Efficacy and Safety of OTX-101, a Novel Nanomicellar Formulation of Cyclosporine A, for the Treatment of Keratoconjunctivitis Sicca: Pooled Analysis of a Phase 2b/3 and Phase 3 Study.

BACKGROUND: OTX-101 (CEQUA™) is approved in the United States for treatment of keratoconjunctivitis sicca (KCS). This pooled analysis of 2 studies (phase 2b/3 and phase 3) evaluates the efficacy and safety of OTX-101 0.09% in the intent-to-treat (ITT) population and the subgroup of patients with a baseline Schirmer score less than 10 mm. METHODS: In these randomized, multicenter, double-masked, vehicle-controlled studies, patients received 1 drop of either OTX-101 or vehicle in both eyes twice daily. A Schirmer's test was performed at baseline and day 84/early discontinuation. Symptom Assessment iN Dry Eye (SANDE) scores and adverse events were monitored at each visit. RESULTS: The pooled analysis included 523 and 525 patients randomized to OTX-101 0.09% and vehicle, respectively. In the ITT population, 16.6% of eyes receiving OTX-101 and 9.0% of eyes receiving vehicle showed a day 84 increase in Schirmer score ≥10 mm from baseline (P<0.0001). In the subgroup with Schirmer score less than 10 mm at baseline, 18.7% and 10.2% of eyes receiving OTX-101 and vehicle, respectively, exhibited this outcome (P=0.0001). The mean (SD) percent change from baseline in global SANDE scores on day 84 in the ITT population was -29.0% (39.0%) and -30.4% (39.5%) for OTX-101 and vehicle groups, respectively. In the subgroup, the mean (SD) percent change was -27.3% (39.7%) and -31.4% (38.3%) for OTX-101 and vehicle groups, respectively. Adverse events were mostly mild to moderate. CONCLUSIONS: OTX-101 improved tear production compared with vehicle. Both OTX-101 and vehicle showed improved SANDE scores over baseline. OTX-101 was well tolerated in patients with KCS.

Lifitegrast for the Treatment of Dry Eye Disease: Results of a Phase III, Randomized, Double-Masked, Placebo-Controlled Trial (OPUS-3).

PURPOSE: Lifitegrast is a lymphocyte function-associated antigen-1 antagonist developed to reduce inflammation in dry eye disease (DED). We report the results of OPUS-3 (NCT02284516), a phase III study evaluating the efficacy and safety of lifitegrast versus placebo in participants with DED. DESIGN: Twelve-week, phase III, randomized, double-masked, multicenter, placebo-controlled study. PARTICIPANTS: Adults aged ≥18 years with Schirmer tear test (without anesthesia) ≥1 and ≤10 mm, corneal fluorescein staining score ≥2.0 (0-4 scale), eye dryness score (EDS) ≥40 (0-100 visual analogue scale [VAS]), and history of artificial tear use within 30 days of study entry. METHODS: After a 14-day placebo run-in, participants were randomized 1:1 to lifitegrast ophthalmic solution 5.0% or placebo twice daily for 84 days. MAIN OUTCOME MEASURES: The primary efficacy end point was change from baseline to day 84 in EDS. Key secondary efficacy end points were change from baseline to days 42 and 14 in EDS. Other secondary efficacy end points included additional VAS items (burning/stinging, itching, foreign body sensation, eye discomfort, photophobia, pain), ocular discomfort score (ODS), and safety/tolerability of lifitegrast versus placebo. RESULTS: In the study, 711 participants were randomized: placebo, 356; lifitegrast, 355 (intention-to-treat [ITT] population). At day 84, lifitegrast-treated participants experienced significantly greater improvement from baseline in EDS versus those receiving placebo (treatment effect [TE], 7.16; 95% confidence interval [CI], 3.04-11.28; P = 0.0007). Mean changes from baseline in EDS also significantly favored lifitegrast on days 42 (TE, 9.32; 95% CI, 5.44-13.20; P < 0.0001) and 14 (TE, 7.85; 95% CI, 4.33-11.37; P < 0.0001). No statistically significant differences were observed in ODS between treatment groups at days 84, 42, or 14. A greater improvement was observed in lifitegrast-treated participants at day 42 in itching (nominal P = 0.0318), foreign body sensation (nominal P = 0.0418), and eye discomfort (P = 0.0048) versus participants receiving placebo. Most treatment-emergent adverse events were mild to moderate in severity; no serious ocular adverse events were reported. CONCLUSIONS: Lifitegrast significantly improved symptoms of eye dryness, as measured by EDS, versus placebo in participants with DED. Improvement in EDS was observed as early as day 14. Lifitegrast appeared well tolerated.

