Dry eye disease (DED) is a chronic condition affecting millions of people worldwide.1 It can cause significant discomfort, irritation, and vision problems.
This article explores the current state of dry eye research, diagnosis, and treatment—highlighting advancements made in 2024 and promising developments on the horizon.
The current landscape of dry eye disease
Dry eye is a multifactorial condition characterized by insufficient tear production, poor tear quality, or excessive tear evaporation.2 It leads to discomfort, irritation, and inflammation of the ocular surface. DED affects people of all ages, but it's more common in older adults, particularly women over 50.1
According to data from the National Health and Wellness Survey, 6.8% of the US adult population—approximately 16 million people—have been diagnosed with DED. The number approaches 30 million when considering those who are undiagnosed.1 The Eyes On Eyecare 2024 Dry Eye Report estimates that over half of patients may have DED, with millions more experiencing symptoms without diagnosis.3
Factors that influence DED
A single factor doesn't cause dry eye disease (DED), but rather a combination of influences, including:
- Age: As we age, our risk of DED increases.1,3,4
- Sex: Women are also more likely to experience DED than men.1,3,4
- Climate: With dry, arid environments accelerating tear evaporation and worsening symptoms.5
- Environment: Air quality matters; allergens, smoke, pollution, and even wind can irritate the ocular surface and disrupt the tear film.5
- Diet: Deficiencies in omega-3 fatty acids and antioxidants may contribute to the condition.
- Omega-3s have anti-inflammatory properties and have been shown to increase tear breakup time and Schirmer’s scores, while antioxidants help combat oxidative stress that can damage the lacrimal system.6
- Water consumption: A recent study by Nguyen et al. investigated the association between habitual water intake and DED.7 Interestingly, the findings challenged the common assumption.
- While recommending adequate hydration seems intuitive for DED management, the study did not identify a statistically significant association between higher water intake and reduced DED risk.
- Sleep: Chronic sleep deprivation disrupts tear production and worsens DED symptoms.8
- Excessive screen time: Staring at screens for extended periods can decrease the blink rate, leading to tear evaporation.8 While extended screen time can certainly decrease blink rate, recent research suggests a more nuanced relationship with eye health.
- The frequency of complete blinks may not be the sole culprit; studies by Korb et al. and Hirota et al. have shown that partial blinking, where the eyelids don't fully close, might play a more significant role in DED.9,10
- Tobacco use: Smoking and secondhand smoke exposure irritate the ocular surface and reduce tear production, further contributing to DED.4
- Contact lens use: Finally, contact lens wearers, especially those who use extended-wear lenses or have improper lens care habits, are more prone to DED.4
Dry eye and systemic health conditions
In addition to these lifestyle factors, systemic health conditions can also exacerbate dry eye disease. Autoimmune disorders like Sjögren's disease, lupus, and rheumatoid arthritis can attack the lacrimal glands, reducing tear production. Sjögren's disease specifically targets the lacrimal and salivary glands, leading to dryness in both the eyes and mouth.
Other health conditions like thyroid disease, rosacea, and certain medications can also contribute to DED. A recent study utilized Google Trends to investigate how often people across the United States search for information about DED.5
The researchers analyzed data spanning 2004 to 2019 and discovered a significant upward trend in internet searches related to DED, suggesting a growing public awareness of the condition. This trend highlights a potential increase in the prevalence of DED or simply a greater interest in understanding the symptoms and management options.
Environmental influences on DED
The search queries also exhibited interesting seasonal patterns, with peaks in the spring and lows in the fall. While dry eye symptoms may be more pronounced in drier fall and winter months due to factors like reduced humidity, search volume for "dry eye" might peak in the spring. This could be because of heightened awareness of allergies, which can worsen dry eye symptoms, or a difference in self-care practices during different seasons.
Additionally, the study revealed a geographic disparity in search volume, with urban areas generating more DED searches compared to rural areas. This could be due to several factors, including greater access to technology in urban centers or a higher prevalence of DED risk factors like air pollution in urban environments.
