FEATURE

Emerging developments in dry eye

BY ROD MCNEIL

n estimated 344 million people DED. Of the 615 subjects with symptomatic severity of the condition to improve patient worldwide suffer from dry eye DED at baseline, 37.1% showed resolution of outcomes. [1]. This chronic syndrome is symptoms two years later. Factors associated A differential diagnosis is achieved characterised by a vicious cycle of with persistence of symptomatic DED were through patient examination involving a A osteoarthritis, increasing age and female series of clinical assessments and diagnostic tear film hyperosmolarity, tear instability and corneal stress, leading to increased gender. The results suggest that symptomatic techniques. Patients with DTS are classified friction, inflammation, ocular surface DED can be highly variable over time. into one or more of four DTS subtypes, allowing damage and decreased visual acuity. The for a directed treatment approach: aqueous deficiency, / author reviews emerging developments Practice patterns Ophthalmologists continue to prefer the use dysfunction (MGD), goblet cell deficiency focused on improving treatment success. of traditional dry eye tests in practice, with the / mucin deficiency, and exposure-related The Tear Film & Ocular Surface Society most common test being corneal fluorescein DTS. Meibomian gland dysfunction is a (TFOS) Dry Eye Workshop II (DEWS II) global staining, followed by tear break-up time and leading cause of evaporative DED and is also consensus report represents the first evidence- anaesthetised Schirmer’s test, according to often present in conjunction with primary based reexamination of multiple aspects a survey of dry eye practice patterns among aqueous-deficient DED. The authors note that of dry (DED) since the initial US ophthalmologists [3]. Sjogren’s disease adjustments in lid hygiene, warm compresses international seminal DEWS report issued in represents a significant but often overlooked and massage may also be necessary for 2007. TFOS DEWS II sought over the past two subset of DED patients. Continuing under- patients with blepharitis / MGD. years to update the definition, classification referral of dry eye patients for Sjogren’s Artificial , gels, ointments and inserts and diagnosis of DED, critically evaluate the syndrome work-ups may contribute to under replenish the tear film, and tears may be epidemiology, pathophysiology, mechanism, diagnosis of this autoimmune disorder, conserved via punctal plugs, cautery and and impact of this disorder, address its concluded researchers [3]. moisture chamber eyewear. Anti-inflammatory management and therapy and develop Similarities and divergences in self-reported and immunomodulatory treatment options recommendations for the design of clinical dry eye clinical practice between Australian include ciclosporine, lifitegrast (Xiidra®, trials to assess pharmaceutical interventions and UK optometrists were noted by Downie et Shire Ophthalmics), steroids and nutritional for DED treatment. al. [4]. Optometrists in both regions generally supplements. In clinical practice in the UK, DEWS II has redefined dry eye as a tailored DED therapy to severity, with mild DED people with severe DED use several drops of multifactorial disease of the ocular surface predominantly managed with eyelid hygiene artificial tears per day. If the disease does not characterised by a loss of homeostasis of and tear supplementation. However, Australian respond to artificial tears, treatment with the tear film, and accompanied by ocular optometrists prescribed topical corticosteroid other anti-inflammatory formulations and symptoms, in which tear film instability and therapy significantly more often than UK corticosteroids is considered. Punctal plugs hyperosmolarity, ocular surface inflammation practitioners for moderate (14% vs. 6%) and remain an option for people with severe DED and damage, and neurosensory abnormalities severe (52% vs. 8%) disease (p<0.05). that does not respond to artificial tears and play aetiological roles. are often considered after treatment with Review of recent dry eye literature ciclosporin. Incidence and persistence rates New diagnostic techniques and treatment A Cochrane database meta-analysis The prevalence of DED is higher in women options provide an opportunity for better evaluating the effectiveness and toxicity of and in older people, with a reported 15-33% of patient management. For example, TearLab over-the-counter (OTC) artificial tear drops people aged 65 years or over impacted by the Corporation announced in March 2017 CE for concluded that they condition. Approximately 20% of people with Marking for its next-generation in-vitro may be a safe and effective means for treating DED have severe disease. diagnostics testing platform, offering eye dry eye syndrome [7]. The literature indicates A longitudinal study assessed rates of care professionals the ability to assess that most OTC artificial tears produce similar incidence and also resolution / persistence of multiple biomarkers in human tears with a symptomatic relief. The authors noted that DED in 3136 subjects (mean age 59 years, 91% single nanolitre volume tear collection. In additional work is needed to systematically female) from the population-representative a presentation at ARVO 2017, researchers determine if one OTC artificial tear formulation TwinsUK cohort [2]. Of those without DED at outlined good comparative discrimination is superior to another, with additional research baseline (2310 subjects), two years later 9.8% results evaluating the fractal dimension required to determine if there are advantages had incident symptomatic DED, 3.5% had an (FD) based method to differentiate between to using newer tear lipid-containing OTC incident clinical diagnosis and treatment of normal and dry eye subjects using high speed artificial tear formulations. DED, and 4.1% had incident DED as defined by videokeratoscopy [5]. Punctal occlusion aims to block the the Women’s Health Study. Milner and colleagues, on behalf of the tear drainage system in order to aid in the Risk factors associated with incidence , External Disease and Refractive preservation of natural tears on the ocular of symptomatic DED were female gender, Society (CEDARS) Dysfunctional Tear surface. An updated Cochrane systematic asthma, osteoarthritis, chronic pain Syndrome (DTS) Panel, recently presented review of evidence evaluating punctal syndromes, depression, higher copper intake, a consensus compilation of strategies for occlusion for dry eye syndrome concluded lower coffee intake, and increased body mass diagnosis and treatment of DTS [6]. A directed that it was unclear whether punctal plugs are index. Tear osmolarity at baseline was also treatment plan is recommended based on a effective for treating dry eye syndrome, i.e. the associated with incidence of symptomatic four-stage differential diagnosis and relative evidence suggests that punctal plugs do not