Dysfunctional tear syndrome: dry eye disease and associated tear film disorders - new strategies for diagnosis and treatment.

Dysfunctional tear syndrome (DTS) is a common and complex condition affecting the ocular surface. The health and normal functioning of the ocular surface is dependent on a stable and sufficient tear film. Clinician awareness of conditions affecting the ocular surface has increased in recent years because of expanded research and the publication of diagnosis and treatment guidelines pertaining to disorders resulting in DTS, including the Delphi panel treatment recommendations for DTS (2006), the International Dry Eye Workshop (DEWS) (2007), the Meibomian Gland Dysfunction (MGD) Workshop (2011), and the updated Preferred Practice Pattern guidelines from the American Academy of Ophthalmology pertaining to dry eye and blepharitis (2013). Since the publication of the existing guidelines, new diagnostic techniques and treatment options that provide an opportunity for better management of patients have become available. Clinicians are now able to access a wealth of information that can help them obtain a differential diagnosis and treatment approach for patients presenting with DTS. This review provides a practical and directed approach to the diagnosis and treatment of patients with DTS, emphasizing treatment that is tailored to the specific disease subtype as well as the severity of the condition.

Lifitegrast Ophthalmic Solution 5.0% versus Placebo for Treatment of Dry Eye Disease: Results of the Randomized Phase III OPUS-2 Study.

PURPOSE: Lifitegrast is an integrin antagonist that decreases T-cell-mediated inflammation associated with dry eye disease (DED). We report the results of OPUS-2, a phase III study evaluating the efficacy and safety of lifitegrast compared with placebo for the treatment of DED. DESIGN: A 12-week, multicenter, randomized, prospective, double-masked, placebo-controlled clinical trial. PARTICIPANTS: Adults aged ≥18 years with use of artificial tears within 30 days, inferior corneal staining score ≥0.5 (0-4 scale), Schirmer tear test (without anesthesia) ≥1 and ≤10 mm, and eye dryness score ≥40 (0-100 visual analogue scale [VAS]). METHODS: Subjects were randomized 1:1 after 14-day placebo run-in to lifitegrast ophthalmic solution 5.0% or placebo twice daily for 84 days. MAIN OUTCOME MEASURES: Co-primary efficacy end points were change, from baseline to day 84, in eye dryness score (VAS, both eyes) and inferior corneal fluorescein staining score in the designated study eye. Secondary end points were change, from baseline to day 84, in ocular discomfort score (0-4 scale) in study eye, eye discomfort score (VAS), total corneal staining score in the study eye, and nasal conjunctival lissamine green staining score (0-4 scale) in the study eye. Treatment-emergent adverse events (TEAEs) were recorded. RESULTS: A total of 718 subjects were randomized: placebo, n = 360; lifitegrast, n = 358 (intent-to-treat population). Lifitegrast-treated subjects experienced greater improvement in eye dryness than placebo-treated subjects (treatment effect, 12.61; 95% confidence interval [CI], 8.51-16.70; P < 0.0001). There was no between-group difference in inferior corneal staining (treatment effect, 0.03; 95% CI, -0.10 to 0.17; P = 0.6186). There was nominally significant improvement of secondary symptom end points among lifitegrast-treated subjects: ocular discomfort (nominal P = 0.0005) and eye discomfort (nominal, P < 0.0001). There were no between-group differences on secondary signs: total corneal staining and nasal lissamine staining. More lifitegrast-treated subjects (33.7%) than placebo-treated subjects (16.4%) experienced ocular TEAEs; no ocular TEAEs were serious. CONCLUSIONS: Lifitegrast met the co-primary symptom end point (eye dryness) but not the co-primary sign end point (inferior corneal staining). Secondary end point findings were consistent with this pattern. Most ocular TEAEs were mild to moderate; there were no unexpected TEAEs. Lifitegrast warrants further consideration as a treatment for DED.

