Mr Anthony Khawaja is President of the European Eye Epidemiology (E3) consortium, which promotes the sharing of knowledge and research between 31 groups originating from 13 different European countries.

They recently published their most recent research in the sector-leading Ophthalmology journal on the association of common systemic medications with glaucoma and intraocular pressure (IOP).

The study found that calcium channel blockers (CCBs) had a modest and statistically significant association with glaucoma.

Glaucoma and blood pressure drugs

Patients with a history of CCB treatment had a 23% higher likelihood of having glaucoma as compared with individuals who never used the antihypertensives. In contrast, beta-blocker therapy was associated with modestly reduced intraocular pressure (IOP), which is associated with a reduced risk of glaucoma.

“While our novel findings require further studies to determine whether the associations are causal, these findings will be of interest to physicians caring for glaucoma patients with systemic comorbidities,” Mr Anthony Khawaja explains.

“A potentially harmful association of CCBs for glaucoma is particularly noteworthy, as this is a commonly prescribed class of medication,” he added. “If further studies confirm a casual nature for this association, this may inform alternative treatment strategies for hypertensive patients with, or at risk of, glaucoma.”

Coverage of the study was widespread and Mr Anthony Khawaja was also delighted to be included in Bottom Line newsletter, the largest subscription newsletter in the US which offers expert advice on everything health related. They covered the study in their most editorial round-up.

This article was originally written by Mr Anthony Khawaja for The Ophthalmologist.

Although glaucoma can cause irreversible, irreparable damage to vision, treatment can slow or halt disease progression, so early detection is important. Unfortunately, our current screening tests – if applied to a general population – don’t work well enough; as a result, population screening for glaucoma is not currently recommended in some countries, including the UK and the US.

Using people’s genetic codes to identify a subset of the population that will benefit from screening may be the solution to this problem. In the last decade, there has been huge progress in discovering many of the genetic variants that contribute to glaucoma risk. It was back in 2018 when we first realized that the great number of risk variants we had discovered could be considered collectively to predict – with surprising accuracy – whether someone would end up developing glaucoma. This approach of combining thousands of risk variants into a single number, a polygenic risk score, has become popular across many common diseases, including glaucoma.

Instead of having to screen whole populations, genotyping enables targeted screening for those at a higher risk for glaucoma. Our current screening tests will perform much better when applied to a subset of the population with a higher prevalence of undetected glaucoma. In other words, there will be far fewer false positive referrals to secondary care if our current screening tests are applied to this enriched subset of the population.

A separate challenge in glaucoma care comes after diagnosis. At present, we cannot accurately predict which of our patients are at the highest risk of progressing and losing vision. If we could better predict this, we could ensure our limited healthcare resources are used optimally, focusing on the highest risk patients, but also saving costs, unnecessary treatment, and follow-up for those at lower risk.

It remains unclear whether the genetic variants which increase the risk of developing glaucoma also increase the risk of vision loss among patients with glaucoma. Instead of comparing people with glaucoma to people without glaucoma in the general population, we need more longitudinal genetic studies amongst cohorts of glaucoma patients, identifying the genetic variants that lead to worse disease.

This article was originally written for Ophthalmology Times by Caroline Richards.

Genotyping and artificial intelligence are together starting to predict the progression of glaucoma in individual patients, sparing them from suboptimal treatments and adverse effects. Recent research efforts are exploring modifiable risk factors such as caffeine consumption.

I have previously interviewed glaucoma specialist Anthony Khawaja, PhD, MA (Cantab), FRCOphth, on the therapeutic area of precision medicine, and I was interested in talking with him again to revisit the rapidly developing field and discuss the latest promising research. Here is our interview.

Why is there a need for precision management in glaucoma?

AK: Because the way we currently practice medicine is very much evidence based, which, as I will describe, has its shortcomings. We all know that the highest-quality evidence comes from randomized controlled trials. For example, the ocular hypertension treatment study [randomly assigned] people with ocular hypertension who did not have glaucoma to eye pressure lowering or no eye pressure lowering.2

Those whose eye pressure was lowered had a dramatically reduced chance of converting to glaucoma over the subsequent 5 years. This means that if we treat everybody with ocular hypertension, fewer people will convert to glaucoma.

However, around 90% of untreated people did not convert to glaucoma. Therefore, if we treated everybody with ocular hypertension, as [findings from] the randomized controlled trial might suggest is a good idea, then we would be treating many people unnecessarily: some would benefit but others would receive treatment they did not need. And, of course, some people will develop [adverse] effects to the treatment, and treatments have costs to the health care providers and to the patients, depending on the health care setting.

