Study claims that the combination of sodium hyaluronate (HA)nd BAK on the cornea is a Bad Thing, and that HA has a tendency to hang around awhile. Implications?
Study: Effect of certain glaucoma meds, with and without preservatives, on meibomian glands
Study: Tafluprost (with, without preservative) and how it affects meibomian glands
Study: Glaucoma meds and dry eye (again)
ARVO Monday morning: Dry Eye I
This is why I love ARVO.
You go to another conference, and any “dry eye” session with the number 1 on it is going to be running along some fairly familiar themes. All good, just not, you know, new, fascinating, or all that sophisticated. They’re also more likely to have a commercial flavor.
At ARVO, dry eye, or any disease really, is a different animal. The Dry Eye 1 session here was a collection of really exciting cutting edge presentations.
On benzalkonium chloride (BAK)
If you follow my stuff in general, you’re already bracing yourself for my soapbox as soon as you see the acronym for this ubiquitous preservative.
The first speaker in the dry eye lineup:
“An optimized model of dry eye disease using benzalkonium chloride in C57BL/6 mice: effects on the ocular surface”
Richard Zhang (University of New South Wales)
Lurking under the fancy presentation titles and the animal research that may seem so far removed from our everyday lives, there is often something surprisingly relevant. The context for Dr Zhang’s presentation is actually how they use BAK to cause dry eye in mice for medical studies. Yes, you read that correctly. It’s a complicated world out there in research and this kind of thing reminds me of when, long ago when I was advocating for people with complications like RCE after laser eye surgeries, I first came across the use of PRK to induce RCE in mice. Sigh. Anyway.
Dr Zhang talked about how, while we know BAK causes dry eye, we don’t actually know very much about how and why, and this is what he explored. His research debunked some assumptions and was aimed at narrowing down how much BAK, applied how often, can reliably cause dry eye specifically, as opposed to other types of damage, and they discovered some other interesting things along the way.
There was one series of photos in particular that struck me. It showed the progressive effects of very low concentrations (lower than they would use for the “let’s give mice dry eye” purposes) in cultured limbal epithelial stem cells. At 0.01%, on a picture with some sparse signs of life, there was a comment like “They weren’t all dead right away”. If I understood correctly, they showed that a single exposure at 0.01% was enough to induce cell necrosis. On those same cells in vivo, though, they weren’t seeing the same effect and don’t know why.
But we’re talking about research on only days’ worth of exposure. 0.01% BAK is actually the concentration of BAK that is in >20 over-the counter eye medications such as Zaditor and Lumify, as well as even some artificial tears, like two of Bausch & Lomb’s. I’m trying to meet with Dr Zhang later today to learn more.
Can meibomian glands be regenerated from atrophy?
Whew - talk about a hot topic for our dry eye world!
“Meibomian Gland (MG) Acinar Regeneration from Atrophy in a Fgfr2 Conditional Knockout Mouse Model”
Lixing Reneker (University of Missouri)
Fun fact: While we know MGD is a big cause of dry eye, MGD is much more prevalent amongst Asians (42-68%) than Caucasians (4-31%).
Dr Reneker started with some excellent context on how MGD works - the different types (obstruction vs change in quality/quantity of meibum) and also how little is really known about the underlying causes. I really enjoyed the graphics and explanations of how those glands work - she walked us through the life cycle of a cell all the way to when it disintegrates and turns into the stuff our glands are meant to secrete.
So the question is: Are our meibomian glands capable of repair and regeneration?
The answer, based on their research of inducing severe atrophy in various ways and following the progress over time, is: YES, meibomian glands absolutely are capable of acinar tissue repair, regrowth and regeneration, but it depends on whether the ductal structures have remained intact.
All in all, very encouraging research! I know this is a big ‘mystery’ area for patients, and a frustrating area for those who have visited multiple doctors, because they are so likely to receive conflicting answers about both their diagnosis and their prognosis.
So to me, the take-home message is, just because you’ve been told you have gland atrophy… doesn’t necessarily mean there’s no hope of MG recovery, depending on specifics, but please don’t blame your doctor if you’re not getting what seem to be straightforward or consistent answers, because there’s so much more that science hasn’t figured out yet.
Of mice and mice
Next up:
“Increased conjunctival monocyte/macrophage antigen presenting cells in Pinkie RXRα deficient mice with accelerated dry eye”
Stephen Pflugfelder (Baylor)
I know several of you have visited Dr Pflugfelder or his colleagues at Baylor somewhere in the course of your dry eye journeys!
This is one of the ones that went “whoosh” right over my head, except for the part about retinoids being essential for ocular surface health, and the predictable question from David Sullivan afterwards about how we reconcile that with the fact that retinoids (his words) “literally make the meibomian glands run away screaming”.
Does Vitamin D play a role in dry eye?
