Dry Eye in Focus at ARVO

The 2011 meeting offers a more detailed picture of dry eye and its possible treatments.

By Andrew Mathis, PhD, Medical Editor, and René Luthe, Senior Associate Editor

Our understanding of dry eye and how to treat it remains hazy, to the consternation of a growing number of patients and the ophthalmologists who care for them. At the recent Association for Research in Vision and Ophthalmology meeting in Fort Lauderdale, however, new information on risk factors, diagnosis and potential new therapies offers—well, if not yet answers, a more detailed picture. And with new drugs demonstrating their efficacy, clinicians may soon have more options for relieving their patients' symptoms. Below are a few notable developments to come out of ARVO this year:

■ SAR 1118 completes phase 2 trial. A potential dry eye treatment, SAR 1118, is inching closer to approval for the US market after it successfully completed a phase 2 clinical trial. SAR 1118 works by specifically inhibiting T-cell mediated chronic inflammation. According to lead investigator Charles Semba, MD—chief medical officer of developer SARcode Corp.—the small-molecule LFA-1 antagonist showed a rapid onset of action and improved both clinical signs and patient-reported symptoms.

SAR 1118 was administered to 230 dry eye subjects in a five-site, randomized, double-masked, placebo-controlled study. Principle eligibility criteria included exacerbation in corneal staining and ocular symptoms using a controlled adverse environmental model during screening. Eligible subjects were randomized 1:1:1:1 to receive one of three concentrations of SAR 1118 ophthalmic solution (0.1%, 1.0%, 5.0%) or placebo eyedrops administered BID for 12 weeks. Patients with active meibomian gland disease/blepharitis were excluded.

Ocular signs and symptoms were assessed at baseline, two, six and 12 weeks; no artificial tears were allowed during the course of study. The primary efficacy variable was the inferior corneal fluorescein staining score.

At 12 weeks, investigators found significant improvement (p<0.05) in inferior corneal staining relative to baseline for SAR 1118 (1.0%, 5.0%) compared to placebo with a dose response. Subjects reported significant symptomatic improvement (p<0.05) in the Ocular Surface Disease Index (OSDI) score and visual-related function sub-scale (improved ability to drive at night, read, use a computer) and total OSDI score. Additionally, Schirmer tear test indicated improved tear production at two weeks (p<0.05) with a consistent dose response through week 12 for patients randomized to SAR 1118. Researchers report that adverse events were generally transient in nature and mild-to-moderate in severity.

SARcode anticipates that the phase 3 development program will begin in the third quarter of this year. Should the drug win regulatory approval, the company notes that it would be the first drug indicated for improving both signs and symptoms of dry eye.

Semba C, Torkildsen G, Lonsdale J, McLaurin E, Geffin J, Mundorf T, Kennedy K, Ousler G. A Phase 2 Multicenter, Double-masked, Placebo-controlled Study Of A Novel Lymphocyte Function-associated Antigen-1 (LFA-1) Antagonist (SAR 1118) For Treatment Of Dry Eye.

■ Azithromycin proves efficacy in treating ocular surface disease. Azithromycin treatments for ocular surface disease continue to wend their way toward regulatory approval, with new studies demonstrating their safety and efficacy. Presentations at ARVO filled in additional details on the performance of two drugs.

One study investigated use of azithromycin to treat meibomian gland dysfunction and ocular rosacea. Seeking to evaluate the efficacy of topical azithromycin vs. oral doxycycline in the treatment of meibomian gland dysfunction (MGD), researchers randomized subjects with MGD to either treatment—topical azithromycin for one month or oral doxycycline for two months. Clinical evaluation of signs and symptoms was performed, as well as mechanical expression of the meibomian glands both before and after therapy. All subjects had abnormal lipid structure and function before treatment, with evidence of increased lipid ordering and higher than normal phase transition temperature.

