Noninfectious Posterior Uveitis Research Articles

Brief research report: ETS-1 blockade increases ICAM-1 expression in activated human retinal endothelial cells

Intercellular adhesion molecule 1 (ICAM-1) is a central cell adhesion molecule for retinal transendothelial migration of the leukocytes in non-infectious posterior uveitis. Inhibiting ICAM1 gene transcription reduces induction of ICAM-1 in inflamed retinal endothelium. Based on published literature implicating transcription factor ETS-1 as an activator of ICAM1 gene transcription, we investigated the effect of ETS-1 blockade on ICAM-1 levels in cytokine-stimulated human retinal endothelial cells. We first examined ICAM1 and ETS1 transcript expression in human retinal endothelial cells exposed to tumor necrosis factor-alpha (TNF-α) or interleukin-1beta (IL-1β). ICAM1 and ETS1 transcripts were increased in parallel in primary human retinal endothelial cell isolates (n = 5) after a 4-hour stimulation with TNF-α or IL-1β (p ≤ 0.012 and ≤ 0.032, respectively). We then assessed the effect of ETS-1 blockade by small interfering (si)RNA on cellular ICAM1 transcript and membrane-bound ICAM-1 protein. ETS1 transcript was reduced by greater than 90% in cytokine-stimulated and non-stimulated human retinal endothelial cell monolayers following a 48-hour treatment with two ETS-1-targeted siRNA, in comparison to negative control non-targeted siRNA (p ≤ 0.0002). The ETS-1 blockade did not reduce ICAM1 transcript expression nor levels of membrane-bound ICAM-1 protein, rather it increased both for a majority of siRNA-treatment and cytokine-stimulation conditions (p ≤ 0.018 and ≤ 0.004, respectively). These unexpected findings indicate that ETS-1 blockade increases ICAM-1 transcript and protein levels in human retinal endothelial cells. Thus ETS-1-targeting would be expected to promote rather than inhibit retinal transendothelial migration of leukocytes in non-infectious posterior uveitis.

Effectiveness of Triamcinolone Acetonide Injection for the Treatment of Non-infectious Intermediate and Posterior Uveitis

Effectiveness of Triamcinolone Acetonide Injection for the Treatment of Non-infectious Intermediate and Posterior Uveitis

The Efficacy of Adalimumab in Children with Chronic Non-infectious Posterior Uveitis and Panuveitis: A Retrospective Cohort Study.

This study aimed to assess the efficacy and safety of adalimumab in pediatric patients with chronic non-infectious posterior uveitis and panuveitis (not associated with juvenile idiopathic arthritis). The medical records of children (< 18years old) with chronic non-infectious posterior uveitis and panuveitis were collected and analyzed in this retrospective cohort study. Children were allocated to a conventional adalimumab-free treatment (CT) or adalimumab (ADA) group based on whether they additionally received adalimumab. In total, 69 children (138 eyes) were included, with 21 (42 eyes) and 48 (96 eyes) in the CT and ADA groups, respectively. During the average follow-up period of 24months, the improvement in all ocular parameters (best-corrected visual acuity, intraocular inflammation, fluorescein angiography score) was better in the ADA group than in the CT group, except for changes in central macular thickness, which did not significantly differ between the groups. The mean time of first alleviation, which was after 1.03 ± 0.12months of therapy, was earlier in the ADA group than in the CT group (2.30 ± 0.46months). In the ADA group, 90.6% of children had remission within 3months, and 47.9% had no relapse during follow-up. Cough and cold were the most common adverse events in the ADA group; however, the number of adverse events was similar between both the groups. Adalimumab was effective in the treatment of chronic noninfectious posterior uveitis and panuveitis in pediatric patients, and disease inactivity was accomplished in the majority of the patients, thereby improving visual outcomes and maintaining disease stability. Adverse events were limited and tolerable.

Uveitis Onset and Flare-Up: Does the Time of Year Matter?