Finally, environmental factors appeared to influence search trends beyond just seasonality. Coastal areas, for example, generated more searches for DED. While lower humidity levels, prevalent in some coastal areas, can potentially worsen dry eye symptoms, it is not the only underlying factor that contributes to a higher search volume. Humidity levels themselves vary significantly between coastlines—the East Coast tends to be more humid, while the West Coast experiences dramatic regional variations.
Other factors unique to coastal environments could be at play. Higher population densities in many coastal cities might lead to increased air pollution, as previously mentioned, which can irritate the eyes and contribute to DED. Furthermore, factors like increased exposure to wind, salt spray, and sunlight, all common along coastlines, could also potentially exacerbate dry eye symptoms, prompting more searches for DED information.4,5
Advancements in clinical diagnosis of DED
Dry eye diagnosis has seen significant advancements in recent years, with new technologies complementing the traditional approach of clinical history and examination.
Osmolarity
Tear osmolarity, a measurement of the tear film's solute concentration, is a widely studied marker of DED. A healthy tear film has a specific balance of electrolytes and other components, including water, proteins, and mucins. This balance is crucial for tear film stability and function.
When the tear film evaporates too quickly due to factors like low humidity or meibomian gland dysfunction (MGD), the concentration of salts and other solutes in the remaining tears increases. This is reflected in a higher tear osmolarity measurement.
Measuring tear osmolarity with the TearLab device
The ScoutPro Osmolarity System (Trukera Medical) is a commercially available device that measures tear osmolarity using a small sample of tears collected directly from the patient's eye.
Figure 1: The ScoutPro Osmolarity System.
Figure 1: Courtesy of Trukera Medical.
The ScoutPro device is a portable and easy-to-use instrument, making it suitable for use in both clinical settings and research studies. The test is quick and painless, typically taking less than a minute to complete. A normal tear osmolarity is generally considered to be around 302mOsm/L.11
However, it's important to note that tear osmolarity can fluctuate throughout the day and can be influenced by factors such as dehydration, medications, and environmental conditions.12 Therefore, a single tear osmolarity measurement may not be enough to diagnose DED.
Serial tear osmolarity measurements over time can be a valuable tool for monitoring the effectiveness of dry eye treatment.
Inflammation and the role of MMM-9 in DED
Inflammation plays a key role in DED, and new tests can detect subclinical inflammation and assess its severity. One such test is InflammaDry (Quidel), which measures levels of matrix metalloproteinase-9 (MMP-9), a protein involved in the inflammatory response.
MMP-9 is an enzyme produced by the cornea and other tissues in the eye. It plays a crucial role in tissue breakdown and remodeling, which are normal processes that occur during wound healing and development.12
However, in dry eye disease, the inflammatory process can lead to excessive production of MMP-9. This can eventually damage the entire ocular surface and affect the efficacy of the lacrimal glands.
Cells within the lacrimal system, such as goblet and acinar cells, become dismantled by MMP-9s, leading to dwindling tear production with thinner, less stable tear film.12 This damage can further contribute to tear film instability and worsen dry eye symptoms.
Studies on MMP-9 levels in DED patients
In a testament to its role in DED, numerous studies have found a strong correlation between the quantity of MMP-9 and the severity of dry eye disease. One particular study revealed significantly higher levels of MMP-9 in the tears of dry eye patients compared to healthy individuals.13
The control group had an average MMP-9 level of 7.2U/mg, whereas the MGD group measured 473U/mg, and the Sjögren's disease group showed the highest levels at 651U/mg.
These findings suggest that measuring MMP-9 levels can be a valuable tool for not only diagnosing DED but also gauging its severity. The severity of dry eye symptoms often correlates with the level of MMP-9 measured in the tears. Therefore, a positive InflammaDry test, indicating elevated MMP-9 levels, can help guide treatment decisions.
In such cases, anti-inflammatory medications are utilized to target the underlying inflammation and reduce MMP-9 production. Controlling inflammation and MMP-9 activity improves dry eye symptoms and promotes healing of the ocular surface.
Imaging for dry eye diagnosis
Beyond tear analysis, advancements in imaging techniques have shed new light on DED. There are several that have proven particularly useful.
