When we think about dry eye disease (DED) today, we most likely envision a highly complex disorder with a variety of contributory elements and a wide range of therapeutic interventions, including over-the-counter drops, prescription agents, and minor procedures such as intense pulsed light (IPL) therapy. But it wasn’t always like this.
A mere 20 years ago, DED was generally considered to be a deficiency of tear production, somehow linked to inflammation, with only a variety of lubricants and a single prescription therapy available as our first-line treatment options.
Meibomian gland dysfunction (MGD) was thought to be a related but clinically distinct condition, typically addressed through the use of warm compresses and other hygienic lid measures, with the occasional use of topical or oral antibiotics (e.g., doxycycline) thrown in for more severe cases.
The shifting understanding of DED
In 2007, the Tear Film & Ocular Surface Society (TFOS) published the first truly comprehensive reports on DED, based upon a series of meetings referred to as the International Dry Eye WorkShop, or DEWS. The original TFOS DEWS reports attracted many researchers and clinicians to the intriguing world of DED.
These reports established a new definition of the disease, providing expert consensus regarding its epidemiology, diagnostic methodologies, management strategies, and clinical research guidelines for future discovery.1-5
Although the concept of evaporative DED had been advanced prior to the TFOS DEWS reports, these publications helped to firmly entrench MGD as a leading cause of evaporative dry eye, and recommended treatment of this chronic lid condition as a possible means of ameliorating DED.5
According to the 2017 TFOS DEWS II definition, “Dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.”6
While this description might not specifically mention evaporation or MGD, the implications are clear, particularly within the context of tear film instability. The report goes on to state that “...the current understanding [is] that an evaporative component to DED is more common than an aqueous deficient component. Indeed, MGD, a contributor to [evaporative dry eye], is considered the leading cause of dry eye in clinic and population based studies.”7-10
To better understand this dichotomy of DED, let’s take a deeper dive into the literature to help provide a framework and perspective.
Aqueous-deficient and evaporative dry eye: Two sides of the same coin
Our current understanding of DED recognizes two broad etiological subtypes: (1) aqueous-deficient dry eye (ADDE), and (2) evaporative dry eye (EDE).1,6,11 While both of these subtypes are believed to be driven by tear film instability and excessive tear hyperosmolarity, the pathophysiology by which this clinical state is reached differs according to etiology.
More to the point, hyperosmolarity in ADDE is believed to result from diminished lacrimal output, resulting in a higher concentration of salts, ions, proteins, and other components in the tear film.
By contrast, EDE begins with essentially normal tear secretions from the lacrimal gland, however excessive evaporation from the ocular surface leads to a similar outcome—namely, tear film hyperosmolarity.12
What is aqueous-deficient dry eye?
As mentioned, ADDE is characterized by decreased tear production, which typically implicates some form of lacrimal gland dysfunction. Etiologies here are numerous, but include well-known conditions such as Sjögren’s, lacrimal gland infiltration secondary to sarcoidosis or lymphoma, trigeminal neuropathy, graft-versus-host disease (GvHD), or diabetes mellitus.12
ADDE may be seen in up to ⅓ of individuals with DED, and is often associated with systemic autoimmune co-morbidities, although it can also occur secondary to environmental insult.13,14
How to distinguish between ADDE and EDE
Alternatively, EDE describes a scenario in which tear production and volume may be adequate, however, the residence time of the tear film on the ocular surface is diminished, leading to premature tissue exposure and desiccation.
EDE is most commonly associated with dysfunction of the lids, usually in the form of MGD, but also potentially related to incomplete lid closure, diminished blink frequency or quality, or simply an abnormally large palpebral aperture.
Additionally, it may be attributable to other ocular surface-related issues, including mucin deficiency and/or contact lens-related problems.6,15,16
Figure 1 describes the etiologies and contributory elements of ADDE and EDE.
Figure 1: Adapted from TFOS DEWS II Pathophysiology Report.
While the distinction between ADDE and EDE may appear absolute based upon their respective definitions, the two categories are far from mutually exclusive.6,8 According to a seminal research publication by Lemp and associates, roughly 50% of individuals with DED were found to have only MGD as an etiologic factor, whereas about 14% were attributable purely to ADDE.
The remaining 36% had contributory characteristics of both evaporative and aqueous-deficient disease, which the authors described as a “mixed” or “hybrid” subtype.6,8 Further, it has been suggested that many cases initially thought to be due solely to one DED phenotype may evolve over time to include its counter-component.
Aqueous-deficient dry eye and Sjögren’s disease
For example, primary Sjögren’s, perhaps the most classic example of ADDE, is well-known to induce acute damage to the lacrimal gland, resulting in the loss of acinar, ductal, and myoepithelial cells.12 Nonetheless, studies have found patients with DED secondary to primary Sjögren’s often manifest MGD as well, placing these individuals squarely in the “mixed” DED phenotype.7,17,18
In a study of subjects with primary Sjögren’s (n=49), researchers found that individuals with the diagnosis for <3 years had decreased tear production and increased corneal staining as compared to a cohort of subjects (n=52) with non-Sjögren’s associated MGD.
