DED-ology: Epidemiology, etiology, and pathophysiology
Dry eye disease (DED) can be an overwhelmingly challenging topic, given its myriad of contributory factors, variable expression in both signs and symptoms, and diverse pathophysiology as well as the ever-growing arsenal of new and varied therapeutic strategies targeting this disease state.
Like many other chronic disorders, however, DED is also exceedingly common, affecting a significant percentage of the population worldwide.
Prevalence of dry eye disease
Estimates are difficult to confirm, given the large number of currently undiagnosed and self-managed cases, but a recent systematic review and meta-analysis found that the pooled prevalence of DED was 17.4% (95% confidence interval [CI], 8.9% to 31.4%; 13,546,368 participants) across 10 studies judged to be representative of the population in the United States.1
Extrapolation of that value to the overall US population suggests that roughly 58 million Americans suffer from DED in some capacity. If we ascribe this population to the current number of eyecare providers in the US (approximately 45,000), it amounts to nearly 25 patients with DED per practitioner per week.
Such prevalence exceeds even some systemic disorders that have been recognized as “public health crises,” for example, diabetes. According to the US Centers for Disease Control and Prevention (CDC), 11.6% of the US population—roughly 38.4 million Americans—have diabetes of some type, including 29.7 million with a confirmatory diagnosis along with another 8.7 million who remain undiagnosed.2
Etiology of dry eye disease
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.”3 Within this condition, we recognize two broad etiological subtypes: (1) aqueous-deficient dry eye (ADDE), and (2) evaporative dry eye (EDE).3-5
In ADDE, the precipitating tear film instability and hyperosmolarity are believed to result from diminished lacrimal output, resulting in a higher concentration of salts, ions, proteins, and other components in the tear film. Characteristics predisposing patients toward ADDE may involve advanced aging, the use of certain systemic medications, reflex block from prior refractive surgery, and autoimmune disorders such as Sjögren’s.5
In contrast, EDE begins with essentially normal aqueous tear secretions that are impacted by excessive evaporation from the ocular surface. This in turn leads to tear film hyperosmolarity and secondary instability.6 The most common cause of EDE is meibomian gland dysfunction (MGD), which results in an inadequate lipid tear component.
However, numerous other etiologies have been identified, including incomplete lid closure, diminished blink frequency or quality, or simply an abnormally large palpebral aperture. Additionally, EDE may be attributable to other ocular surface-related issues, including mucin deficiency and/or contact lens problems.3,7,8
Comparing aqueous deficient and evaporative dry eye
Both ADDE and EDE mechanisms are important drivers of DED; however, it’s crucial to understand the relationship between these two disease subtypes. According to a landmark publication in 2012, about half of the cases seen clinically are considered evaporative in nature, while only 14% are purely aqueous-deficient.9
The remaining 36% of individuals with DED have elements of both subtypes (i.e., “mixed'' dry eye disease).9 Hence, DED may be seen to exist on a continuum, not only in terms of severity, but also in terms of instigating and perpetuating factors (Figure 1).
Figure 1 illustrates the representative distribution of dry eye disease, including aqueous-deficient and evaporative etiologies.
Figure 1: Adapted from Craig et al.
Mixed-mechanism dry eye disease
As an added element in this complexity of etiologies, we must also recognize that cases that initially begin as primarily aqueous-deficient may, over time, begin to develop evaporative components.
A prime example of this is primary Sjögren’s, which is well-known to induce acute damage to the lacrimal gland, resulting in loss of acinar, ductal, and myoepithelial cells and a resultant decrease in aqueous production.6 However, studies have found patients with DED secondary to Sjögren’s often manifest MGD as well, placing these individuals squarely in the “mixed” DED phenotype.10-12
According to research, this is a gradual change that takes place over years, as patients with longer disease duration tend to show greater degrees of meibomian gland involvement.11 In a similar fashion, patients with primarily evaporative DED can, over time, develop aspects of ADDE, as factors that drive evaporation naturally lead to a depletion of the overall tear volume on the ocular surface.