“Characterization of Vitamin D Levels in Ocular Surface Tissues and their Association with Dry Eye Disease”
Ashley Bascom, U of Houston School of Optometry
This research presented how they identified active Vitamin D in the tear film for the first time, and showed that it was significantly decreased in dry eye patients. They hypothesize that it may play a role in the inflammatory component of dry eye. There were interesting responses and questions afterwards, including whether the prevalent vitamin D deficiencies may be contributing.
Blah blah blah blah DRY EYE blah blah blah
There was another presentation that made my eyes cross. I am sure it must have been amazing, both because it happened here, and because the research came from Schepens (Harvard)… I just don’t know what it MEANS.
High fat diet messing with lacrimal glands?
“High fat diet induced functional and pathological changes in lacrimal gland”
Xin He (Xiamen University)
Back to the immediately practical world (maybe). Obesity, high fat diets and what, if anything, this means for dry eye - in this presentation, limited to the lacrimal gland function.
In this research, they looked at both whether a high fat diet impairs the meibomian glands, and whether it was reversible (yes and yes).
Dr He first walked us through the process whereby a high fat diet leads to, progressively: lipid accumulation, oxidative stress injury and inflammation, proliferation, apoptosis, and finally lacrimal gland dysfunction.
Then they looked at reversal - did the lacrimal glands return to normal when the mice were returned back to a standard diet? Only in part, but inflammation was reduced. After that they looked again at another approach to the diet change (standard diet plus fenofibrate) and in that case they were able to complete reverse the pathological changes in the LGs.
Lots of audience questions including role of sex (they only studied males) and whether they checked for indirect effect of systemic parameters (no).
Note: In a later session there is a presentation on the impact of a high fat diet on MEIBOMIAN glands.
And one more
Function of lacrimal gland myoepithelial cells in homeostasis, aging and disease
Helen Makarenkova
I was running on overload at this point. The part I enjoyed most (and judging from the oohs and aahs, I was not alone!) was some amazing color videography of expansion and contraction of myoepithelial cells, and how inflammation impairs the contractions. Very cool stuff.
Got dry eye? Why you should take heart:
There may, or there may not, be anything that is presented at this conference, or anything that I happen to blog about, that you feel is directly relevant to you personally. But there’s still a broader theme of good news that matters for all of us.
The numbers of PEOPLE involved in dry eye research at all levels just takes my breath away, and it is underscored in this environment. For every 15 minute presentation, we see long lists of names and pictures of teams involved, and the nature of a lot of the research is resource-intensive . The packed rooms and the discussions and debates further reveal the level of commitment to this disease area.
We have so many reasons to take heart and to know that scientific breakthroughs are happening and will continue to happen in the dry eye space.
Rebecca
The damaging effects of preservative BAK (from TFOS DEWS II Iatrogenic Report)
It's no secret that BAK is damaging to the cornea. It both causes and worsens dry eye. This is well studied and well documented.
Nevertheless, even today:
BAK is the preservative used commonly in prescription eyedrops (excluding, obviously, the unpreserved ones like Restasis and Xiidra) such as corticosteroids, antibiotics, antihistamines, etc. Historically, it has been used in the vast majority of glaucoma eyedrops; this latter has been changing, because of the well documented and profound effects on glaucoma patients, but even that single trend away from BAK in one single drug group has been happening far too slowly.
BAK is also the preservative used in a large number of over-the-counter eyedrops, including allergy and decongestant (redness reliever) drops, many combination drops, and even some lubricant drops intended solely for dryness. These products have no warning on their labels specific to the effects of the preservative, so people who self-treat minor eye irritations over the long term without guidance from an eye doctor on what's safe (this happens commonly - they think it's not worth seeing a doctor about) can experience lasting harm without any way to know or prevent it.
The excerpt below from the Iatrogenic (i.e. medically caused) dry eye report summarizes what we know about all the different ways BAK can harm us:
Causes damage to the goblet cells and mucous (sticky) layer of the tear film
Causes damage to the lipid layer
Increases tear osmolarity
Causes inflammation and leads to an inflammatory vicious cycle
Is more damaging to people who already have dry eye (poorer tissue defenses)
Is toxic to trigeminal nerve endings
Reduces nerve density and corneal sensitivity (meaning people who don't seem to have symptoms from the BAK may have damage all the same)
It's a long and painful list. We need to keep raising awareness.
TFOS DEWS II Iatrogenic Dry Eye Report
4.3.2.1 Role of preservatives and excipients
....BAK may cause or aggravate DED through various mechanisms such as its toxic and proinflammatory effects, as well as its detergent properties, which have been well demonstrated in numerous experimental and clinical investigations [125]. Goblet cells produce soluble mucins and contribute to tear film stability and immune defenses. These cells are extremely sensitive to toxic and inflammatory stress, decreased in density in humans after short exposure to BAK or BAK-containing timolol [127]. MUC1 and MUC16 were found to be reduced after exposure to BAK in human corneal and limbal epithelial cells. Transmission electron microscopy revealed alteration of the mucus layer after exposure to 0.01% BAK for 5 or 15 min, whereas more prolonged exposure (60 min) to 0.01% BAK destroyed the mucous layer [128]. These toxic effects were also found by Kahook and Noecker, who reported significantly lower densities of goblet cells in animals receiving BAK-containing latanoprost compared to preservative-free artificial tears, even though the specific effects of latanoprost alone were not addressed [129].