Effect of OTX-101 in Patients with Dry Eye Disease at Day 14 of Treatment: Ocular Surface Endpoint Results from the Phase 2b/3 Clinical Trial.

Dry eye disease (DED) is a multifactorial disorder characterized by loss of tear film homeostasis, which initiates a cycle of ocular surface inflammation and damage. As ocular discomfort symptoms associated with DED can decrease quality of life, affected patients prefer treatments that rapidly improve the underlying disease process. OTX-101 0.09% (CEQUA®) is indicated to increase tear production in patients with DED. The current analysis assessed early efficacy of OTX-101 0.09% in adult patients with bilateral DED by evaluating ocular surface endpoints after 14 days of treatment in the phase 2b/3 trial. In this randomized, double-masked, vehicle-controlled, dose-ranging study, patients received one drop of OTX-101 0.05%, OTX-101 0.09%, or vehicle per eye twice daily for 84 days. Corneal staining, conjunctival staining, tear breakup time (TBUT), and modified Symptom Assessment iN Dry Eye (SANDE) total global symptom score were assessed at baseline and Days 14, 28, 42, 56, and 84/early discontinuation. Overall, 455 patients were randomized (OTX-101 0.05%, n=151; OTX-101 0.09%, n=152; vehicle, n=152); only baseline and Day 14 results for the approved OTX-101 0.09% formulation and vehicle are presented. Least squares (LS) mean (standard error [SE]) change from baseline in conjunctival staining score was -1.3 (0.1) for OTX-101 and -1.0 (0.1) for vehicle. LS mean (SE) change from baseline in corneal staining score was -1.1 (0.17) for OTX-101 and -0.7 (0.17) for vehicle. LS mean (SE) change from baseline in TBUT was 0.52 (0.15) for OTX-101 and 0.36 (0.15) for vehicle. LS mean (SE) change from baseline in modified SANDE total global symptom score was -4.93 (1.54) for OTX-101 and -9.1 (1.54) for vehicle. OTX-101 0.09% demonstrated a numerically greater treatment effect compared with vehicle in conjunctival staining, corneal staining, and TBUT after 14 days.

Phase 3 Efficacy (Worse-Eye Analysis) and Long-Term Safety Evaluation of OTX-101 in Patients with Keratoconjunctivitis Sicca.

BACKGROUND: OTX-101 is approved for treatment of keratoconjunctivitis sicca (KCS). We present results of a phase 3 worse-eye efficacy analysis and 1-year safety extension. METHODS: During the double-masked treatment phase, patients with bilateral KCS were randomized 1:1 to 12 weeks OTX-101 or vehicle 1 drop per eye twice daily. Efficacy assessments included Schirmer's test and corneal and conjunctival staining. All patients who completed the treatment phase were eligible for enrollment in the open-label extension and received 1 drop OTX-101 twice daily for up to 52 weeks. Safety endpoints included adverse event (AE) monitoring, Snellen visual acuity (VA), intraocular pressure (IOP), slit-lamp examination (SLE), and dilated fundoscopy. RESULTS: Overall, 745 and 258 patients enrolled in the treatment and safety extension phases, respectively. At 12 weeks, number (%) of patients with Schirmer's score increase of ≥10 mm from baseline was 76 (20.5%) vs. 42 (11.3%) for OTX-101 vs. vehicle (P=0.0005). OTX-101 significantly improved total conjunctival staining vs. vehicle at week 12 (least squares mean change from baseline -1.65 [0.12] vs. -1.12 [0.12], P=0.0013), and number (%) of patients with clear central corneas vs. vehicle at week 12 (222 [64.0%] vs. 199 [55.3%], P=0.0179). In the 1-year safety extension, AEs were mostly mild; instillation site pain was most common in 59 (22.9%) patients (17 [13.2%] vs. 42 [32.6%] patients receiving prior OTX-101 and vehicle). No safety concerns were raised by VA, IOP, SLE, and fundoscopy. CONCLUSION: OTX-101 efficacy was confirmed in the eye with lower baseline Schirmer's score. OTX-101 was well tolerated long term. CLINICAL TRIAL: Registered at ClinicalTrials.gov on July 27, 2016. NCT02845674 https://clinicaltrials.gov/ct2/show/NCT02845674?term=OTX-101&draw=2&rank=1.