The inflammatory story behind DED
We’ve known for quite some time that ocular surface inflammation plays an etiological role in DED,3 although experts disagree as to whether inflammation is inherent in all cases.
Of course, we have methods of identifying inflammation in a given patient, whether via simple observation of the eyes (i.e., conjunctival hyperemia, corneal epithelial disruption, lid swelling, etc.) or more direct point-of-care testing (e.g., tear cytokine levels, specifically matrix metalloproteinase 9 [MMP-9]). The question arises as to whether the inflammatory aspect of DED is inherent to ADDE or EDE, or whether it transcends these categories.
According to the TFOS DEWS II report, the innate immune system provides a physical barrier between the eye and its external environment, with crucial elements including the gel mucin, glycocalyx, corneal epithelium, and a host of antimicrobial defense proteins within the normal tear composition.5 However, this defense system can be hijacked by hyperosmolar stress, with major downstream effects that amplify the inflammatory immune response.13
According to prevailing theories, desiccation of the ocular surface that cannot be overcome by normal homeostatic mechanisms leads to a quantitative (ADDE) and/or qualitative (EDE) deficiency of tears, resulting in increased friction and chronic mechanical irritation at the ocular surface. This, in turn, initiates a chain of both inflammatory events and surface damage that are inherent to DED.5
Whether a patient’s disease is attributable to diminished tear production or to increased tear evaporation—or a combination of the two—the resultant stimulus toward inflammation remains the same. To state this more definitively, both ADDE and EDE can give rise to inflammatory DED (IDED) if not properly addressed.
Reading the signs (and symptoms) of DED
The symptoms associated with DED are quite well-known and have been delineated across numerous clinical reports. These may commonly include burning, dryness, itching, stinging, grittiness, scratchiness, sandy-feeling or foreign body sensation in the eyes; photophobia; intermittent blurriness; heavy or tired eyes, and discomfort when performing activities that require prolonged focus (e.g., reading, driving, computer, television).14
Unfortunately, none of these symptoms is specific to any dry eye subtype, whether it be ADDE, EDE, or IDED, although a longer history of disease symptoms may indicate a greater likelihood for inflammation to be present.
Regarding clinical signs, these too are non-specific for the most part. Conjunctival hyperemia is characteristic of inflammation, which may be related to any subtype of DED (as previously discussed) as well as a host of other ocular surface abnormalities, including allergy, infection, or inflammation from systemic causes. Eyelid signs may include excessive blinking or eyelid twitching.
The tear volume can also be impacted in dry eye disease. Intermittent, excess tearing (i.e., epiphora) may be seen as a response to discomfort in more symptomatic DED. However, in advanced cases of ADDE (usually with underlying systemic autoimmune disorders) patients may report an inability to produce tears, even in response to emotional stimuli where crying might be expected.
In order to differentiate ADDE from EDE, at least at a basic level, examination findings of specific tests may be helpful. Tear volume assessment is likely the most helpful diagnostic technique for classifying ADDE, and can be accomplished using any of the following: (1) Schirmer’s tear test; (2) phenol red thread test; or (3) tear meniscometry (i.e., tear meniscus measurement). Reduced values on these tests are suggestive of diminished aqueous tear production, although patients with mixed DED can also demonstrate diminished tear volume (Figure 2).
Figure 2 outlines tear volume assessment tools and normal values.
Figure 2: Courtesy of Alan Kabat, OD, FAAO.
Diagnostics that are most helpful in identifying EDE include: (1) tear lipid layer thickness and quality (as depicted by interferometry); (2) meibography (i.e. evaluation of the meibomian gland integrity using transillumination and/or infrared evaluation); and (3) meibomian gland expression, which can yield both quantitative and qualitative information regarding the contributory tear lipids.
Again, it must be reiterated that abnormal findings on these tests may occur simultaneously with diminished tear volume in those with mixed DED. Many other tests for DED are by nature non-specific, in that they reflect tear film instability and ocular surface desiccation, which can occur regardless of the initial underlying etiology. Of course, even non-specific tests can provide important, useful information that help to guide therapy.
