Advancing Our Knowledge of Dry Eye Disease

Gaining a better understanding of new and advanced technology to diagnose, treat and manage dry eye disease.

By Paul M. Karpecki, OD, FAAO; Whitney Hauser, OD; and Katherine Mastrota, OD

Release Date:

December 15, 2016

Expiration Date:

December 31, 2017

Goal Statement:

On completion of this educational activity, participants should have a better understanding of conventional testing for dry eye disease, new and advanced diagnostic technology making diagnosis less time consuming and more precise, along with intermediate and long-term therapeutic interventions for treating and managing the dry eye patient.

Faculty/Editorial Board:

Paul M. Karpecki, OD, FAAO, Whitney Hauser, OD, and Katherine Mastrota, OD

Credit Statement:

This course is COPE approved for 2 hours of CE credit.COPE ID is 51862-AS. Please check your state licensing board to see if this approval counts toward your CE requirement for relicensure.

Joint-Sponsorship Statement:

This continuing education course is joint sponsored by the University of Alabama School of Optometry.

Disclosure Statement:

Dr. Karpecki is a consultant for AcuFocus, Alcon, AMO, Akorn, Allergan, Arctic Dx, Bausch + Lomb, BioTissue, Bruder Healthcare, Beaver Visitech, Eyes4Lives, OcuSoft, Freedom Meditec, Focus Labs, Eyemaginations, J&J, iCare USA, Konan Medical, Regeneron, Enchroma, Essilor, Eye Solutions, SightRisk, Reichert, Cambium Pharmaceuticals, Shire Pharmaceuticals, Science Based Health, Smart Vision Lab, TearScience, Topcon, TLC Vision, Vision Care Inc., Vmax and Visiometrics; a research grant principal investigator for Eleven BioTherapeutics, Fera Pharmaceuticals, Shire Pharmaceuticals; has received honoraria for the speaker's bureaus of Glaukos and Oculus; director/clinical advisor for Optometric Medical Solutions; and is on the board of directors for TearLab.
Dr. Hauser is a consultant for Allergan, Bonsai Beta, Lumenis, Shire and TearScience; founder of/senior consultant to Signal Ophthalmic Consulting; advisory board member for TearLab, Paragon BioTeck, BioTissue, Science Based Health and 1800DOCTORS; and CEO/founder of
Dr. Mastrota is a consultant for Allergan, B+L, Paragon, Bioteck, NovaBay, Science Based Health, Shire; a stockholder in TearLab; receives royalties from OcuSoft; and is on the speaker's bureau for Shire.

Supported by: 
An unrestricted educational grant from Shire.

The dry eye population is estimated to be more than 10 times that of other common conditions such as glaucoma.1 The ongoing Beaver Dam Offspring Study (BOSS) provided a baseline for estimating the level of dry eye disease (DED) in the general population of US adults.2 In that study of 3,257 participants, ages 21 to 84 years, Paulsen and coworkers reported an overall prevalence of DED symptoms of 14.5%—or nearly 30 million people.2

As high as this may seem, these numbers are likely to increase dramatically in the near future as a result of the aging US population. There are currently more than 100 million adults in the US over the age of 50, with another 10 million expected by the year 2020.3,4

Diabetes is also likely to have an impact on dry eye disease prevalence. Diabetes rates have been steadily rising for the last 40 years and there is no indication that this rate is going to decline any time soon.5,6 Twenty-nine million Americans (9.3%) have diabetes,6 and an older study found that half of this population had dry eye.7

Digital device use may be another huge driver of dry eye disease in coming years, with their use creeping into almost every part of our lives. A recent study by the Vision Council found that, on average, roughly 88% of adults spend more than two hours per day using a digital device, while approximately one in 10 people spend at least three-fourths of their waking hours on a digital device.8

Unfortunately, despite rising prevalence, only a small fraction of patients receive treatment for their dry eye,2,9 and the consequences of this cannot be overstated. Dry eye is much more than a nuisance. Complications include greater risk of eye infection and ocular surface damage, which can lead to inflammation, corneal surface abrasion and ulcers, contact lens intolerance and vision problems if left unaddressed.10 The relevance of degradation in quality of life, likewise, should not be minimized as it is known to heighten the risk of psychosomatic disorders, such as depression, stress and anxiety.11,12 And, in severe cases, patient utility assessment scores are comparable to those of acute angina and dialysis patients.13,14

The time to act is now. We must actively embrace the advanced knowledge of dry eye that now exists and utilize any tools at our disposal to help diagnose disease sooner and treat it more effectively.