Late-onset fungal interface keratitis following endothelial keratoplasty with positive donor fungal culture.

PURPOSE: To describe late-onset fungal keratitis after Descemet's stripping endothelial keratoplasty (DSEK) with positive fungal culture of the donor corneal rim. OBSERVATIONS: A case report of a patient undergoing DSEK is described whereby the donor corneal rim culture grew fungus. No infection was initially noted, but the patient developed fungal keratitis 1 year after the original DSEK procedure, despite prophylactic treatment at the time of the positive donor culture. The patient responded to antifungal therapy, but fungal keratitis recurred following completion of a 1-year course of antifungal treatment. The patient eventually underwent full thickness keratoplasty. CONCLUSIONS AND IMPORTANCE: A positive fungal culture of the donor rim tissue at the time of endothelial keratoplasty is a risk factor for fungal keratitis. Even with prophylactic antifungal treatment, fungal keratitis may eventually develop as late as 1 year after the initial endothelial keratoplasty procedure. Treatment may need to be aggressive, but keratitis may recur despite resolution with antifungal treatment.

Changes in preoperative corneal measurements following same-day intraocular pressure testing with rebound tonometry.

PURPOSE: To evaluate the extent to which rebound tonometry affects corneal surface properties and preoperative corneal measurements. SETTING: Four cornea specialty private practices. DESIGN: Prospective case series. METHODS: Visual acuity testing, corneal topography, keratometry, and grading of corneal staining were performed on both eyes of 60 randomly selected, previously scheduled patients. Technicians then performed rebound tonometry on one randomly selected eye only. Immediately following, intraocular pressure measurement, corneal topography, keratometry, and corneal staining were repeated on both eyes. RESULTS: None of the 60 study eyes developed increased staining scores following intraocular pressure testing with the Icare ic100. For corneal staining, mean keratometry, and total corneal cylinder, no statistically significant difference was found from the first measurement to the second measurement between the study eyes and control eyes. CONCLUSION: Rebound tonometry with the Icare ic100 may be used on any patient at any time during the exam without affecting the results of other tests, allowing clinicians to test intraocular pressure prior to preoperative cataract or refractive surgery measurements on the same day. This may allow for significant improvement in patient flow in the office and save patients from the cost and time of extra visits.

Managing Dry Eye Disease and Facilitating Realistic Patient Expectations: A Review and Appraisal of Current Therapies.

Dry eye disease (DED) is a multifactorial disease of the ocular surface characterized by loss of homeostasis of the tear film and accompanied by ocular signs and symptoms such as corneal and conjunctival damage, patient discomfort, and visual disturbance. The prevalence of DED ranges from 5%-33%. Patients with DED may have a reduced quality of life due to their discomfort and visual disturbances. The multifactorial nature of DED requires a multi-targeted treatment approach to address the signs and symptoms. Treatment for DED should follow a step-wise approach beginning with education, dietary modification, and lid and lash hygiene, and progressing to pharmacologic and nonpharmacologic interventions. Ocular lubricants, a mainstay of DED therapy, provide temporary symptomatic relief for the patient, but do not address the underlying pathophysiology. Some currently available pharmacologic treatments that address the underlying pathophysiology of DED may have a delay of 3-6 months in the onset of therapeutic effect; however, these treatment options may also have tolerability issues. These challenges highlight the need for newer pharmacologic treatments with an earlier onset of observable clinical effect and the potential for improved tolerability profile. Patient education is vital to DED management and should convey the complex and chronic nature of DED. It is important for the eye care practitioner to set realistic expectations with the patient when managing DED to help improve treatment success. This helps the patient understand the need for ongoing treatment and that results will likely not be seen immediately. This review covers the current management of DED, focusing on pharmacologic management, and offers recommendations for the practitioner to help facilitate realistic patient expectations for the treatment of DED.

Safety and efficacy of amniotic cytokine extract in the treatment of dry eye disease.

