study included 71 eyes (52.1% right eye) of 71 patients. At baseline, there was a correlation between the size of the EZ and ELM damaged area and BCVA (R = -0.39, p = 0.001 and R = -0.47, p < 0.001, respectively). The EZ and ELM damaged areas maintained correlation with BCVA at 6 months (R = -0.28, p = 0.01 and R = -0.39, p = 0.001, respectively). Central retinal thickness did not correlate with BCVA at the time of switch (p = 0.38) or at 6 months (p = 0.36). CONCLUSIONS: The extent of damage to the EZ and ELM correlates with BCVA following a switch in treatment.

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.

Prospective study of morphologic and functional parameter changes post intravitreal therapy for macular edema.

PURPOSE: Retinal sensitivity (RS) can be a valuable indicator of retinal function in response to intravitreal steroid or anti-VEGF treatment in the eyes with diabetic macular edema (DME), macular edema post retinal vein occlusion (RVO), or uveitis. METHODS: This prospective longitudinal study included 68 patients (96 eyes) with macular edema (ME) secondary to diabetes mellitus (42 eyes), uveitis (36 eyes), or RVO (18 eyes). In addition to best corrected visual acuity (BCVA) and retinal thickness, Nidek MP1 microperimetry was used to quantify RS at baseline visit and to look at the mean difference (MD) at 3-6 months and 1-2 years post intravitreal therapy with corticosteroids or anti-VEGF. RESULTS: There was a significant negative correlation between the central RS and BCVA (r = - 0.47, p < 0.001), including DME (r = - 0.42, p = 0.006) and uveitis (r = - 0.60, p < 0.001), but not RVO (r = - 0.37, p = 0.12). At 2-year follow-up, the overall CST was reduced from baseline (MD - 147 µm, 95% C.I - 192 to - 102, p < 0.001) with improved BCVA (MD - 0.12 LogMAR, 95% C.I - 0.23 to - 0.01, p = 0.01), but no improvement in the RS in any of the disorders. Both anti-VEFG and steroid groups showed significant improvement in CST at 2 years from baseline (MD - 101 µm, p = 0.001 and - 167 µm, p < 0.001, respectively) with only improvement in BCVA among anti-VEGF group (MD - 0.16 LogMAR, 95% C.I - 0.26 to - 0.07, p = 0.008). CONCLUSION: The long-term follow-up of ME cases did not show a significant improvement in RS following treatment even with reduced macular thickness at 2-year follow-up.

Outcome and risk of ocular complications of managing children with chronic anterior uveitis with topical rimexolone 1.

PURPOSE: To investigate the efficacy and safety of 1% rimexolone ophthalmic suspension in children with chronic anterior uveitis under real-life conditions in a tertiary center. METHODS: This is a retrospective longitudinal study. Medical records were analyzed at baseline, 1, 3, 6 and 12 months before and after switching to rimexolone for best-corrected visual acuity (BCVA), oral steroid use, number of flares, IOP and anti-glaucoma management. RESULTS: Twenty-four patients (41 eyes) diagnosed with either anterior uveitis (n = 25, 60.0%) or panuveitis (n = 16, 40%) were enrolled. The mean age was 10.5 years (4-16 years). The number of patients requiring oral prednisolone reduced from 8 patients (32.0%) at baseline to 3 patients (20.0%) at 12 months (P < 0.001). Following baseline, the median number of uveitis flares reduced from 2.0 (inter-quartile range (IQR) 1.0-2.75) to 1.0 (IQR 0.0-1.0) compared to the 12 months before baseline (P < 0.001). The mean IOP reduced from baseline (22.0 ± 7.3 mmHg) to 1 month (18.8 ± 8.7 mmHg, P = 0.01) and remained stable up to 12 months (15.9 ± 5.0 mmHg, P < 0.001). Average BCVA, dose of oral prednisolone and anti-glaucoma treatments did not change compared to the baseline. The development for IOP ≥ 30 mmHg was associated with a known corticosteroid response [odds ratio (OR) 6.8, P = 0.003] and a dose > 7.5 mg/day oral prednisolone (OR 4.4, P = 0.033). CONCLUSIONS: Rimexolone 1% ophthalmic suspension is an effective and safe topical steroid for pediatric anterior uveitis.

Differentiating Multifocal Choroiditis and Punctate Inner Choroidopathy: A Cluster Analysis Approach.