The Evolving Role of Diagnostic Technology in Clinical Practice

The signs of dry eye that doctors see and the symptoms that patients feel always begin at a cellular level. Indeed, the impetus of inflammation is appreciated at a biochemical level before its impact is seen at the slit lamp. Ocular surface stress and damage trigger an acute inflammatory response. The body's innate reaction to the initial insult is a release of acute response cytokines that increase inflammatory cell production, expression of intercellular adhesion molecules and activation of antigen presenting cells.15 T cells migrate to ocular surface tissues and potentiate a chronic autoimmune response that results in a decrease in goblet cell density and apoptosis. This inflammatory domino effect results in overexpression of MMP3 and MMP9 (matrix metalloproteinase) and breakdown of the epithelium.15

Our goal, of course, is to intervene sooner and to recognize that first acute response that will inevitably morph into a state of perpetual inflammation that ultimately leads to chronic, progressive ocular surface disease. Indeed, without timely diagnosis, dry eye disease will only get worse and more difficult to manage. As such, all eye care practitioners should be actively looking for dry eye in our patients—whether or not they are symptomatic.

There's no question that can be a challenge. Research shows that fewer than 60% of dry eye patients are symptomatic.16 As such, the use of symptoms alone in diagnosis will likely result in missing a significant percentage of dry eye disease patients, particularly those with early or mild disease.16 Furthermore, this could have considerable impact—particularly in patients undergoing cataract or refractive surgery, as patients with dry eye disease have less than optimal visual results.16

Fortunately, a better understanding of conventional testing as well as new diagnostic technology have made dry eye diagnosis far less time consuming and much more precise. Of course, as is the case with many conditions, no single finding or test alone will provide all of the answers we need to initiate effective treatment; but together, our enhanced knowledge, combined with improved tools can help better inform our clinical decision-making for the short- and long-term benefit of patients suffering from or at risk of developing dry eye disease.

Conventional Testing

One way to raise your probability of success in diagnosing dry eye disease is to employ advanced testing, such as osmolarity and meibography.17 But since many doctors may not yet have access to these technologies, it's important to know how to make the most of conventional testing. This includes the case history, surveys, visual acuity, slit lamp observation, dye testing, tear volume testing and topography.

History. Case histories are not the be-all and end-all of diagnosis, but they are essential when diagnosing dry eye disease. When evaluating the history, look at the number of predisposing factors a patient may display (see "Key Predisposing Factors"). This approach alone may not be 100% accurate in establishing a diagnosis, but combined with testing, it can help confirm the disease. A patient with a significant number of predisposing factors should heighten your suspicion and prompt testing.

• Surveys. These have come a long way and have an important place in dry eye diagnosis. They help bridge the gap when there is a disconnect between signs and symptoms and offer objectivity where none might otherwise exist. Furthermore, many useful surveys are now in circulation. One of the most widely used is the Ocular Surface Disease Index (OSDI). Despite some limitations,18,19 the OSDI has excellent reliability and validity, as well as good sensitivity and specificity.19 It also discriminates well between normal, mild to moderate and severe cases. The Standard Patient Evaluation of Eye Dryness (SPEED) and the Dry Eye Questionnaire 5 (DEQ-5)20 are also commonly used to give objective value to subjective complaints. Other surveys, such as Impact of Dry Eye on Everyday Life (IDEEL), National Eye Institute's Visual Function Questionnaire (NEI VFQ-25) and The Short Form-36 (SF-36) provide information about the patient's quality of life, which is an important measure in any chronic disease. 

• Visual acuity. Visual acuity is tricky because it's not qualitative. For example, 20/20 doesn't mean much if you have to help a patient along by prompting her to blink. That's 20/struggle—not 20/happy. Furthermore, the urge to blink is frequently a response to blur, which is a strong indicator that a patient has dry eye. Unfortunately, clinicians don't often consider dry eye as the primary diagnosis when they encounter a complaint of blurred vision, although in fact this may be the only key symptom reported with almost all levels of dry eye disease. Whether it's transient blurred vision secondary to tear film instability in early disease or persistent blurred vision secondary to central corneal staining in advanced disease, blurred vision is a diagnostic sign worth careful investigation.