Purpose: Evaluate the safety and efficacy of cryopreserved amniotic cytokine extract (ACE) in the treatment of subjects with dry eye disease (DED). Patients and methods: This was a retrospective, multicenter, chart review of adult patients with DED that instilled cryopreserved ACE drops twice-daily for 4 or 12 weeks. Patients had corneal fluorescein staining (0-20 range) and/or a lissamine green conjunctival staining score (0-18 range) of ≥3 and ≤9 in at least 1 eye and a score ≥40 (0-100 range) of eye dryness/irritation on a visual analog scale (VAS). Following completion of a treatment course, medical records were reviewed from the initiation of therapy (baseline), and at post-treatment visits (4 weeks, 8 weeks, and 12 weeks). Patient records for visual acuity, adverse events, corneal fluorescein staining, conjunctival lissamine green staining, and symptom scores of ocular dryness/irritation were reviewed for each visit, as available. Safety and tolerability were assessed through the evaluation of patient-reported adverse events recorded in the medical records. Results: A total of 54 eligible patients were identified at 7 clinical sites; 16 patients administered ACE drops for 4-weeks, and 38 patients instilled ACE drops for 12 weeks. Significant improvements in the mean changes from baseline were observed for corneal fluorescein staining, lissamine green staining, visual acuity (LogMar) and VAS ocular symptom scores at the 4-week post-treatment visit (p<0.01). Additional improvements continued out to the 12-week follow-up assessment visits. Two patients discontinued therapy due to reports of ocular burning or foreign body sensation. Conclusion: The cryopreserved ACE formulation was well-tolerated and effective in reducing the clinical signs and symptoms of DED. Conduct of a vehicle-controlled prospective study is warranted.

Effect of OTX-101, a Novel Nanomicellar Formulation of Cyclosporine A, on Conjunctival Staining in Patients with Keratoconjunctivitis Sicca: A Pooled Analysis of Phase 2b/3 and 3 Clinical Trials.

Purpose: Keratoconjunctivitis sicca (KCS), a multifactorial disease, is the most common ocular condition for patients seeking medical treatment and is characterized by ocular burning, stinging, and dryness. This pooled analysis examined the effect of OTX-101 0.09% versus vehicle on the total and individual conjunctival staining in patients with KCS from phase 2b/3 and phase 3 studies. Methods: In these randomized, multicenter, double-masked, and vehicle-controlled studies, patients received 1 drop of OTX-101 0.09% or vehicle in both eyes twice daily. The time points for the pooled analysis were baseline (day 0) and study days 28, 56, and 84/early discontinuation. Conjunctival staining was graded on a 0- to 3-point scale per zone and averaged over both eyes at each assessment. Pooled safety assessments included adverse event (AE) reporting. Results: The total mean (standard deviation) conjunctival staining scores at baseline were 5.4 (1.7) for OTX-101 (n = 523) and 5.5 (1.7) for vehicle (n = 525). OTX-101 versus vehicle significantly reduced the total conjunctival staining scores (P = 0.0316, <0.0001, and 0.0002) for days 28, 56, and 84, respectively. The most common treatment-related AE was instillation site pain (21.8% OTX-101 vs. 4.0% vehicle); most AEs were mild in nature. Conclusions: Treatment with OTX-101 versus vehicle significantly improved the conjunctival staining in KCS as early as 4 weeks, and the improvement was maintained through 12 weeks. OTX-101 was effective and well tolerated for use in KCS.

Effect of OTX-101, a Novel Nanomicellar Formulation of Cyclosporine A, on Corneal Staining in Patients With Keratoconjunctivitis Sicca: A Pooled Analysis of Phase 2b/3 and Phase 3 Studies.

