Anyone who has received a birdshot diagnosis, learnt to live with its effects on vision and experienced the side-effects of treatment, knows that all this has a marked effect on health-related quality of life (QoL). Knowing more about QoL would not only help doctors to understand how birdshot affects patients’ lives but also influence wider healthcare decision-making.

A Health Utility Value for birdshot is a patient estimate of their overall health state. This has not previously been calculated for birdshot. Health Utility Values enable treatment effects to be evaluated, not only for their impact on patients but also for heath economic purposes, for example, when comparing different treatments to make official recommendations on best treatment choices based on calculations involving the cost per quality adjusted life year (QALY).

Professor Philip Murray and colleagues at University of Birmingham recruited birdshot patients to complete a series of established, standardised medical questionnaires on health and vision. The results of the questionnaires were analysed alongside a standard set of clinical eye observations for each patient.

Preliminary results indicate that QoL is affected in birdshot patients but not to the same degree as in patients with other types of uveitis who have poor vision in both eyes. More statistical analysis of the results is planned to look for any links between QoL and patients’ clinical findings.

January 2020 update: the researchers were aware that birdshot had an impact on patients’ QoL yet their results showed this was not as great as was expected. Future studies could include asking patients to complete specific depression and anxiety questionnaires. This was not done during the study to avoid overloading the patients with questionnaires.

You can read more about the health utility that has been developed here: Creating a Health Utility Value for Birdshot Chorioretinopathy.

Dr Graham Wallace at the University Hospitals Birmingham NHS Foundation Trust wants to investigate an interesting association recently found between the HLA-A29 genetic marker, which is present in the majority of people with birdshot, and an alteration in a nearby gene, HFE H63D.

“Iron is essential in the retina for photoreceptor cell function and is generally controlled by iron-regulating proteins. However free iron is highly toxic for photoreceptors, leading to an increase in oxidative stress. Iron is also involved in inflammation as it is essential for the proliferation of immune cells,” says Dr Wallace.

“Given a recent association between HLA-A29 and HFE H63D – a gene implicated in patients with iron overload – we think this could be an important route to explore with regard to birdshot. Iron overload is treatable and so may give us other options."

The study will make use of 75 samples from the Birdshot Biobank which will be genetically examined for the presence of HLA-A29 and HFE H63D and blood serum iron levels will also be measured. HFE H63D age and sex-matched controls without birdshot will be similarly tested. Ten patients from both of the above groups will then be followed up at intervals to detect any alterations in their iron levels.

January 2020 update: the UK Birdshot Biobank took much longer to set up than anticipated. This meant that only a small number of patient samples were available to the researchers. However, the other materials needed to conduct the research have been stored. As the number of samples increases in the biobank, this research should be able to proceed.

Changes in the retina are seen in birdshot uveitis and in particular the retinal pigment epithelium (RPE) cells are affected. How and why do these retinal cells in birdshot differ from those in a normal eye? Until now, these have been difficult questions to answer because eye tissue from birdshot patients was scarce and often not suitable for analysis. The pioneering technique of induced pluripotent stem-cell (iPS) modelling could be about to change this.

iPS has already been used successfully in laboratories to generate RPE cells from patient blood samples. The RPE cells can then be studied to detect subtle genetic and immunological differences between normal retinal cells and retinal cells affected by eye conditions.

Dr Anai Gonzalez-Cordero and colleagues at University College London Institute of Ophthalmology; Moorfields Eye Hospital, London; Bristol University and Bristol Eye Hospital, and University Medical Centre, Utrecht, Netherlands, want to use iPS to generate RPE cells from birdshot patient blood samples and then to look for genetic and other markers. They will compare the markers with those found in RPE cells generated from people who do not have birdshot.

"Subtle changes to RPE can be seen in some patients during the early stages of birdshot. This is not an obvious feature of the condition but current examination methods are limited, identifying only severe dysfunction,” says Dr Gonzalez Cordero.

“We do know that RPE can modulate the choroid and that RPE cells show HLA-A29 gene activity. Almost everyone with birdshot has a particular variation of this gene. We can develop mature RPE in the lab from stem cells derived from blood of living patients. This will allow us to explore the role of RPE in detail as well as providing a much-needed test bed for future treatments that can also be used by other researchers in the field.”

The investigators propose to collect blood samples from birdshot patients attending Moorfields and Bristol Eye Hospitals, as well as through the Birdshot Uveitis Society, and to set up three cell lines to generate birdshot RPE cells to study. Blood samples will also be taken from European ancestry donors who carry HLA-A29 but who do not have birdshot, and these will also be used to generate RPE cells for comparison in the study.

As well as being used for the proposed study, the birdshot iPS-derived RPE cell lines will become a continuing research resource. They will provide an enduring means of laboratory testing of future uveitis treatments or gene therapies, not only for birdshot but also for other autoimmune diseases.