Slit lamp observation. The search for dry eye at the slit lamp doesn't begin and end at the cornea. Indeed, you want to look for superficial punctate keratitis, filaments and corneal dystrophies, but the lids and the conjunctiva provide many other clues. When examining the lids, pay careful attention to positioning, laxity, lash alignment and overall lid hygiene. When examining the conjunctiva, be on the lookout for conjunctivochalasis, exposed concretions, pinguecula, pterygium, hyperemia and papillary reaction.

• Dye testing. Vital dye staining information may be the first indicator that the patient's signs and symptoms don't match up. The three ophthalmic dyes are 2% sodium fluorescein, 1% lissamine green and rose bengal. Fluorescein is the most commonly employed dye in optometric and ophthalmological practices; however, lissamine can help you obtain excellent images that will allow you to recognize early signs of disease. Also, to get a truly detailed picture, both are required. Fluorescein is used to identify desiccated or injured cells and to perform a fluorescein tear break-up time (FTBUT). Corneal staining—particularly central, macropunctate or confluent—is an indicator of late-stage dry eye disease. Lissamine green, on the other hand, stains dead or devitalized cells.21 Lissamine green is useful in evaluating conjunctival damage, conjunctivalchalsis and the line of Marx along the lid margin. The line of Marx is a distinct zone of histologically parakeratinized cells that anchor the tear film. It's important to pay special attention to this since anything that changes the line of Marx will change the way the tear film operates. (See Figures 1 and 2). Rose bengal can provide valuable information too. However, patients frequently complain that it stings.   

Figure 1. Appearance of the lissamine green-stained Line of Marx in a healthy eyelid. The Line of Marx represents the muco-cutaneous junction of the eyelid. Photos: Whitney Hauser, OD
Figure 1. Appearance of the lissamine green-stained Line of Marx in a healthy eyelid. The Line of Marx represents the muco-cutaneous junction of the eyelid. Photos: Whitney Hauser, OD. Click image to enlarge.

• Tear volume testing. For obvious reasons, tear volume testing is a staple in dry eye diagnosis. Options include Schirmer's testing and phenol red thread. Schirmer's is the gold-standard in terms of research, but it does require anesthesia and it takes about five minutes. Phenol red thread, on the other hand, can be performed without anesthesia and takes only takes 15 seconds, making it a valuable alternative.

• Topography. Though not often thought of as a test for diagnosing dry eye, if properly reviewed, this test is often a first indicator of dry eye disease, especially when used in surgical practices prior to cataract surgery. Topography can detect subtle irregularities to the ocular surface and, as such, is an excellent tool for the detection of dry eye.22 The appearance of inferior steepening due to epithelial dehydration is a tell-tale sign that sometimes looks a bit like keratoconus.23 Other topographical findings of dry eye disease include irregularly shaped placido discs and differences in average keratometry readings between eyes.22,23 

Advanced Testing 
With good reason, point-of-care testing is finding its way into more and more practices. These reliable diagnostic tests can quickly provide clinical direction, tracking progress, helping determine the most appropriate therapy and, more importantly, determining who has true dry eye and who doesn't. Newer tests include, meibography, lipid layer thickness (LLT) assessment, blink analysis, tear osmolarity, matrix metalloproteinase-9 (MMP-9) analysis, noninvasive Keratograph break-up time (NIKBUT), microscopy, allergy testing, and the Sjögren's disease (Sjö) test.

• Meibography. Our ability to image the meibomian glands has significantly changed how we treat dry eye and how we educate patients about the importance of treating their disease. Meibomian glands plug, swell, become serpiginous, truncate and atrophy—in that order.24 As such, simply seeing a capped gland doesn't tell you much. Without looking inside, you will never really know how many of them are truly viable, which means you might suggest a treatment, like warm compresses, that will never offer meaningful relief to a patient who only has three or four viable meibomian glands.   

• Lipid layer thickness (LLT) assessment. Fluctuating vision is a hallmark of dry eye and an insufficient lipid layer is believed to be the most likely cause.25 While fluorescein TBUT is still used in most clinics, automated assessments of the lipid layer have taught us a lot about the ocular surface and provide a wealth of useful knowledge. For example, the Lipiview II employs interferometry to evaluate the lipid layer thickness, and the Keratograph 5M evaluates noninvasive TBUT. Armed with the knowledge that a patient's dry eye is driven by a deficient lipid layer will let you know that treatment should include a lipid-containing artificial tear and therapies that encourage meibomian gland expression. 