BACKGROUND: Keratoconjunctivitis sicca affects 5% to 33% of the population and is often accompanied by symptoms such as burning and dryness. This pooled analysis evaluated total and central corneal fluorescein staining (CFS) in patients receiving OTX-101 0.09% or vehicle in phase 2b/3 and 3 studies and whether improvements in corneal staining correlated with improved visual acuity. METHODS: In these randomized, vehicle-controlled studies, patients received 1 drop of OTX-101 or vehicle in both eyes twice daily. Corneal staining was performed at baseline and days 28, 56, and 84. CFS was evaluated in each zone (0-to-4 scale); total corneal staining (0-to-20 scale per eye) was averaged over both eyes. Pooled safety assessments included adverse event monitoring. RESULTS: Mean baseline CFS total scores (SD) were 4.2 (2.5) and 4.3 (2.6) for the OTX-101 (n = 523) and vehicle (n = 525) groups, respectively. For total corneal staining, least squares mean changes from baseline (standard error) were -0.9 (0.08) versus -0.5 (0.08) for OTX-101 and vehicle, respectively (P = 0.0008), on day 28 and -1.4 (0.09) versus -0.9 (0.09) on day 84 (P = 0.0002). There was a significantly high correlation (P = 0.0117) between reduced central corneal staining and improved visual acuity on day 84. Treatment-related adverse events were mostly mild, with instillation site pain reported by 21.8% and 4.0% of patients receiving OTX-101 and vehicle, respectively. CONCLUSIONS: Treatment with OTX-101 led to greater improvements versus vehicle in corneal surface staining as early as 4 weeks, and further improvements were seen up to 12 weeks. OTX-101 was well tolerated in patients with keratoconjunctivitis sicca.

Visual outcome and bacterial sensitivity after methicillin-resistant Staphylococcus aureus-associated acute endophthalmitis.

PURPOSE: To determine the frequency, visual outcome, and bacterial sensitivity in cases of methicillin-resistant Staphylococcus aureus (MRSA)-associated acute postoperative endophthalmitis occurring after cataract surgery. DESIGN: Retrospective, consecutive, observational case series. METHODS: Sixty-four cases of acute endophthalmitis occurring within six weeks after cataract surgery were identified over a three-year interval at a single vitreoretinal practice. Cases related to MRSA were studied and visual outcomes and bacterial sensitivities were recorded. RESULTS: Thirty-three of the 64 eyes were culture positive, and six of the 33 cases (18.2%) demonstrated MRSA infection. All six eyes were started on fluoroquinolone antibiotics two or three days before surgery. Corneal abnormalities were noted in five of the six cases (83.3%), ranging from wound infection to diffuse corneal opacification. Visual acuity at last follow-up was no light perception (NLP) in two eyes, hand movements in two eyes, and 20/30 or better in two eyes. One eye with NLP vision underwent enucleation within three days of presentation because of panophthalmitis and impending sepsis. All six organisms were sensitive in vitro to both gentamicin and vancomycin. No organism was sensitive to any fluoroquinolone antibiotic, although not all organisms were tested against all fluoroquinolones. CONCLUSIONS: MRSA infection accounts for 18% of culture-positive cases of endophthalmitis in this study and was associated with a poor visual outcome in two-thirds of our patients. MRSA organisms may be resistant in vitro to all generations of fluoroquinolone antibiotics, but do seem to be sensitive to gentamicin and vancomycin. The incidence of MRSA endophthalmitis seems to have increased significantly since the Endophthalmitis Vitrectomy Study was published in 1996.

Efficacy of topical azithromycin ophthalmic solution 1% in the treatment of posterior blepharitis.

INTRODUCTION: Azithromycin, a broad-spectrum antibiotic with potent anti-inflammatory activities, has the potential to effectively treat blepharitis, an inflammatory disease of the eyelid with abnormal eyelid flora as an etiologic determinant. The present study compared the efficacy of topical azithromycin ophthalmic solution 1% (AzaSite; Inspire Pharmaceuticals, Inc, NC, USA) combined with warm compresses (azithromycin group) to warm compresses alone (compress group) in patients with posterior blepharitis. METHODS: Twenty-one patients diagnosed with posterior blepharitis were randomized in an open-label study to receive either azithromycin plus warm compresses (10 patients), or compresses alone (11 patients). All patients were instructed to apply compresses to each eye for 5-10 minutes twice daily for 14 days. Each eye in the azithromycin group also received azithromycin solution (1 drop) twice daily for the first 2 days followed by once daily for the next 12 days. Patients were evaluated at study initiation (visit 1) and at end of treatment (visit 2) for the severity of five clinical signs: eyelid debris, eyelid redness, eyelid swelling, meibomian gland (MG) plugging, and the quality of MG secretion. At visit 2, patients also rated their degree of overall symptomatic relief. RESULTS: Twenty patients completed the study. At visit 2, patients in the azithromycin group demonstrated significant improvements in MG plugging, MG secretions, and eyelid redness as compared with the compress group. In the azithromycin group, MG plugging resolved completely in three patients and MG secretion returned to normal in two patients; no such results were seen in the compress group. Furthermore, a higher percentage of patients in the azithromycin group rated overall symptomatic relief as excellent or good. Visual acuity measurements and biomicroscopic evaluation revealed no ocular safety issues. CONCLUSION: Azithromycin ophthalmic solution in combination with warm compresses provided a significantly greater clinical benefit than warm compresses alone in treating the signs and symptoms of posterior blepharitis.