Examples of these techniques include tear breakup time (TBUT), non-invasive tear breakup time (NIBUT), tear osmolarity, and vital dye staining (i.e., fluorescein and lissamine green) of the ocular surface tissues. Corneal sensitivity testing is also typically performed as part of the dry eye evaluation, although this is done to identify more insidious cases of neurotrophic keratopathy rather than any specific form of DED.
Detecting inflammatory DED with diagnostics
In terms of IDED, the primary diagnostic instrument that is available for clinical use is the InflammaDry test (QuidelOrtho). This handheld, disposable, point-of-care device is capable of detecting the presence of elevated MMP, an enzyme which is expressed in the tears secondary to ocular surface inflammation. The test is easy to perform, delegatable, and takes only 10 minutes to obtain results.
Moreover, it has a sensitivity of 85% and a specificity of 94% for DED.15 Additionally, lactoferrin levels may provide an indication of DED severity and inflammatory potential. Lactoferrin is a naturally occurring protein that has antioxidant, antimicrobial, and anti-inflammatory properties; in human tears, diminished levels of lactoferrin have a high correlation with aqueous-deficient DED.16,17
The T-POC Quantitative Testing Platform (Verséa Ophthalmics) is available for in-office assessment of tear lactoferrin. While other inflammatory markers such as HLA-DR, Th1, Th17, and ICAM-1 can be detected using impression cytology and/or flow cytometry, these are typically restricted to clinical research due to their complexity and cost.18,19
Identifying the contribution of comorbidities to DED
One important additional consideration in identifying IDED is to assess the history for accompanying comorbidities. It is well-known that individuals with certain systemic autoimmune conditions, for example, have a greater propensity to develop DED.
In addition to Sjögren’s, rheumatoid arthritis, thyroid eye disease, lupus, sarcoidosis, fibromyalgia, and inflammatory bowel disease (including Crohn’s disease) are paramount among these considerations.20,21 Further, some ocular conditions that are inflammatory in nature can hasten the cascade in DED while causing “collateral damage.”
Such notable conditions as ocular rosacea and Demodex blepharitis may be indicators of secondary IDED. Other factors that may have an association with IDED include smoking, poor gut health (including previous stomach/colon surgeries), and treatments for systemic diseases that can cause dysfunction of the lacrimal functional unit (i.e., cancer and chemotherapy).
Dr. Koetting notes that in day-to-day practice, she assumes that nearly all of her DED patients have some level of inflammation. While she sometimes utilizes point-of-care testing for confirmation, she relies heavily on biomicroscopy with vital dyes and meibomian gland evaluation, as well as a detailed systemic history.
In cases where the patient has systemic issues that cause chronic inflammation, then she recognizes the need for chronic inflammatory control of the ocular surface, regardless of accompanying findings.
Searching for a targeted therapy in a sea of options
One really has to marvel at all of the treatment options available for DED in 2024. Where there was once only “artificial tears” and punctal plugs as interventional therapy, we now have a range of choices from over-the-counter eye drops to nutritional supplements to prescription medications and even minimally invasive procedures, such as intense pulsed light (IPL) or vectored thermal pulsation for MGD.22
Of course, the problem with having multiple treatment modalities is the tendency to employ them indiscriminately without realizing that their mechanisms of action are somewhat different and may target specific etiological factors or sequelae with varying degrees of efficacy.
Let’s examine these treatment options in their broadest categorical identities, discussing potential areas where they may be beneficial in the management of DED.
Ocular lubricants (aka “artificial tears”)
Artificial tears, as they are known by most patients and clinicians, have historically been directed toward tear insufficiency, primarily an aqueous-deficient condition. There are countless formulations, both branded and generic, with a wide range of active and inactive ingredients to improve biocompatibility, protect against desiccation, and enhance residence time on the ocular surface.