Another similar example is the United Kingdom Glaucoma Treatment Study (UKGTS), [whose data] showed that treatment with latanoprost can halve the chance of established open-angle glaucoma getting worse, compared with placebo.3 This, again, suggests that if all patients were the same—if everyone was average—then treating them would be a good idea.

But not everybody is the same and three-[fourths] of people in the placebo group in this study did not measurably progress over the 2-year study period. This suggests that some people who fulfil our diagnostic criteria for glaucoma might not actually need treatment.

On the flip side of that, 15% of the people who received latanoprost progressed, meaning that they perhaps needed a different treatment or a more intensive treatment strategy. The overall message here is that evidence-based medicine is great to tell us what is best to do on average, but not what is best for an individual patient.

There is a great picture of Barack Obama from when he was launching the Precision Medicine Initiative in 2015.4 He stood by a model of DNA, the double helix, since one of the key enablers for personalising our approach to managing patients lies in genetics and genomics: leveraging an individual patient’s genetic code to better understand how they will individually respond to different treatment strategies.

One reason that this is an exciting time for personalised or precision medicine is that measuring the genetic code has become so cheap: You can have it done at a local high street pharmacy in the UK for less than £150 [$174].

One genotyping study that is going to start in the UK soon, called the Our Future Health study,5 will measure common variations in the genetic code in 5 million adults at a cost of around £20 [$23] each. This 1 test can inform us about how best to manage people at risk of not only common blinding eye conditions but also cardiovascular disease, dementia, breast cancer, prostate cancer, and almost any medical condition you can think of. This demonstrates that we are at a very exciting point in time in precision medicine and I think we are going to see big changes within the next decade.

What specific benefits can precision medicine bring to glaucoma patients?

We usually assess a person’s personal risk according to how bad their glaucoma is when they first present, but we tend to have to monitor them for at least a couple of years before we can fully or better understand that risk.
Genetics will help us stratify our patients right from the outset, to better identify those who will be on a downward trajectory in 5 years’ time, so we can treat them better, and those who will have barely changed in 5 years—the really low-risk patients who we can spare [from] the costs and [adverse] effects of treatment, freeing up precious health care resources and giving the glaucoma specialist time to focus on patients who have a much higher risk of going blind.

Given the rapidly increasing number of [patients with] glaucoma and our limited health care resources, we need these kinds of innovations. This is not a hope but an absolute must. Secondly, we have so many different glaucoma treatments now: many classes of drops, different forms of laser, [and] different forms of surgery from very minimally invasive to highly effective but much more invasive and risky.

However, we are not very good at predicting who will respond well, and we tend to treat patients in a trial-and-error manner. It is rare that a patient comes to severe long-term harm from this—[adverse] effects are often temporary—but it does not provide patients with a great experience and is also a massive waste of resources.

There is growing evidence to suggest we can predict using genomics who will respond well to treatment such as selective laser trabeculoplasty. Work is…ongoing, so watch this space!

What research are you most excited about at present?

I am really excited about genetic data, not just from patients with glaucoma versus patients without glaucoma, but also from patients with established glaucoma, where we know what their treatment pathway has been, their response to treatments, and their vision loss trajectory. Once we have these large data sets, we can start to accurately validate prediction algorithms that incorporate genetics for clinically meaningful outcomes such as risk of progression, rate of progression, and response to different treatments.

Another exciting area is modifiable risk factors for glaucoma. Knowing which lifestyle factors influence glaucoma risk has been a challenge, as studies have tended to be small and results inconsistent. But now, with large studies such as the UK Biobank,6 we are better able to ask these questions.

We recently brought together a multidisciplinary collaboration of nutritionists, nutritional epidemiologists, statistical geneticists, ophthalmic epidemiologists, and glaucoma specialists from multiple institutions around the world, such as Harvard [University], Mount Sinai, the Pasteur Institute, and beyond.

The first thing we looked at was caffeine, partly because all the investigators enjoy consuming caffeine. We were interested to know whether it influences the pressure in the eye and the chances of having glaucoma.

A high genetic risk of glaucoma is in some ways a proxy for how well developed the aqueous fluid outflow channels are: If they are not adequately developed, such that they are starting to fail at an older age, then the outflow channels cannot handle the additional aqueous that is produced as a result of consuming more caffeine. This pushes up the pressure and increases the chance of developing glaucoma.

