Abstract Ocular inflammatory disease is a leading cause of vision loss worldwide. Uveitis encompasses a wide spectrum of pathology, both with respect to its etiology and the anatomic location within ...the eye. Inflammation can be confined to the eye and may also be seen systemically. The cornerstone of management of ocular inflammatory disease historically has been corticosteroids, which are invaluable in the immediate control of inflammation; however, corticosteroids are inappropriate for long-term use as they are associated with a wide array of toxic side effects. As we continue to learn more about the various etiologies and elucidate the basic science pathways and mechanisms of action that cause intraocular inflammation, new therapeutic approaches have evolved. They include employment of immunomodulatory agents (corticosteroid-sparing therapies) that have expanded our treatment options for these vision-threatening diseases. These pharmacologics provide therapy for ocular and systemic inflammation in an individualized, patient-tailored, stepladder approach with the ultimate goal of durable, corticosteroid-free remission. We review the preferred practice patterns of a tertiary care center specializing in ocular inflammatory disease.
Single-cell RNA-seq is a powerful tool in decoding the heterogeneity in complex tissues by generating transcriptomic profiles of the individual cell. Here, we report a single-nuclei RNA-seq ...(snRNA-seq) transcriptomic study on human retinal tissue, which is composed of multiple cell types with distinct functions. Six samples from three healthy donors are profiled and high-quality RNA-seq data is obtained for 5873 single nuclei. All major retinal cell types are observed and marker genes for each cell type are identified. The gene expression of the macular and peripheral retina is compared to each other at cell-type level. Furthermore, our dataset shows an improved power for prioritizing genes associated with human retinal diseases compared to both mouse single-cell RNA-seq and human bulk RNA-seq results. In conclusion, we demonstrate that obtaining single cell transcriptomes from human frozen tissues can provide insight missed by either human bulk RNA-seq or animal models.
To provide recommendations for the use of anti-tumor necrosis factor α (TNF-α) biologic agents in patients with ocular inflammatory disorders.
Ocular inflammatory diseases remain a leading cause of ...vision loss worldwide. Anti-TNF-α agents are used widely in treatment of rheumatologic diseases. A committee of the American Uveitis Society performed a systematic review of literature to generate guidelines for use of these agents in ocular inflammatory conditions.
A systematic review of published studies was performed. Recommendations were generated using the Grading of Recommendations Assessment, Development, and Evaluation group criteria.
Numerous studies including controlled clinical trials have demonstrated that anti-TNF-α biologic agents (in particular infliximab and adalimumab) are effective in the treatment of severe ocular inflammatory disease. Based on these studies, the expert panel makes the following recommendations.
Infliximab and adalimumab can be considered as first-line immunomodulatory agents for the treatment of ocular manifestations of Behçet's disease. Infliximab and adalimumab can be considered as second-line immunomodulatory agents for the treatment of uveitis associated with juvenile arthritis. Infliximab and adalimumab can be considered as potential second-line immunomodulatory agents for the treatment of severe ocular inflammatory conditions including posterior uveitis, panuveitis, severe uveitis associated with seronegative spondyloarthropathy, and scleritis in patients requiring immunomodulation in patients who have failed or who are not candidates for antimetabolite or calcineurin inhibitor immunomodulation. Infliximab and adalimumab can be considered in these patients in preference to etanercept, which seems to be associated with lower rates of treatment success.
To evaluate safety and efficacy of adalimumab in patients with noninfectious intermediate, posterior, or panuveitis.
Phase 3, open-label, multicenter clinical trial extension (VISUAL III).
Adults ...meeting treatment failure (TF) criteria or who completed VISUAL I or II (phase 3, randomized, double-masked, placebo-controlled) without TF.
Patients received adalimumab 40 mg every other week. Interim follow-up data were described from VISUAL III weeks 0 through 78.
Disease quiescence, steroid-free quiescence, active inflammatory chorioretinal/retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, best-corrected visual acuity (BCVA), and corticosteroid dose. Binary data were reported using nonresponder imputation (NRI), continuous data using last observation carried forward and as-observed analysis, and corticosteroid dose using observed-case analysis. Adverse events (AEs) were reported from first adalimumab dose in VISUAL III through interim cutoff.
