Harnessing the benefits of hyaluronic acid in lubricating eye drops

At the completion of this article, the reader should be able to improve their management of dry eye disease, including:

Artificial tears have been a mainstay dry eye treatment, but as manufacturers bring new products to market it can be challenging for optometrists to remain abreast of the best-performing therapies. MARTIN ROBINSON explains why hyaluronic acid is considered a lubricant with desired properties and performance.

Martin RobinsonBApp Sc(Optom)Optometrist and Principal OwnerMartin’s Eyecare, Hobart, TASState President of the Cornea and Contact Lens Society of Australia TAS (CCLSA)National Vice President CCLSA

Educating ourselves out of outdated clinical routines

At my recent dry eye workshop series at the AVC conference, I was a little surprised at the prevalence of some outdated treatments recommended in response to poll questions I presented. The treatment suggestions improved rapidly as I outlined the logical reasons why I offer somewhat different treatments. This give and take, to me, showed the power of historical cognitive biases. We can, and often do, automatically prescribe a treatment based on knowledge that we learned years or even decades ago. It’s something I think we’re all guilty of at times. In a rushed clinic, we fall prey to a snap diagnosis and treatment path, which can sometimes be based on old knowledge, especially in what was once considered a dry topic such as dry eye disease (DED).

When I see a patient for an initial consultation, I always ask them what eye drops they’ve had prescribed in the past, which worked and which did not. Commonly, I hear eye drops listed that I have not used for many years, drops that I stopped prescribing as evidence emerged of inferior performance compared to newer generation products. I see that as further evidence of historical cognitive bias at play; we prescribe what we were taught was the ideal eye drop for the symptoms. But what if that education was five or 10 years ago?

One of the aims of self-directed learning plans is to identify areas of knowledge deficit and plan to upskill these fields. However, what if we feel confident in our own knowledge? We may then choose to study another topic and carry on confidently using our historical wisdom. I feel this is why I still read reports from referring optometrists that state: “I prescribed lid scrubs with baby shampoo.” Considered appropriate practice 20 years ago, baby shampoo was explicitly mentioned in The Tear Film and Ocular Surface Society Dry Eye Workshop II (TFOS DEWS II) reports. They pointed out that baby shampoos are pro-inflammatory,1 and obviously baby shampoos were not designed for application to the eyes. There are far better products for cleaning eyes of blepharitis today.

Not all eye drops are equal

Hyaluronic acid (HA) is an ingredient present in several currently-available eye drops in Australia and New Zealand. I believe there’s enough evidence to support changing your own historical cognitive biases, whatever they may be, and to consider prescribing HA-containing lubricating eye drops more frequently.

What is HA? My patients recognise it as an essential ingredient in ‘youth restoring’ face creams and makeup. HA, or hyaluronan, has an important function in the body – in fact, our connective tissue, skin, intervertebral discs, joints and nerve tissue, the vitreous and cornea – all contain HA.

Although the cornea is avascular, hyaluronic acid occurs in the intercellular spaces. One of its roles is to supply nutrients and dispose of metabolic products. Additionally, it is thought to play a part in such processes as cell differentiation, cell renewal and wound healing.2 It was first used as a viscoelastic for vitreous surgery in 1969,3 first discussed as a DED treatment in 1982 and first appeared as a commercial eye drop in 1987. One of the most important characteristics of HA is the ability to be produced in a low osmolarity or hypotonic form.4

There are dozens of eye drops containing HA available around the world, some single ingredient, some with multiple ingredients.

Hyaluronic acid in the literature

A recent meta-analysis was published comparing HA-containing eye drops to non-HA eye drops. There were statistically significant improvements found in several key areas, but not always superior to other artificial tears (ATs):4

• HA eye drops significantly improved Schirmer test scores, compared with non-HA eye drops (p<0.05)

• Tear Breakup Time (TBUT) after using HA improved significantly versus saline (p<0.05) and was similar to that of ATs

• Corneal fluorescein staining scores after using HA eye drops was similar to that of ATs

• The HA group showed similar improvements in OSDI scores to the non-HA group

Hyaluronic acid vs autologous human serum eye drops

Some studies stand out as very interesting. In a small-scale study, high-molecular-weight HA was explored as an alternative to autologous human serum eye drops, (ASED).5 ASED treatment has been identified as a stage 3 treatment in TFOS DEWS-II.1 High-molecular-weight HA was found to be an acceptable alternative to ASED, with 50% of the participants continuing with the HA drops after the study. Another small, randomised, double-blind study examined using HA to dilute ASED.6 The HA dilution was stable compared to the original preparation in all areas. The exciting findings were significant improvements in TBUT (p = 0.03), fluorescein and rose Bengal staining (p = 0.02) and corneal/conjunctival cell squamous metaplasia levels (p = 0.008) in the HA dilution group.

Does this mean we should start considering HA as a stage 3 treatment, as per TFOS DEWS II?1 More appropriate perhaps to consider it as stage 2, along with non-preserved drops? (Table 1).

In the clinic

There are limitations in studies of all designs and although research findings can be exciting and surprising, they may not always reflect what practitioners find in clinic.