Interestingly, we found that there does not seem to be a strong association in the population overall, other than when you focus on people at high genetic risk of glaucoma. So only in the high-risk people, who can be determined with inexpensive genotyping tests, [is] high caffeine intake associated with a higher eye pressure and a greater chance of having glaucoma.

What does this mean for patients? Currently, if a patient’s glaucoma is well controlled, I certainly would not advise them to stop consuming caffeine or reduce their caffeine intake. But if a patient is getting worse despite best medical or surgical treatment, then I think they need to know this information. I would say that, although it is not proved, if you do consume a lot of caffeine, you may wish to consider reducing or stopping, given what we know.

It may work, it may not work; but certainly if I was a patient and I was getting worse despite all best efforts, this is the type of information I would like to know. In the future, I think we will be giving people lifestyle advice according to their genotype.

Where does artificial intelligence (AI) fit in?

We have used AI to look at retinal photographs of patients in the UK Biobank. Doing this, we processed around 80,000 photographs in less than a day, assessing whether there are features of glaucoma and measuring the vertical cup disc ratio. This is something which would take a decade for human graders to undertake.

Genetic data are available for everyone in the UK Biobank, so this allowed us to carry out the largest genome-wide association study for vertical cup disc ratio,7 identifying many new genetic markers for glaucoma. These genetic markers were very predictive for glaucoma prevalence in the independent EPIC-Norfolk study [European Prospective Investigation Into Cancer in Norfolk Prospective Study; NCT03424668].8

The other thing with AI is that it will complement genetic prediction models. Currently, using all our clinical skills, OCT [optical coherence tomography] scans, and visual fields, we can only phenotype a patient so far. There are extra clues in their genetic markers that will tell us about that patient’s profile, their prognosis, their susceptibility to disease, and their response to different treatments.

There are also hidden signatures that humans cannot currently interpret, while AI can. So I think that AI assessment of imaging in particular is going to give us some extra clues that can further help personalize the care of our patients.

Where will we be 10 years from now?

I think we will have started pilot programs in which health care users meeting quite broad criteria are genotyped, which will inform personalized care strategies. For glaucoma, it might be a personalized screening strategy.

For example, patients with the top 10% risk of glaucoma might be advised to start having annual eye checks at the age of 40, whereas the bottom 10% will not have any specific eye tests and will just go to the optometrist opportunistically. People who are somewhere in the middle might start at the age of 50 and be screened every 2 years.

In 10 years, the best management is going to be an intersection of genomic prediction models and AI models.

This article was originally written for Optometry Today.

Study finds high coffee intake increases odds of developing glaucoma among patients with genetic predisposition towards elevated eye pressure

Researchers have published new findings connecting coffee intake to glaucoma among patients with a family history of elevated intraocular pressure (IOP).

The study, which was published in Ophthalmology, involved analysing UK Biobank records of 120,000 people collected between 2006 and 2010.

Scientists examined the relationship between IOP, caffeine intake and self-reported glaucoma diagnosis. They also assigned each participant an IOP genetic risk score.

Coffee and glaucoma risk

Overall, high caffeine intake was not associated with a risk of developing elevated IOP or glaucoma.

However, among people with a genetic predisposition towards high IOP, greater caffeine consumption was linked to a higher IOP and higher glaucoma prevalence.

Those in the highest genetic risk category had a 3.9 times greater chance of developing glaucoma if they consumed three cups of coffee a day, compared with those in the lowest genetic risk group who drank no caffeine.

Co-author Anthony Khawaja, from University College London and Moorfields Eye Hospital, shared that the study illustrated those with a high genetic risk of glaucoma may benefit from moderating their caffeine intake.

“It should be noted that the link between caffeine and glaucoma risk was only seen with a large amount of caffeine and in those with the highest genetic risk,” he said.

This article on menopause and glaucoma development was originally written by Anthony Khawaja and Kian Madjed for Insight magazine.

We still don’t fully understand why some people get glaucoma and others don’t. This leads many glaucoma experts to seek out causes of high eye pressure, or to look past eye pressure at other reasons why glaucoma may develop. We know that genetics can increase a person’s chances of developing glaucoma, but it is complicated and there are other things that may also increase someone’s risk.

Why are we talking about menopause?

Overall, more men are diagnosed with glaucoma than women. So why would researchers be interested in exploring potential links between menopause and glaucoma?

