Say the words “dry eye disease” to 100 busy eyecare practitioners (ECPs), and you’re sure to see a wide range of responses.
Some may smile knowingly, armed with a broad knowledge of the disease and its multifactorial nature, as well as the many available treatments, including over-the-counter (OTC) and prescription agents, lifestyle changes, medical devices, and procedures up to and including minor surgery.
Other ECPs may recoil slightly, recalling troubling cases—perhaps challenging contact lens wearers or post-laser-assisted in situ keratomileusis (LASIK) patients—with seemingly inexhaustible complaints and a string of failed therapies.
Still, others may shrug, having learned that it’s sometimes easier to reassure patients that their eyes are healthy overall while dismissing them with a sample bottle of artificial tears and a 1-year recall for their annual exam.
What does dry eye disease mean to you?
The way in which we approach this pervasive disorder that we call dry eye disease (DED) can say quite a bit about our practice overall. Are we on the “cutting edge?” Are we just going through the motions, or do we land somewhere in the middle?
If we want to be in the former group, then we need to remain open to new concepts and developments, breaking free from outdated dogma and prescribing habits to embrace new therapies with demonstrated efficacy.
Dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, according to the Tear Film and Ocular Surface Society Dry Eye Workshop (TFOS DEWS) II report.1 It is accompanied by ocular symptoms, while factors such as tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities all play etiological roles.1
It is no surprise that addressing DED can be a daunting task, since its underlying causes may be elusive, ranging from deep-seated lacrimal gland disorders to iatrogenic causes, such as surgery or long-term topical drug therapy, with a myriad of contributory elements in between (see the table below).
Taming the dry eye “beast”
Likewise, the clinical management of DED has evolved considerably over the last 25 years. In that brief period, the prevailing approach has changed from viewing and treating DED as a symptomatic “annoyance” with sporadic and task-dependent complaints to a pervasive disease state with underlying neurosensory issues and the potential for inflammatory sequelae.
Whereas reactive therapy was once the standard of care, proactive detection and intervention for DED, particularly in some at-risk populations (e.g., cataract and refractive surgery candidates, contact lens wearers) is considered the “new normal.”
And, while there are now substantially more options for DED management than in previous millennia (see table below), some ECPs are still practicing with the mindset of employing palliative therapy rather than intervening with newer, targeted medications, devices, and procedures.
Such a narrow approach is arguably self-defeating, since there is high subjective variability among patients, and a significant percentage are not adequately controlled with the simple use of artificial tears.2
Addressing inflammation in dry eye disease
One discovery within the field of DED that must be considered when determining treatment selection is that inflammation plays an inherent role, according to expert consensus.3-10
And, while some components within certain brands of artificial tears may help to address inflammation and corneal wound healing at a rudimentary level (e.g., trehalose, hyaluronic acid, cationic emulsions), it is widely accepted that patients with more significant DED often require targeted therapy, usually resulting in the selection of an anti-inflammatory agent such as a topical corticosteroid or immunomodulator (e.g., cyclosporine, lifitegrast).11-13
These same patients may often be found to have an underlying systemic disease, or a longer duration of the disease state. “My practice is unique in that so many patients are referred in to see me,” says Mitch Ibach, OD, FAAO, optometrist and residency coordinator at Vance Thompson Vision, as well as a member of the Intrepid Eye Society.
“They’ve often tried two to three artificial tears already before getting to my chair. We utilize a modified SPEED (Standard Patient Evaluation of Eye Dryness) questionnaire score for screening symptoms, and asking the right questions helps to make treatment clearer. But patient motivation and symptoms are the big ones for me. I think it helps guide how aggressive I should be. I don’t recommend artificial tears in any situation where I think a patient has signs or symptoms of more significant dry eye.”
Dr. Ibach continues, “The presence of punctate keratitis and/or a positive inflammatory test very commonly pushes me to write some sort of anti-inflammatory medication, such as a steroid or immunomodulator, or both. I think of needing anti-inflammatory medications as being farther downstream in the dry eye cycle/disease. We’re more reactive that way.”
Healthy human tears, a more natural alternative
A more recent introduction into the realm of DED management is the application of neuroactive stimuli to help augment natural tear production. Normal tears contain inherent anti-inflammatory factors, such as transforming growth factor beta (TGF-𝛽), which are secreted by the lacrimal gland and conjunctival goblet cells.13,14
Vitamin A (in the form of retinol), lactoferrin, lipocalins, and numerous other components of the tear film also reportedly have inherent anti-inflammatory properties.15-17 It has been theorized that increasing the natural reservoir of tears to support the ocular surface may not only improve the signs and symptoms of DED, but may also help to ameliorate concurrent inflammation which may be present.