eye news | AUGUST/SEPTEMBER 2017 | VOL 24 NO 2 | www.eyenews.uk.com FEATURE

conclusively improve dry eye symptoms [8]. The grittiness, and painful / sore eyes at month 3 of lifitegrast showed that the majority of review included 18 trials with 711 participants with the multi-ingredient eye drop (p≤0.039) adverse events were mild and resolved over (1249 eyes), most of whom were women, [10]. time. conducted from March 1998 to May 2014, with The SICCANOVE study found that EvoTears® (Novaliq / Ursapharm) is a the search for trials covering publication up ciclosporine A cationic emulsion (CsA CE, multi-dose, preservative-free eye lubricant for to 8 December 2016. The results show that Ikervis®, Santen) was well tolerated and stabilisation of the lipid layer commercially no type of punctal plug used in the trials that effectively improved signs and symptoms in available in Europe since 2015. The product were assessed was significantly better than patients with moderate to severe DED over offers a new mode of action by acting as another for relieving symptoms of dry eye. six months, especially in patients with severe a lubricating lipid layer substitute and Reviewers noted that it is still unclear if punctal disease who are at risk of irreversible corneal evaporative barrier for improved tear film plugs are better than oral treatment (oral damage [11]. Ciclosporin A cationic solution stability / quality. A follow-on product pilocarpine) or eye drops such as ciclosporine is a sterile, positively charged, oil-in-water, development with the addition of omega-3 or artificial tears. The use of punctal plugs is unpreserved ophthalmic emulsion for the fatty acids is anticipated. Novaliq’s EyeSol commonly associated with epiphora and, less treatment of severe keratitis in adult patients drug delivery technology is based on novel commonly, with inflammatory conditions such with DED that has not improved despite and exclusive water-free excipients which as dacryocystitis. treatment with tear substitutes. The definition have been established and validated as key of ‘severe keratitis’ is a corneal function score ingredients for innovative ophthalmic products. Clinical evaluations (modified Oxford scale (CFS)) of 4, a Schirmer In January 2017 Heidelberg-based Novaliq Results of a phase III, randomised multicentre score (without anaesthesia) of 2-10mm and an announced positive topline results of a phase 2 study demonstrate that the bioprotective Ocular Surface Disease Index (patient reported clinical trial evaluating a clear, preservative-free trehalose (3%) solution (hyaluronic acid outcome (OSDI)) score of 23 or more. cyclosporine A solution (CyclASol) in adults with moderate to severe DED. Groups treated [HA]-trehalose; Thealoz / Duo® / Théalose®, Lifitegrast ophthalmic solution 5% is a new with CyclASol (0.05% and 0.1%) showed a Laboratoires Théa) is at least as effective as topical medication approved by the United significant improvement in corneal staining HA in the treatment of dry eye syndrome, and States (US) Food and Drug Administration for compared with vehicle control over the four- is better tolerated than HA. Symptomatic the treatment of the signs and symptoms of month treatment period (n=207). relief with preservative-free HA-trehalose was DED in adult patients. Lifitegrast is an integrin A prospective, investigator-masked study evident as early as day 35, encouraging longer antagonist that decreases inflammation on the assessed the ocular efficacy, tolerance and term treatment compliance [9]. A randomised ocular surface, thereby improving DED. Results safety