Inflammation and dry eye

Inflammation and Dry Eye: What Do We Know?

The more we know about inflammation and its effect on dry eye, the better we can manage the condition.

Dr. Brujic is a partner of Premier Vision Group, a four-location optometric practice in northwest Ohio. He has received honoraria in the past two years for speaking, writing, participating in an advisory capacity, or research from Alcon Laboratories, Allergan, Bausch + Lomb, Odyssey Medical, Optovue, Nicox, Paragon, TelScreen, Transitions, Valeant Pharmaceuticals, Vistakon, Valley Contax, and VMax Vision.

Dr. Kading is in practice in Seattle and is an adjunct faculty member at Pacific University. He has been a consultant/advisor to and has received research/education grants from Optometric Insights, Alcon Laboratories, Allergan, Art Optical, Bausch + Lomb, Contamac, CooperVision, Visionary Optics, Nicox, Paragon, TruForm Optics, SynergEyes, RPS Detectors, Unilens, Valeant, Valley Contax, and Vistakon.

By Mile Brujic, OD, & David Kading, OD

Our understanding of dry eye has evolved significantly over the last decade. Ten years ago, much of the dry eye treatment revolved around palliative therapies: either adding moisture for aqueous deficient dry eye or using warm compresses and eyelid hygiene to help the meibomian glands produce more normalized meibum in evaporative dry eye, both in contact lens wearers and in non-lens wearers (Paugh et al, 1990). Today, controlling the inflammatory cascade has become one of the mainstay strategies in controlling the escalating effects of the disease (Stern et al, 2004; Stern and Pflugfelder, 2004).

Clinically, we must be cognizant of the role that inflammation may play in our contact lens wearers, specifically when managing symptoms of contact lens-related dryness.

Evaluating Dry Eye Markers

There are a number of tools that we utilize in clinical practice to elicit and quantify the clinical signs and symptoms that patients may experience from dry eye disease. The questionnaire that most readily comes to mind is the Ocular Surface Disease Index (OSDI). This validated questionnaire has been utilized extensively as a research tool to quantify the effects of dry eye on patients’ visual function, symptoms, and environmental triggers (Schiffman et al, 2000). It ranks patient symptoms as mild, moderate, or severe depending on the score acquired, with 0 to 12 being the normal range, 13 to 22 being mild, 23 to 32 being moderate, and 33 and above being severe.

Although not commonly utilized in clinical practice, the OSDI has demonstrated the value of scaling a patient’s symptoms. As we know with dry eye treatment, the further we minimize inflammation, the more likely our patients are to experience an improvement of symptoms (McCabe and Narayanan, 2009; Gumus and Cavanagh, 2009). While the OSDI serves as the gold standard to measure subjective symptoms, at a minimum you should have your patients grade the severity of their symptoms and then follow up over time to manage the success or failure of whatever dry eye treatment you initiate.

A number of other tests are also available to aid with diagnosis as well as to monitor treatment success or failure. Schirmer tear strip testing provides a gross look at tear production. It can be performed with or without anesthetic. A normal reading is 10mm of tear production within a five-minute time period.

The Schirmer test is relatively time consuming, so many practitioners have instead embraced phenol red thread (Zone-Quick from Menicon) testing (Figure 1) to measure the quantity of tears produced. This test allows you to measure tear production over a 15-second time period without the need for anesthetic, and compared to the strip the thread is much more comfortable for patients (Baudouin et al, 2007). Although neither of these tests assesses for inflammation, both are important for dry eye diagnosis and for monitoring treatment.

Figure 1. A patient undergoing phenol red thread testing.

However, the most common tools used to diagnose and monitor treatment for dry eye are the vital dyes. Fluorescein application provides a wealth of knowledge about the viability of the ocular surface, including the tear film. You can optimize its visibility on the ocular surface by using a cobalt blue light and a Wratten #12 filter (Nichols, 2005).

Clinically, we can also measure tear meniscus height, tear film breakup time (TBUT), corneal and conjunctival staining (Figure 2), and lid wiper epitheliopathy (LWE). LWE is the presence of staining on the small area directly posterior to the meibomian glands on the superior eyelid that performs much of the “wiping” activity over the surface of the eye during a typical blink. LWE was reportedly observed in 80 percent of contact lens wearers and 75 percent of non-contact lens wearers experiencing dry eye symptoms (Korb et al, 2002; Korb et al, 2005).

Figure 2. Punctate epitheliopathy in dry eye.

