Outcomes for posterior segment-involving uveitis: from heterogeneity to a core outcome set

Uveitis describes a group of diseases characterised by intraocular inflammation. Uveitis is the fifth commonest cause of visual loss in the developed world and accounts for about 10–15% of total blindness. Intermediate, posterior and panuveitis are the most critical forms of uveitis named as Posterior Segment-Involving Uveitis (PSIU). They often share common clinical features and higher risk of complications (e.g. uveitic macular oedema (UMO)), requiring additional treatment either systemic or local injection-based therapy. UMO describes the accumulation of fluids at the central part of the retina, known as the macula. It is the leading cause of sight-loss in PSIU affecting around one-third of patients. To date, there has been a lack of consensus guidelines over the treatment of UMO. Furthermore, trials include a range of heterogeneous outcomes which may lack relevance to key stakeholders (patients and carers) and means that it is challenging to compare results from trials and undertake evidence synthesis. The doctoral research forming my thesis aimed to: (i) assess the effectiveness of the available pharmacological therapies used in the treatment of UMO; (ii) develop an international consensus on a standardised set of outcomes using a multi methods approach to create a core outcome set (COS) for non-infectious PSI

Outer Retinopathies Associated with COVID-19 Infection:Case Reports and Review of Literature

Background. The coronavirus disease (COVID-19) is a highly contagious disease with profound health implications. It can affect any part of the body with variable severity. Various ophthalmic manifestations of coronavirus disease have been documented. Case Presentations. We reported three cases of outer retinopathies associated with COVID-19 infection. All three patients were young females. The first two patients presented within days of COVID-19 infection with complaints of black spots in the eyes. Multimodal retinal imaging showed lesions consistent with acute macular neuroretinopathy. Lesions were bilateral in the first patient and unilateral in the second one. Our third patient presented with blurred vision in one eye, 3 months after a suspected COVID-19 infection. Retinal imaging showed outer retinopathy. Our patients’ vision was good and maintained during the follow-up. All three were monitored on observation only, and symptoms and lesions improved with time. Conclusion. In conclusion, COVID-19-related thromboinflammatory response can result in localized vascular inflammation and hypoperfusion in any of the retinal capillary plexuses or choriocapillaris resulting in ischemia of the corresponding retinal or choroidal layers

Outcomes important to patients with non-infectious posterior segment-involving uveitis:a qualitative study

Objective: Uveitis, a group of disorders characterised by intraocular inflammation, causes 10–15% of total blindness in the developed world. The most sight-threatening forms of non-infectious uveitis are those affecting the posterior segment of the eye, collectively known as posterior-segment involving uveitis (PSIU). Numerous different clinical outcomes have been used in trials evaluating treatments for PSIU but these may not represent patients’ and carers’ concerns. Therefore, the aims of this study were to understand the impact of PSIU on adult patients’ and carers’ lives, and to explore what outcomes of treatment are important to them.Methods: Four focus group discussions were undertaken to understand the perspectives of adult patients (n=18) and carers (n=10) with PSIU. Participants were grouped according to whether or not their uveitis was complicated by the sight-threatening condition uveitic macular oedema (UMO). Discussions were audio recorded, transcribed and analysed using the framework analytical approach. Outcomes were identified and grouped into outcome domains. Results: Eleven core domains were identified as important to patients and carers undergoing treatment for PSIU comprising: (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.Conclusion: The domains identified represent patients and carers experience and perspectives and can be used to reflect on outcomes assessed in PSIU. They will directly inform the development of a core outcome set for PSIU clinical trials.Ethical approval: Ethical approval was obtained from the United Kingdom National Research Ethics Service (Reference 17-WM-0111).<br/

Anti-tumour necrosis factor biological therapies for the treatment of uveitic macular oedema (UMO) for noninfectious uveitis