Figure 2. Lissamine green staining of the Line of Marx. Notice the abnormal undulations of Marx line in lid margin disease and anterior shift of the line. In the healthy eyelid, the Line of Marx smoothly parallels the contour of the lid margin and the line is positioned posterior to the glands.
Figure 2. Lissamine green staining of the Line of Marx. Notice the abnormal undulations of Marx line in lid margin disease and anterior shift of the line. In the healthy eyelid, the Line of Marx smoothly parallels the contour of the lid margin and the line is positioned posterior to the glands. Click image to enlarge.

• Blink analysis. Don't underestimate the value of a healthy blink. You might be surprised by how many of your patients' dry eye problems are caused by or made worse as a result of blink pattern. New technology can evaluate patients' routine blink characteristics, including blink rate and partial or incomplete closure. You can also use this information and video footage to help educate patients about how blinking contributes to their condition. The information can be used to help encourage treatment compliance and/or blinking exercises.

• Tear osmolarity. Osmolarity testing indicates whether or not the patient has a higher salt content than normal: As the volume of aqueous declines, the salt concentration in tears increases. Hyperosmolar status, whether through decreased tear production or an increased evaporative state, indicates reduced aqueous levels.26 This test can help make a dry eye diagnosis without relying on symptoms alone. Indeed, this is the primary purpose of tear osmolarity testing. However, it also useful for monitoring patients to determine whether they are responding favorably to treatment.

• Matrix metalloproteinase-9 (MMP-9) analysis. This point-of-care diagnostic test provides both qualitative and quantitative information that can aid the diagnosis of dry eye. MMP-9, a proteolytic enzyme produced by stressed epithelial cells, has been shown to increase in dry eye patients.27 A positive reading indicates that the sample contains more than 40ng/ml, which indicates inflammation. Elevated MMP-9 does not automatically imply that a patient has dry eye since this can also be increased in other ocular surface disorders. However, MMP-9 has been correlated with dry eye28 and is a good indicator that further investigation is warranted.

• Noninvasive Keratograph break-up time (NIKBUT). Aside from sparing the patient from the instillation of dye, this technology is much more precise than a slit lamp observation. Compared to putting in some fluorescein, asking your patient to blink, and then silently counting "one Mississippi, two Mississippi," this scientific technology is light years ahead in terms of objectivity. NIKBUT uses placido disc ring-based corneal topography to measure initial and average breakup. This unit also can help determine tear film quality. Using white or infrared illumination, you can measure the amount of tears at the lower tear meniscus. Finally, interferometry can be performed, allowing you to see particle spread while capturing lots of images and video.

• Microscopy. These non-contact devices reveal cell loss in the endothelial cell layer. Cell loss can be set in motion by several factors, such as extended contact lens wear, corneal disease, ocular surgery and, of course, dry eye. One benefit of specular microscopes is that they offer objective data that can be monitored over time to measure improvement. The images they provide also can be valuable for patient education.

Figure 3. Waxy debris covering the miebomian orifices can be mechanically removed to clear the way for lipid flow from the gland.
Figure 3. Waxy debris covering the miebomian orifices can be mechanically removed to clear the way for lipid flow from the gland. Click image to enlarge.

• Allergy testing. There's no question that allergy and dry eye overlap. Diagnosing dry eye disease can be challenging in this population, particularly when a patient is taking antihistamines. In such cases, it is helpful to dig deeper. New point-of-care allergy testing is quick and easy to perform. It takes approximately three minutes to perform and 10 to 15 minutes later, you get information on a panel of 60 allergens that are ocular-specific and regionally specific. The Ocular Allergy Diagnostic System (OADS) is very similar to a prick test that you might receive in an allergist's office. However, it uses a plastic applicator instead of needles.

• Sjögren's testing. Sjögren's is notoriously underdiagnosed but, thanks to new tests, optometrists may be able to detect it sooner. Sjögren's syndrome is associated with a 16-fold increased risk of development of lymphoma,29 so finding it sooner not only helps guide ocular treatment, it could also save lives. To perform the Sjö test, a doctor or technician obtains blood on a collection card and sends it to a lab for analysis. The results are usually back in seven to 10 business days. Alternately, patients can be referred for a blood draw that is then sent to the proprietary lab for processing.

Eliminate Guesswork
Like diabetes and hypertension, dry eye disease is a chronic, progressive disease that affects millions of people.30 While there is no "cure" for dry eye, timely identification and more specific knowledge about a patient's individual presentation can help guide treatment decisions, providing symptomatic relief and preventing escalation.