Besides unique demulcents, such as carboxymethyl cellulose, hydroxypropyl-guar, and hyaluronic acid, other components of artificial tears may include various osmoprotectants (e.g., L-carnitine and erythritol), buffers, and electrolytes.22
Preservatives in artificial tears
Preservatives are also a component of most multidose artificial tears, serving a necessary function by preventing contamination of the solution and extending the shelf-life of the product.
Unfortunately, some preservatives—particularly benzalkonium chloride (BAK), which is the most commonly used of these compounds in ophthalmic preparations—may be associated with toxicity and detrimental changes to ocular surface tissues. This is particularly true when exposure to BAK is prolonged and/or frequent. In vitro studies have shown that BAK can decrease epithelial cell viability and increase the release of pro-inflammatory mediators.23
Lipid-based artificial tears
More recently, however, some manufacturers of artificial tears have begun to incorporate lipid components into their formulations, recognizing that the oil component is also crucial for prolonging residence time as well as helping to enhance lubricity and minimize frictional forces.
Those “lipid-based” tears, which may contain low concentrations of castor oil, mineral oil or flaxseed oil,24,25 tend to be marketed toward patients with a strong evaporative component, whether they be categorized as EDE or mixed DED. Hence, while we can select individual products from this very basic therapeutic category to address both ADDE and EDE, artificial tears as a treatment option are not specifically indicated for one form of DED over another.\
The role of artificial tears in DED management
While the evidence suggests that artificial tears really do not address the underlying causes of DED, they nonetheless can provide temporary relief of symptoms. The use of these agents is to be encouraged as a palliative therapy, but patients should be directed toward the selection of good quality products that are safe and appropriate for use given their individual clinical scenarios.
Dr. Koetting’s perspective on artificial tears is consistent with the prevailing literature and sentiment; she describes these solutions as little more than a “Band-Aid” for DED, and suggests that anti-inflammatory therapies are far more effective for both short-term and long-term disease management.
Nutritional supplements
Similarly, nutritional supplements for DED may be somewhat beneficial in its management, although the utilization and efficacy of these agents is not specific to any particular etiology.
Supplements marketed for DED typically contain two main ingredients: some form of essential fatty acid [usually high in omega-3 oils such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)]; and (2) one or more antioxidants, including vitamins A, C, D and E, bilberry extract, lutein, zeaxanthin, and curcumin.26,27
The incorporation of omega-3 fatty acids is typically thought to address EDE, since in conditions like MGD there is diminished quality and/or quantity of meibomian secretions, and these supplements are believed to provide stronger “building blocks” for tear lipid production.
However, since these agents and other antioxidants target free radical production and may help to downregulate inflammation, nutritional supplements may also be beneficial in patients with aqueous deficient, or certainly in mixed forms of DED. In essence, nutritional supplements appear to target multiple facets of DED and cannot truly be ascribed to one subtype over another.
Nonetheless, a recent prospective, randomized, placebo-controlled study demonstrated that once-daily nutritional supplementation—in this case, using a proprietary blend of lutein, zeaxanthin isomers, curcumin, and vitamin D3—significantly improved tear production, stability and quality, while reducing ocular surface damage and inflammation and improving participants' symptoms vs. placebo.27
Pharmacotherapy: Anti-inflammatory agents
Since the approval of cyclosporine ophthalmic emulsion in 2003, we have seen an increasing number of pharmacologic therapies emerge for the treatment of DED (Figure 3).