BackgroundNon‐infectious uveitis describes a heterogenous group of ocular disorders characterised by intraocular inflammation in the absence of infection. Uveitis is a leading cause of visual loss, most commonly due to uveitic macular oedema (UMO). Treatment is aimed at reducing disease activity by suppression of the intraocular inflammatory response. In the case of macular oedema, the aim is to restore macular architecture as quickly as possible, in order to prevent irreversible photoreceptor damage in this area. Acute exacerbations are typically managed with corticosteroids, which may be administered topically, locally or systemically. Whilst these are often rapidly effective in achieving disease control, long‐term use is associated with significant local and systemic side effects, and 'steroid sparing agents' are typically used to achieve prolonged control in severe or recalcitrant disease. Anti‐tumour necrosis factor (TNF) drugs block a critical cytokine in the inflammatory signalling process, and have emerged as effective steroid‐sparing immunomodulatory agents in a wide range of non‐ocular conditions. There is mechanistic data to suggest that they may provide a more targeted approach to disease control in UMO than other agents, but to date, these agents have predominantly been used 'off label' as the majority are not licensed for ocular use. This review aims to summarise the available literature reporting the use of anti‐TNF therapy in UMO, thus developing the evidence‐base on which to make future treatment decisions and develop clinical guidelines in this area.ObjectivesTo assess the efficacy of anti‐TNF therapy in treatment of UMO.Search methodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 2), which contains the Cochrane Eyes and Vision Trials Register; Ovid MEDLINE; Ovid Embase; LILACS; Web of Science Conference Proceedings Citation Index‐ Science (CPCI‐S); System for Information on Grey Literature in Europe (OpenGrey); the ISRCTN registry; ClinicalTrials.gov and the WHO ICTRP. The date of the search was 29 March 2018.Selection criteriaWe planned to include all relevant randomised controlled trials assessing the use of anti‐TNF agents in treatment of UMO. No limits were applied to participant age, gender or ethnicity. The primary comparisons of this review were: anti‐TNF versus no treatment or placebo; anti‐TNF versus another pharmacological agent; comparison of different anti‐TNF drugs; comparison of different doses and routes of administration of the same anti‐TNF drug. The primary outcome measure that we assessed for this review was best‐corrected visual acuity (BCVA) in the treated eye. Secondary outcome measures were anatomical macular change, clinical estimation of vitreous haze and health‐related quality of life.Data collection and analysisTwo review authors independently screened titles and abstracts retrieved through the database searches. We retrieved full‐text reports of studies categorised as 'unsure' or 'include' after we had reviewed the abstracts. Two review authors independently reviewed each full‐text report for eligibility. We resolved discrepancies through discussion.Main resultsWe identified no completed or ongoing trial that was eligible for this Cochrane Review.Authors' conclusionsOur review did not identify any evidence from randomised controlled trials for or against the role of anti‐TNF agents in the management of UMO. Although there are a number of high‐quality randomised controlled trials that demonstrate the efficacy of anti‐TNF agents in preventing recurrence of inflammation in uveitis, the reported study outcomes do not include changes in UMO. As a result, there were insufficient data to conclude whether there was a significant treatment effect specifically for UMO. Future trials should be designed to include quantitative measures of UMO as primary study outcomes, for example by reporting the presence or absence of UMO, or by measuring central macular thickness for study participants. Furthermore, whilst UMO is an important complication of uveitis, we acknowledge that uveitis is associated with many significant structural and functional complications. It is not possible to determine treatment efficacy based on a single outcome measure. We recommend that future reviews of therapeutic interventions in uveitis should use composite measures of treatment response comprising a range of potential complications of disease.<br/

COSUMO: study protocol for the development of a core outcome set for efficacy and effectiveness trials in posterior segment-involving uveitis