While this has yet to be proven conclusively through direct clinical investigations, outcomes of clinical trials evaluating neuroactive agents that stimulate tear production (e.g., varenicline solution) compare favorably with those for topical anti-inflammatory drugs (e.g., cyclosporine, lifitegrast) based upon indirect comparisons.18,19
Comparing artificial tears and healthy human tears
Indeed, it can be argued that there is no substitute for natural, healthy tears when we consider the use of artificial lubricants or more intensive therapies like topical immunomodulators. The robust nature of tears, complete with essential electrolytes, proteins, and growth factors to help maintain ocular surface homeostasis is the ideal milieu for supporting and sustaining a healthy ocular surface.
In contrast, artificial tear products contain numerous foreign elements, including, in some cases, harsh preservatives that can be detrimental to ocular surface tissues. These consumer products also have the capacity to dilute and flush away the essential and beneficial elements of natural tear biochemistry, particularly with excessive use, to the point of being counterproductive.
Additionally, while immunomodulatory/anti-inflammatory agents may be necessary in certain instances, these agents all have some potential for adverse events that can be deleterious to patient compliance, allowing the disease to continue progressing when treatments are prematurely discontinued.20-22
Asked whether she believed that all dry eye disease is inflammatory in nature, Selina McGee, OD, FAAO, Founder and CEO of BeSpoke Vision in Edmond, Oklahoma, responded, “Once desiccating stress occurs that is beyond the ocular structures’ ability to protect itself and hyperosmolarity ensues, epithelial cell apoptosis begins and the inflammatory cascade is triggered.
Remember that hyperosmolarity results when the evaporation of the body’s own real tears occurs at a rapid rate. The multifactorial ways that deplete our natural tear film cause this cascade into inflammation. If we can help the body make its own real tears and keep those tears from evaporating, could that also help the body protect itself from desiccating stress, thereby preventing the inflammatory cascade? I believe so, yes.”
Want to learn more about artificial tears, check out the article A Comparative List of Artificial Tears and download the guide!
Options for augmenting tear volume
Since the earliest consensus papers on DED, the options for maximizing tear volume and its residence time on the ocular surface have been very limited.
Tear conservation is a therapeutic consideration that has been employed for nearly 50 years;23-25 however, the two main approaches—lacrimal occlusion and moist-chamber devices—are basic mechanical strategies that have a number of limitations.
Punctal occlusion
Permanent punctal occlusion may be helpful in some patients, although known potential complications associated with this procedure include ocular surface irritation, epiphora, plug migration or displacement, biofilm formation, pyogenic granuloma, and even secondary infections such as canaliculitis or dacryocystitis.26-27
The most recent addition to the punctal occlusion arena involves a cross-linked hyaluronic acid formulation that is injected into the canaliculus, protecting and conforming to the tissues while blocking outflow. According to a recent press release, Lacrifill canalicular gel (Nordic Pharma) demonstrated both safety and effectiveness for both signs and symptoms of dry eye in recent clinical trials.”28
Moist-chamber spectacles
Moist-chamber spectacles represent an arguably safer and less invasive means of increasing tear volume on the ocular surface (by inhibiting tear evaporation), although this treatment modality is quite limited by:29
- The selection and cosmesis of available frames and devices
- The potential for lens fogging
- Inconvenience
- The need for a consistently well-maintained fit to avoid unwanted air flow to the ocular surface
Topical and oral secretagogues
At the opposite extreme, certain pharmaceuticals are classified as secretagogues, i.e., agents that promote the secretion of hormones, neurohormones, chemical neurotransmitters, enzymes, or other molecules synthesized and secreted by cells.
Topical secretagogues such as diquafosol and rebamipide, which are available in a number of countries outside the United States, have both been shown to improve tear and mucin secretion in experimental dry eye models.30 Unfortunately, neither of these agents has performed adequately in human clinical trials to gain approval by the US Food and Drug Administration (FDA).
Oral secretagogues, including pilocarpine and cevimeline, are both indicated to treat the symptoms of dry mouth often experienced by patients with Sjögren's syndrome; however, their use for associated DED is considered “off label.”