The best strategy is not to depend on any single test or marker. Dry eye disease (DED) is one of the most pervasive eye conditions in society today. As such, less common diseases can be misdiagnosed as dry eye, forcing the patient to undergo a potentially unnecessary regimen while simultaneously delaying treatment for the real problem. As in glaucoma diagnosis, no single test should be called upon to provide all of the information needed. Instead, a serial approach of multiple tests based on presentation is preferred. Though it may be viewed by some as more expensive or time consuming, going the extra mile in the diagnostic phase can save your patient both clinically and financially in the months and years to come. 

New Understanding in the Treatment of Dry Eye Disease

Although tens of millions of patients suffer from dry eye disease in the United States alone, less than one million are receiving medical treatment.2,9 Early, ineffective approaches to treatment may partially explain this unfortunate statistic. However, our evolved understanding of the disease combined with new treatments and well-informed ways to employ them offer more than just hope.  We can change the course of this disease and give patients an opportunity to live a less symptomatic life, despite the chronic nature of the condition.

Key Predisposing Factors

  • Advanced age
  • Female gender
  • Hormone replacement therapy
  • Systemic antihistamine use
  • Lack of healthy essential fatty acid intake (e.g. omega-3 fatty acids)
  • Connective tissue disorders
  • Refractive surgery
  • Androgen deficiency
  • Contact lens use
  • Rosacea
  • Certain medications (e.g., some antidepressants, diuretics, beta-blockers, isotretinoin)
  • Diabetes
  • Chemotherapy
  • Low humidity environments
  • Cigarette smoking

Immediate Intervention
There are a lot of dry eye treatments on the market and many of them are fantastic. But dry eye is complex. Unless it is very mild and a patient is in the beginning stages of disease, no one treatment alone is likely to provide satisfactory results if used exclusively for months and years to come.

When treating dry eye and ocular surface disease, you have to look at the big picture and the whole patient. There's no one silver bullet, especially when the patient has meibomian gland dysfunction (MGD) or lid disease. MGD is an important cause of evaporative dry eye syndrome and may be the most common cause of dry eye worldwide. MGD results in a deficient lipid layer, which in turn allows excessive evaporation of the aqueous layer of the tear film and consequent dry eye signs and symptoms. Conditions like this require immediate short-term intervention followed by long-term maintenance treatment.

Regardless of what we presume may be triggering a patient's dry eye, the goal is to get the lids, glands and the ocular surface functioning at their best. This involves four essential steps. Many clinicians will advocate for one or the other of these. However, none of these should be neglected. By systematically considering the need for treatment in all four areas, you can get your patient on the right path sooner, and prevent this chronic disease from getting worse. 

The four areas that ought to be addressed right away in a patient with dry eye are:

 Obstruction. Treating gland obstruction is like good dental cleaning. It can include lid margin debridement and scaling, hydrating compresses, manual expression and thermal pulsation. (See Figure 3).  

• Bacterial biofilm. If a patient has biofilm, address it head on with scrubs or a mechanical treatment such as Blephex, a surfactant cleaner or hypochlorus acid, or antibiotics as needed, depending on severity. Don't overlook this important step toward faster health and comfort for your patient.

• Inflammation. Try to knock out the inflammation right away in all forms of dry eye disease. For the immediate short-term, you can initiate steroids, doxycycline or a combination agent. Later or concurrently, you can add a longer-term medication to get inflammation under control. For example, cyclosporine or lifitegrast can be utilized with or without the addition of nutritional supplements. 

• Tear film instability. Artificial tears get a bad reputation because they will not treat dry eye disease. However, like brushing your teeth every day, artificial tears are important for maintenance and comfort. The key to effective tear supplementation lies in choosing a product that's appropriate for each patient's unique surface condition. A patient with high osmolarity will benefit from a different tear than a patient who is lipid or aqueous deficient with low osmolarity.

Traditional Risk Factors Need Not Exist

It is worth noting that although DED has traditionally been associated with aging, in the overall BOSS group, symptoms were also prevalent among younger subjects.1 In other words, dry eye should not be ruled out simply because a patient is young—particularly if the patient is a contact lens wearer. Indeed, younger age, male gender and the lack of other traditional risk factors should no longer limit further investigation into a patient's dry eye status.