A Phase II/III, randomized, double-masked, vehicle-controlled, dose-ranging study of the safety and efficacy of OTX-101 in the treatment of dry eye disease.

PURPOSE: The aim of this study was to evaluate the safety and efficacy of OTX-101, a clear nanomicellar aqueous solution of cyclosporine, in the treatment of dry eye disease (DED). PATIENTS AND METHODS: This was a 12-week multicenter, randomized, prospective, double-masked, vehicle-controlled, dose-ranging clinical trial. Subjects were adults aged ≥18 years, with a total conjunctival staining score of ≥3 and ≤9, and global DED symptom score ≥40 (0-100 visual analogue scale). Following a 14-day vehicle run-in, subjects were randomized in a 1:1:1 ratio to twice daily treatment with OTX-101 0.09%, OTX-101 0.05%, or vehicle for 84 days. Co-primary efficacy end points were changes, from baseline to Day 84, in the total lissamine green conjunctival staining score in the designated study eye and in the global symptom score (both eyes). Secondary end points included total corneal fluorescein staining score, tear breakup time, and Schirmer's test score. RESULTS: In total, 455 subjects were randomized. Subjects treated with active drug experienced greater improvement in conjunctival staining than vehicle-treated patients (P<0.01 for both concentrations). All groups demonstrated improvements in global symptom score, but there were no differences among groups. Nominally significant differences were found between the active drug arms and vehicle for corneal staining scores and Schirmer's test scores. Most treatment-emergent adverse events were mild in severity; no serious ocular adverse events were reported. CONCLUSIONS: Both concentrations of OTX-101 met the co-primary sign end point (conjunctival staining) but not the co-primary symptom end point. OTX-101 0.09% demonstrated a notable impact on multiple signs of DED relative to vehicle and was well-tolerated.

The Potential Role for Early Biomarker Testing as Part of a Modern, Multidisciplinary Approach to Sjögren's Syndrome Diagnosis.

Sjögren's syndrome (SS) is a chronic and progressive multisystem autoimmune disease typically managed by rheumatologists. Diagnostic delays are common, due in large part to the non-specific and variable nature of SS symptoms and the slow progression of disease. The hallmark characteristics of SS are dry eye and dry mouth, but there are a broad range of other possible symptoms such as joint and muscle pain, skin rashes, chronic dry cough, vaginal dryness, extremity numbness or tingling, and disabling fatigue. Given that dry eye and dry mouth are typically the earliest presenting complaints, eye care clinicians and dental professionals are often the first point of medical contact and can provide critical collaboration with rheumatologists to facilitate both timely diagnosis and ongoing care of patients with SS. Current diagnostic criteria advocated by the American College of Rheumatology are predicated on the presence of signs/symptoms suggestive of SS along with at least two objective factors such as traditional biomarker positivity, salivary gland biopsy findings, and/or presence of keratoconjunctivitis sicca. Traditional biomarkers for SS include the autoantibodies anti-Sjögren's syndrome-related antigen A (SS-A/Ro), anti-Sjögren's syndrome-related antigen B (SS-B/La), antinuclear antibody (ANA) titers, and rheumatoid factor (RF). While diagnostically useful, these biomarkers have low specificity for SS and are not always positive, especially in early cases of SS. Several newly-identified biomarkers for SS include autoantibodies to proteins specific to the salivary and lacrimal glands [SP-1 (salivary gland protein-1), PSP (parotid secretory protein), CA-6 (carbonic anhydrase VI)]. Data suggest that these novel biomarkers may appear earlier in the course of disease and are often identified in cases that test negative to traditional biomarkers. The Sjö® test is a commercially available diagnostic panel that incorporates testing for traditional SS biomarkers (anti-SS-A/Ro, anti-SS-B/La, ANA, and RF), as well as three novel, proprietary early biomarkers (antibodies to SP-1, PSP, and CA-6) which provide greater sensitivity and specificity than traditional biomarker testing alone. Timely diagnosis of SS requires appropriate clinical vigilance for potential SS symptoms, referral and collaborative communication among rheumatology, ophthalmology, and oral care professions, and proactive differential work-up that includes both physical and laboratory evaluations.