ABSTRACT Purpose This retrospective chart review tests the hypothesis that initial presentation and flare-up of non-infectious anterior, intermediate, and posterior uveitis varies by month, temperature season, and calendar season among the patient population in Connecticut. Methods The medical records of all adult patients presenting with a chief concern or diagnosis of “uveitis” at a university-based clinic between March 2013 and February 2019 and a community-based clinic between January 2016 and February 2019 in Connecticut were reviewed. Ongoing, chronic uveitis and infectious/traumatic uveitis were excluded. Patient age, sex, comorbid autoimmune conditions, time of onset, and anatomical location of uveitis was collected. χ 2 testing evaluated variation in uveitis presentation based on month, calendar season, and temperature. Results 353 cases of endogenous uveitis were identified among 272 patients. There was no significant variation by month, calendar season, or temperature across the entire population. There was no significant variation by temperature when assessing anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis cases separately. Though flare-ups did not show any significant seasonal trends, there was significant variation by temperature for new uveitis episodes. Uveitis episodes in patients with autoimmune conditions were shown to have significant variation by temperature. Uveitis episodes in HLA-B27 positive patients were found to have significant variation by both temperature and month. Conclusion While variation by month, calendar season, or temperature is not present for all uveitis patients, a subset of patients with comorbid autoimmune conditions, specifically HLA-B27 positive, experience temperature variations with increasing incidence of flare-ups in transitional months in Connecticut.

Healthcare professionals’ views on the most important outcomes for non-infectious uveitis of the posterior segment: A qualitative study

Background Uveitis comprises a range of conditions that result in intraocular inflammation. Most sight-threatening uveitis falls into the broad category known as Non-infectious Posterior Segment-Involving Uveitis (PSIU). To evaluate treatments, trialists and clinicians must select outcome measures. The aim of this study was to understand healthcare professionals’ perspectives on what outcomes are important to adult patients with PSIU and their carers. Methods Twelve semi-structured telephone interviews were undertaken to understand the perspectives of healthcare professionals. Interviews were audio recorded, transcribed and thematically analysed. Findings were compared with the views of patients and carers and outcomes abstracted from a previously published systematic review. Results Eleven core domains were identified as important to healthcare professionals: (1) visual function, (2) symptoms, (3) functional ability, (4) impact on relationships, (5) financial impact, (6) psychological morbidity and emotional well-being (7) psychosocial adjustment to uveitis, (8) doctor / patient / interprofessional relationships and access to health care, (9) treatment burden, (10) treatment side effects, (11) disease control. Healthcare professionals recognised a similar range of domains to patients and carers but placed more emphasis on certain outcomes, particularly in the disease control domain. In contrast the range of outcomes identified via the systematic review was limited. Conclusion Healthcare professionals recognise all of the published outcome domains as patients/carers in the previous publication but with subtly differing emphasis within some domains and with a priority for certain types of measures. Healthcare professionals discussed the disease control and side effects/complications to a greater degree than patients and carers in the focus groups

Corticosteroid implants for chronic non-infectious uveitis.

Corticosteroid implants for chronic non-infectious uveitis.

Review on imaging methods in non-infectious posterior uveitis, principles, relevance, and practical clinical applications to disease entities

The work-up and diagnosis of posterior uveitis rely heavily on multiple imaging methods that have become available beyond the mere photographic imaging and fluorescein angiography (FA) used to image uveitis in the past. Global assessment and precise follow-up of posterior uveitis were achieved with the development of indocyanine green angiography (ICGA) since the mid-1990ties that, together with FA, made it possible to perform dual FA and ICGA giving information on both the retina and the choroidal compartment. Further non-invasive imaging methods were developed subsequently that contributed to additional valuable information completing the dual FA/ICGA basic appraisal of uveitis, including (1) optical coherence tomography (OCT) giving a quasi-histological morphology of retinal structures of the posterior pole, (2) enhanced-depth imaging OCT (EDI-OCT) allowing to image the choroidal compartment and (3) blue light fundus autofluorescence (BAF) showing the integrity or damage of the retinal pigment epithelium, the photoreceptors and the outer retina. OCT-angiography (OCT-A) became available more recently and presented the advantage to image the retinal and choroidal circulations without needing dye injections, necessary for dual FA/ICGA. This review article will illustrate the principles, relevance and practical applications of these different imaging methods used in uveitis by examining the main categories of non-infectious posterior uveitis entities including (1) retinal inflammatory disorders, inflammatory diseases of the outer retina and of the choriocapillaris (choriocapillaritis) and stromal choroiditis.