1. Meibography
Meibography is a non-invasive imaging technique that utilizes infrared light to capture detailed pictures of the meibomian glands. Unlike a standard photograph, infrared light allows visualization beneath the surface of the eyelid, revealing the structure and function of the meibomian glands.14
This information is critical for diagnosing MGD, as it can identify abnormalities, such as gland dropout, where the glands have atrophied or disappeared entirely, or blockages that prevent proper oil secretion, causing gland truncation.
The benefits of meibography extend beyond diagnosis. By visualizing the extent of MGD, treatment plans can be tailored more effectively. Overall, meibography plays a key role in the fight against dry eye disease, offering a window into the meibomian glands and paving the way for personalized and effective management strategies.
2. Slit lamp
Another imaging modality, the slit lamp camera, offers a different perspective. It can capture tear breakup time (TBUT) videos as well as provide insight into the blinking dynamics of the eyelids.
Additionally, the slit lamp camera can measure tear film height and provide general images of the ocular surface, allowing for a comprehensive examination. Usefulness is amplified when used in conjunction with vital dyes, such as fluorescein, lissamine green, and rose bengal.
Fluorescein highlights disruptions in the tear film by staining the corneal epithelium, specifically dead epithelial cells. By observing the tear film break up after a blink, the tear film's stability can be quantified.
Of note, lissamine green stains damaged and dying conjunctival and corneal epithelial cells, which can be helpful in diagnosing dry eye-related conjunctival staining. Rose bengal also stains dead and dying cells on the ocular surface but can cause more ocular discomfort.
Figure 2: Fluorescein tear film breakup pattern of a patient with severe DED.
Figure 2: Courtesy of Mile Brujic, OD, FAAO.
By differentiating between dead and devitalizing ocular surface epithelial cells, staging and subtypes of DED can be more readily made. Furthermore, other potential causes for DED could be revealed, such as conjunctivochalasis, lagophthalmos, and other anatomical lid disorders.
3. Optical coherence tomography (OCT)
Moving beyond the surface, anterior segment OCT utilizes interferometry to measure tear volume by quantifying the tear meniscus height.15 This measurement correlates well with TBUT,15 providing another metric for assessing tear film stability. In essence, OCT offers a more objective and quantitative way to assess tear film stability.
While TBUT relies on observing the tear film's breakup visually, OCT provides a non-invasive tear breakup time (NIBUT), which offers an objective way to asses tear stability. TBUT depends on the examiner's interpretation of when the tear film breaks up, while NIBUT removes this subjectivity by analyzing the tear film's reflection to detect disruptions.16 No dyes are needed for NIBUT and serial measurements can be taken very readily.
This additional data point helps doctors gain a more comprehensive understanding of the severity of dry eye and guide treatment decisions more effectively. For instance, if both TBUT and tear meniscus height measurements indicate tear film instability, it suggests a more aggressive treatment approach might be necessary.
Of interesting potential value is the ability to measure tear film thickness using OCT. While tear meniscus height offers valuable insight, tear film thickness itself might be an even more precise indicator of tear film stability.
One study found highly reproducible measurements of tear film volume and thickness using OCT. The average central tear film thickness was 4.79±0.88μm. This suggests that OCT could not only aid in the diagnosis of dry eyes but could also gauge the success of particular therapies based on before and after measurements of tear film thickness.17
Advancements in DED treatment
The outlook for DED treatment is very optimistic. The landscape of dry eye disease treatment is evolving rapidly, offering a wider array of options than ever before to manage this complex condition. However, due to the chronic nature of DED, it's important to set realistic expectations.
DED is a life-long condition that requires ongoing management, and the most effective approach often combines various therapies. The good news is that there are a growing number of treatment options available, enabling physicians to target the underlying causes of DED and address the specific needs of each patient.
These treatment approaches can be broadly categorized into three areas: prescription medications, in-office procedures, and at-home therapies. Prescription medications can address inflammation and stimulate tear production, while in-office procedures can improve meibomian gland function, clear blockages, or conserve tears. At-home therapies can provide relief through eyelid hygiene, environmental modifications, and stimulation of tear production.
Prescription medications
Recently, several new prescription medications have received US Food and Drug Administration (FDA) approval for the treatment of dry eye disease.