Of 424 patients enrolled, 371 were included in intent-to-treat analysis. At study entry, 242 of 371 (65%) patients had active uveitis; 60% (145/242, NRI) achieved quiescence at week 78, and 66% (95/143, as-observed) of those were corticosteroid free. At study entry, 129 of 371 (35%) patients had inactive uveitis; 74% (96/129, NRI) achieved quiescence at week 78, and 93% (89/96, as-observed) of those were corticosteroid free. Inflammatory lesions, anterior chamber grade, and vitreous haze grade showed initial improvement followed by decline in patients with active uveitis and remained stable in patients with inactive uveitis. BCVA improved in patients with active uveitis from weeks 0 to 78 (0.27 to 0.14 logMAR; left and right eyes; as-observed) and remained stable in patients with inactive uveitis. Mean corticosteroid dose decreased from 13.6 mg/day (week 0) to 2.6 mg/day (week 78) in patients with active uveitis and remained stable in those with inactive uveitis (1.5–1.2 mg/day). AEs (424 events/100 patient-years) and serious AEs (16.5 events/100 patient-years) were comparable with previous VISUAL trials.
Patients with active uveitis at study entry who received adalimumab therapy were likely to achieve quiescence, improve visual acuity, and reduce their daily uveitis-related systemic corticosteroid use. Most patients with inactive uveitis at study entry sustained quiescence without a systemic corticosteroid dose increase. No new safety signals were identified.
•Uveitis is a heterogeneous collection of diseases.•Despite the heterogeneity of uveitis, specific RNA transcripts expressed by cells in peripheral blood as well as pathways involving multiple genes ...are common to different forms of uveitis.•The shared expression of mRNA from different forms of uveitis is consistent with a prior publication based on peripheral blood and thus independently validated.•Transcripts that are implicated in multiple forms of uveitis could suggest therapeutic targets that could benefit multiple forms of uveitis.
Uveitis is a heterogeneous collection of diseases. We tested the hypothesis that despite the diversity of uveitides, there could be common mechanisms shared by multiple subtypes, and that evidence of these common mechanisms may be detected as gene expression profiles in whole blood.
Cohort study.
Ninety subjects with uveitis including axial spondyloarthritis (n = 17), sarcoidosis (n = 13), inflammatory bowel disease (n = 12), tubulointerstitial nephritis with uveitis (n = 10), or idiopathic uveitis (n = 38) as well as 18 healthy controls were enrolled, predominantly at Oregon Health & Science University. RNA-Seq data generated from peripheral, whole blood identified 19,859 unique transcripts. We analyzed gene expression pathways via Kyoto Encyclopedia of Genes and Genomes and Gene Ontology (GO). We validated our list of upregulated genes by comparison to a previously published study on peripheral blood gene expression among 50 subjects with diverse forms of uveitis.
Both the Kyoto Encyclopedia of Genes and Genomes and GO analysis identified multiple shared pathways or GO terms with a P value of <.0001. Almost all pathways related to the immune response and/or response to an infection. A total of 119 individual transcripts were upregulated by at least 1.5-fold and false discovery rate <.05, and 61 were downregulated by similar criteria. Comparing mRNA from our study with a false discovery rate <.05 and the prior report, we identified 10 common gene transcripts: ICAM1, IL15RA, IL15, IRF1, IL10RB, GSK3A, TYK2, MEF2A, MEF2B, and MEF2D.
Many forms of uveitis share overlapping mechanisms. These data support the concept that a single therapeutic approach could benefit diverse forms of this disease.
To evaluate long-term efficacy and safety of extended treatment with adalimumab in patients with noninfectious intermediate, posterior, or panuveitis.
Open-label, multicenter, phase 3 extension study ...(VISUAL III).
Adults who had completed a randomized, placebo-controlled phase 3 parent trial (VISUAL I or II) without treatment failure (inactive uveitis) or who discontinued the study after meeting treatment failure criteria (active uveitis).
Patients received subcutaneous adalimumab 40 mg every other week. Data were collected for ≤ 362 weeks. Adverse events (AEs) were recorded until 70 days after the last dose.