All who are familiar with these drugs will note that the majority of these are classified as anti-inflammatory agents, including the following:
- Cyclosporine ophthalmic emulsion 0.05% (RESTASIS, Allergan/Abbvie)
- Cyclosporine ophthalmic solution 0.09% (CEQUA, Sun Pharma)
- Cyclosporine ophthalmic solution 0.1% (VEVYE, Novaliq/Harrow)
- Lifitegrast ophthalmic solution 5% (XIIDRA, Shire/Novartis/Bausch+Lomb)
- Loteprednol etabonate ophthalmic suspension 0.25% (EYSUVIS, Kala/Alcon)
Cyclosporine
Cyclosporine, the active ingredient in three US Food and Drug Administration (FDA)-approved products for DED, functions as a calcineurin inhibitor to exert immunomodulatory effects by blocking infiltration and the subsequent release of inflammatory cytokines by activated T-cells.28 Clinical trials have demonstrated this drug’s efficacy in keratoconjunctivitis sicca, a more advanced and inflammatory form of ocular surface disease and a term used synonymously with DED today.29
Improvements in the delivery of topical cyclosporine have enabled pharmaceutical companies to develop new products over the years with increased drug concentrations, allowing for greater bioavailability as well as improved biocompatibility and efficacy.30-33
Notably, the most recently approved agent for the treatment of the signs and symptoms of DED incorporates cyclosporine with a semi-fluorinated alkane vehicle (perfluorobutylpentane).34 The product, named VEVYE, is a twice-daily formulation dispensed in a 10μL drop that is preservative- and water-free, with a low surface tension and viscosity.
The unique vehicle permits VEVYE to purportedly deliver a more rapid onset of action and greater tolerability than prior formulations of cyclosporine.32,33,35 In clinical trials, the study criteria included a reduced Schirmer test score (≥1mm and ≤10mm) and both corneal and conjunctival staining.32,33,36 Subjects with blepharitis or MGD were specifically excluded from these trials.
Lifitegrast
Lifitegrast is a small-molecule integrin antagonist that, like cyclosporin, has the capacity to treat DED by inhibiting the inflammatory cascade in both active and inactive T-cells. This drug has an affinity for lymphocyte function-associated antigen-1 (LFA-1), a cell surface protein found on leukocytes.37
It effectively blocks the interaction of LFA-1 with its cognate ligand intercellular adhesion molecule-1 (ICAM-1), which may be overexpressed on the ocular surface in DED.37 A series of robust clinical trials demonstrated efficacy for both clinical signs (i.e., inferior corneal staining score) and symptoms (i.e., visual analog eye dryness score) as compared with vehicle control at 12 weeks.38-40
Dr. Koetting indicates that she often gravitates toward lifitegrast in cases of IDED, especially for those patients with systemic autoimmune conditions. “If I have the choice, I will reach for lifitegrast first because it works on both active and inactive T-cells, and patients may demonstrate improvement in signs and symptoms in as little as 2 weeks.
However, if patients experience adverse effects or do not improve for whatever reason, I will switch to cyclosporine 0.09% or 0.1%. Alternatively, some patients may have better insurance coverage with cyclosporine and/or have to fail prior to coverage of lifitegrast, so I will start a patient there. If the patient does well and has improvement in signs and symptoms, then we continue. If they do not, then we pivot and go to lifitegrast.”
Loteprednol etabonate
Finally, loteprednol etabonate is a corticosteroid, the most potent and widely recognized class of anti-inflammatory agents known to medicine. Like all corticosteroids, loteprednol induces phospholipase A2 inhibitory proteins, which block the release and activity of arachidonic acid and the biosynthesis of potent mediators of inflammation, including prostaglandins and leukotrienes.
While numerous topical corticosteroids exist, loteprednol is unique in its chemical structure, demonstrating an ester at its C-20 position rather than a ketone group like prednisolone or dexamethasone. This modification imparts highly lipophilic properties, permitting increased binding at the glucocorticoid receptor sites.
Additionally, it permits rapid metabolism after activation, lowering the risk of adverse effects that have traditionally been associated with topical ophthalmic corticosteroids (e.g., cataractogenesis and elevation of intraocular pressure).41 Loteprednol is also unique among topical agents for DED in that it is only approved for short courses (i.e., up to 2 weeks) of therapy to treat symptomatic “flares,” as opposed to cyclosporine and lifitegrast, which are chronic care medications.42
According to Dr. Koetting, she occasionally prescribes corticosteroids in the short-term treatment of dry eye flares, though more commonly, she uses them to onboard patients toward more long-term therapy. “I will typically start a patient on a 2-week, BID pulse of topical corticosteroid at the same time as I initiate therapy with lifitegrast or cyclosporine, provided they are not a known steroid responder.”