VEVYE (Harrow)
VEVYE (cyclosporine ophthalmic solution 0.1%, Harrow, Inc) is a prescription medication designed to target the underlying inflammation associated with DED and is the first and only cyclosporine‑based product indicated for treating both the signs and symptoms of DED.18
Unlike some older cyclosporine options, VEVYE utilizes a unique water-free, semifluorinated alkane delivery system. This innovation offers two potential benefits: increased comfort during application and potentially better tear film residence time compared to traditional formulations.18
Clinical trials suggest VEVYE may also boast a faster onset of action, with improvements in corneal staining observed within two weeks.18 Additionally, patients often report better tolerability and comfort compared to other cyclosporine options.18
MIEBO (Bausch + Lomb)
MIEBO (perfluorohexyloctane ophthalmic solution, Bausch + Lomb) is a recent addition to the DED treatment arsenal, offering a unique approach to managing tear film stability.
Unlike traditional lubricants or artificial tears, which primarily act as a replacement for the tear film, MIEBO targets the root cause of tear film evaporation. This prescription medication is formulated with perfluorohexyloctane (PFHO), a single-ingredient solution that acts as a temporary barrier on the tear film's surface.
According to one study, PFHO has a high oxygen-carrying capacity, may reduce friction on blinking, and spreads quickly over the tear film surface to form a monolayer that inhibits evaporation. These effects can lead to stabilization of the tear film to promote ocular surface healing.19
This innovative approach offers several potential benefits. By creating a barrier on the tear film, MIEBO helps reduce tear evaporation, keeping the eyes moist for a longer period. This can lead to significant improvement in symptoms like dryness, irritation, and burning.
Additionally, MIEBO is a preservative- and steroid-free formulation, making it a safe and viable option for many patients. Clinical studies have shown positive results, with patients experiencing improvements in DED symptoms as early as 2 weeks after starting treatment.19
XDEMVY (Tarsus)
XDEMVY (lotilaner ophthalmic solution 0.25%, Tarsus) represents a significant advancement in the targeted treatment of Demodex blepharitis, a common comorbid condition of DED.
Figure 3: The characteristic collarettes with lid telangiectasia associated with Demodex blepharitis.
Figure 3: Courtesy of Bradley Daniel, OD, FAAO, Dipl ABO.
This prescription medication addresses the underlying etiology: infestation of eyelash follicles with Demodex mites. These microscopic mites, while naturally present on human skin, can overpopulate on the eyelids in some individuals. This overgrowth contributes to inflammation and disrupts tear film stability, leading to the signs and symptoms of Demodex blepharitis.20,21
Unlike traditional therapies that focus on managing symptoms or inflammation, XDEMVY offers a targeted approach by directly eliminating the Demodex population. The active ingredient in XDEMVY, lotilaner, is a parasiticide with specific activity against Demodex mites. Its mechanism of action involves disrupting the mite's nervous system, leading to paralysis and subsequent death.22
This targeted approach provides several advantages. By eradicating Demodex mites, XDEMVY addresses the root cause of Demodex blepharitis, potentially resulting in significant improvement in clinical signs like eyelid erythema, irritation, and lash collarettes.
There are two species of Demodex mites found on humans, Demodex folliculorum, which inhabit the lash follicles, and Demodex brevis, which are found in the meibomian glands and disrupt the delicate balance of the meibum's composition. This disrupts its flow and ultimately leads to symptomatic DED secondary to MGD.21 Currently, XDEMVY is the only FDA-approved medication for treating Demodex blepharitis and is being evaluated as an investigational therapy for treating MGD in patients with Demodex.22
While XDEMVY offers a convenient treatment regimen administered topically as eye drops twice daily for 6 weeks, it's important to understand the Demodex lifecycle. Most patients will experience significant improvement in symptoms, potentially even complete resolution, within 3 weeks.
However, continuing the full 6-week course is crucial. Completing the full treatment regimen ensures the eradication of both adult mites and developing eggs, preventing them from hatching and repopulating the eyelid, as this corresponds to two lifecycles of the mites.21 This approach helps prevent the recurrence of Demodex blepharitis and ensures long-lasting relief from symptoms.21
In-office treatments for dry eye disease
In-office treatments for the underlying causes of DED have continued to evolve throughout the years. However, it is important to understand that almost all of these in-office procedures are not covered by medical insurance. Currently, evaporative DED has many treatment options addressing meibomian gland dysfunction.