Although the meibomian gland parameters (i.e., gland count, atrophy, secretion quality, and lid margin score) were similar between groups. Surprisingly, individuals with a primary Sjögren’s diagnosis > 3 years had worse MGD parameters than the comparison group.17 This suggests that individuals with Sjögren’s typically start with ADDE as the primary driver of DED, but progress toward the development of concomitant MGD over time.18
Hence, while it is relatively uncommon to encounter a dry eye patient in clinical practice who demonstrates ADDE in isolation, a diagnosis of MGD—or a combination of MGD and aqueous deficiency—is present in at least 50% and perhaps as many as 86% of those with DED, according to the literature.8,19-21
Therefore, it is crucial to understand the role of EDE in ocular surface disease, and to be knowledgeable about the diagnostic and therapeutic approaches to managing this pervasive condition.
The nuts and bolts of MGD and EDE
Taking a step back, let’s discuss the “why” of MGD, which, in scientific terms relates to an understanding of the disease pathophysiology. Starting with the basics, meibum is a highly complex, lipid-rich secretion that is produced by meibocytes in the holocrine meibomian glands, which are situated throughout the upper and lower lids and nested within the tarsal plate (Figure 2a).22
Meibum is an essential part of the eye’s defense mechanism, protecting the cornea and ocular surface from hazardous environmental factors, and perhaps most importantly, from the deleterious effects of desiccation.
The lipid composition of meibum is unique, and differs substantially from other lipid secretions, including sebum, which is the closest bodily fluid produced by the anatomically, physiologically, and biochemically related sebaceous glands.22
Meibum is primarily comprised of neutral, nonpolar lipids, including wax esters, cholesteryl esters, free cholesterol, and triacylglycerols, as well as smaller amounts of more polar compounds, e.g., free fatty acids, phospholipids, sphingomyelins, etc.23,24
According to current theory, the nonpolar tear lipids are designed to prevent tear evaporation, ensure a transparent and regular optical surface, and provide a barrier for external microbes and other pathogens.
The polar tear lipids are believed to impart amphiphilic properties that allow for an interphase between the nonpolar lipid layer and the aqueous/mucin component of tears.24,25
Figure 2 compares (a) healthy meibomian gland morphology and (b) meibomian gland in advanced MGD; note obstructive damage to the ductal system and blockade of meibum egress.
Figure 2: Adapted from Knop et al.
Etiologies of meibomian gland dysfunction
MGD occurs when the terminal ducts within the meibomian glands become obstructed. The pathophysiology is believed to be rooted in hyperkeratinization of the ductal epithelium, leading to thickened, opaque, and more viscous meibum containing keratinized cell material.26
Retrograde obstruction of the individual ductules leads to cystic dilatation within the glands, with subsequent meibocyte atrophy and gland dropout (seen in Figure 2). The result of this process is diminished meibum secretion, which directly impacts the tear film by provoking instability, increased evaporation, and ultimately, hyperosmolarity leading to EDE.
Secondary effects may include enhanced bacterial growth along the lid margin, and, in more severe cases, ocular surface inflammation and damage.26,27 MGD is further influenced by a variety of both endogenous (e.g., age, sex, and hormonal disturbances) and exogenous factors (e.g., topical medications and contact lens wear).26
Table 1 lists the most commonly recognized local, systemic, and external drivers of MGD.
Table 1: Adapted from TFOS DEWS II Definition and Classification Report.
Lid and ocular surface-related etiologies of EDE
In addition to MGD, EDE can also be influenced by a variety of other lid- and ocular surface-related maladies. The first of these categories, according to the TFOS DEWS II Pathophysiology Report, includes disorders of lid aperture, congruity, and dynamics.12
Incomplete eyelid closure is not uncommon in asymptomatic, normal patients during blinking.28 However, when the condition occurs over an extended period of time (e.g., nocturnal lagophthalmos, where the eyes are partially exposed over several hours per day), or remains constant due to physical abnormality or injury (e.g., thyroid eye disease, eyelid coloboma, facial nerve palsy or trauma), exposure and inadequate tear film resurfacing invariably lead to excessive ocular surface desiccation.