Paulsen AJ, Cruickshanks KJ, Fischer ME, et al. Dry eye in the beaver dam offspring study: prevalence, risk factors, and health- related quality of life. Am J Ophthalmol. 2014 Apr;157(4):799-806.

Beyond Palliative Relief
The treatments above, particularly steroids, can offer rapid relief but are by no means a long-term solution. While it is true that you can see outstanding results when you get rid of biofilm, if you put a patient on steroids and follow up with warm compresses, it fails to address the chronicity of dry eye disease. Dry eye is chronic, and once steroids are discontinued, you are left with palliative options alone, as dry eye will once again progress. In fact, research has shown that when artificial tears alone were used for one year, patients experienced a 40% increase in T cells, which is equivalent to no treatment at all.31

Given the progressive nature of dry eye disease, the inflammatory cascade needs to be shut down, rather than merely slowed down. T cell recruitment and migration must be arrested to prevent cytokine release.

Don't Overlook Chronicity
Dry eye disease occurs when tears no longer provide adequate support to the ocular surface.15 The lacrimal functional unit (consisting of the lacrimal glands, conjunctival goblet cells, meibomian glands, and their neural and hormonal support structures) is central to the maintenance of a stable tear layer. Without this, tear dysfunction results. 

Many environmental and endogenous factors can trigger dysfunction of the lacrimal functional unit, but regardless of what triggers it, dysfunction of the lacrimal functional unit sets into motion a chronic inflammatory reaction that ultimately produces dry eye disease.15 Furthermore, the dysfunction of the lacrimal functional unit is perpetuated and sustained by the inflammation itself, and the result is a lacrimal functional unit that cannot produce tears of adequate quantity or quality.

Without an adequately protective tear film, there is continued stress on the ocular surface, leading to a cycle of dry eye disease in which inflammation produces tissue damage, which in turn causes cytokine release. The resulting inflammation then leads to further cytokine release in an ongoing cycle that becomes progressively worse in many patients.25 It is important to note that even if lacrimal functional unit dysfunction is caused by meibomian gland obstruction and evaporative dry eye, these events will trigger an inflammatory cycle that must be addressed.

The Complex Chemistry of Chronicity
T cells contribute to ocular inflammation through the production and release of proinflammatory cytokines.32 T cell target recognition occurs through a complex reaction in which a T cell surface receptor, called lymphocyte function-associated antigen-1 (LFA-1), is able to bind to a ligand on the target cell. This ligand is called intercellular adhesion molecule-1 (ICAM-1). ICAM-1 is normally expressed in low levels on epithelial (and endothelial cells) of ocular tissues, including the cornea, conjunctiva and lacrimal glands, as well as on antigen presenting cells. However, in patients with dry eye, ICAM-1 is overexpressed.33

How to Help Patients Understand Their Dry Eye

Perhaps the most important thing you can do when you're talking about dry eye disease is to set appropriate patient expectations. It's essential that patients leave your exam room with the understanding that dry eye is a chronic condition. One way to convey this is by emphasizing the "-itis." For instance, try mentioning conditions such as blepharitis, keratitis and meibomitis. This will help you draw a parallel between dry eye and other diseases that patients are more familiar with, such as arthritis. Patients understand that if you have arthritis, it's a life-long condition that requires ongoing medical treatment for effective control. Dry eye, like arthritis, can cause flare-ups, which are not a reflection of a doctor's inability to manage condition. Rather, these episodes are an expected manifestation of this chronic, progressive disease.

The binding of ICAM-1 to LFA-1 integrin on the surface of T cells plays an important role in the inflammatory process of dry eye. 36 When ICAM-1 binds to LFA-1, it sets in motion the three key components of an inflammatory response: T cell activation, recruitment and cytokine release. 33-35 As such, researchers hypothesized that LFA-1/ICAM-1 blocking would be a logical target for treatment.

Indeed, as our understanding of the inflammatory response has evolved, so too has our ability to address it clinically. As we first saw in patients treated with cyclosporine, arresting inflammation is at the heart of successful dry eye treatment. More recently, we are seeing that lifitegrast, a small molecule integrin antagonist, blocks binding of ICAM-1 to LFA-1 on the T-cell surface, inhibiting T-cell recruitment and activation associated with dry eye disease inflammation.36-38

Clinical Data
In July 2016, the FDA approved the first in a new class of drugs known as lymphocyte function-associated antigen-1 (LFA-1) antagonists. Commercially known as Xiidra (lifitegrast ophthalmic solution 5%, Shire Pharmaceuticals), the new drug is indicated for the treatment of signs and symptoms of DED. Specifically, this small molecule integrin antagonist blocks the binding of ICAM-1 to LFA-1 on the T-cell surface, inhibiting T-cell recruitment and activation associated with DED inflammation.36-38 This preservative-free drop comes in individual vials and is dosed BID.