Noninfectious posterior uveitis

Noninfectious posterior uveitis (NPU) comprises aheterogeneous group of vision-threatening, immune-mediated ocular and systemic diseases. It is predominantly bilateral and recurrent and, if not treated properly, leads to severe tissue damage that threatens the eyesight. In industrialized countries ca. 10-20% of all cases of blindness are caused by NPU. An NPU can occur at any age but is most common between the ages of20 and50 years. Laboratory diagnostic and imaging procedures enable an increasingly better differentiation of the disease spectrum. This makes it possible to better assess the course and prognosis of individual disease entities. An increasing repertoire of systemic and intravitreal forms of treatment has already led to more favorable long-term treatment outcomes. It can be expected that further progress can be achieved with better knowledge of the pathophysiology of the different clinical disorders and appropriate, targeted treatment.

OCT Angiography in Noninfectious Uveitis: A Description of Five Cases and Clinical Applications.

Optical coherence tomography angiography (OCTA) is a noninvasive imaging modality used to analyze the retinochoroidal vasculature and detect vascular flow. The resulting images can be segmented to view each vascular plexus individually. While fluorescein angiography is still the gold standard for the diagnosis of posterior uveitis, it has limitations, and can be replaced by OCTA in some cases. This case series describes five patients with posterior noninfectious uveitis and their description by OCTA. Cases included lupus retinopathy (n = 1) for which OCTA showed ischemic maculopathy as areas of flow deficit at the superficial and deep capillary plexus; choroidal granulomas (n = 1) with a non-detectable flow signal in the choroid; active punctate inner choroiditis and multifocal choroiditis (n = 1) with OCTA that showed active inflammatory chorioretinal lesions as non-detectable flow signals in choriocapillaris and choroid; dense type 2 inflammatory secondary neovascularization (n = 1) associated with active choroiditis; and acute posterior multifocal placoid pigment epitheliopathy (APMPPE) (n = 1) without flow abnormalities at the superficial and deep retinal plexuses but non-detectable flow at the levels of the choriocapillaris and choroid. Ophthalmologists can use OCTA to identify inflammatory changes in retinal and choroidal vasculature, aiding in the diagnosis, management, and monitoring of posterior uveitis.

Intravitreal Fluocinolone Acetonide Implant (ILUVIEN®) for the Treatment of Retinal Conditions. A Review of Clinical Studies.

Fluocinolone acetonide (FAc) intravitreal implant (Iluvien®) is a corticosteroid implant indicated for the treatment of diabetic macular oedema (DMO) in patients who have previously received conventional treatment without good response, non-infectious posterior uveitis, and as an off-label treatment of the macular oedema secondary to retinal vein occlusion. FAc is a non-biodegradable 0.19 mg intravitreal implant which is designed to release FAc over 3 years at a rate of approximately 0.2 mcg per day. The aim of this review is to describe the special pharmacological properties of Iluvien and display the outcomes of the most important clinical trials and real-world studies regarding its efficacy and safety for the management of the above retinal disorders.

Treatment of Non-Infectious Posterior Uveitis with Dexamethasone Intravitreal Implants in a Real-World Setting.