Lissamine green and rose bengal may also expose ocular surface compromise including staining of the cornea, conjunctiva, and the LWE in patients who have dry eye disease. As valuable as these dyes are, frequently there is significant variability between the symptoms that patients experience and the clinical signs that they exhibit, in part because of decreased corneal sensitivity that may occur in patients who have dry eye syndrome (Xu et al, 1996; Bourcier et al, 2005).

TearLab Corporation has developed the TearLab Osmolarity System, a clinically usable tool for measuring tear osmolarity. This instrument functions on the principle that as tear volume decreases, the solutes present in the tear film represent a higher concentration in the tear film. This is measured through a small probe that collects tears from the lower tear meniscus (www.tearlab.com). As a general rule, the higher the osmolarity, the more severe the dry eye. Although increased osmolarity is not a direct measure of the level of inflammation, a number of studies have demonstrated the close relationship that exists between osmolarity and inflammation. For instance, in a study on mice eliciting hyperosmolarity, treating the mice with a hyperosmotic saline solution caused an increased production of pro-inflammatory markers including IL-1beta, TNF-alpha, and matrix metalloproteinase-9 (MMP-9) compared to control mice (Luo et al, 2005). Additionally, tear hyperosmolarity has also been linked to tear instability (Liu et al, 2009).

MMP-9 is a non-specific inflammatory marker that increases as the severity level of dry eye increases. In the presence of ocular surface disease, the levels of MMP-9 are known to be elevated. Likewise, MMP-9 levels are low in the absence of ocular surface disease. One study has demonstrated that a normal individual who does not have ocular surface disease can have up to 41ng/ml of MMP-9 in the tears (Acera et al, 2008).

Chotikavanich et al (2009) measured MMP-9 levels in dry eye patients and found the following levels of MMP-9 associated with the following levels of dry eye severity: 8.39ng/ml in normals, 35.57ng/ml for those who have severity level 1, 66.17ng/ml for severity level 2, 101.42ng/ml for severity level 3, and 381.24ng/ml for severity level 4. Additionally, Soloman et al (2001) demonstrated increased levels of MMP-9 in patients who had Sjögren’s syndrome and meibomian gland dysfunction (MGD).

Although not yet available in the United States, an interesting point-of-care test called InflammaDry (Rapid Pathogen Screening, Figure 3) is available in Canada and Europe that measures the presence of the inflammatory protein MMP-9 in the tear film. The InflammaDry does not measure the level of MMP-9 on the ocular surface—rather, it provides a positive result when the level of MMP-9 is greater than 39ng/ml (www.rpsdetectors.com; Sambursky et al, 2013). This may provide valuable insights relating to the possible benefits of punctal occlusion. From a clinical perspective, those of us who utilize punctal plugs know that they provide significant relief for some patients, but not for others. This may be due in part to the level of inflammatory markers on the surface of the eye—retaining tears on the surface that contain high levels of pro-inflammatory mediators will not reduce inflammation and therefore will not help relieve dry eye symptoms. This point-of-care test allows us to determine whether MMP-9 levels are below 40ng/ml, which may ultimately help us determine when to use punctal plugs and may help improve outcomes when using them.

Treating the Cause

There is a consensus in the professional community that inflammation is associated with dry eye. An apparent point of contention is whether decreased quality of the tear film causes increased resistance to blinking and ocular moisture, resulting in an inflammatory response—or whether an underlying inflammatory component decreases the quality of the tear film and increases resistance of the blink over the ocular surface. Regardless of the origin of the inflammation, they will each exacerbate the other in a continuous cycle, leading to increased clinical signs and symptoms of dry eye disease.

Ultimately, the goal of managing patients who have dry eye revolves around decreasing ocular surface inflammation. Often the absence of conjunctival injection may lead to a conclusion that there is no inflammation present on the surface of the eye, but research has shown that there can be inflammation even in the absence of visible bulbar hyperemia in dry eye patients (Chotikavanich et al, 2009).

Many initial treatment strategies involve modifying environmental factors that may cause symptoms. Initial strategies also usually include increasing the lubrication on the ocular surface to improve lubricity, which is simply the measure of how much a lubricant reduces friction.

For most patients, additional therapeutic agents will be required to decrease inflammation present on the ocular surface. Many resort to topical corticosteroids for patients who continue to have symptoms. Steroids offer a broad spectrum of anti-inflammatory therapy by inhibiting both the transcription of proinflammatory factors and many of the inflammatory factors that were already secreted and are propagating the inflammatory response (Clinical Ocular Pharmacology, Third Edition). When utilized to treat dry eye, steroids improve clinical signs and symptoms of the disease including reducing ocular surface inflammation (Avunkuk et al, 2003; Pflugfelder, 2004; Pflugfelder et al, 2004).