Globe prominence and ocular posturing can also contribute to EDE. Thyroid eye disease (TED) has a well-known association with DED, although its impact can be described as multifactorial. Not only does TED involve infiltration of the lacrimal gland and orbital tissues, imparting an aqueous-deficient influence, but proptosis of the globe also causes increased exposure and evaporation, further driving hyperosmolarity of the tear film.29
A similar impact on the tear film may be observed with ocular prostheses, although these patients are typically less symptomatic.30 It has been proposed that meibomian gland dropout, which is evident in those with both TED and long-term ocular prosthetic wear, may result from the stasis of meibum as a direct result of incomplete lid closure.12
Digital eyestrain, allergies, and DED
To a lesser extent, but of increasing importance within the realm of DED management, the use of digital devices has been linked to EDE. It is well-established that both blinking frequency and the proportion of complete blinks may be greatly diminished while individuals are engaged with digital platforms, including computer terminals, tablets, or smartphones.31
In such scenarios, patients may report end-of-day dryness, the need for frequent screen breaks, or regular use of ocular lubricants due to characteristic dry eye symptoms. Though more involved, this pattern of diminished blink frequency and incomplete lid closure is often encountered in those with Parkinson’s disease, where up to 70% of patients may show evidence of DED.32,33
EDE can also be related to deeper-seated ocular surface issues, including allergy. We recognize that ocular allergy and DED frequently coexist, often with clinical overlap, and hence identifying and differentiating the greatest causative factor is paramount in managing the patient’s complaints.
Allergy patients can develop DED, aggravating their symptoms; likewise, patients with DED can develop ocular allergies, so these two pathological entities should be considered as mutual conditions that share a similar background. By employing a careful medical history and keen observation skills, one can often determine the driving factor and initiate appropriate treatment.
However, in cases that truly pose a diagnostic dilemma, point-of-care testing can help to identify soluble levels of proteins in the tears (e.g., lactoferrin, immunoglobulin E) that may reveal the most likely underlying etiology and provide direction for appropriate therapy.34,35
Finally, EDE may be instigated by treatments for other ocular disorders, particularly those that require the ongoing use of topical therapies, such as glaucoma. When a new disease state results from a physician’s treatment, whether the intervention is medical or surgical, we refer to it as iatrogenic, i.e., from the Greek ἰατρός (meaning “doctor”) and γένεσις (meaning “origin”).
Targeting evaporation—a crucial step in managing dry eye
While not all eyecare providers (ECPs) make the clinical distinction between ADDE and EDE in clinical practice, it is important to consider treatment options that target these underlying conditions.
The majority of artificial tear products, which represent first-line dry eye therapy for most ECPs, consist primarily of water, aiming to increase the overall volume of the tear film. This treatment speaks more to ADDE than EDE.
Likewise, topical anti-inflammatory agents such as cyclosporine have historically been approved with an indication to “increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca.”36
Existing therapies for evaporative dry eye
Treatments that specifically target the evaporative component of DED attempt to prevent desiccation of the ocular surface, which can both exacerbate dry eye symptoms and potentially lead to secondary inflammation by permitting frictional forces to remain unchecked.
Until recently, the options for effective EDE-directed therapies have been limited.
Warm compresses
Daily application of warm compresses has been advocated as a first-line MGD therapy for decades; however, clinicians today recognize that its efficacy is limited by patient compliance, and the technique is not as straightforward as we may choose to believe.
Blackie and associates demonstrated that, in order for this therapy to be effective using the traditional “wet washcloth” method, the compress must be reheated every 2 minutes to maintain precise temperatures and remain in contact with the lids for 6 to 8 minutes to achieve the ideal temperature for expression.
Even then, the maximum attainable temperature of less than 41°C (105.8°F) may not be sufficient to achieve melting in all cases of obstructed glands.37
In-office treatments for MGD
In-office gland heating/expression using automated devices (e.g., LipiFlow [Johnson & Johnson Vision], TearCare [Sight Sciences], Systane iLux [Alcon], MiBo Thermoflo [MiBo Medical Group], and Thermal 1-Touch [OcuSoft]) may be more effective at alleviating meibomian gland blockage in the short-term.
However, these treatments also have limitations, including the need for repeated and/or prolonged treatment sessions, additional out-of-pocket expense, and potential discomfort, especially those procedures that employ manual gland compression.
Similarly, IPL therapy has recently emerged as a new, powerful treatment option for MGD/EDE, although the expense and time-consuming nature of this procedure may limit its applicability to a proportion of patients.
Artificial tears
Bringing the conversation back to artificial tears, there are several products specifically targeted toward patients with EDE. These formulations incorporate an oil component such as castor oil or mineral oil.