The present study aimed to assess the efficacy and safety associated to the treatment of patients with non-infectious posterior uveitis with intravitreal dexamethasone (DEX) implants in a real-world clinical setting. This is a retrospective, single center analysis of the data from 29 patients with non-infectious posterior uveitis in whom 38 eyes were treated with dexamethasone intravitreal implants in routine clinical practice between January 2012 and October 2017. The parameters of visual acuity (VA), intraocular pressure (IOP) and central retinal thickness (CRT) were recorded 6 weeks after the first implant was administered, in accordance with the clinical guidelines for the use of these implants, and after a 6-month follow-up period. In addition, the formation of cataracts was evaluated at 12 months. Treatment with the DEX implant caused a significant improvement in the VA from baseline at 6 weeks in eyes treated with 2-6 implants and for eyes without cataracts. A significant decrease in CRT was observed relative to the baseline at 6 weeks for eyes treated with 1 and 2-6 implants, which was maintained at 6 months for those eyes treated with 2-6 implants. This significant improvement in CRT at 6 weeks and 6 months was evident in eyes with and without cataracts. During the study period, the IOP was found to increase significantly from baseline at 6 weeks in some eyes but this was managed topically, and no surgical intervention was necessary. Intravitreal DEX implants represent an effective and safe therapy for the treatment of non-infectious uveitis in routine clinical practice, producing favorable visual and anatomical outcomes after the administration of just 2-6 DEX implants.

Corticosteroid implants for chronic non-infectious uveitis.

Corticosteroid implants for chronic non-infectious uveitis.

A new small molecule DHODH-inhibitor [KIO-100 (PP-001)] targeting activated T cells for intraocular treatment of uveitis - A phase I clinical trial.

[https://www.clinicaltrials.gov/ct2/show/NCT03634475], identifier [NCT03634475].

Expression of Long Non-Coding RNAs in Activated Human Retinal Vascular Endothelial Cells

ABSTRACT Purpose Retinal endothelial cell activation is a central event in non-infectious posterior uveitis. There is recent interest in long non-coding (lnc)RNA-targeted therapeutics for retinal diseases. We aimed to identify human retinal endothelial cell lncRNAs that might be involved in activation. Methods Eleven candidate lncRNAs were identified: GAS5, KCNQ1OT1, LINC00294, MALAT1, MEG3, MIR155HG, NEAT1, NORAD, OIP5-AS1, SENCR, TUG1. Expression was assessed by RT-PCR in human retinal endothelial cells, at baseline and following activation with interleukin (IL)-1β and tumor necrosis factor (TNF)-α. Results IL-1β significantly upregulated MEG3 and SENCR at 4 and 24 hours; LINC00294, NORAD, OIP5-AS1 and TUG1 at 24 hours; and MIR155HG at 4, 24 and 48 hours; but downregulated GAS5 at 24 and 48 hours. TNF-α significantly upregulated KCNQ1OT1, LINC00294, MEG3, NORAD and SENCR at 4 hours; SENCR and TUG1 at 24 hours; and MIR155HG at all time points. Conclusions Future studies involving manipulation of MIR155HG may be warranted to explore potential therapeutic applications for non-infectious posterior uveitis.

APRIL and BAFF play a key role in differentiating vitreoretinal lymphoma from uveitis

BackgroundEarly diagnosis of vitreoretinal lymphoma (VRL) is critical for the successful treatment of this rare intraocular malignancy. However, fast and reliable diagnosis of VRL in patients presenting with intermediate or posterior non-infectious uveitis remains a challenge. A proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) are vital factors in the pathophysiology, diagnosis, and prognosis of primary central nervous system lymphoma (PCNSL) and systemic autoimmune diseases. However, their utility as biomarkers for the diagnosis of VRL and uveitis remains unclear. MethodsIn this retrospective study, we analyzed APRIL and BAFF levels in the aqueous humor (AH) of 43 eyes of 40 patients, including 23 eyes of 20 patients with VRL, eight eyes of eight patients with uveitis, and 12 eyes of 12 patients with other ocular diseases (OODs). Additionally, we measured their levels after induction of chemotherapy in five eyes of five patients with VRL. ResultsAH levels of APRIL reliably distinguished VRL from uveitis, with a specificity of 78.3% and sensitivity of 75%. BAFF also showed similar potential. Serial AH analysis of patients with VRL during chemotherapy demonstrated a corresponding decline in AH levels of APRIL and BAFF. ConclusionThis study extends the spectrum of valuable diagnostic biomarkers for VRL and uveitis. In patients with uveitis, the assessment of AH APRIL may help accelerate the diagnosis of VRL. Moreover, our results underline the important role of APRIL and BAFF in therapeutic monitoring of VRL.