In 2002, topical cyclosporine 0.05% was approved and marketed as Restasis (Allergan) for patients who have dry eye. Cyclosporine is an immunomodulator that acts on T cells to prevent further propagation of the inflammatory cascade associated with dry eye, and it helps increase patients’ tear production (www.allergan.com). Studies show that topical cyclosporine has demonstrated significant benefits to patients including reducing surface inflammation and increasing goblet cell density (Kunert et al, 2002; Perry and Donnenfeld, 2004). Traditionally, cyclosporine has been considered ideal for managing aqueous deficient dry eye, but it may benefit patients who have MGD as well. Recent evidence shows that patients who used topical cyclosporine 0.05% for three months exhibited improvement in mean OSDI scores, TBUT, lid margin inflammation, meibomian gland expressibility, and tarsal injection; cyclosporine also demonstrated a viable role in MGD (Prabhasawat et al, 2012).

Oral doxycycline has been used for years to treat moderate to severe MGD because of its strong anti-inflammatory activity (Foulks et al, 2013). Topical azithromycin (AzaSite, Merck) has also been used successfully in this capacity because of its ability to both control the microflora present on the eyelid margins and to decrease MMP-9 levels (McDermott et al, 2005).

Inflammation and Contact Lens Wear

Up to this point we have discussed some of the diagnostic tools available to identify and monitor treatment for our dry eye patients as well as the mounting evidence to support the notion that inflammation is associated with dry eye. Contact lens wear presents a greater challenge as it introduces yet another variable to the ocular surface. Adding a contact lens to the ocular surface further challenges it, but also provides opportunities to better understand it and ultimately to improve patient outcomes.

In the larger context of dry eye disease, similar considerations may apply when discussing contact lens wear. Just as decreased lubricity on the ocular surface can cause an eye to feel dry, decreased lubricity on a contact lens can cause uncomfortable lens wear. Ultimately, the goal with our contact lens wearers is to maximize lubricity. We can accomplish this by optimizing contact lens surface characteristics as well as the tear film that supports lens wear.

LWE, as discussed earlier in regard to dry eye patients, should also be measured in contact lens wearers. Korb et al (2005) showed that LWE is associated with symptoms of contact lens-related dryness. Yeniad et al (2010) also found that LWE was associated with symptomatic contact lens wear. In this study, 67 percent of symptomatic lens wearers versus 32 percent of asymptomatic patients demonstrated LWE. LWE should be assessed particularly when contact lens wearers are symptomatic, as this will indicate reduced lubricity over the contact lens surface, causing lid wiper staining.

Figure 3. InflammaDry device.

The physical characteristics that describe the relationship between the tear film and contact lens are becoming increasingly important in understanding contact lens comfort. Specifically, rapid pre-lens tear film thinning (Figure 4) was associated with dry eye symptoms with contact lens wearers (Nichols and Sinnott, 2006). Additionally, decreased goblet cell density was found in contact lens wearers who had dry eye symptoms (Albietz, 2001).

Figure 4. Contact lens drying in between blinks.

Laser confocal microscopy has been able to demonstrate some of the morphological changes to the meibomian glands that occur in contact lens wearers, which may contribute to contact lens dry eye. Contact lens wearers showed significantly decreased basal epithelial cell density, lower acinar unit diameters, and higher glandular orifice diameters when compared with controls (Villani, 2011).

Additionally, in experienced lens wearers who have worn contact lenses for longer than a year, the subepithelial nerve plexus was reduced in density compared to patients who were not contact lens wearers. There was not a significant difference between nerve plexus density in symptomatic and non-symptomatic contact lens wearers. Interestingly, nerve growth factor, which is increased in conditions that damage corneal nerves, was increased in the tear film of symptomatic contact lens wearers when compared with asymptomatic contact lens wearers (Liu et al, 2009).

An in-depth look at the lipids that are present in contact lens wearers reveals vast differences in symptomatic versus non-symptomatic wearers. Symptomatic lens wearers had higher levels of lipases and degraded lipids, specifically malondialdehyde and 4-hydroxy-2(E)-nonenal, compared to their non-symptomatic contact lens-wearing counterparts (Glasson et al, 2002). Degraded lipids have an increased melting point and are associated with thickened meibum.

