The role of the Tear Film and Ocular Surface Society (TFOS) Dry Eye Workshop (DEWS) II Diagnostic Methodology Subcommittee was 1) to identify tests used to diagnose and monitor dry eye disease (DED), 2) to identify those most appropriate to fulfil the definition of DED and its sub-classifications, 3) to propose the most appropriate order and technique to conduct these tests in a clinical setting, and 4) to provide a differential diagnosis for DED and distinguish conditions where DED is a comorbidity. Prior to diagnosis, it is important to exclude conditions that can mimic DED with the aid of triaging questions. Symptom screening with the DEQ-5 or OSDI confirms that a patient might have DED and triggers the conduct of diagnostic tests of (ideally non-invasive) breakup time, osmolarity and ocular surface staining with fluorescein and lissamine green (observing the cornea, conjunctiva and eyelid margin). Meibomian gland dysfunction, lipid thickness/dynamics and tear volume assessment and their severity allow sub-classification of DED (as predominantly evaporative or aqueous deficient) which informs the management of DED. Videos of these diagnostic and sub-classification techniques are available on the TFOS website. It is envisaged that the identification of the key tests to diagnose and monitor DED and its sub-classifications will inform future epidemiological studies and management clinical trials, improving comparability, and enabling identification of the sub-classification of DED in which different management strategies are most efficacious.

TFOS DEWS II Diagnostic Methodology report

Ten years after Fire and Melo’s Nobel Prize for discovery of gene silencing by double-stranded RNA, a remarkable progress was achieved in RNA interference (RNAi). Changes in the chemical structure of synthetic oligonucleotides make them more stable and specific, and new delivery strategies became progressively available. The attention of pharmaceutical industry rapidly turned to RNAi, as an opportunity to explore new drug targets. This review addresses nine small-interfering RNAs (siRNAs) and one unique microRNA (miRNA) inhibitor, which entered the phase 2–3 clinical trials. The siRNAs in focus are PF-04523655, TKM-080301, Atu027, SYL040012, SYL1001, siG12D-LODER (phase 2), QPI-1002, QPI-1007, and patisiran (phase 3). Regarding miRNAs, their content can be down- or up-regulated, by using miRNA inhibitors (AntimiRs) or miRNA mimics. Miravirsen is an AntimiR-122 for hepatitis C virus infection. The flexibility of RNAi technology is easily understood taking into account: (i) the different drug targets (i.e. p53, caspase 2, PKN3, β2-adrenergic receptor, mutated KRAS, microRNAs); (ii) therapeutic conditions, including ophthalmic diseases, kidney injury, amyloidosis, pancreatic cancer, viral hepatitis; and (iii) routes of administration (ocular, intravenous, subcutaneous, intratumoral). Although some issues are still matters of concern (delivery, toxicity, cost, and biological barriers), RNAi definitively opens a wide avenue for drug development.

The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market

Dry eye disease is a chronic condition of the corneal surface marked by persistent symptoms of irritation or burning that can cause inflammatory damage to the cornea and conjunctiva if untreated. Common risk factors for this syndrome include advancing age, female sex, low humidity environments, systemic medications, and autoimmune disorders. Treatments to relieve symptoms include tear replacement, humidification, improved nutrition, and anti-inflammatory ocular agents. Home healthcare nurses can identify signs and symptoms of dry eye syndrome and initiate strategies that range from warm compresses to physician referrals for more aggressive treatment. Consistent management of this condition improves quality of life and minimizes damage to the ocular surface.

Dry Eye Disease: Prevalence, Assessment, and Management.

Cequa®, a unique and first-in-class preservative free cyclosporine-A (CsA) nanomicellar topical formulation was recently approved by US FDA for treatment of dry eye disease or keratoconjuntivitis sicca (KCS). Being highly hydrophobic, CsA is currently available as an oil based emulsion, which has its own shortcomings. Developing an aqueous and clear formulation of CsA is imperative yet a challenging need in the quest for a safe and better drug product. In this regard, a novel, clear, aqueous nanomicellar solution of CsA was developed which has the potential to deliver therapeutic concentrations of CsA with minimal discomfort to patients. Highly promising pre-clinical results of Cequa® (OTX-101), has led to its advancement to the clinical trials. Phase III clinical trials have demonstrated that OTX-101 is highly effective, safe, and has a rapid onset of action in treating KCS. This review presents a comprehensive insight on formulation development, preclinical and clinical pharmacokinetic results of Cequa®. Additionally, the translational development of Cequa® from the laboratory benchtop to patient bedside has been discussed.

Ocular Pharmacokinetics of a Topical Ophthalmic Nanomicellar Solution of Cyclosporine (Cequa®) for Dry Eye Disease

Conventional skin and blood sampling techniques for disease diagnosis, though effective, are often highly invasive and some even suffer from variations in analysis. With the improvements in molecular detection, the amount of starting sample quantity needed has significantly reduced in some diagnostic procedures, and this has led to an increased interest in microsampling techniques for disease biomarker detection. The miniaturization of sampling platforms driven by microsampling has the potential to shift disease diagnosis and monitoring closer to the point of care. The faster turnaround time for actionable results has improved patient care. The variations in sample quantification and analysis remain a challenge in the microsampling field. The future of microsampling looks promising. Emerging techniques are being clinically tested and monitored by regulatory bodies. This process is leading to safer and more reliable diagnostic platforms. This review discusses the advantages and disadvantages of current skin and blood microsampling techniques.

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A review of microsampling techniques and their social impact

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.

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

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

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=OPHTH&articleId=1556875&pdfFileName=ect120009_17_22.pdf

Sensitivity and specificity of the AdenoPlus test for diagnosing adenoviral conjunctivitis

Re: Keen et al.: Treatment of acute conjunctivitis in the United States and evidence of antibiotic overuse: isolated issue or a systematic problem? (Ophthalmology. 2017;124:1096-1098).

Thomas Boland

Papers

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

Sensitivity and specificity of the AdenoPlus test for diagnosing adenoviral conjunctivitis

Re: Keen et al.: Treatment of acute conjunctivitis in the United States and evidence of antibiotic overuse: isolated issue or a systematic problem? (Ophthalmology. 2017;124:1096-1098).