Microvascular changes in the recurrent cystoid macular edema secondary to posterior noninfectious uveitis on optical coherence tomography angiography

BackgroundPosterior uveitis represents the second most frequent type of uveitis (15–30% of all uveitis). Noninfectious posterior uveitis complicated with secondary cystoid macular edema (CME) affects the visual prognosis negatively. The objective of the current study is to detect possible microvascular changes causing relapsing uveitis-related CME using optical coherence tomography angiography (OCTA).MethodsThis is an interventional, observational, retrospective study with 1 year follow-up. Patients with noninfectious, posterior uveitis-related CME undergoing dexamethasone (DEX) implant were evaluated. Following the DEX-implant were carried out control visits after 1 month, 2-months, 4-months, 6-months, and for up 1-year. A total of 76 eyes of 38 consecutive patients with noninfectious posterior uveitis were enrolled (consecutive sample). Complicated noninfectious posterior uveitis with secondary CME was diagnosed in 56 eyes of uveitis patients (73.7%) and reviewed.ResultsOur investigation showed (1) a reduction in superficial vessel plexus (SVP) measurements within 2-month (84%), reaching 96.4% for up 1-year, (2) an irregular profile of SVP in 69.6% of cases, persisting for up 1-year; relapsing uveitis-related CME eyes with irregular superficial foveal avascular zone (FAZ) profile were in 51%, while the SVP measurements reestablished in 100% of cases. Conversely, (3) the deep vascular plexus (DVP) parameters restored in a lower number of eyes within the 2-month (39.3%), remaining abnormal in 46.4% of cases for up 1-year; despite DVP restored in 53.6% of cases for up 1 year, (4) a capillary rarefaction ring around the FAZ appeared in 80.4% of cases; the relapsing uveitis-related CME eyes with abnormal DVP parameters were present in 41% of cases, of which 92.1% showed a rarefaction ring had abnormal DVP.ConclusionsThe use of OCTA enabled the evaluation in detail of retinal microvascular changes. We suggested that the possibility of the recurrence of the uveitis-related CME depends on the persistence of modifications of the superficial and deep layers. In this regard, we propose to implement the current imaging armamentarium with OCTA for the follow-up of patients with noninfectious uveitis-related CME.

Key Multimodal Fundus Imaging Findings to Recognize Multifocal Choroiditis in Patients With Pathological Myopia.

Myopia represents a major socioeconomic burden with an increasing prevalence worldwide. Pathologic myopia refers to myopic patients with structural changes in the posterior pole including different patterns of chorioretinal atrophy, choroidal neovascularization (CNV) and vitreomacular tractional diseases. Multifocal choroiditis (MFC) is one of the most frequent noninfectious posterior uveitis, and epidemiologically typically affects young myopic females. Acute and chronic chorioretinal atrophic changes are the hallmark feature of MFC, with CNV developing in almost one third of cases. Thus, differentiation of inflammatory lesions due to MFC or neurodenegerative lesions due to pathologic myopic is key in order to establish a particular prognosis, follow-up schedule, and therapeutic approach. The aim of the present manuscript is to summarize and illustrate the main multimodal imaging features of these diseases.

A comprehensive review of intravitreal immunosuppressants and biologicals used in ophthalmology.

Systemic immunosuppressants and biologicals have been a valuable tool in the treatment of inflammatory diseases and malignancies. The safety profile of these drugs has been debatable, especially in localized systems, such as the eye. This has led to the search for fairly local approaches, such as intravitreal, subconjunctival, and topical route of administration. Immunosuppressants have been used as a second-line drug in patients intolerable to corticosteroids or those who develop multiple recurrences on weaning corticosteroids. Similarly, biologicals have also been used as the next line of therapy, when adequate control of inflammation could not be attained or immunosuppressants were contraindicated to patients. Intravitreal immunosuppressants, such as methotrexate and sirolimus, have been extensively studied in noninfectious posterior uveitis, whereas limited studies have established the efficacy of intravitreal biologicals, such as infliximab and adalimumab. Most of these drugs have shown good safety profile and tolerability in animal studies alone and have not been studied further in human subjects. However, most of the studies in literature are single-case reports or case series which limits the level of evidence. In this comprehensive review, we discuss the mechanism of action, pharmacodynamics, pharmacokinetics, indications, efficacy, and side effects of different intravitreal immunosuppressants and biologicals that have been studied in literature.