These so-called “lipid-based eye drops” require unique development to integrate the necessary oils into an aqueous solution, relying on such mechanisms as liposomes, emulsions (both anionic and cationic), and lipid nanocarriers to facilitate stability of the product in consumer-friendly dropper bottles.38
Additionally, while these products may help patients achieve symptomatic relief, there are still compliance issues to overcome; these include: (1) navigating the overwhelming variety of artificial tear preparations available, along with their wide-ranging degrees of efficacy; and (2) the limited residence time and duration of action associated with all artificial tear solutions.39
MIEBO: The latest therapy for evaporative dry eye
In May of 2023, the US Food and Drug Administration (FDA) approved MIEBO (perfluorohexyloctane ophthalmic solution), a semifluorinated alkane product “indicated for treatment of the signs and symptoms of dry eye disease.”40
According to the manufacturer (Bausch + Lomb), MIEBO is the first and only prescription eye drop that directly targets tear evaporation; it also has the benefit of being both water-free (as well as vehicle-free) and preservative-free.
Perhaps most unique is that MIEBO is currently the only FDA-approved prescription eye drop for DED that does not contain an anti-inflammatory agent, such as cyclosporine, lifitegrast, or loteprednol.
While the precise mechanism of action for MIEBO is not fully understood, it is theorized that this agent spreads across the ocular surface and prevents depletion of tear volume by augmenting the natural lipid component of tears, essentially forming an anti-evaporative barrier.
Additionally, perfluorohexyloctane seems to mimic several key functions of natural meibum, promoting healing on the ocular surface and helping to reduce frictional forces that can ultimately induce inflammation and discomfort.41,42
MIEBO clinical trial findings (GOBI and MOJAVE)
There is also strong clinical evidence supporting the use of MIEBO for evaporative DED. Two pivotal clinical trials, GOBI and MOJAVE, were conducted in parallel between July 2020 and August 2021.
Both studies employed a multicenter, double-masked, saline-controlled design and looked specifically at adult patients (≥18 years of age) with a self-reported history of DED in both eyes for ≥6 months, along with clinical signs of MGD.43,44 Patients were instructed to instill one drop of solution (either MIEBO or saline) four times daily in both eyes for the duration.
The primary outcome measures for both studies included: (1) the change from baseline in total corneal fluorescein staining (using the National Eye Institute [NEI] scale) at Day 57; and (2) the change from baseline in eye dryness score (using a visual analog scale ranging from 0 to 100) at Day 57.
As displayed in the accompanying images, both of the primary outcome measures were met with statistical significance as compared to the control (saline) group in pooled analyses of the data (P<0.0001) as seen in Figures 3 and 4.
Additionally, statistical significance was achieved for both the change in corneal fluorescein staining and eye dryness score from baseline to Day 15 (P<0.0001).
Figure 3 shows the change from baseline in total corneal fluorescein staining (tCFS) incorporating pooled data from GOBI and MOJAVE (n=1,217).
Figure 3: Courtesy of Tauber et al. and Sheppard et al.
Figure 4 demonstrates the change from baseline in eye dryness score (visual analog scale) incorporating pooled data from GOBI and MOJAVE (n=1,217).
Figure 4: Courtesy of Tauber et al. and Sheppard et al.
Between GOBI and MOJAVE, 614 patients received at least one dose of MIEBO. Regarding tolerability, there were no instances of serious ocular adverse events (AE) in the MIEBO group. The discontinuation rate due to AEs was 0.2% for those receiving MIEBO in the pooled studies, which was comparable to the control (saline) group (0.5%).
Additionally, the reported rate of burning and stinging, which is commonly associated with various eye drops upon instillation, was 0.5% in the pooled analysis.
Findings from the KALAHARI extension study
A year-long extension study designated as KALAHARI was also performed to assess long-term safety and tolerability. Of note, 208 patients from the GOBI trial, including 97 in the MIEBO group and 111 in the control (saline) group were rolled over into KALAHARI and followed for an additional 52 weeks, bringing the total follow-up period to 60 weeks.45
Throughout this study, ocular AEs leading to discontinuation of the study medication were reported in five patients (2.4%), with only three classified as treatment-related; moreover, no serious ocular AEs were observed. The overall safety profile was consistent with that reported in previous short-term studies, including both GOBI and MOJAVE.
No single ocular AE occurred at an incidence ≥2.0%, and there was a low rate of instillation site reaction (1.0%), which confirmed the favorable tolerability profile seen in both GOBI and MOJAVE.
Conclusion
Evaporative dry eye likely constitutes the majority of the patients seen in clinical practice who present with dry eye signs and symptoms.
Most experts in the field agree that differentiating between predominantly aqueous-deficient and evaporative etiologies is an important consideration when determining which therapeutic strategies to employ, and gauging the long-term success of their patients.
While our understanding and diagnostic tools have significantly advanced over the last quarter of a century, it is only within the last 5 to 10 years that targeted therapies have truly emerged to address specific subtypes of DED.
We now have excellent treatment options for patients with both inflammatory and evaporative forms of dry eye disease, including over-the-counter lubricants, prescription drugs, medical devices, and clinical procedures.
With the knowledge and tools now available, we can effectively address this exceedingly common and often frustrating condition for the benefit of our collective patients.