Thermal pulsation
One popular approach is thermal pulsation. Technologies like LipiFlow (TearScience) and iLux (Alcon) deliver a gentle combination of heat and controlled pressure (either automated or manual) to the eyelids. LipiFlow is an automated treatment, while the iLux is a manual treatment. These treatments aim to soften and unblock the meibomian glands, promoting healthy oil secretion and ultimately leading to a more stable tear film.
Thermal-only options where manual expression is performed at the slit-lamp after 10 to 15 minutes of heat treatment are also available. Devices like TearCare (Sight Sciences), MiBo Thermoflo (MiBo Medical), EyeXPress Eye Hydration System (Holbar Medical Products), and Thermal 1-Touch (OcuSoft) can be easily integrated into practice.
Carousel 1: The MiboFlo and Thermal 1-Touch devices.
Carousel 1: Courtesy of MiboFlo Medical and OcuSoft.
The video below demonstrates manual meibomian gland expression with a Mastrota meibomian paddle directly after 15 minutes of thermal heat with Thermal 1-Touch.
Video 1: Courtesy of Bradley Daniel, OD, FAAO, Dipl ABO.
Debridement
Manual debridement of the meibomian gland orifices, lash line, and eyelid margins has been proven beneficial for DED patients suffering from blepharitis and other eyelid conditions contributing to DED symptoms.23
Several tools can aid in this process, such as:
BlephEx (BlephEx Inc): This handheld rotary device removes debris and biofilm associated with blepharitis. It gently exfoliates the eyelids, potentially clearing blockages in the meibomian glands, while also cleaning lashes and improving overall lid hygiene.
Figure 4: The BlephEx device.
Figure 4: Courtesy of BlephEx Inc.
NulidsPro (NulidsPro Ltd): The Nulids Pro device is equipped with a vibrating tip that delivers controlled mechanical stimulation to the eyelid margins. This stimulation helps to loosen debris, unclog meibomian glands, and promote healthy oil secretion.
Figure 5: The NuLids Pro device.
Figure 5: Courtesy of NulidsPro Ltd.
ZEST (Zocular): The Zocular Eyelid System Treatment (ZEST) offers a targeted in-office approach utilizing a proprietary okra-based gel The gel is applied to lashes and lid margin in a circular motion to facilitate gel lathering, promoting the removal of biofilm and debris while mitigating inflammatory processes.24
Intense pulsed light and radiofrequency
Intense pulsed light (IPL) and radiofrequency (RF) are emerging non-invasive treatments gaining traction for dry eye disease. IPL targets the eyelid skin, delivering pulses of light to reduce inflammation and improve meibomian gland function. RF, on the other hand, uses radio waves to gently heat the inner eyelid, stimulating oil production and improving tear quality.
OptiLight (Lumenis), Lumecca-1 (InMode), and LacryStim IPL (Quantel Medical) are popular IPL options found commonly in many eyecare clinics. However, Lumenis’ light therapy is currently the only IPL technology that is FDA-approved specifically for the management of DED due to MGD.25 OptiPlus (Lumenis), Forma-1 (InMode), and TempSure (Cynosure) are popular RF devices currently in use.
Figure 6: The TempSure device.
Figure 6: Courtesy of Cynosure.
With emerging studies showing superior outcomes for patients undergoing dual RF+IPL treatment for DED, many manufacturers offer platforms that offer both treatments.26,27 The devices can either be standalone devices or combination units.
OptiLight and OptiPlus (Lumenis) are standalone IPL and RF units, respectively, that allow for a high degree of customization and can be used in conjunction. A combination device is the Envision (InMode).
The platform consists of three different treatment modalities that work synergistically: the Forma-1 bipolar RF, the Lumecca-1 IPL, and the Morpheous8 minimally-invasive RF fractional technology.
Figure 7: The Envision RF and IPL combination device.
Figure 7: Courtesy of InMode.