In addition, as a tensioactive compound, BAK is also a detergent for the lipid layer of the tear film. Thus, while an unpreserved betablocker did not impact upon tear stability, decreased TBUT was observed with a preserved betablocker [118]. Increased tear osmolarity was also observed in patients receiving preserved eyedrops compared to those who received unpreserved topical medication [122]. Following the loss of its protective properties, the impaired tear film not only results in dry eye symptoms and corneal damage, but also may convey cytotoxic inflammatory mediators throughout the ocular surface. Hence, increased corneal epithelial permeability has been shown in dry eye with additional impairment when using artificial tears containing BAK compared to nonpreserved eyedrops [130]. Tear film alterations may therefore stimulate a series of biological changes in the ocular surface, leading to subsequent neurogenic inflammation and further impairment of the tear film, creating a vicious cycle [131].
BAK causes disruption of the tight junctions of the corneal epithelium, an effect that has led to BAK being considered an enhancer of drug penetration into the anterior chamber [125]. The cytotoxic effects of BAK have been shown to be increased experimentally when cells are previously subjected to a hyperosmotic stress mimicking dry eye in vitro. Therefore, BAK can cause some level of toxicity in normal or glaucomatous eyes, which can be compensated by tissue defenses, but causes a much greater level in dry eyes, consistent with clinical findings. However, as BAK may progressively cause tear instability and hence hyperosmolarity, this compound is likely to change the conditions of its own tolerance and result in increasing toxicity levels [132].
Additionally BAK has shown neurotoxic effects to the trigeminal nerve endings [133], consistent with the results of a large study comparing the effects of preserved and unpreserved antiglaucoma drugs on corneal nerves using in vivo confocal microscopy (IVCM) [134]. The density of superficial epithelial cells and the number of sub-basal nerves were reduced in the preservative-containing groups, and stromal keratocyte activation and bead-like nerve shaping were higher in the glaucoma preservative therapy groups than in the control and preservative-free groups. Moreover, this study identified decreased corneal sensitivity, based on esthesiometry, in all preserved groups compared to control or unpreserved prostaglandin and betablocker groups. This neurotoxic property of BAK could thus contribute to apparent tolerance in some patients receiving BAK-containing eyedrops.
Experimental data also demonstrated direct proinflammatory effects of BAK with the release of inflammatory cytokines or increased expression of receptors to chemokines and cytokines [135,136]. Additionally, BAK breaks down conjunctival immunological tolerance in a murine model [137]. In humans, using immunocytological and flow cytometry methods, higher expression of HLA-DR, a marker of inflammation, occurred in impression cytology specimens over the ocular surface with preserved eyedrops [138]. Other inflammation-related markers, such as ICAM-1, interleukin (IL)-6, IL-8, IL-10, CCR4 or CCR5, were also found to be overexpressed in glaucoma patients and even more with multiple therapies and preserved eyedrops [139]. A significant infiltration of the central cornea with dendritic inflammatory cells is observed with IVCM in healthy volunteers receiving BAK-containing eye drops compared to a non-preserved solution [140].
New preservatives recently developed as alternatives to BAK, such as Polyquad®, Purite® and sofZia®, result in significantly lower cytotoxic effects [125,136,141143]. However, their possible effects on the tear film and tolerance in dry eye patients have not been fully investigated.
References in this excerpt:
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[127] Herreras JM, Pastor JC, Calonge M, Asensio VM. Ocular surface alteration after long-term treatment with an antiglaucomatous drug. Ophthalmology 1992;99(7):10821088.
[128] Chung SH, Lee SK, Cristol SM, Lee ES, Lee DW, Seo KY, et al. Impact of short-term exposure of commercial eyedrops preserved with benzalkonium chloride on precorneal mucin. Mol Vis 2006;12:415421.
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[130] Göbbels M, Spitznas M. Corneal epithelial permeability of dry eyes before and after treatment with artificial tears. Ophthalmology 1992;99(6):873878.
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[134] Martone Gianluca, Frezzotti Paolo, Tosi Gian Marco, Traversi Claudio, Mittica Vincenzo, Malandrini Alex, et al. An in vivo confocal microscopy analysis of effects of topical antiglaucoma therapy with preservative on corneal innervation and morphology. Am J Ophthalmol 2009;147(4):725735.
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[139] Baudouin Christophe, Liang Hong, Hamard Pascale, Riancho Luisa, Creuzot-Garcher Catherine, Warnet Jean-Michel, et al. The ocular surface of glaucoma patients treated over the long term expresses inflammatory markers related to both t-helper 1 and t-helper 2 pathways. Ophthalmology 2008;115(1):109115.
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