If you break the number of people with glaucoma down by age group, older women and older men are quite even in terms of how likely they are to have glaucoma; it is mainly at younger ages that men seem to have a higher chance of developing glaucoma. This difference appears to even out after the average age for menopause, leading to researchers asking whether some of the female reproductive hormones may be protective against glaucoma. Does the reduction in these hormones that occurs during menopause mean that women lose the level of protection against glaucoma that they were providing? There have been many studies to explore this link.

What is the science saying?

During the 2000s, there was a notable rise in interest regarding the investigation of possible connections between female reproductive factors and glaucoma. These factors included the number of pregnancies a person had experienced, the age they had their first period, the age they went through menopause, and whether they were taking hormone replacement therapy (HRT). Lots of these studies were big population studies and, as each study showed that there may be a link, the interest was maintained and more research evolved.

It is important to note that, whilst there is a lot of research into this topic, the majority of such studies are observational. This means that they are looking for associations between menopause and glaucoma and they are not showing that one will cause the other. Most of the non-observational studies (e.g. looking at changes following an “intervention” of HRT medication) are small scale, usually involving 50-100 people. However, when you look at the results of all the studies together, there does seem to be some kind of link between menopause and glaucoma. One recent study has been presented, suggesting that if a person has a later menopause and goes on to develop glaucoma, they will develop glaucoma later. Conversely, if a person goes through menopause earlier and goes on to develop glaucoma, their glaucoma will develop at a younger age.

If the reduction of female reproductive hormones may increase the risk of glaucoma, can we do anything about it?
At the moment, the only way that we can treat glaucoma is to reduce the eye pressure. Could this research mean that there are other available treatments for women with glaucoma? There is some evidence that some HRT may be associated with lower eye pressure. There are two main types of HRT, estrogen-based HRT and estrogen and progesterone HRT. They are essentially two different blends of female hormones, and it is the estrogen-based HRT that has shown these lower eye pressure associations in the studies. The same results were not found with estrogen and progesterone HRT. In some studies, where eye pressure was taken at the time of beginning HRT, and then measured again six months to a year on, eye pressure had reduced by an average of 1-2 mmHg. These types of study give more support for a relationship between HRT and eye pressure, but overall, estrogen-based HRT reducing eye pressure a small amount is still an educated best guess based on the research.

So, should all women be starting HRT when they start their menopause?

No. The evidence is not robust enough to be making this suggestion. If a person who has glaucoma, or has other risk factors making glaucoma more likely, is about to go through menopause their eye specialist does not yet have the evidence to tell them what is best to do. The eye specialist would be making a best educated opinion based on the studies available. They may say that if a person is interested in using HRT to treat their symptoms of menopause, they may want to discuss the estrogen-based HRT as it may also aid a small reduction in eye pressure or give some protection to the optic nerve. Certainly, we do not see evidence that HRT increases the risk of glaucoma.

How big a risk is menopause likely to be then?

It is unlikely that eye specialists are going to be telling people with glaucoma that they particularly need to look out for the signs of menopause. If we get to the point where we can prove any kind of cause and effect, the effect is probably a small one – not unimportant but still small and very unlikely to be the sole cause of a person’s glaucoma. The focus should still be on monitoring the field of vision, OCT scans and the eye pressure to make sure that the pressure has been lowered enough to stabilise the disease. Using the traditional medications, laser or surgery is still going to be the best way of saving sight. It is a hot topic as it is something that hasn’t been discussed much in the past and now we are talking about it, with lots still to understand. There are still studies looking into the relationship between menopause and glaucoma, so watch this space.

What about menopause and dry eye?

Like glaucoma, dry eye is a complex disease with lots of causes, and menopause may be one of them. There are so many things that contribute to dry eye and menopause could be one of them for any individual woman. The range of causes sometimes makes dry eye difficult to treat. Often they can’t be individually identified and so we end up treating the symptoms. Causes might include meibomian glands (oil producing glands in the edge of the eye lids) not working properly, the environment, lots of screen use, etc.

Previous studies suggest there is probably a link between HRT and people reporting less dry eye. Again, it is hard to say whether this is cause and effect. If we do think there is some association between menopause and dry eye, relieving those symptoms with an estrogen-based HRT has been suggested in the literature but it isn’t a guideline or recommendation.

If you’re concerned about menopause and glaucoma development, or you would like to know more about HRT, please speak with your eye specialist about this at your next appointment. They will be best placed to advise and provide reassurance based on your individual circumstances.