of Cationorm (Santen), a preservative- controlled trial in moderate to severe dry from prospective, placebo-controlled studies free cationic ophthalmic emulsion, in eye showed that an eye drop combining in more than 2000 patients demonstrate that comparison with reference treatment 0.18% osmoprotectants, carboxymethylcellulose and lifitegrast was effective for improvement in hyaluronate sodium (HS) solution in patients HA is noninferior to HA. More patients reported both the signs and symptoms of DED [12]. A with bilateral moderate to severe DED with less severe stinging / burning, sandiness / subsequent study evaluating the safety profile keratitis or keratoconjunctivitis [13]. Cationorm Table 1: Management of dry eye, a common eye condition. was similar and non-inferior to HS with regards to safety and efficacy for objective signs, but Dry eye syndrome is a common condition and becomes more common with age, especially in was superior to HS in improving symptoms women. Up to a third of people age 65 or older may have dry eye syndrome. It is more common in patients with moderate to severe DED, in those with connective tissue disorders, in blepharitis and contact lens wearers. including greater alleviation of itching and eye Symptoms Feelings of dryness, grittiness, soreness, tired eyes which get worse dryness. throughout the day Mildly sensitive to light Research: novel therapies for dry Slight blurred vision eye under investigation Zhang and colleagues emphasised that Both eyes are usually affected successful clinical management of dry eye Signs Redness of the eyes should aim to restore the homeostasis of the Stringy discharge or foamy tears ocular surface environment [14]. Few new treatments for DED have emerged over the Spotty (“punctate”) fluorescein staining past decade, supporting the growing need for May be associated with blepharitis validated biomarkers and endpoints for dry eye Eye examination Observe lids, and cornea with white light clinical research [15]. Research findings suggest that multiple Instil one drop of proxymethacaine 0.5% with fluorescein 0.25% factors contribute to dry eye and developments Observe for corneal staining preferably using a blue light remain focused on longer-lasting therapies Consider Schirmer tear test (wetting of tear test strip in five minutes, <5- requiring less frequent dosing. Current dry eye 7mm abnormal) treatments such as steroids, antibiotics and artificial tears provide short-term symptomatic Treatment Tear substitutes: mild to moderate cases of dry eye syndrome can usually be relief, require frequent reapplication and also successfully treated using over-the-counter artificial tear drops; if a patient do not address the underlying causes of dry has severe symptoms, and needs to use eye drops more than six times a eye. The National Eye Institute (NEI) in the US day, or if they wear contact lenses, advise them to use preservative-free eye recently pointed to several novel therapies drops under investigation for dry eye. Eye ointment can also be used to help lubricate eyes, but it can often cause A phase I/II clinical trial sponsored by blurred vision, so it is probably best used only at night TearSolutions Inc. is underway to investigate More severe cases may require specialist medication or lacrimal punctal the use of a topical synthetic peptide in plugs people with dry eye associated with Sjogren’s syndrome. By restoring a more normal ocular *Moorfields Eye Hospital. Common eye condition management. Available at: http://www.moorfields.nhs.uk/content/dry-eyes surface condition, lacritin appears to remove