The 22 subjects in the topical azithromycin group showed reduction of the abnormal lipid layer behavior at two and four weeks of treatment, while the seven subjects in the oral doxycycline group also showed reduction of lipid abnormality. However, the researchers found that the oral doxycycline group's response occurred after a longer response time and was less vigorous compared with that seen in the azithromycin group.

In another study, Italian researchers investigated the use of azithromycin as a treatment for ocular rosacea in a retrospective study of 37 patients. Ocular signs and symptoms, lacrimal function and meibomian gland clogging were evaluated, and severity of ocular involvement was assessed with the OSDI score. Subjects were assigned to three groups: 12 patients with moderate-to-severe blepharitis were treated with 100 mg of systemic doxycycline for one month; 16 patients with moderate-to-severe blepharitis were treated with preservative-free topical azithromycin BID for six days; and nine patients with mild-to-moderate blepharitis were dosed with preservative-free artificial tears six times daily for one month. All subjects performed lid hygiene BID for one month.

At one month, all patients reported a “significant” reduction in ocular burning, tearing, hyperemia, secretion, foreign body sensation and visual symptoms (p<0.05). Additionally, researchers reported a “significant” improvement in tear film break-up time, meibomian gland clogging and superficial punctate keratitis in all patients (p<0.05). All treatments were well tolerated by the subjects. However, while all therapies showed efficacy in reducing the signs and symptoms of ocular rosacea, researchers concluded topical azithromycin therapy showed an advantage in requiring a shorter duration of treatment.

Foulks GN, Borchman D, Yappert MC. Comparative Effectiveness Of Azithromycin And Doxycycline In Therapy Of Meibomian Gland Dysfunction.

Mantelli F, Di Zazzo A, Dianzani C, Lambiase A, Bonini S.Topical Azythromicin In The Treatment Of Ocular Rosacea.

■ Dry eye risk factors. A Japanese study involving 2,791 patients examined associations between dry eye disease (DED) and other demographic factors. The researchers examined the residents of Kuomi Town aged 40 years and older who had previously been diagnosed for DED by an ophthalmologist, or who demonstrated severe symptoms of DED (the presence of both dryness and irritation, experienced constantly or often). They used logistic regression analysis to evaluate the associations between DED and possible risk factors such as age, gender, alcohol consumption, smoking, contact lens use, height and weight, visual display terminal (VDT) use, history of some common systemic diseases, and education level. Women were significantly more likely to have a composite outcome of clinically diagnosed DED or severe symptoms (21.6%) than men (12.5%). While contact lens wear was a common risk factor for both genders, DED was more likely to be found in men with low body mass index and a history of hypertension. In women, history of myocardial infarction or angina and VDT use were risk factors; high BMI was found to be a preventive factor in women.

Uchino M, Nishiwaki Y, Michikawa T, Dogru M, Schaumberg DA, Kawakita T, Takebayashi T, Tsubota K. Prevalence and Risk Factors of Dry Eye Disease in Japan: Koumi Study.

■ Proteomic biomarkers provide insights into dry eye disease. A researcher seeking proteomic biomarkers of ocular surface diseases used quantitative mass spectrometry to discover molecular representatives in the tear film. Such bio-markers, hopefully, could be validated for clinical application and drug development. Tear samples were collected with a type I Schirmer's test from patients with dry eye, with pterygium or on glaucoma medications, as well as from a control group.

In the 50 dry eye patients included, 93 tear proteins were identified including six up-regulated proteins, four down-regulated proteins, including lactoferrin and lysozyme. The diagnostic accuracy was judged to be 96%. In chronic glaucoma patients, 128 tear proteins were identified. Two of the up-regulated proteins found in both dry eye and glaucoma patients, S100 A8 and A9, belong to the S100 calcium-binding protein family and are associated with inflammation, the investigator notes; they may reflect the inflammatory status of the ocular surface. Two peptide fragments from S100 A8 were found in pterygium patients.

“Proteomic biomarkers provide new insights into the disease process as with the inflammatory S100 proteins found here and which provide measurable end points for drug development, diagnosis and response to treatment,” the author concluded.