Abstract Background Uveitis, a group of disorders characterised by intraocular inflammation, causes 10–15% of total blindness in the developed world. The most sight-threatening uveitis affects the posterior segment of the eye (posterior-segment involving uveitis (PSIU)). Numerous different outcomes have been used in clinical trials evaluating alternative treatments for uveitis, limiting inter-trial comparison and aggregation of data. We aim to develop a core outcome set (COS) that would provide a standardised set of outcomes to be measured and reported in all effectiveness trials for PSIU. Methods A three-phase design will be used informed by recommendations from the Core Outcome Measures in Effectiveness Trials (COMET) initiative. Phase 1: a comprehensive list of outcomes will be identified through both a systematic review of effectiveness trials of PSIU and qualitative research with stakeholders. The qualitative study will comprise focus groups with patients and their carers in parallel with one-to-one telephone interviews with health professionals and policy-makers. In the focus groups, patients will be grouped according to whether or not their uveitis is complicated by the sight-threatening condition uveitic macular oedema (UMO) since it is hypothesised that the presence of UMO may significantly impact on patient experience of PSIU. Phase 2: Delphi methodology will be used to reduce the range of potential outcomes for the core set. Up to three Delphi rounds will be used through an online survey. Participants will be asked to rate the importance of each outcome on a 9-point Likert scale where 9 is most important. Phase 3: a consensus meeting will be held with key stakeholders to discuss the Delphi results and ratify the final outcomes to be included in the COS. Discussion The development of an agreed COS for PSIU would help ensure that outcomes which matter to key stakeholders are captured and reported in a consistent way. A COS for PSIU would allow greater comparison and aggregation of data across trials for the better evaluation of established and emerging therapies through evidence synthesis and meta-analysis to inform clinical guidelines and health policy. Trial registration COMET. http://comet-initiative.org/studies/details/640 . August 2015

Sudden onset peripheral visual deficit secondary to retinal artery spasm in Raynaud's phenomenon.

A 32-year-old doctor, who has a medical history of primary Raynaud's disease and previous scotomas, presented to eye clinic with sudden onset blurring of vision (infero-nasally) with no other associated symptoms. The patient had good visual acuity bilaterally (6/6) and no anterior chamber activity or conjunctival hyperaemia. Findings consistent with a nerve fibre layer infarct were noted in the right eye, with unremarkable examination of the left eye. Optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) images were obtained, which showed an area of capillary shut down in keeping with a nerve fibre layer lesion. Previous literature pertaining to similar symptoms is sparse with symptoms such as migraines, epilepsy and visual loss being stated. This case provides further evidence of Raynaud's associated retinal artery spasm, with complete resolution at 4 weeks. We also demonstrate the accessibility of OCT and more importantly OCTA for investigation of sudden onset visual deficit

Development of a Core Outcome Set for Clinical Trials in Non-infectious Uveitis of the Posterior Segment.

PURPOSE To develop an agreed set of outcomes known as a core outcome set (COS) for Non-Infectious Uveitis of the Posterior Segment (NIU-PS) clinical trials. DESIGN Mixed-methods study design comprising a systematic review and qualitative study followed by a two round Delphi exercise and face-to-face consensus meeting. PARTICIPANTS Key stakeholders including: patients diagnosed with NIU-PS; their caregivers; healthcare professionals involved in decision-making for patients with NIU-PS including ophthalmologists, nurse practitioners and policymakers/commissioners. METHODS A long list of outcomes was developed based on the results of (1) a systematic review of clinical trials of NIU-PS and (2) a qualitative study of key stakeholders including focus groups and interviews. The long list was used to generate a two-round Delphi exercise of stakeholders rating the importance of outcomes on a nine-point Likert scale. The proportion of respondents rating each item was calculated, leading to recommendations of 'include', 'exclude' or 'for discussion' that were taken forward to a face-to-face consensus meeting of key stakeholders at which the final COS was agreed. MAIN OUTCOME MEASURE Items recommended for inclusion in the COS for NIU-PS RESULTS: A total of 57 outcomes grouped in 11 outcome domains were presented for evaluation in the Delphi exercise, resulting in 9 outcomes directly qualifying for inclusion and 15 outcomes being carried forward to the consensus meeting of which 7/15 were agreed for inclusion. The final COS contained 16 outcomes organized into 4 outcome domains comprising visual function, Health Related Quality of Life (HRQoL), treatment side effects and disease control. CONCLUSION This study builds on international work across the clinical trials community and our qualitative research to construct the world's first COS for NIU-PS. The COS provide a list of outcomes that represent the priorities of key stakeholders and provides a minimum set of outcomes for use in all future NIU-PS clinical trials. Adoption of this COS can improve the value of future uveitis clinical trials and reduce non-informative research. Some of the outcomes identified do not yet have internationally agreed methods for measurement and should be the subject of future international consensus development. TRIAL REGISTRATION The study was registered with COMET (http://comet-initiative.org/studies/details/640)