Tear osmolarity is also altered during contact lens wear. In one study, two daily disposable contact lenses were worn, and the osmolarity of the tear film was measured at baseline without the contact lens, then at 4 hours and 8 hours after lens wear was initiated. Wearing the contact lenses increased tear film osmolarity during the day, but was below the cut-off value for dry eye (Sarac et al, 2012). It is still unclear how tear osmolarity relates to symptomatic contact lens wear. There are studies that demonstrate a clear relationship between symptomatic contact lens wear and increased osmolarity, while others have failed to duplicate these findings (Nichols and Sinnott, 2006; Chen et al, 2013).

How Can We Help Contact Lens Wearers?

Our increasingly sophisticated understanding about the ocular surface and tear film allows us to better utilize that knowledge to mitigate symptoms of uncomfortable contact lens wear. Manufacturers have continued to improve wettability of contact lens surfaces through a number of unique strategies. Contact lens care has evolved to incorporate a number of agents that attempt to mitigate the effects of friction from the upper lid. Bausch + Lomb introduced hyaluronan into its Biotrue multipurpose disinfecting solution to help maximize contact lens comfort (http://solution.biotrue.com). Alcon’s Opti-Free PureMoist contains the company’s new surfactant polyoxyethylene-polyoxybutylene, commonly known as HydraGlyde, which is designed to bind to hydrophobic areas on contact lenses while exposing its hydrophilic component, promoting comfortable lens wear (Campbell et al, 2012).

Additionally, a number of new surface technologies are now available to help increase lubricity over the contact lens, thus improving comfort. Surface treatments are intended to optimize comfort with silicone hydrogel lenses. Other silicone hydrogels contain internal wetting agents that have been added to improve comfort. Alcon recently introduced in the United States its Dailies Total1, the first water gradient contact lens that transitions from a low water content at the center of the lens to an average surface water content of 80 percent. (Thekveli et al, 2012; Pruitt et al, 2012).

Ideally, optimized contact lens surfaces and lens care would improve lubricity and therefore reduce symptomatic contact lens wear. But is there anything currently available that can improve symptoms in lens wearers by directly decreasing pro-inflammatory changes to the ocular surface?

We have already discussed topical cyclosporine 0.05% (Restasis), which has been used for a decade to successfully manage ocular surface inflammation associated with dry eye. The question becomes whether utilizing an immunomodulatory agent such as topical cyclosporine may benefit contact lens wearers. Hom (2006) recruited 17 symptomatic contact lens wearers and randomized them to utilize either cyclosporine 0.05% or a placebo b.i.d. before and after lenses were worn. After five weeks, there was a significant improvement in symptoms and wearing time in the cyclosporine group. Willen et al (2008) performed a similar study with contact lens wearers but had patients utilize either treatment or placebo for three months; they found no difference between the groups. Although these two studies present conflicting information, it is worthy to consider topical cyclosporine 0.05% for symptomatic lens wearers.

AzaSite may provide significant anti-inflammatory activity on the ocular surface by regulating nuclear factor kappa B (NFκB), suppressing the production of cytokines, chemokines, and MMP-9s (D’Acquisto et al, 2002). Recently, researchers randomized symptomatic contact lens wearers to receive either topical azithromycin 1% for 30 days, 1gt b.i.d. for the first two days and then q.d. for the remainder of the 30 days, or placebo 1gt q.i.d. for 30 days. The mean comfortable wearing time increased more than two hours in the group utilizing topical azithromycin (Nichols et al, 2012).

Additional studies have looked at the effect of supplementation with oral essential fatty acids on patients experiencing contact lens dryness. A specific form of omega-6, evening primrose oil (EPO), was studied. Patients were randomized to either EPO or placebo and were assessed at three months and six months. Significant improvement in the specific symptom of “dryness” was realized at three months and six months, and also a significant improvement in overall lens comfort at six months was evident in the EPO group (Kokke et al, 2008).

Further studies on omega-3 fatty acids are currently underway to determine their effectiveness in symptomatic contact lens wearers.

Conclusion

Ultimately, comfortable contact lens wear will result from a combination of optimizing both the ocular surface and the contact lenses that we prescribe to our patients. Through increased knowledge of the inflammatory cascade and its potential role in contact lens-related dryness, we will better position ourselves clinically to provide our patients with the best options available to alleviate their discomfort with contact lens wear. CLS

For references, please visit www.clspectrum.com/references. asp and click on document #212.