Beuerman RW. Proteomic Biomarkers of Ocular Surface Disease.

■ Predicting Sjögren's. A study by researchers at Johns Hopkins sought to establish the predictors of primary Sjögren's syndrome by comparing affected subjects with non-Sjögren's patients in a cohort of clinically significant aqueous-deficient dry-eye patients.

The 23-site study evaluated 327 patients in a prospective, randomized clinical trial. The participants underwent conjunctival staining with lissamine green, fluorescein corneal staining, a Schirmer's test (with and without anesthesia) and a general medical review for previously established collagen vascular diseases; serological testing for antinuclear antibodies, rheumatoid factor and Sjögren-specific antibodies A and B was also performed.

Patients with Sjögren's had significantly worse symptom scores as measured by the OSDI, as well as with the lissamine green conjunctival and fluorescein staining corneal tests and the Schirmer's test, both with and without anesthesia and in the majority of the other tests. However, no significant difference was seen in tear break-up time between Sjögren's and non-Sjögren's patients, nor was any correlation between the lissamine green staining test and an actual diagnosis of primary Sjögren's syndrome, leading the researchers to dismiss the lissamine test as a conclusive predictor.

Nevertheless, the Johns Hopkins team was able to conclude that the symptomatology of Sjögren's patients was significantly worse than that of non-Sjögren's patients. The most significant correlative measurement they were able to identify was a positive antinuclear antibody test, which indicated nearly a 14 times greater likelihood of developing the condition.

Akpek E, Zhang M, Liew SHM. Severity of Sicca and Predictors of Sjögren's Syndrome in Patients With Dry Eye.

■ Of tears, pain and symptoms. To determine whether there is any correlation between DED symptoms and tear osmolarity and pain sensitivity, researchers in the United Kingdom culled data from the 1,000-patient Twins UK study, applying a cross-sectional analysis to determine their data.

Of the patients in the Twin UK study, thus far 311 female subjects had been asked about their use of ocular lubricants. Using the OSDI and the short questionnaire of dry eye symptoms (SQ-DES) and a measurement of tear osmolarity using the TearLab Osmolarity System, DED symptoms were measured in these volunteers, and their pain thresholds were examined also.

After statistical analysis, the researchers calculated the DED incidence in the cohort as 12.3% based on the SQ-DES criteria, while it was much higher (38%) based on tear-osmolarity measurements. Furthermore, the researchers were not able to identify any correlation between pain sensitivity and DED symptoms based on the OSDI criteria and only a weak correlation between osmolarity and OSDI score.

The researchers concluded that diagnosing DED is highly dependent on which measurement metric is being used. High tear osmolarity may be considered only a mild predictor of DED symptoms, but the hypothesis of greater pain sensitivity among patients with DED was rejected.

Vehof J, Kozareva D, Hysi PG, Fahy SJ, Direk K, Hammond CJ. Relationship Between Dry Eye Symptoms, Tear Osmolarity and Pain Sensitivity in a Population-representative Cohort of British Women.

■ The DED/blepharitis combination. A large retrospective study sponsored by Inspire Pharmaceuticals sought to evaluate the assessments used to diagnose ocular surface disease, to measure the severity of symptoms, and to describe trends in treatment. The ophthalmologists recruited by Inspire examined the medical charts of 1,157 patients from several centers across the United States.

Among the charts studied, 35% of patients had diagnoses of dry eye, followed by blepharitis (29%) and a mixed diagnosis of both (29%). Conjunctivitis and other forms of ocular surface disease made up the rest of the cohort. The most commonly reported symptoms were ocular dryness and burning. Corneal staining and meibomian gland expression were the most common forms of assessment to which the patients were submitted; regarding therapies prescribed, artificial tears and mechanical therapies, consisting of lid hygiene and warm compresses, made up the two treatments most commonly recommended.

While results of the study are not terribly ground-breaking, the finding that a combined diagnosis of DED and blepharitis amounted to nearly a third of all diagnoses, and patients having either one or both of the diseases accounted for fully 94% of all diagnoses, is significant. Clearly, DED and blepharitis are incredibly common conditions.