While all of the aforementioned agents are specifically approved for either “keratoconjunctivitis sicca” or “dry eye disease,” they also carry an expressed (or implied) indication toward IDED. Case in point, the verbiage within the RESTASIS prescribing information describes it as “...a calcineurin inhibitor immunosuppressant indicated to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca.”43
And although more recently approved agents tend to carry the non-specific “treatment of the signs and symptoms of dry eye disease” indication, most eyecare providers recognize that these drugs all impact the inflammatory cascade in their mechanisms of action.
Figure 3 lists FDA-approved pharmaceuticals with indications for DED.
Figure 3: Courtesy of Alan Kabat, OD, FAAO.
Pharmacotherapy: Neurostimulatory agents
In 2021, the US FDA granted approval for the first DED medication that utilizes a non-ophthalmic route of delivery.44 Varenicline solution is a cholinergic agonist, delivered via nasal spray to target trigeminal nerve endings in the nasal mucosa, subsequently stimulating the production of basal tears.44,45
While its non-specific indication is also “for the treatment of the signs and symptoms of dry eye disease”, all of the patients in the clinical trials had aqueous tear deficiency as defined by a baseline, anesthetized Schirmer test score ≤10mm.46-48
Hence, this product likely has its greatest utilization in patients with primarily aqueous-deficient DED. The efficacy of varenicline solution nasal spray in quelling ocular inflammation associated with DED has yet to be demonstrated in prospective clinical trials.
Pharmacotherapy: Anti-evaporative agents
May of 2023 saw the FDA approval of two unique new agents, both incorporating the first completely water-free vehicle technology in topical ophthalmic preparations. MIEBO, consisting of 100% perfluorohexyloctane, is an anhydrous, semi-fluorinated alkane that directly targets tear evaporation, and is indicated for treatment of the signs and symptoms of DED.49,50
This agent, by virtue of its small drop size and low surface tension rapidly spreads to create a monolayer at the tear/air interface, minimizing evaporation and contributing to its therapeutic effect in managing DED.51 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.52,53
Two pivotal clinical trials, GOBI and MOJAVE, were conducted in support of FDA approval for perfluorohexyloctane ophthalmic solution. Both studies employed a multicenter, double-masked, saline-controlled design specifically aimed at patients with a self-reported history of DED for ≥6 months, along with clinical signs of MGD.54,55
Primary outcome measures included the change from baseline in both total corneal fluorescein staining and eye dryness score at Day 57 as compared to saline control, which were met with statistical significance in pooled analyses of the data (P < 0.0001).
Regarding long-term tolerability, there were no instances of serious ocular adverse events (AE) in the perfluorohexyloctane group. In a pooled analysis of the two studies, the discontinuation rate due to AEs was 0.2% in the perfluorohexyloctane group vs 0.5% in the control group.54,55
Dr. Koetting says of EDE, “If I identify a decreased TBUT and/or some level of MGD, then I consider that patient to have a contributory evaporative etiology. This indicates potential benefit from not only treating the underlying dysfunction with in-office and at-home therapies, but also prescribing perfluorohexyloctane to help supplement the depleted meibum. The use of this topical agent helps to stabilize the tear film, mitigate patients’ symptoms, and most importantly, diminish the epithelial stress and exposure to help improve signs of ocular surface disease.”
Mechanical therapies
The majority of mechanical therapies for DED available today specifically target tear film evaporation in the form of MGD and obstruction removal. Notable technologies include vectored thermal pulsation (i.e., LipiFlow), which aims to liquify stagnated meibum within the glands while simultaneously employing gentle, rhythmic pressure to express the glands in an attempt to restore normal flow.56
Similar devices abound in the US market, albeit with different designs, attributes, and performance capabilities; a few of note include MiBo Thermoflo, TearCare, Systane iLux2, and the OCuSOFT Thermal 1-Touch.
