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Welcome to Ocular Surface News! This is the second issue, and if you missed the inaugural issue, you can see it here.

Management of moderate to severe dry eye is a challenge we all have faced. The patient is unhappy, the doctor is unhappy, and it seems like "the kitchen sink approach" where everything has been tried, yields limited success. Your reflex response in this situation may be to change something, or even everything, that your patient is doing. Hold on—it is important to step back and carefully review the management history while assessing success (or lack of) of each therapy, duration, and compliance, including an assessment of your patient's understanding of the condition.

In the last issue you were asked in the quick poll to respond to how you would manage a difficult case with significant corneal staining with filaments. It is important to note that many would say the patient was unresponsive to her current therapies, yet we do not know how bad she would be if she discontinued these therapies; my guess is much worse. What is clear is that she needs more.

The results of the quick poll were interesting with 44% selecting oral doxycycline as the next adjunct therapy. Wouldn't it be great if we had InflammaDry to assess her MMP9 levels (see this week's Abstract)? Alternatively, autologous tears are an option that might not readily come to mind. Depending on where you practice, this may require co-management or referral to an ophthalmologist, and is a wonderful opportunity to additionally discuss co-management of ocular surface disease in your pre-and post-operative cataract patients. I hope you enjoy this week's issue; please keep sending me your ideas and comments.

Kelly K. Nichols, OD, MPH, PhD
Editor


May 24, 2013
Editor's Commentary
News
Rigel to Initiate R348 Phase 2 Clinical Trial

R-Tech Ueno Starts Patient Enrollment of Phase I/II Clinical Study of RU-101

Clinician's Corner
Research Update
Abstract
Dry Eye 101: Medical Coding & Compliance



Results from last poll:

What would you do for the patient presented in Clinician's Corner in this issue?

1. Add oral doxycycline
44%
2. Fit with a large diameter GP or scleral lens
20%
3. Refer for autologous serum
18%
4. Add ointment, with or without steroid at night
18%
NEWS

Rigel to Initiate R348 Phase 2 Clinical Trial
Rigel Pharmaceuticals, Inc. has developed a topical ophthalmic (eye drop) formulation of R348, a JAK/SYK inhibitor, aimed at reducing the underlying inflammation responsible for causing the symptoms of dry eye disease. According to the company, a recently completed Phase 1 study of R348 in patients with dry eye disease showed that the drug candidate is well tolerated and Rigel expects to begin a Phase 2 study, titled DROPS (Dry eye Rigel Ophthalmic Phase 2 Study), shortly.

This multi-center, randomized, double-masked study, will evaluate two doses of R348 versus placebo administered twice a day over a three-month period in approximately 210 patients with dry eye disease. The efficacy endpoints will include change from baseline in corneal staining, tear production and dry eye symptom scores. Results of this Phase 2 study are expected in the first half of 2014.


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R-Tech Ueno Starts Patient Enrollment of Phase I/II Clinical Study of RU-101
Following their recent FDA IND approval, R-Tech Ueno announced the start of the patient enrollment of the first stage of a Phase I/II clinical study of RU-101 ophthalmic solution, recombinant human serum albumin-containing ophthalmic solution, which is being developed for the treatment of severe dry eye.

The trial consists of two stages. During the first stage, the safety will be mainly assessed using placebo as control to evaluate maximum dosage of RU-101 ophthalmic solution for treatment of patients with severe dry eye. In the next stage, RU-101 ophthalmic solution of maximum dosage, the safety of which will have been confirmed at the first stage, will be instilled for 12 weeks, and the safety and effectiveness will be evaluated using placebo as control.

The trial will be double masked at each stage. A maximum 120 study subjects will be involved in the first and second stage studies in ten U.S. medical facilities.


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CLINICIAN'S CORNER: SEVERE OCULAR SURFACE DISEASE
Victor Perez, MD

Question: I have a dry eye patient for whom I have tried everything, and symptoms and staining are not improving. I have thought of autologous tears—how do they work?