Toxic retinopathy and optic neuropathy in long-term tacrolimus intake

Tacrolimus is an effective immunosuppressive agent that is widely used in transplant surgery. Rare complications of its usage include optic neuropathy or maculopathy development.&#x0D; AIM: To present a clinical case of tacrolimus-induced optic neuropathy and retinopathy&#x0D; CLINICAL CASE. A family with a 17-year-old boy was referred to Helmoltz National Medical Research Center of Eye Diseases with complaints of sudden painless decreased vision in his right eye. The best-corrected visual acuity was the right eye of 0.3 and the left eye of 1.0. Ophthalmoscopy of his right eye revealed pigment mottling in the macula and paramacular region, mid-peripheral patchy pigment deposition in 2, 4, and 8 clock meridians. No pathological findings were revealed in his fellow eye. From the anamnesis, 15 years ago, the patient underwent liver transplantation (Alagille syndrome). From the moment of surgery to the date he received tacrolimus. Optical coherence tomography highlighted foveal smoothing, ellipsoid zone and retinal pigment epithelium disruption, macular and paramacular choroid thinning, and neuroretinal rim thickening. Computed microperimetry revealed a significantly decreased sensitivity in the central retinal zone of the right eye. Autofluorescence examination showed multiple punctate hypoautofluorescent spots in the macula and paramacula in the right eye, as well as hyperautofluorescent zones in the posterior pole in both eyes. Electric activity analysis has revealed decreased full-field electroretinogram parameters and P100 amplitude in visually-evoked potentials in the right eye and a decreased a-wave full-field electroretinogram of the left eye. The data provided by the parents suggest that the target tacrolimus concentration in plasma was exceeded 2 times just before the patient noticed vision impairment. Differential diagnoses included infectious and non-infectious posterior uveitis.&#x0D; CONCLUSION: The first case of combined retinopathy and optic neuropathy in adolescents induced by long-term tacrolimus treatment was described.

Efficacy of 0.19mg Fluocinolone Acetonide Implant in Non-infectious Posterior Uveitis Evaluated as Area Under the Curve.

IntroductionThis study reports the outcomes of fluocinolone acetonide intravitreal implant (FAc, Iluvien®, SIFI, Italy) in patients affected by macular edema secondary to chronic non-infectious uveitis of the posterior segment (NIU-PS).MethodsThis was a retrospective study of patients with NIU-PS and macular thickening undergoing FAc implant at San Raffaele Hospital (Milan, Italy). Clinical data, including best-corrected visual acuity (BCVA), intraocular pressure (IOP), and central macular thickness (CMT), were collected at the time of FAc administration (baseline) and at 1, 6, and 12 months. The area under the curve (AUC) of the BCVA (AUCBCVA) and CMT (AUCCMT) was correlated with baseline factors; β estimates and 95% confidence interval (CI) are provided.ResultsTen eyes of seven patients (60 ± 12 years; 4 male, 57%) were included. The BCVA significantly improved from month 6 (p = 0.03). The CMT improved from month 1 and was persistently lower than baseline until month 12 (p < 0.001). The AUCBCVA correlated with baseline BCVA (β = 2.5 logMAR; 95% CI 1.59–3.41; p < 0.001), while the mean AUCCMT positively correlated with the baseline CMT (β = 2.1 μm; 95% CI 0.41–3.80; p = 0.02). No adverse events were recorded over 1 year.ConclusionsBetter visual acuity at the time of FAc administration was associated with better visual function after FAc. Less severe macular edema correlated with better anatomic response. The FAc implant was a safe option for resolving macular edema secondary to NIU-PS.