In terms of ADDE, the iTear100 is a novel, sonic device which, when applied to the external skin around the nose, initiates a neurostimulatory effect targeting the same trigeminal nerve pathway as varenicline nasal spray. Research has demonstrated that this device can help to significantly increase tear production (as measured via the Schirmer test score) and improve symptoms within 30 days.57
Another form of mechanical therapy that may potentially address both evaporative disease and inflammation in some respects is IPL therapy. IPL is a non-laser, high-intensity light with wavelengths in the 400 to 1200nm range, delivered in controlled pulses that last several milliseconds.58
The technology has long been used in dermatology to treat inflammatory conditions such as rosacea, telangiectasia, and hemangiomas.59 The utilization of IPL in DED therapy began in the early 2000’s, and today it represents one of the most successful, non-pharmacologic treatments employed for patients with DED and MGD.60
IPL is believed to have several benefits in this disease state, most notably:60
- Enhancing tear lipid quality and availability via photothermal energy targeting the meibomian glands
- Promoting changes to meibomian gland architecture
- Enhancing anti-inflammatory factors and/or suppressing pro-inflammatory factors within the ocular surface tissues and tear film
- Diminishing the bioburden of associated Demodex mites
- Inducing local destruction of superficial abnormal blood vessels, thereby reducing the source of inflammatory mediators
Advanced therapies and procedures for DED
There are of course more advanced therapies for DED, most targeting the inflammatory aspects of the disease. Those that are specifically approved for use in this capacity include autologous serum and platelet rich plasma eye drops, and amniotic membrane therapy.
All of these are intended to provide nutrient rich alternatives for corneal metabolism to suppress inflammation and foster regenerative healing. Oral tetracycline derivatives and azithromycin may also be employed for their anti-inflammatory capabilities, although these typically are used to target recalcitrant MGD with inflammatory complications.
Similarly, oral secretagogues such as pilocarpine and cevimeline, which are indicated for the treatment of dry mouth in patients with primary and secondary Sjögren’s, may be beneficial for ADDE in these patients as well.
Finally, for severe, advanced disease with a risk of corneal decompensation and/or perforation, surgical procedures like tarsorrhaphy and salivary gland transplantation may be considered as a means of preventing permanent scarring and vision loss.
When all else fails…
In some cases, patients may continue to worsen despite seemingly appropriate therapies. In such instances, the eyecare provider should instinctively reevaluate for alternative diagnoses, including those conditions that can present as comorbidities (e.g., Demodex blepharitis, chronic allergic conjunctivitis, conjunctivochalasis) or sequelae of DED, and treat accordingly.
One condition that bears specific mention due to its capacity for irretrievable vision-threatening complications is neurotrophic keratopathy (NK). Recall that NK involves progressive damage to sensory neurons that subserve the cornea, leading to degenerative tissue changes with simultaneous loss of sensation; in other words, these patients tend to show progression in disease signs with a discordant stability in their ocular symptoms.
We must actively delineate these cases of “stain without pain” and employ more aggressive and targeted therapy, which may include regenerative therapies previously discussed, surgical intervention, and/or the use of topical recombinant human nerve growth factor (cenegermin).61 Employing corneal sensation testing (i.e., corneal aesthesiometry) in these individuals is vital for proper identification, and should be part of any dry eye disease workup where the signs and symptoms are disproportionate.62
Conclusions
Dry eye disease is an exceedingly common and complex ocular disorder, with a multitude of contributory elements and various clinical subtypes, each demanding targeted therapy for maximal impact. We recognize the two primary categories of DED to be aqueous deficient and evaporative, but we also firmly acknowledge that inflammation plays a significant role in the pathophysiology of dry eye.
We now have more diagnostic tools than ever before, affording us the opportunity to identify, in many cases, the most significant element or elements that drive this disease. Likewise, we have more potential options for DED in our therapeutic armamentarium than ever before, and while this can certainly benefit our patients, the obligation to determine the most appropriate therapy for each individual rests squarely on our shoulders.
Only by thoroughly understanding the disease and its various treatment approaches can we rise to the occasion and meet the challenge of appropriate prescribing in DED.