Answer: There is good evidence to support the use of autologous serum tears in dry eye syndrome. Autologous tears are produced by drawing a patient's blood and separating its components via centrifuge. The serum component is removed and mixed with preservative free sodium chloride solution to create serum tears of variable concentration (typically 20-40%). These tears are typically dosed four times a day. The theory behind serum tears is that they contain growth factors, anti-inflammatory molecules, and other proteins that help propagate their effect. Several trials have shown improvement in the signs and symptoms of DES with the use of serum tears.1,2

A recent study retrospectively reviewed the records of Kaiser Permanente Northern California members treated with autologous serum tears. Of 30 dry eye patients with a follow-up visit within 3 months of initiating therapy, 16 reported improved symptoms during their first follow up visit and 12 had improvement in corneal staining. Furthermore, topical lubrication and corticosteroid use decreased.3

We have extensive personal experience with the use of autologous serum tears in dry eye syndrome having treated more than 400 patients with this modality. We generally consider this therapy in patients who continue to have bothersome symptoms while using frequent artificial tears and topical cyclosporine 0.05% (Restasis, Allergan, CA). We generally start patients with a concentration of 20% and then increase if needed based on response. Typically, one blood draw session produces enough to last for 1 month and we usually schedule follow-up visits every 2 to 4 months based on severity. The process is not covered by medical plans, but in our opinion is a very viable treatment option for recalcitrant dry eye.

Most recently, evidence suggests that a new type of autologous eye-drop consisting of a formulation enriched in plasma and platelet-derived growth factors and proteins be used for its regenerative potential in different cell types from the ocular surface.4 Furthermore, this technology, known as plasma rich in growth factors (PRGF) has also been shown to be safe and effective in promoting tissue regeneration in other medical fields.5,6

References:
1. Urzua CA, Vasquez DH, Huidobro A, et al. Randomized double-blind clinical trial of autologous serum versus artificial tears in dry eye syndrome. Curr Eye Res 2012;37(8):684-8.
2. Kojima T, Ishida R, Dogru M, et al. The effect of autologous serum eyedrops in the treatment of severe dry eye disease: a prospective randomized case-control study. Am J Ophthalmol 2005;139(2):242-6.
3. Dalmon CA, Chandra NS, Jeng BH. Use of Autologous Serum Eyedrops for the Treatment of Ocular Surface Disease: First US Experience in a Large Population as an Insurance-Covered Benefit. Arch Ophthalmol 2012;130(12):1612-3.
4. Anitua E, Sanchez M, Merayo-Lloves J, De la Fuente M, Muruzabal F, Orive G. Plasma rich in growth factors (PRGF-Endoret) stimulates proliferation and migration of primary keratocytes and conjunctival fibroblasts and inhibits and reverts TGF-beta1-Induced myodifferentiation. Invest Ophthalmol Vis Sci. 2011 Aug 1;52(9):6066-73.
5. Anitua E, Sánchez M, Orive G. Potential of endogenous regenerative technology for in situ regenerative medicine. Adv Drug Deliv Rev. 2010 Jun 15;62(7-8):741-52.
6. Sánchez M, Anitua E, Orive G, Mujika I, Andia I. Platelet-rich therapies in the treatment of orthopedic sport injuries. Sports Med. 2009;39(5):345-54.


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RESEARCH UPDATE
Blair Lonsberry, MS, OD, MEd., FAAO

Dry eye disease (DED) is an often overlooked ocular condition in clinical practice and is hampered by the currently available diagnostic testing. Alterations in the tear film result in hyperosmolarity and inflammation on the ocular surface, which causes damage to the ocular surface epithelium. Matrix metalloproteinase-9 (MMP-9) is an inflammatory mediator that is produced when the ocular surface is damaged. MMP-9 is elevated in patients with dry eye disease and has been linked to tear film instability and poor wound healing. In healthy eyes, MMP-9 levels range from 3 to 40 ng/mL. Higher levels of MMP-9 (>40 ng/mL) are present in patients with moderate to severe dry eyes and correlate with clinical examination findings.

The purpose of the article summarized in the abstract below is to determine the clinical sensitivity, specificity, negative predictive value, and positive predictive value of InflammaDry (Rapid Pathogen Screening, Inc), which is a 10-minute in-office immunoassay designed to detect abnormally elevated MMP-9 levels (>40 ng/mL). In this prospective, sequential, masked, multicenter clinical trial, InflammaDry was performed on 206 patients (143 with DED and 63 healthy controls, age range between 18-88, majority white females). The Ocular Surface Disease Index, Schirmer tear test, tear breakup time, and keratoconjunctival staining were used to differentiate between healthy controls and dry eye sufferers.