Long-term safety and quiescence; other efficacy variables included inflammatory lesions, anterior chamber cell and vitreous haze grade, macular edema, visual acuity, and dose of uveitis-related systemic corticosteroids.
At study entry, 67% of patients (283/424) showed active uveitis and 33% (141/424) showed inactive uveitis; 60 patients subsequently met exclusion criteria, and 364 were included in the intention-to-treat analysis. Efficacy variables were analyzed through week 150, when approximately 50% of patients (214/424) remained in the study. Patients showing quiescence increased from 34% (122/364) at week 0 to 85% (153/180) at week 150. Corticosteroid-free quiescence was achieved by 54% (66/123) and 89% (51/57) of patients with active or inactive uveitis at study entry. Mean daily dose of systemic corticosteroids was reduced from 9.4 ± 17.1 mg/day at week 0 (n = 359) to 1.5 ± 3.9 mg/day at week 150 (n = 181). The percentage of patients who achieved other efficacy variables increased over time for those with active uveitis at study entry and was maintained for those with inactive uveitis. The most frequently reported treatment-emergent AEs of special interest were infections (n = 275; 79 events/100 patient-years PY); AEs and serious AEs occurred at a rate of 396 events/100 PY and 15 events/100 PY, respectively.
Long-term treatment with adalimumab led to quiescence and reduced corticosteroid use for patients who entered VISUAL III with active uveitis and led to maintenance of quiescence for those with inactive uveitis. AEs were comparable with those reported in the parent trials and consistent with the known safety profile of adalimumab.
To test the hypothesis that idiopathic uveitis can be categorized into subtypes based on gene expression from blood.
Case control study.
We applied RNA-Seq to peripheral blood from patients with ...uveitis associated with 1 of 4 systemic diseases, including axial spondyloarthritis (n = 17), sarcoidosis (n = 13), inflammatory bowel disease (n = 12), tubulo-interstitial nephritis with uveitis (n = 10), or idiopathic uveitis (n = 38) as well as 18 healthy control subjects evaluated predominantly at Oregon Health and Science University. A high-dimensional negative binomial regression model implemented in the edgeR R package compared each disease group with the control subjects. The 20 most distinctive genes for each diagnosis were extracted. Of 80 genes, there were 75 unique genes. A classification algorithm was developed by fitting a gradient boosting tree with 5-fold cross-validation. Messenger RNA from subjects with idiopathic uveitis were analyzed to see if any fit clinically and by gene expression pattern with one of the diagnosable entities.
For uveitis associated with a diagnosable systemic disease, gene expression profiling achieved an overall accuracy of 85% (balanced average of sensitivity plus specificity, P < .001). Although most patients with idiopathic uveitis presumably have none of these 4 associated systemic diseases, gene expression profiles helped to reclassify 11 of 38 subjects.
Peripheral blood gene expression profiling is a potential adjunct in accurate differential diagnosis of the cause of uveitis. Validation of these results and characterization of the gene expression profile from additional discrete diagnoses could enhance the value of these observations.
•Idiopathic uveitis is the most frequent subtype of uveitis in a referral clinic, but the term idiopathic fails to convey prognostic or therapeutic implications to providers or patients.•Analysis of gene expression from cells in peripheral blood shows that subtypes of uveitis associated with systemic disease display distinctive patterns of gene expression.•The pattern of gene expression can help classify some examples of idiopathic uveitis.