While these drugs may be employed in the management of Sjögren's dry eye, most commonly by corneal surgeons and/or rheumatologists addressing severe ocular complications, they are generally not used in most instances of DED due to their propensity for systemic adverse effects, including the potential for sweating, nausea, rhinitis, diarrhea, chills, flushing, urinary frequency, excessive salivation, dizziness and lethargy, among other issues.31,32
Nasal pathways to neurostimulation
Strategies to directly leverage the neural pathways that naturally control tear production and secretion have been a topic of interest for over 10 years, first coming to our attention with a clinical trial involving a prototype intranasal electrical stimulation device.33
It has been theorized that activation of the nasolacrimal reflex can be initiated by stimulating the anterior ethmoidal nerve in the recesses of the intranasal space, a sensory subunit of the ophthalmic branch of the trigeminal nerve. Such stimulation leads to an increase in activity in the superior salivatory nucleus of the brain, which is ultimately responsible for the control of natural lacrimation.33
Neurostimulation and tear production
This study, as well as subsequent clinical trials, demonstrated significantly higher tear production versus unstimulated or sham treatments; in addition, corneal and conjunctival staining as well as symptom scores were significantly reduced, with no serious device-related adverse events.33-36
Following on this research, alternative strategies to stimulate the anterior ethmoid nerve for enhanced tear production were pioneered, including external mechanical stimulation (iTear100; Olympic Ophthalmics) as well as intranasal topical pharmacological stimulation using varenicline solution.
And, while both of these modalities have shown success under controlled conditions, the clinical evidence in support of intranasal varenicline far exceeds that of any other neurostimulatory modality that is currently available to dry eye sufferers.37
Varenicline solution (Tyrvaya nasal spray, 0.03mg; Viatris Inc) is indicated for the treatment of the signs and symptoms of dry eye disease.38 Varenicline is a highly-selective nicotinic acetylcholine receptor agonist that promotes tear production through the previously described trigeminal parasympathetic pathway when administered intranasally.39
Clinical trials on varenicline nasal spray
In pivotal clinical trials involving more than 1,000 randomized subjects collectively, statistically significant improvement was seen in the study cohort versus the vehicle control group with regard to improvement in tear film production (as noted by anesthetized Schirmer test scores) as well as a reduction in the eye dryness score (visual analog scale) by Day 28.40,41
Likewise, in a longer-term study, subjects treated with intranasal varenicline solution 0.03mg saw statistically significant increases in tear production at Day 84 versus those using vehicle control.42
The most common treatment-emergent adverse event (TEAE) seen across these trials was sneezing (82% vs. 22% in the vehicle control group); other TEAEs associated with varenicline solution nasal spray included cough (16% vs 1.5%), throat irritation (13% vs. 1.5%) and nasal irritation (8% vs. 1%).43 Of note, the vast majority of subjects experiencing these adverse events described them as mild (vs. moderate or severe).
Clinical pearls for prescribing varenicline nasal spray
Dr. McGee noted, “If a patient is utilizing artificial tears every day, that tells me they need more of their own real tears. If I want to spare the ocular surface, the neurostimulatory approach is very helpful. For patients that are having interventional procedures in the office (e.g., intense pulsed light [IPL], vectored thermal pulsation), I like to use neurostimulation to continue to activate the lacrimal functional unity (LFU) between sessions.
I will also add it to the regimen of patients who are currently utilizing dry eye therapy but need additional relief. I find it particularly useful in those whose ocular symptoms start to become bothersome at the end of the work day. For those patients, I recommend neurostimulation in the morning and then again at about 4:00 to 5:00pm. This allows them to move through their evening hours more comfortably and enjoyably. This has been my biggest learning over the past years utilizing neurostimulation.”
Dr. Ibach also weighed in on this approach to DED management. “For patients who are pre- or post-surgical, or who are hesitant to use more drops, I will lean heavier on punctal plugs. In general, I’ve rarely been disappointed when I put a punctal plug in a patient during the perioperative period.
As for neurostimulation, I tend to employ this most commonly in younger patients, homeopathic-type patients, patients who get relief from artificial tears but want less of them, glaucoma patients who desire not adding more drops, contact lens wearers, and women who use eye makeup.”
Conclusion
Few can debate the complexity of dry eye disease as we understand it today. Despite significant advances in the diagnosis and management of this chronic and pervasive condition, the majority of ECPs continue to employ antiquated treatment strategies that are minimally effective for most and provide only short-term, symptomatic relief.
As newer treatment options become available to address the underlying mechanisms of DED with the potential to restore ocular surface homeostasis, providers need to evolve accordingly in their therapeutic selections.
It’s time to realize that most artificial tear drops are merely a “drop in the bucket” when it comes to dry eye therapy. We should also recognize that, by the time a patient visits our offices with dry eye complaints, they have most likely already tried two or more artificial tear solutions without success.
Effective DED treatment must consist of targeted approaches, employing the latest technologies that permit symptomatic improvement, amelioration of inflammation, and restoration of homeostasis, while remaining comfortable and easy to use so as to ensure optimal compliance and outcomes.