eye news | AUGUST/SEPTEMBER 2017 | VOL 24 NO 2 | www.eyenews.uk.com FEATURE

triggers that give rise to inflammation. indicates that PADciclo is effective in reducing 5. Quintana CL, Szczesna-Iskander DH, Iskander Preclinical study results showed lacritin was corneal staining and global symptoms of dry R. Automated non-invasive method for dry eye prediction. Presentation at ARVO 2017 annual effective in promoting tear , restoring eye. The global symptom score improved meeting, Baltimore, USA; May 7-11 2017. ocular surface integrity, and reducing focal in 13/22 patients with a mean change of 0.7 6. Milner MS, Beckman KA, Luchs JI, et al. Dysfunctional infiltration of inflammatory CD4+ T cells in (p<0.01) and the Oxford scale score reduced tear syndrome: dry eye disease and associated tear lacrimal glands. Clinical study results are in 16/22 patients with a mean change of 0.8 film disorders - new strategies for diagnosis and expected in early 2018. (p<0.001). The response to treatment increased treatment. Curr Opin Ophthalmol 2017;27 Suppl 1:3- In addition, researchers at Weill Cornell with severity at baseline for global symptoms 47. Medical College in New York are exploring and corneal staining. Only one patient in this 7. Pucker AD, Ng SM, Nichols JJ. Over the counter (OTC) factors that influence the ability of corneal cohort discontinued treatment because of poor artificial tear drops for dry eye syndrome.Cochrane Database Syst Rev 2016;2:CD009729. nerves to sense basal tear evaporation and tolerance. 8. Ervin AM, Law A, Pucker AD. Punctal occlusion for other NEI-funded researchers are evaluating Lubricin is an endogenous dry eye syndrome. Cochrane Database Syst Rev approaches that promote the regrowth of expressed in areas of high shear stress and 2017;6:CD006775. corneal nerves. Researchers at Stanford friction including the tear film where it binds 9. Chiambaretta F, Doan S, Labetoulle M, et al; HA- University have developed an implantable to and protects tissues of the ocular surface. trehalose Study Group. A randomized, controlled device that electrically stimulates the lacrimal Lubricin protein deficiency is observed in dry study of the efficacy and safety of a new eyedrop gland to produce tears. In addition, it stimulates eye patients. ECF843 is a recombinant form of formulation for moderate to severe dry eye the nerves linking the brain and sensory human lubricin protein and potential first-in- syndrome. Eur J Ophthalmol 2017;27(1):1-9. neurons in the eye, further prompting the class therapeutic in dry eye, recently in-licensed 10. Labetoulle M, Chiambaretta F, Shirlaw A, et al. lacrimal gland to produce tears containing by Novartis from Lubris LLC for ophthalmic Osmoprotectants, carboxymethylcellulose and hyaluronic acid multi-ingredient eye drop: a lipid, mucins as well as water that more closely indications worldwide (outside Europe). Results randomised controlled trial in moderate to severe dry resemble the consistency of naturally-occurring of a small phase II study showed ECF843 eye. Eye (Lond) 2017 [Epub ahead of print] basal tears. has the potential to provide instant relief of 11. Baudouin C, Figueiredo FC, Messmer EM, et al. A The NEI is funding studies to define the symptoms and improve signs [17]. In this study, randomized study of the efficacy and safety of 0.1% molecular composition of the tear lipid layer lubricin supplementation achieved greater cyclosporine A cationic emulsion in treatment of and to evaluate stem cell therapy to repair the than a 72% reduction from baseline in foreign moderate to severe dry eye. Eur J Ophthalmol 2017 lacrimal glands. body sensation (p<.013), burning / stinging, [Epub ahead of print]. Several OTC dietary supplements containing pain, sticky feeling (p<.0432), blurred vision 12. Godin MR, Gupta PK. Lifitegrast ophthalmic solution in the treatment of signs and symptoms of dry eye omega-3s are already