Purpose To identify a clinically meaningful threshold for change in retinal thickness measured by optical coherence tomography for patients with uveitic macular edema using correlation with change in ...visual acuity. Design Cross-sectional and longitudinal study. Methods One hundred twenty-eight eyes (101 individuals) with macular edema enrolled in the Multicenter Uveitis Steroid Treatment (MUST) trial. At enrollment and after 6 months of follow-up, retinal thickness was measured at the central subfield with time-domain optical coherence tomography and visual acuity was measured with logarithmic (Early Treatment Diabetic Retinopathy Study) visual acuity charts. Participants were classified as having macular edema if the retinal thickness was 260 μm or more. Results A threshold for change in retinal center subfield thickness of 20% balanced the percentage of false positives and false negatives for predicting more than a 10-letter change in visual acuity with a sensitivity of 77% and a specificity of 75%. The results were similar for more than 5-letter changes and for 15-letter or more changes. Those with a 20% or more reduction in retinal thickness had a mean 11.0-letter improvement (95% confidence interval, 7.7 to 14.3) as compared with a −0.4-letter change (95% confidence interval, −4.1 to 3.3) in visual acuity for those without a 20% reduction ( P < .01). Conclusions In addition to being above the level of measurement uncertainty, a 20% change in retinal thickness in patients with macular edema seems to be optimal for clinically important changes in visual acuity and may be considered as an outcome for clinical trials of treatments for uveitic macular edema.
The purpose of this study was to evaluate the role of systemic steroids in post-procedural endophthalmitis as the role of intravitreal steroids in treatment algorithms of endophthalmitis remain ...controversial.
This is a retrospective analysis from a single tertiary referral center of all patients older than 18 years old that developed presumed post-procedure endophthalmitis and were treated at our center from 2009 to 2018.
Eighty-three patients were followed after being treated for post-procedural endophthalmitis that either received systemic steroids or did not around the time of diagnosis. Almost 30 % of all patients regained a final visual acuity of 20/40 or better, while 31.2% had poor visual outcomes of count fingers or worse. Non-clearing debris was the most significant long-term complication. Visual improvement plateaued in 67.7% by 1 month after diagnosis and initial treatment in both groups. There was no difference in visual outcomes when comparing the sixteen patients that received systemic steroids and the sixty-seven that did not; however, no enucleation or evisceration was required in patients receiving systemic steroids. Five patients that did not receive systemic steroids required an enucleation or evisceration due to a blind, painful eye.
The use of systemic steroids does not seem to worsen long-term outcomes of endophthalmitis compared to those patients that did not receive them and they may prove beneficial in the most severe cases by reducing the risk of losing the globe altogether.
To evaluate agreement between fluorescein angiography (FA) and optical coherence tomography (OCT) results for diagnosis of macular edema in patients with uveitis.
Multicenter cross-sectional study.
...Four hundred seventy-nine eyes with uveitis from 255 patients.
The macular status of dilated eyes with intermediate uveitis, posterior uveitis, or panuveitis was assessed via Stratus-3 OCT and FA. To evaluate agreement between the diagnostic approaches, κ statistics were used.
Macular thickening (MT; center point thickness, ≥ 240 μm per reading center grading of OCT images) and macular leakage (ML; central subfield fluorescein leakage, ≥ 0.44 disc areas per reading center grading of FA images), and agreement between these outcomes in diagnosing macular edema.
Optical coherence tomography (90.4%) more frequently returned usable information regarding macular edema than FA (77%) or biomicroscopy (76%). Agreement in diagnosis of MT and ML (κ = 0.44) was moderate. Macular leakage was present in 40% of cases free of MT, whereas MT was present in 34% of cases without ML. Biomicroscopic evaluation for macular edema failed to detect 40% and 45% of cases of MT and ML, respectively, and diagnosed 17% and 17% of cases with macular edema that did not have MT or ML, respectively; these results may underestimate biomicroscopic errors (ophthalmologists were not explicitly masked to OCT and FA results). Among eyes free of ML, phakic eyes without cataract rarely (4%) had MT. No factors were found that effectively ruled out ML when MT was absent.
Optical coherence tomography and FA offered only moderate agreement regarding macular edema status in uveitis cases, probably because what they measure (MT and ML) are related but nonidentical macular pathologic characteristics. Given its lower cost, greater safety, and greater likelihood of obtaining usable information, OCT may be the best initial test for evaluation of suspected macular edema. However, given that ML cannot be ruled out if MT is absent and vice versa, obtaining the second test after negative results on the first seems justified when detection of ML or MT would alter management. Given that biomicroscopic evaluation for macular edema erred frequently, ancillary testing for macular edema seems indicated when knowledge of ML or MT status would affect management.
Proprietary or commercial disclosure may be found after the references.
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