At-home treatments for DED
At-home treatment for DED is essential for the acute and long-term management of this life-long condition. The standard of warm compresses and maintenance of good lid hygiene can be achieved in more ways than ever.
NuLids (NuLids) is a device used at home for treating DED and lid hygiene. It consists of an oscillating tip to clear debris and stimulate the meibomian glands.
iTear100 (Olympic Ophthalmics) uses precise vibrations delivered from outside the nose to target only the external nasal nerve. This electromechanical neurostimulator elicits natural tears as quickly as 30 seconds.28
At-home thermal compresses can now be performed more readily with clinically effective results due to products like Eyedration by Bruder (Hilco Vision Company).
Hypochlorous acid (HOCl) sprays are becoming more popular amongst practitioners as an at-home treatment for various causes of blepharitis and MGD.29 Hypochlor Spray (OcuSoft) and Avenova (NovaBay Pharmaceuticals) are two HOCL options for at-home treatment.
What’s in the DED pipeline?
Medication
Reproxalap (Aldeyra Therapeutics) is a new anti-inflammatory medication that inhibits reactive aldehyde species (RASP). RASP causes conjunctival injection and chemosis, can alter the meibum layer of the tear film, and decreases lacrimation.30,31
Currently, the medication is undergoing evaluation by the FDA for approval. Phase 3 studies showed a rapid onset of action with high tolerability and minimal side effects.31
Drug delivery
One area of promise in the dry eye disease pipeline is the use of nanotechnology for drug delivery. Researchers are exploring how nanoparticles can be engineered to improve medication delivery to the eye.
Conventional eye drops are quickly eliminated by blinking, but nanoparticles can be designed to adhere to the ocular surface and release medication slowly.32 This could potentially lead to prolonged ocular surface retention time, better penetration through the ocular surface, and more targeted delivery of medication.
Studies have shown that drugs delivered through nano-based delivery systems have shown enhanced adhesion to the ocular surface and reduced washout from reflex tearing and blinking, with a consequently longer retention time on the ocular surface.32
Contact lenses for DED
Another application of nanoparticle technology gaining traction is its use in drug-eluting contact lenses. These lenses, designed for comfort and sustained medication release, offer significant advantages over traditional eye drops. Studies have shown they can dramatically increase the medication's residence time on the ocular surface compared to drops.33
Drug-eluting contact lenses, made from conventional hydrogels or silicone hydrogels, can be loaded with medication in two ways: soaking or directly incorporating the drug into the lens material. Researchers are exploring incorporating various medications into these lenses, including hyaluronic acid (HA) for lubrication and anti-inflammatory drugs like corticosteroids (dexamethasone, betamethasone) and Cyclosporine A to target underlying inflammation.33
Neox Flo (BioTissue)—a micronized tissue derived from amniotic membrane and umbilical cord that is then reconstituted with saline—is providing another promising avenue for dry eye management. This unique solution is being investigated for its ability to treat various ocular surface disorders that contribute to DED.34
This innovative approach could offer an alternative to dehydrated or cryopreserved amniotic membrane grafts (AMGs). It should be noted that Neox Flo is cryopreserved as well.
Encouragingly, a recent study found treatments incorporating amniotic fluid (AF) were as effective as AMGs for treating severe dry eye, with patients reporting better tolerability with AF.34
Figure 8: Dehydrated amniotic membrane treatment for chronic DED
- Top left: Coalesced superficial punctate keratitis (SPK) with punctate epithelial erosions (PEE)
- Top right: Patient status post superficial keratectomy
- Bottom left: Same-day dry amnio placement
- Bottom right: Patient 1 week later
Figure 8: Courtesy of Bradley Daniel, OD, FAAO, Dipl ABO.
In conclusion
The future of DED is brimming with promise from new prescription medications specifically targeting DED to in-office procedures targeting meibomian gland dysfunction and at-home therapies that make self-management more convenient and effective. And, looking ahead, the DED pipeline promises continued innovation.
While DED remains a chronic condition, the advancements in diagnosis, treatment, and ongoing research offer significant hope for a future where dry eye symptoms can be effectively managed, allowing patients to experience a better quality of life.