Making the diagnosis of Sjögren's syndrome in patients with dry eye.

Sjögren's syndrome (SS) is a chronic and progressive systemic autoimmune disease that often presents initially with symptoms of dry eye and dry mouth. Symptoms are often nonspecific and develop gradually, making diagnosis difficult. Patients with dry eye complaints warrant a step-wise evaluation for possible SS. Initial evaluation requires establishment of a dry eye diagnosis using a combination of patient questionnaires and objective ocular tests, including inflammatory biomarker testing. Additional work-up using the Schirmer test and tear film break-up time can differentiate between aqueous-deficient dry eye (ADDE) and evaporative dry eye. The presence of ADDE should trigger further work-up to differentiate between SS-ADDE and non-SS-ADDE. There are numerous non-ocular manifestations of SS, and monitoring for SS-related comorbid findings can aid in diagnosis, ideally in collaboration with a rheumatologist. The clinical work-up of SS can involve a variety of tests, including tear function tests, serological tests for autoantibody biomarkers, minor salivary gland and lacrimal gland biopsies. Examination of classic SS biomarkers (SS-A/Ro, SS-B/La, antinuclear antibody, and rheumatoid factor) is a convenient and non-invasive way of evaluating patients for the presence of SS, even years prior to confirmed diagnosis, although not all SS patients will test positive, particularly those with early disease. Recently, newer biomarkers have been identified, including autoantibodies to salivary gland protein-1, parotid secretory protein, and carbonic anhydrase VI, and may allow for earlier diagnosis of SS. A diagnostic test kit is commercially available (Sjö(®)), incorporating these new biomarkers along with the classic autoantibodies. This advanced test has been shown to identify SS patients who previously tested negative against traditional biomarkers only. All patients with clinically significant ADDE should be considered for serological assessment for SS, given the availability of new serological diagnostic tests and the potentially serious consequences of missing the diagnosis.

Sensitivity and specificity of the AdenoPlus test for diagnosing adenoviral conjunctivitis.

OBJECTIVE: To compare the clinical sensitivity and specificity of the AdenoPlus test with those of both viral cell culture (CC) with confirmatory immunofluorescence assay (IFA) and polymerase chain reaction (PCR) at detecting the presence of adenovirus in tear fluid. METHODS: A prospective, sequential, masked, multicenter clinical trial enrolled 128 patients presenting with a clinical diagnosis of acute viral conjunctivitis from a combination of 8 private ophthalmology practices and academic centers. Patients were tested with AdenoPlus, CC-IFA, and PCR to detect the presence of adenovirus. MAIN OUTCOME MEASURES: The sensitivity and specificity of AdenoPlus were assessed for identifying cases of adenoviral conjunctivitis. RESULTS: Of the 128 patients enrolled, 36 patients' results were found to be positive by either CC-IFA or PCR and 29 patients' results were found to be positive by both CC-IFA and PCR. When compared only with CC-IFA, AdenoPlus showed a sensitivity of 90% (28/31) and specificity of 96% (93/97). When compared only with PCR, AdenoPlus showed a sensitivity of 85% (29/34) and specificity of 98% (89/91). When compared with both CC-IFA and PCR, AdenoPlus showed a sensitivity of 93% (27/29) and specificity of 98% (88/90). When compared with PCR, CC-IFA showed a sensitivity of 85% (29/34) and specificity of 99% (90/91). CONCLUSION: AdenoPlus is sensitive and specific at detecting adenoviral conjunctivitis. APPLICATION TO CLINICAL PRACTICE: An accurate and rapid in-office test can prevent the misdiagnosis of adenoviral conjunctivitis that leads to the spread of disease, unnecessary antibiotic use, and increased health care costs. Additionally, AdenoPlus may help a clinician make a more informed treatment decision regarding the use of novel therapeutics. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00921895.