Don't Overlook Demodex

Ocular Demodex infestation is highly age-dependent. In a study of 435 people, infestation was only 13% in individuals ages 3 to 15 vs. 69% in those ages 31 to 50 and 95% in those 71 to 96 years of age. Always be on the lookout for cylindrical dandruff and abnormal lash growth. Overpopulation of Demodex mites induces change of tear cytokine levels, IL-17 especially, which cause inflammation of the lid margin and ocular surface.1

Kim JT, Lee SH, Chun YS, et al. Tear cytokines and chemokines in patients with Demodex blepharitis. Cytokine 2011 Jan;53(1):94-9.

Lifitegrast went though four separate multicenter, prospective, placebo-controlled, randomized, double-masked FDA clinical trials involving more than 2,000 subjects ranging in age from 19 to 97 with a predominance of female patients, at about 75%.39 Both the active drug and placebo were administered BID for 84 days, and safety and efficacy were determined between the groups.

The study results revealed that the groups using lifitegrast had a statistically significant clinical improvement in signs (inferior corneal staining) and symptoms (eye dryness) compared with placebo. In the OPUS-3 study on symptoms of eye dryness, which involved 355 patients on lifitegrast and 356 on placebo, lifitegrast had a highly statistical improvement compared with placebo at day 84 (p=0.0007), day 42 (p<0.0001) and at 14 days after initiating therapy (p<0.0001).

The most common (>5%) ocular finding associated with lifitegrast was burning, and the most common (>5%) nonocular finding was dysgeusia, or a change in taste sensation. Most adverse events were reported as being mild to moderate in severity and transient.

