Award Title: Developing imaging based and patient reported disease metrics to stratify childhood inflammatory eye disease: Childhood Uveitis Signs and Symptoms Study (ChUSS)
Funder: Department of Health and Social Care

Abstract: Childhood uveitis (intraocular inflammation) comprises a heterogenous group of conditions, the most common being juvenile idiopathic arthritis (JIA). However, 20% - 50% of childhood uveitis occurs as isolated idiopathic ocular disease. One in five children with uveitis reach adulthood having already permanently lost vision in at least one eye. Disease activity can continue through to mid-adulthood. The key to preventing uveitis related blindness is prompt control of disease. Novel immunomodulatory therapies have been shown to be effective in JIA uveitis (JIAu), but up to a quarter of children with JIAu do not respond to these new therapies, and we lack high level comparative therapeutic research for other forms of paediatric uveitis. We also lack disease classification and quantification metrics sufficiently sensitive and robust to allow prognostication research. Uveitis is currently qualified and quantified using slit-lamp biomicroscopic examination, and graded using a subjective, qualitative scale which is open to interobserver variability when used in adults, and not validated for use in children. Optical coherence tomography (OCT), is a non-invasive, high speed, high resolution modality, with a recent adaptation (OCT angiography, OCTA) capable of imaging uveal vasculature. Childhood uveitis is conventionally described as 'asymptomatic', but arguably this reflects the absence of tools to capture the child's experience of disease, which is sometimes subtle but nevertheless tangible. Additionally, for children with uveitis, symptoms may be an informative discriminator of disease subtype. I hypothesise that A) disease symptomatology, and B) imaging (optical coherence tomography / OCT-angiography) can be captured with precision in childhood uveitis, and can:	quantify disease activity, acting as diagnostic and monitoring tools, and providing a surrogate endpoint 	describe clusters of separate disease subgroups 	provide (as a disease biomarker) a method of predicting disease stratification by response to treatment and / or risk of adverse outcome.I propose to undertake three invstigations	Application of emerging technology to develop imaging based prognostic and monitoring biomarkers Methods: Investigation of feasibility, repeatability, reliability and reproducibility of OCT/OCTA imaging in childhood (ages 2-18) across age groups and across sites, and clinical validation of imaging derived disease biomarkers.	Development of age-specific subjective disease activity scoresMethods: Information gathering from children / families affected by childhood uveitis, face validity analysis of items through council of clinical expertise, piloting of tool and investigation of construct validity and internal consistency.	Multicentre prospective cohort studyMethods: Harmonised collection of clinical and sociodemographic data. Longitudinal follow up of this cohort (providing currently unavailable data on natural history), and logistic and Cox regression modelling of the association between imaging derived and patient reported parameters and outcomes of interest (therapeutic response, adverse ocular structural outcomes) with adjustment for potential confounders. My ambition is to deliver the metrics needed to classify and quantify disease type and severity in childhood uveitis, enabling disease stratification and sensitive, robust, validated measurement of therapeutic response, in order to improve prognostication and disease management precision.

Lay Abstract: Background:Childhood uveitis is a rare inflammatory eye disease. One in every five affected children loses vision in at least one eye before reaching the age of 16, due to structural damage caused by uncontrolled inflammation. The uveitis can continue to be active into mid-adulthood. Uveitis can affect the front (anterior), middle (intermediate) or back (posterior) section of the eye. In childhood the most common type of disease is a chronic (long-lasting) anterior uveitis. Many different infectious and non-infectious diseases can result in uveitis, but for the majority of children (>80%) the disease is 'idiopathic', that is, no cause has yet been found. Approximately half of all children with uveitis also have a disease causing inflammation of the joints: juvenile idiopathic arthritis (or JIA). Children with JIA must travel to a specialist centre every three months to have eye examinations in an attempt to pick uveitis up early enough to prevent visual loss. This is necessary as not all children with uveitis are aware of the inflammation, and the disease can start at a young age before children are able to describe what's happening to them. Study Aims - filling the evidence gaps identified by patients:A recent national priority setting (James Lind) exercise involving patients and families affected by inflammatory eye disease identified key gaps in our understanding of disease for the majority of affected children:	We do not understand the causes of disease 	We cannot predict response to our existing therapies 	We cannot predict long term outcomesNewly emerging 'biological' therapies have proven themselves to be effective for certain populations of children with uveitis, but: 	We do not know if children with milder disease truly benefit from these (and other) powerful systemic medications which require frequent blood monitoring, frequent hospital admissions, and carry significant short and long term risk of adverse events.The current disease scale which we use to monitor response to therapies is based on adult disease (which differs significantly), and is open to variability between specialists. All families who participated in recent patient group events (funded by an NIHR Enabling Involvement award, organised by me) at one of the UK's largest centres for paediatric uveitis supported the development of more objective and sensitive tools. Critically, for a disease which has long been considered as 'silent' or asymptomatic in all but the most advanced stages, almost all families supported the development of patient reported measures of uveitis disease activity. Design and methods: I am going to use new non-contact imaging technologies ('optical coherence tomography' cameras) and assess their ability to	reliably and sensitively monitor disease severity 	identify patterns of disease in different groups of childrenI am also going to develop child and carer reported instruments, guided by affected families, to assess how children are affected by active disease. These new disease measurement tools ('metrics') will be tested within a UK multi-centre study which will recruit children newly diagnosed with uveitis, collect the details of their family, birth and medical history, and watch their disease over time (a 'longitudinal inception cohort study'). This study will allow us to identify the predictors of outcome, including response to therapy. The developed 'metrics' may be able to improve outcomes by personalising our approach to disease counselling and treatment, and go on to help other scientists understand what drives disease at a detailed level. This work will be supported by a patient steering group, and a multi-disciplinary national group of specialists (the Paediatric Ocular Inflammation Group) who will also support the dissemination of study findings, and provide a pathway through which the study findings can improve clinical practice.

Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: EYE