PURPOSE: To develop a robust approach to clinical phenotyping of multifocal choroiditis (MFC) and punctate inner choroidopathy (PIC). DESIGN: Cross-sectional and longitudinal observational study. METHODS: This multicenter study included sites in the United Kingdom and Israel. The study population included 343 eyes of 185 subjects with hospital record diagnoses of MFC or PIC. Eyes were observed over a period of 5 years for clinically relevant characteristics, including demographics and multimodal imaging features, by observers masked to the original diagnoses. Multivariate 2-step cluster analysis was used to identify clusters of eyes in the database with similar clinical phenotypes, which were then analyzed for between-group differences. The primary outcome measure was the difference between clinical phenotype clusters identified using clinical criteria from the multivariate cluster analysis. RESULTS: Subjects ranged from 11 to 89 years of age, with a baseline best-corrected visual acuity of 2.3 to -0.2 logarithm of minimal angle of resolution. Eighty-two percent of eyes were from females, 74% were myopic with a refractive error of +3.00 to -17.00 diopters (spherical equivalent). Cluster analysis prioritized clinical criteria of chorioretinal lesion location and intraocular inflammation and identified 2 distinct phenotype clusters resembling the original descriptions of MFC and PIC. During the 5-year period of observation, the initial clinical diagnosis remained stable for most eyes and only 1 eye (0.3%) changed diagnosis from PIC to MFC because of newly developed peripheral lesions. There were significant between-group differences in clinical characteristics, for example, in choroidal neovascular membrane development and treatment received. CONCLUSIONS: Cluster analysis of this large cohort of eyes identified peripheral lesions and intraocular inflammation as distinct clinical phenotypes of MFC and PIC. The initial diagnosis remained stable for most eyes. This methodology could be useful for future uveitis classification and management.

Long-Term Outcomes of Treatment with Biological Agents in Eyes with Refractory, Active, Noninfectious Intermediate Uveitis, Posterior Uveitis, or Panuveitis.

PURPOSE: To examine a large cohort of patients treated with biologic agents for active noninfectious intermediate uveitis, posterior uveitis, or panuveitis (NIPPU) and to compare their efficacy and long-term effect. DESIGN: Retrospective, longitudinal study. PARTICIPANTS: Eighty-two patients (156 eyes) with active NIPPU after failure of treatment with corticosteroids and a second-line immunosuppression drug and treated with biologic agents who were treated at Moorfields Eye Hospital between 2001 and 2016. METHODS: Information was gathered from the clinical notes of all patients. MAIN OUTCOME MEASURES: Time to first disease flare, rate of treatment failure, best-corrected visual acuity, and risk factors for treatment failure. RESULTS: Patients were followed on average for 4.7±0.4 years (724 eye-years). All patients demonstrated active uveitis at baseline, and 34 patients (41.5%) demonstrated a coexisting active systemic disease. Control of ocular inflammation was achieved in 136 eyes (87.2%). The average oral prednisolone dose at baseline was 16.4±1.7 mg/day, and by 6 months reduced to 6.5±0.7 mg/day (P < 0.0001), remaining stable for up to 5 years follow-up. Best-corrected visual acuity at baseline was 0.5±0.1 logarithm of the minimum angle of resolution (logMAR), improved to 0.4±0.1 logMAR (P = 0.008) at 3 months, and remained stable during follow-up. After baseline, 42.3% of eyes experienced flares, and the average number of flares reduced from 1.8±0.1 flares/year to 0.6±0.1 flares/year (P < 0.0001). Median time to first flare was 5.4 years (95% confidence interval [CI], 2.2-5.4 years) with a 5-year survival rate of 58.7%. Treatment failed in 37 eyes (23.7%), with a 5-year survival rate of 68.0% and an estimated time to 75% survival of 2.9 years (95% CI, 2.1-4.4 years). The risk for treatment failure was lower when treatment used adalimumab (odds ratio, 0.4; 95% CI, 0.2-0.9; P = 0.03) but was greater when systemic disease also was active at baseline (odds ratio, 3.2; 95% CI, 1.5-7.1; P = 0.004). CONCLUSIONS: Overall, eyes treated with biologic agents after failure of treatment with corticosteroids and a second-line immunosuppression drug experienced satisfactory disease control (87.2%), reduced use of systemic immunosuppression, stable visual acuity, and a 23.7% risk of disease relapse. After multivariate adjustment, older age, treatment with adalimumab (versus infliximab), and inactive concomitant systemic disease were associated with a lower risk of treatment failure.

Viral retinitis: diagnosis and management in the era of biologic immunosuppression: A review.

Necrotising retinitis is a rare ocular infection that historically led to high rates of visual morbidity. While acute retinal necrosis occurs in immunocompetent patients, the majority of cases are associated with immunocompromise such as in cytomegalovirus retinitis and progressive outer retinal necrosis. This review summarises the clinical and diagnostic features, management, and outcomes of herpetic retinitis. Iatrogenic immunosuppression is increasingly being utilised for a wide range of indications, and biologic agents especially so due to their targeted nature. While the intended actions are well-studied, the flow-on effects and complex interaction with host immunity are not well understood. Furthermore, biologics are frequently used concomitantly with other immunosuppressive agents, potentiating the immunodepression. This article reviews the literature on biologic immunosuppression and viral retinitis, and presents an approach to the vulnerable or affected patient. Early identification, prompt and aggressive treatment, and a multidisciplinary approach to managing immunodeficiency are the cornerstones of management.