January 2020 update: the researchers successfully generated three cell lines of induced pluripotent stem (iPS) cells from blood samples donated by patients with birdshot uveitis. Although these patients were all receiving immunosuppressant treatment, the retinal pigment epithelium (RPE) cells generated from the birdshot patients’ iPS cells were identical to those obtained from normal control stem cells. Importantly, the birdshot-derived RPE cells were HLA-A29 positive, as were the birdshot blood sample donors.

The researchers now want to study the birdshot RPE cells further. The hope is that this work might lead to the development and testing of new medicines designed to target specific disease pathways in birdshot.

Birdshot chorioretinopathy (also known as birdshot uveitis) is a sight-threatening condition in which there is long-term (chronic) inflammation in both eyes. The inflammatory deposits under the light-sensitive part of the eye (the retina) look like ‘birdshot’.

The condition affects people who are otherwise well. We know that it’s rare, but we don’t have any reliable data on how many new cases there are each year (the incidence).

This project is a 2-year national survey using the British Ocular Surveillance system. This well-tested system is run via a postcard alert sent each month to all UK consultant ophthalmologists. A postal questionnaire is then sent to the ophthalmologist for each new case. This information tells us about the demographics, signs and symptoms of each new case of birdshot in the UK.

The team is particularly interested in how badly vision is affected at the point the case is diagnosed and what things might have an effect on this, for example if the patients are younger. A follow-up questionnaire is sent one year later. This records patterns of treatment, how well treatment is working and its side effects.

This is the first study of its kind in birdshot – we don’t yet have birdshot incidence data anywhere in the world. It should tell us about any regional differences or other factors that affect symptoms and its seriousness and will provide data that can easily be compared to future studies, for example if we want to find out whether birdshot is on the rise.

One of the major challenges in caring for people with birdshot is how difficult it is to tell when the condition is actively causing inflammation. There is no widely available, sensitive way to measure this, which can lead to over-treatment or under-treatment, both of which can cause problems.

The team has demonstrated that the light-based imaging device known as optical coherence tomography (OCT) can be used outside its usual field of action to detect changes in the retina and choroid in birdshot. It can even pick up changes in the vitreous jelly which fills the middle of the eye.

In this project they are using these imaging techniques to study how these features change over time and to assess how good this method could be for detecting ‘flare-ups’ of disease. They believe that this approach will provide a patient-friendly way of monitoring the condition in the future, both in everyday clinical use, and for helping assess new treatments in clinical trials.

Birdshot uveitis is a long-term (chronic) condition that potentially needs lifelong treatment with steroids and medication which reduces the body’s defences against infection (immune suppression).

An odd fact about birdshot uveitis is that its progress is very unpredictable, even with treatment. A significant minority of patients continue to lose their sight even with aggressive immune suppression therapy.

The best results come when treatment starts early, but we do not yet have a good idea about which of the early signs and symptoms are the best for predicting how birdshot will progress. In this project Mr Westcott and co-investigators at Moorfields Eye Hospital, London, Ms Angela Rees and Mr Carlos Pavesio, are trying to spot which early clinical signs are good predictors of poor prognosis later on. The team is looking back, examining and comparing medical records of their large group of birdshot patients who have attended the Moorfields uveitis clinic for over five years.

The investigators hope that their results will mean that patients can have better information about the likely course of their condition. The results could also be very useful for future clinical trials.

January 2020 update: results showed that, at diagnosis, birdshot patients with either normal Humphrey visual fields, or good dark-adapted electroretinogram (ERG) test results or the absence of retinal atrophy were most likely to have a good treatment outcome. Interestingly, having birdshot diagnosed at a young age, or having a birdshot diagnosis which included macular oedema and poor vision, were found not to affect the chances of responding well to treatment.

These results may mean that doctors could have a clearer picture of which signs and symptoms noted early in birdshot can predict how it may progress. Also, doctors may be able to give their newly-diagnosed birdshot patients better information about the likely progression of their condition and its possible treatment outcomes.

Birdshot uveitis is a rare form of uveitis that affects around 200-300 people in the UK. It is hard to diagnose because the symptoms are subtle early on and ophthalmologists are not familiar with it because it is so rare. There is no diagnostic test yet.

In this project, the research team is trying a machine learning method known as ‘supercell analysis’ to see if they can help speed up birdshot diagnosis. The computer program takes in data about hundreds of blood cells taken from patients and from healthy controls without any eye disorder. It looks at lots of different features of the cells and tries to separate out the information that comes from patients. The method has already been used successfully by researchers to tell the difference between people with the eye condition Behçet's syndrome and people with another condition called ocular sarcoidosis.

At the end of the project we should have a better idea of how well this method can tell the difference between birdshot and healthy controls or people with other eye conditions. We should also know more about how the test results relate to the signs and symptoms people show in the clinic. Ultimately this could lead to a reliable diagnostic test that would mean people could start treatment earlier.