The reported sensitivity and specificity of routine dry eye diagnostic methods, such as the Schirmer test, TBUT, corneal staining, and OSDI, show a variable sensitivity (42% to 90%), and specificity (17% to 89%). In this clinical trial, InflammaDry showed a sensitivity of 85%, specificity of 94%, a negative predictive value of 73% and a positive predictive value of 97%.

The variable sensitivity and specificity of current dry eye diagnostic methods make diagnosis of dry eye clinically challenging. An objective measure of dry eye (e.g. elevated levels of MMP-9 in dry eye disease) may lead to more accurate diagnosis, treatment and management.

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ABSTRACT

Sensitivity and specificity of a point-of-care matrix metalloproteinase 9 immunoassay for diagnosing inflammation related to dry eye.

Sambursky R, Davitt WF 3rd, Latkany R, Tauber S, Starr C, Friedberg M, Dirks MS, McDonald M. JAMA Ophthalmol. 2013 Jan;131(1):24-8. doi: 10.1001/jamaophthalmol.2013.561.

OBJECTIVES: To determine the clinical sensitivity, specificity, negative predictive value, and positive predictive value of a rapid point-of-care diagnostic test to detect elevated matrix metalloproteinase 9 levels (InflammaDry).
METHODS: In a prospective, sequential, masked, multicenter clinical trial, InflammaDry was performed on 206 patients: 143 patients with clinical signs and symptoms of dysfunctional tear syndrome (dry eyes) and 63 healthy individuals serving as controls. Participants were assessed as healthy controls or for a clinical diagnosis of dry eye using the Ocular Surface Disease Index, Schirmer tear test, tear breakup time, and keratoconjunctival staining.
MAIN OUTCOME MEASURES: The sensitivity and specificity of InflammaDry were compared with clinical assessment.
RESULTS: InflammaDry showed sensitivity of 85% (in 121 of 143 patients), specificity of 94% (59 of 63), negative predictive value of 73% (59 of 81), and positive predictive value of 97% (121 of 125).
CONCLUSION: Compared with clinical assessment, InflammaDry is sensitive and specific in diagnosing dry eye.
APPLICATION TO CLINICAL PRACTICE: Dry eye is often under-diagnosed resulting from poor communication between the clinical assessment of dry eye severity between clinicians and patients. This often leads to a lack of effective treatment. Matrix metalloproteinase 9 is an inflammatory biomarker that has been shown to be elevated in the tears of patients with dry eyes. The ability to accurately detect elevated matrix metalloproteinase 9 levels may lead to earlier diagnosis, more appropriate treatment, and better management of ocular surface disease. Preoperative and perioperative management of inflammation related to dry eyes may reduce dry eyes that develop after laser in situ keratomileusis, improve wound healing, and reduce flap complications. Recognition of inflammation may allow for targeted perioperative therapeutic management of care for patients who undergo cataract and refractive surgery and improve outcomes.

TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01313351.
PMID: 23307206 [PubMed - indexed for MEDLINE]

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DRY EYE 101: MEDICAL CODING & COMPLIANCE
John Rumpakis, OD, MBA

Question: In an examination specific for dry eye, would a 992XX or a 920XX code be more appropriate?

Answer: There is no difference between dry eye, cataracts or even a retinal problem in that they are all recognized disease processes that require proper anatomical assessment of structure and function. When any physician performs medical eye services, the first area of the medical record that should be assessed is that of the Chief Complaint (CC). The CC must reflect the reason for visit, either it is going to be at the direction of the physician to return to the office for a very specific reason, or if patient directed, as a complaint or symptoms of an eye disease or injury.

Determining the specific CPT code to use is fairly simple. In the 920XX codes, it would be most likely that only the intermediate codes, 92002 or 92012, would be appropriate, however keep in mind that if a 92012 is used, the patient must present with a new condition or an existing condition complicated with a new diagnostic or management problem not necessarily relating to the primary diagnosis. In other words, since most patients in this scenario would be established patients, and unless the patient presents with a new condition or additional complications relating to dry eye not previously noted, the 92012 would not be appropriate to use as the definition of the code has not been met. That would leave the 992XX codes. The beauty of the 992XX codes is that they are structure driven. You, as the physician, get to determine the clinically relevant and pertinent anatomical areas to examine and evaluate. The level of history and medical decision making are in most cases fairly specific and limited. In most cases for dry eye, the coding used in the 992XX system would be 99201, 99202, 99212 and 99213. Always code each patient encounter by the individual case presentation and the individual patient you are examining and treating.


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