1. Gupta P, Zhao D, Guallar E, et al. Prevalence of Glaucoma in the United States: The 2005-2008 National Health and Nutrition Examination Survey. Invest Ophthalmol Vis Sci. 2016;57(6):2577-85.
2. Paulsen AJ, Cruickshanks KJ, Fischer ME, et al. Dry eye in the beaver dam offspring study: prevalence, risk factors, and health- related quality of life. Am J Ophthalmol. 2014 Apr;157(4):799-806.
3. American Association of Retired People (AARP). Available at: (last accessed November 17, 2016).
4. U.S. Census Bureau. Available at: (accessed November 17, 2016).
5. U.S. Centers for Disease Control and Prevention. Available at: (accessed November 17, 2016.)
6. American Diabetes Association. Available at: http://www. (last accessed November 17, 2016)..
7. Seifart U, Strempel I. The dry eye and diabetes mellitus. Ophthalmologe. 1994 Apr;91(2):235-9.
8. The Vision Council. Digital Eye Strain. Available at: (last accessed November 17, 2016).
9. Moss SE, Klein R, Klein BE. Incidence of dry eye in an older population. Arch Ophthalmol. 2004 Mar;122(3):369-73.
10. Dry Eyes: Complications. Mayo Foundation for Medical Education and Research. Available at: (last accessed November 17, 2016).
11. Yilmaz U, Gokler ME, Unsal A. Dry eye disease and depression-anxiety-stress: A hospital-based case control study in Turkey. Pak J Med Sci. 2015; 31(3): 626-31.
12. van der Vaart R, Weaver MA, Lefebvre C, et al. The association between dry eye disease and depression and anxiety in a large population-based study. Am J Ophthalmol. 2015 Mar;159(3):470.
13. Buchholz P, Steeds CS, Stern LS, et al. Utility assessment to measure the impact of dry eye disease. Ocul Surf. 2006;4:155-61.
14. Schiffman RM, Walt JG, Jacobsen G, et al. Utility assessment among patients with dry eye disease. Ophthalmology. 2003;110:1412–9.
15. Stern ME, Schaumburg CS, Pflugfelder SC. Dry eye as a mucosal autoimmune disease. Int Rev Immunol. 2013 Feb;32(1):19-41.
16. Bron AJ, Tomlinson A, Foulks GN. Rethinking dry eye disease: a perspective on clinical implications. Ocul Surf. 2014 Apr;12(2 Suppl):S1-31.
17. Lin H, Yiu SC. Dry eye disease: A review of diagnostic approaches and treatments. Saudi J Ophthalmol. 2014 Jul; 28(3): 173–181.
18. Lemp MA. Report of the national eye institute/industry workshop on clinical trials in dry eyes. CLAO J. 1995;21:221- 32.
19. Schiffman RM, Jacobsen CG, Hirsch J. Reliability and validity of ocular surface disease index. Arch Ophthalmol. 2000 May;118(5):615-21.
20. Chalmers RL, Begley CG, Caffery B. Validation of the 5-Item Dry Eye Questionnaire (DEQ-5): Discrimination across self-assessed severity and aqueous tear deficient dry eye diagnoses. Cont Lens Anterior Eye. 2010 Apr;33(2):55-60.
21. Abelson M, Ingerman A. The dye-namics of dry-eye diagnosis. Review of Ophthalmology. 2005 Nov;12(11). /i/1311/c/25254/
22. 2014 Dry Eye Summit. Accessed from
23. Liu Z, Pflugfelder S. Corneal surface regularity and the effect of artificial tears in aqueous tear deficiency. Ophthalmology. 1999;106(5):939-43.
24. Koh S, Tung C, Aquavella J, et al.  et al. Simultaneous measurement of tear film dynamics using wavefront sensor and optical coherence tomography. Invest Ophthalmology Visual Science. 2010 Jul; 51(7):3441-8.
25. The Definition and Classification of Dry Eye disease: Report of the Definition and Classification Subcommittee of the International Dry Eye Workshop (2007). Ocul Surf. 2007;5(2):75-92.
26. Baudouin C, Aragona P, Messmer EM, et al. Role of hyperosmolarity in the pathogenesis and management of dry eye disease: proceedings of the OCEAN group meeting. Ocul Surf. 2013 Oct;11(4):246-58.
27. Chotiakavanich S, de Paiva CS, Li de Quan, et al. Production and activity of matrix metalloproteinase-9 on the ocular surface increase in dysfunctional tear syndrome. Invest Ophthalmol Vis Sci 2009; 50(7):3203-9.
28. Nichols KK, Mitchell GL, Zadnik K. The repeatability of clinical measurements of dry eye. Cornea. 2004;23(3): 272-85.
29. Goules A, Tzioufas A, Moutsopoulos H. Classification criteria of Sjögren's syndrome. J Autoimmun. 2014;48-49:42-5.
30. Gayton JL. Etiology, prevalence, and treatment of dry eye disease. Clin Ophthalmol. 2009;3:405–12.
31. Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA phase 3 study group. Ophthalmology. 2000 Apr;107(4):631-9.
32. Pflugfelder SC, Corrales RM, Paiva CS. T helper cytokines in dry eye disease. Exp Eye Res. 2013 December;117.
33. Gao J, Morgan G, Tieu D, et al. ICAM-1 expression predisposes ocular tissues to immune-based inflammation in dry eye patients and Sjögrens syndrome-like MRL/lpr mice. Exp Eye Res. 2004 Apr;78(4):823-35.
34. Pavilack MA, Elner VM, Elner SG, et al. Differential expression of human corneal and perilimbal ICAM-1 by inflammatory cytokines. Invest Ophthalmol Vis Sci. 1992 Mar;33(3):564-73.
35. Anderson ME, Siahaan TJ. Targeting ICAM-1/LFA-1 interaction for controlling autoimmune diseases: Designing peptide and small molecule inhibitors. Peptides. 2003 Mar;24(3):487-501.
36. Zhong M, Gadek TR, Bui M, et al. Discovery and development of potent LFA-1/ICAM-1 antagonist SAR 1118 as an ophthalmic solution for treating dry eye. ACS Medicinal Chemistry Letters. 2012;3:203-6.
37. Sun Y, Zhang R, Gadek TR, et al. Corneal inflammation is inhibited by the LFA-1 antagonist, lifitegrast (SAR 1118). J Ocular Pharmacol. 2013;29:395-402.
38. Murphy CJ, Bentley E, Miller PE, et al. The pharmacologic assessment of a novel lymphocyte function-associated antigen-1 antagonist (SAR 1118) for the treatment of keratoconjunctivitis sicca in dogs. Invest Ophthalmol Vis Sci. 2011;52:3174-80.
39. US Food and Drug Administration. FDA approves new medication for dry eye disease. (last accessed November 17, 2016).