Birdshot is a rare, potentially blinding condition. It affects the choroid – a layer of blood vessels that supplies the eye's photoreceptor cells that sense light and send visual signals from the eye to the brain. Inflammation in the rear part of the choroid means that the photoreceptors do not get the oxygen or nutrition they need to work normally.

There is no diagnostic test for birdshot, and clinical signs and symptoms do not give a clear picture of how severe the condition has become. Studies show that recording electrical activity from the eye may be a more reliable way to track the condition and its response to treatment. But the electrical activity test – known as an electroretinogram or ERG – is not available in all clinics, it takes time to do and interpret, and is uncomfortable for patients.

In this project, the team is testing a portable device (RETeval), which uses skin electrodes, and which does not need pupil dilation.  It measures ERG activity.  The team want to find out whether RETeval can monitor birdshot’s progress as reliably as a conventional ERG test. They are

• Measuring clarity of vision and eye pressure in 20 participants with birdshot
• Recording their ERGs using the handheld device
• Comparing the results with standard ERG recording equipment
• Comparing the results with recordings from 200 twin volunteers without birdshot

The portable ERG device is relatively inexpensive.  If it is found to be  effective, it could help guide decisions about treatment and improve care for birdshot patients in many eye departments. It could also make it easier to monitor the effects of new treatments as they are developed.

May 2022 update: research paper published as Birdshot Chorioretinopathy: Flicker Electroretinograms Recorded with a Handheld Device https://doi.org/10.1167/tvst.11.5.23 Results showed that the ERGs from the portable device 'correlated strongly' with conventional ERG recordings, suggesting the potential for using the RETeval portable device in rapid assessment of retinal cell function in practice settings.

Birdshot is thought to be an autoimmune condition, meaning the system that usually defends the body from infection attacks its own body. Treatment with steroids can suppress the immune system but the side-effects can be so bad that some people choose to risk sight loss instead.

Results from studies in mice have shown that shining low levels of light at a specific near-infrared frequency can reduce inflammation caused by autoimmune activity in the eye.

In the project, the team aims to find out whether this near-infrared light treatment can work in a small group of participants with birdshot.

Participants in the study will be given a course of experimental light therapy in one eye only, in addition to their existing treatment. There is no known risk from the light therapy, so if it does work, it could be a good, low-cost treatment option.

Biobanks collect and store donations of anonymised patient samples of blood, urine and other tissues. Approved researchers can then use these materials, feeding back their research data to the biobank. This adds to the original information held about the samples, which increases their usefulness to future researchers.

The project will start by recruiting a small number of birdshot patients from St Thomas’ Hospital, London, Moorfields Eye Hospital, London, and the Birmingham and Midlands Eye Centre, to donate samples to the biobank.

Clinical data from the National Birdshot Uveitis Registry (see below) would accompany the biobank samples. The combined resources of the National Birdshot Uveitis Registry and the National Birdshot Biobank would enable a great variety of statistically-valid and useful studies to be performed on large numbers of birdshot patient samples.

It is hoped that the birdshot biobank will eventually provide the opportunity for all UK birdshotters to contribute to research by donating their samples. Our involvement will provide the keys to help researchers start to unlock some of the mysteries of birdshot and to improve its treatment.

To be statistically significant, medical studies need to be done on large numbers of patients. Because birdshot is a rare disease, it has been difficult up to now to recruit enough patients to do useful research. Although large studies of up to 80 birdshot patients have been carried out in several European centres, similar scale studies have not been conducted in the UK, principally because birdshot patient information is not held in one place. Creating a national registry database of UK birdshot patients would provide a resource of information on birdshot which would have many potential uses.

The  National Birdshot Uveitis Registry (NBUR) will collect and hold clinical data on birdshot patients centrally, including test results such as angiograms and OCT scan images. From the initial pilot study involving data from a few patients at University Hospitals Birmingham and the Birmingham and Midland Eye Centre, the eventual aim is for all UK birdshot patients to be invited to register with the NBUR.

The first step in the proposed study will be to develop a patient details database at University Hospitals Birmingham, test it and perform some data analysis. The database will then be tried out with data from a small number of Birmingham birdshot patients, then modified as necessary, and then piloted at National Birdshot Research Network partner sites in the UK.

One use of the registry data will be to accompany the samples sent to the UK birdshot research biobank (see above). Other proposed uses for the data include identifying patients suitable for clinical trials, collecting drug safety data, especially for newer treatments, and eventually being able to identify ‘best practice’ and promote better care by enabling treatment centres to compare the progress of their patients within the context of a national picture.

University Hospitals Birmingham already develops and operates national databases through their established Rare Disease Service, so this experience will be invaluable in setting up the National Birdshot Uveitis Registry.