Parekh JG, Hardten DR, Milner M, Shamie N, White D, Schiewe M. A Retrospective Study to Assess the Process of Diagnosis and Treatment of Ocular Surface Disease.

■ Protein molecules linked to increased tear osmolarity.

The role of microbiology in DED is not yet fully understood; in particular, the role of protein molecules in the disease's etiology is the subject of much speculation. A team of scientists from Bausch + Lomb reported on the role of two varieties of protein molecules—cytokines and matrix metalloproteinases (MMPs)—and their relationship to tear osmolarity. These proteins are known to appear in elevated levels in patients with DED.

The scientists enrolled 30 healthy volunteers into a small trial in which four dry eye diagnostic methods were applied to them: OSDI, noninvasive tear break-up time, tear osmolarity, and Schirmer's test. Using Schirmer's strips, tears were collected and their proteins extracted and measured. The scientists found that five inflammatory cytokines (four interleukins, plus tumor necrosis factor) and five MMPs were present in the volunteers' tears. Correlating the protein levels with tear osmolarity revealed that two interleukins, two MMPs and TNF had concentrations consistent with increased tear osmolarity.

Although these data will need to borne out in larger, prospective trials that include patients with active DED diagnoses, the authors stress that Schirmer's testing is routine enough in DED diagnosis that the opportunity to evaluate the protein contents of patients' tears already exists. Down the road, the conclusive identification of the biomarkers for DED and treatments targeted at those factors are likely.

VanDerMeid K, Su SP, Krenzer KL, Ward KW, Zhang J. Correlation of Cytokine and Matrix Metalloproteinase Levels in Human Tear Samples Collected by Schirmer's Strips with Tear Osmolarity.

■ Prostaglandins—and dry eye? Prostaglandins, which have been used extensively in treating glaucoma, and bradykinin, a peptide that induces vasodilation, also play roles in the mechanism of pain. In a study by ophthalmologists from South Korea, these molecules were studied in the tears of DED patients.

The study authors gathered 20 µL of tears from the eyes of all volunteers and then submitted the tears to spectral analysis, comparing the results with control results for three prostaglandins (PGE2, PGD2 and PGI2) and bradykinin. The respondents also completed symptom questionnaires, and they were also submitted to irritation threshold testing using a low pH phosphate buffer solution.

PGI2 and bradykinin were both present in elevated levels in the eyes of DED patients. At the same time, levels of PGD2 were lower in dry eyes, and there was no significant difference in levels of PGE2 between eyes. Furthermore, the level of irritation was not different between the eyes of DED patients and control eyes. Interestingly, the irritation score at suprathreshold stimuli in DED patients was higher than that of controls.

Because pain sensations may be higher or lower depending on the particular prostaglandin involved, further studies will be necessary to determine the exact role these molecules play in pain arising from DED.

Shim J, Park C, Kim EK, Lee HK. Levels of Endogenous Prostaglandins and Bradykinin in Dry Eye Patients.

■ Lissamine green staining—are two minutes necessary? Milton Hom, MD, presented data on the use of lissamine green in ocular staining. Beginning with the conventional wisdom that optimal viewing with lissamine green occurs at two minutes, Dr. Hom enrolled 30 subjects into a small study in which he stained the conjunctivas of the volunteers with lissamine green strips and then, using a four-point scale, he graded the staining in six zones of the conjunctiva at zero and two minutes.

Dr. Hom found that the mean grade at zero minutes was significantly higher than at two minutes for all zones of the conjunctiva (infero-temporal, superonasal, inferonasal, nasal, superotemporal and temporal). Based on his findings, Dr. Hom questioned the conventional wisdom of waiting two minutes for optimal visualization when using lissamine green. Stating that staining with fluorescein is most effective immediately, he urged more studies to examine the efficacy of lissamine green staining using a similar time protocol.

Hom M. False Staining Appearance With Lissamine Green. OM