In my experience, HA eye drops are superior to other ATs in nearly every case where I prescribe them. I choose which patients to prescribe them to, based on the signs and symptoms. If patients report burning and stinging, this often indicates the presence of a higher osmolarity tear film, TFOS DEWS II mentions hyperosmolarity as being a common finding in DED. Stinging or burning are the most common symptoms reported in my DED patients. Prescribing low osmolarity eye drops, containing HA, makes sense in the presence of hyperosmolarity.

Sjögren’s syndrome patients treated with hypotonic HA had greater symptom reduction, improved TBUT and showed reduced staining.7 Is this why I find them so successful? There is yet to be a study specifically looking at stinging and burning symptoms, but I’d like to see one looking at the role of HA in treating symptoms of stinging and burning.

One of the most exciting developments are the multi-ingredient HA drops emerging over the past few years. For many years, I’ve been reading papers and attended lectures discussing these new eye drops. Some amazing claims have been made with some, at first glance, showing statistically significant results, but sometimes they compare eye drops that are not similar.8 So, caution should be practised when only reading the conclusions of publications, and not looking at the study details.

In vitro studies are often the first line experiment, done ‘in glass’, or more easily understandable, as cells outside their normal environment. An in vitro study was published in 2015 by Rekha Rangarajan et al9 that looked at the effect of a pairing of hyaluronic acid/hydroxypropyl guar (HP/HPG), currently available as Systane HYDRATION Lubricant Eye Drops. The results were encouraging in multiple areas when the HA/HPG combination was compared to both HPG and HA alone.

Protection and maintenance of hydration from desiccation was statistically greater with HA/HPG compared to either HPG or HA alone (p<0.01). Testing the cells for fluorescein permeability showed significantly better cell and barrier protection after induced trauma with HA/HPG compared to either HPG or HA alone (p≤0.01). Interestingly, when surface friction was assessed in an artificial blink, all three reduced friction compared to saline, and HA/HPG was significantly superior to HA alone (p = 0.02). With results like these it is enough to get excited about the duality of HA/HPG, even if this was an in vitro study.

It is no surprise that we have seen several eye drop offerings launched locally with multiple ingredients and containing HA, from many suppliers with offerings in the dry eye space. Thinking of patient care in multiple demographics, these products are now available in a variety of cost brackets, meaning fewer people will be disadvantaged by cost as a factor. There are even PBS options following the appropriate criteria. The current offerings of preservative-free options in bottles that can be used for 90 days is more affordable than single use vials. Eye drop bottles are becoming easier to use for patients with poor dexterity and arthritis in their fingers and hands. Having a variety of product designs with the same ingredients is an advantage as it allows more of the population to access an eye drop that works, supplied in a product design that they find easy to use.

Systane HYDRATION UD Lubricant Eye Drops

Clinically, I experience greater success with Systane HYDRATION UD Lubricant Eye Drops and a lipid/aqueous combination drop over HA alone – in a similar way to the TFOS DEWS II stepped approach to management of dry eye,1 I use HA as a first line drop, then I upgrade to multi-ingredient Systane HYDRATION UD Lubricant Eye Drops or a lipid/aqueous combination drop as a second tier drop when needed for more moderate dry eye, especially when staining does not reduce adequately with HA alone, or when a patient complains that their current HA drop does not help enough.

I see a superior reduction in staining with Systane HYDRATION UD Lubricant Eye Drops and patients report a greater reduction in their symptoms. My prescribed schedule with Systane HYDRATION UD Lubricant Eye Drops is tiered depending on severity, starting at three times a day, or at breakfast lunch and dinner. Increasing to five to six times a day for more severe cases, which I often describe as ‘almost every time you eat or boil the kettle,’ making it sound achievable.

Admittedly, you cannot expect a single drop to solve all your patients’ symptoms. As per the TFOS DEWS II definition of dry eye as a ‘multifactorial’ condition,1 so too we should consider and treat any signs of B.E.I.S.T.O. found.10 (‘BEISTO’ is a concept first coined by dry eye pioneer Dr Laura Periman. That is: Bugs/Bacteria, Enzymes, Inflammation, Statis, Temperature and Obstruction. When a sign of any of these BEISTO impediments is found, a different treatment pathway is required).

Communication is key in our duty of care

Prescribe the most suitable lubricant eye drop that the patient can afford, but don’t assume what they can afford, so ask them. If a patient is attentive to environmental concerns, discuss the ways companies are tackling plastic waste globally, discuss the differences in waste with unit dose vs multi-use bottles. If your patient has arthritis or weak hands, give them a sample bottle/vial, and see if they can use them successfully.

Eye drops are an essential part of most treatment strategies. It is no longer appropriate to offer our patients a variety bag of eye drops and ask them to see which one works best. The real world presents other challenges for eye drops, environmental waste, cost of supply and ease of use, so discuss these issues with your patients. As optometrists, we should prescribe the eye drops which will best address the clinical signs and symptoms of our patients.

The evidence is sound that HA is a lubricant with desired properties and performance. The mixing of HA with other active ingredients has broad reaching implications that we are only just starting to explore.

More reading

Australia dry eye disease update – 2023

Dry eye disease and nutrition: are we what we eat?

Paediatric dry eye care