available; however, (p<.0013), and photophobia (p<.011) in at least disease: design, development, and place in therapy. one eye, together with an improvement in signs efficacy claims are based on limited, small Clin Ophthalmol 2017;11:951-7. of dry eye within 28 days. studies. An upcoming clinical trial is evaluating 13. Robert PY, Cochener B, Amrane M, et al. Efficacy and the benefits of oral omega-3 fatty acids for dry Instant relief of dry eye symptoms by safety of a cationic emulsion in the treatment of eye, representing the first large, independent, improving signs in a timely manner remains an moderate to severe dry eye disease: a randomized multisite investigation of omega-3s for dry eye. unmet medical need and a relevant factor for controlled study. Eur J Ophthalmol 2016;26(6):546-55. Danish-based MC2 Therapeutics’ MC2-03 patient compliance and treatment success. 14. Zhang X, M VJ, Qu Y, et al. Dry Eye Management: PAD™ Eye Drop (PADciclo™ 0.06% ciclosporin) Targeting the ocular surface microenvironment. Int J Mol Sci 2017;18(7).pii:E1398. is currently being investigated in a large phase II References 15. Roy NS, Wei Y, Kuklinski E, Asbell PA. The growing trial for treatment of moderate-severe dry eye. 1. Market Scope 2016 Dry Eye Products Report: A Global need for validated biomarkers and endpoints for The drug candidate is a once-daily formulation Market Analysis for 2015 to 2021. dry eye clinical research. Invest Ophthalmol Vis Sci of ciclosporin designed for improved 2. Vehof J, Hammond CJ. Incidence, persistence and 2017;58(6):BIO1-BIO19. resolution of dry eye disease: new insights into the penetration and tolerability. 16. Praestegaard M, Gomez F, Heegaard SK, Dart JK. natural history. Presentation at ARVO 2017 annual Real-life performance of the unlicensed Retrospective evaluation of real-life efficacy of meeting, Baltimore, USA; May 7-11 2017. PADciclo™ 0.06% ciclosporin in dry eye patients. PADciclo™ 0.06% ciclosporin was evaluated 3. Fernandez K, Ying G-S, Masssaro-Giordano G, et al. A Presentation at ARVO 2017 annual meeting, in a retrospective study of dry eye patients survey of dry eye practice patterns. Presentation at Baltimore, USA; May 7-11 2017. (n=22) at Moorfields Eye Hospital, London, ARVO 2017 annual meeting, Baltimore, USA; May 7-11 17. Lambiase A, Sullivan BD, Schmidt TA, et al. A two- with the purpose of verifying key elements in a 2017. week, randomized, double-masked study to evaluate prospective clinical trial design [16]. Treatment 4. Downie LE, Rumney N, Gad A, et al. Comparing self-reported optometric dry eye clinical practices safety and efficacy of lubricin (150 μg/ml) eye drops duration ranged from 4 to 52 weeks for the in Australia and the United Kingdom: is there scope versus sodium hyaluronate (Ha) 0.18% eye drops study cohort, while 10/22 patients had used for practice improvement? Ophthalmic Physiol Opt (Vismed®) in patients with moderate dry eye disease. PADciclo for more than 26 weeks. The analysis 2016;36(2):140-51. Ocul Surf 2017;15(1):77-87.

FURTHER INFORMATION

AUTHOR • DEWS II has redefined dry eye as a multifactorial disease of the ocular surface characterised by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play aetiological roles. • New diagnostic techniques and treatment options provide an opportunity for better patient management. • A directed treatment plan is recommended based on a four-stage differential diagnosis and relative severity of the condition to improve patient outcomes. • Multiple factors contribute to dry eye and developments remain focused on longer- Rod McNeil, lasting therapies requiring less frequent dosing. Independent Journalist and Consultant. • Instant relief of dry eye symptoms by improving signs in a timely manner remains an E: [email protected] unmet medical need and a relevant factor for patient compliance and treatment success.

eye news | AUGUST/SEPTEMBER 2017 | VOL 24 NO 2 | www.eyenews.uk.com