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While waiting for DEWS II report, specialists discuss dry eye’s recent advances and unmet needs
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In spring 2017, 10 years after the first report, the second International Dry Eye WorkShop is expected to disclose results, providing an updated definition of dry eye disease, new data on epidemiology, and a critical assessment of current diagnostic means and therapies.
Steps forward have been made in these last 10 years toward understanding the pathophysiology, complex mechanisms and multifactorial nature of dry eye disease (DED). New, better targeted therapeutic agents have become or are in the process of becoming available. However, there are still unmet needs, missing links and challenges that DEWS II experts are currently discussing and that will need to be addressed in future years.
“We need to achieve consensus on a better and clearer definition of dry eye disease, we need to understand the pathophysiology better, to agree on a universally accepted set of criteria for diagnosing and treating dry eye, and we need to work on prevention,” José Manuel Benitez del Castillo, MD, PhD, DEWS Management and Therapy Subcommittee member, said.
“Another major challenge is educating people, furthering awareness. DED can be a very disabling condition which greatly affects quality of life, and yet doctors, family and friends do not fully understand the suffering of these people,” he said.
A new definition
Given the complexity and multifactorial nature of the disease, defining dry eye is not an easy task, Stefano Barabino, MD, PhD, DEWS Clinical Trial Subcommittee member, said.
“We have been working at it for 2 years and still have not come to a univocal agreement. We are dealing with a multifactorial disease that affects a system, the ocular surface system, which undergoes multiple alterations due to variable, multiple factors, leading to variable, multiple symptoms,” he said.
The 2007 consensus definition was a compromise that was not unanimously accepted and sparked controversy because two pathogenetic factors, osmolarity and inflammation, were included.
“This was quite unusual in a definition, and many objected that, to be consequential, all pathogenetic factors should be included, which was of course not feasible. We need a new definition which subsumes all forms of dry eye without referring to pathogenesis,” Barabino said.
“A shorter, broader but at the same time concise and simple definition,” Benitez del Castillo said.
In the last 10 years, research has gone deeper into the multiple and complex factors leading to dry eye disease. The key role of osmolarity and inflammation has been confirmed, but more has been discovered within their interaction mechanisms and cascade of events.
Among the interesting discoveries was that inflammation in dry eye disease affects not only the conjunctiva but also the cornea and involves the activation of lymphocytes (Th1 and Th17) in the lymph nodes.
“This highlights that we are not dealing with simple inflammation but with an immune reaction that involves the entire system of the ocular surface, including the cornea and the lymph nodes. It also gives us new insights into how dry eye becomes a chronic condition,” Barabino said.
Another recent focus of research has been the activation of corneal nerves. The studies of Carlos Belmonte, MD, PhD, showed that a dry ocular surface environment promotes the activation of nerve receptors, leading to nerve sensitization and chronic neuropathic pain.
“The neuropathic component of DED was only marginally taken into account by the previous DEWS because we did not have the data we have now. Belmonte’s research has opened a new, important chapter and has given us a new key to the understanding of ocular pain,” Barabino said.
Diagnostic challenges
A major challenge in the diagnosis of dry eye disease is the frequent discrepancy between clinical signs and subjective symptoms. Patients often complain of severe, persistent symptoms while the ocular surface presents no evident signs of alteration or, conversely, may present with severe ocular surface damage and have no symptoms at all.
One possible explanation is the imprecision of diagnostic tools, according to Jun Shimazaki, MD, PhD, a dry eye specialist in Tokyo.
“We are using traditional methods to detect changes in the tears or ocular surface, but we may not be able to see very subtle changes,” he said.
“The other explanation is that we should focus more on patient sensitivity. Very severe symptoms without notable changes on the ocular surface might be related to damage in the corneal nervous system, to the brain or even to depression and anxiety.”
This is a new research area many dry eye specialists are interested in, Shimazaki said.
“Some of us are trying to look at the subtle changes in tear film with biomarkers, others are looking at changes in corneal nerves using new tools such as confocal microscopy, and others are doing research on the signaling changes between the ocular surface and brain. Many of us believe that inflammation is involved in producing chronic changes in the peripheral and central nervous system, leading to chronic dry eye symptoms,” he said.
Moving from research to the clinic, the limitations of current diagnostic tools are even greater, according to Barabino. Osmolarity is an excellent parameter, but current methods to measure it lack reproducibility. The same applies to inflammation.
“We can measure inflammation by impression cytology and flow cytometry, but these are expensive techniques that cannot be used in the clinical practice,” he said.
Corneal nerves can be seen by confocal microscopy, but there is no method to directly measure nerve function, if not by indirect evaluation of corneal sensitivity.
“It is difficult at present to translate the remarkable progress we have made in relation to DED pathogenesis and DED as the disease of a system into something that looks into and correlates the various parts of this system and is useful for us every day in the clinic,” Barabino said.
New treatment options
Xiidra (lifitegrast ophthalmic solution 5%, Shire) has recently entered the scene of dry eye treatment and promises to be an effective new way of combating inflammation by inhibiting the chronic cycle of immune T-cell activation. Approved by the FDA in the U.S. in July, lifitegrast has created great expectations in Europe.
“It might be a good alternative, safer than steroids, which have the drawback of causing cataract and IOP increase, and it can be used in association with cyclosporine,” Benitez del Castillo said.
Tear substitutes have also evolved to a new generation of products that do not simply aim at replacing the aqueous component of tears but instead interact with the system of the ocular surface. Some interesting products are currently in the pipeline.
Benitez del Castillo uses a staged approach to the treatment of dry eye disease.
“For patients with mild dry eye, I use artificial tears and talk extensively about prevention. I tell them how to use the computer, recommend avoiding air conditioning as much as possible and increasing the intake of omega-3. I also teach them how to use drops and to use them regularly. If this does not work, I start with anti-inflammatory drops. First, a short course of corticosteroids, for 2 to 3 weeks, checking IOP, and if it works I put the patient on cyclosporine, and soon lifitegrast will be a new option,” he said.
Most dry eyes that do not succeed with these treatments are likely to have meibomian gland dysfunction.
“Now we have new treatments for MGD, such as doxycycline or azithromycin, and new devices, such as BlephEx (BlephEx LLC), MiBo Thermoflo (MiBo Medical Group), LipiFlow (TearScience) and IPL [intense pulsed light]. If this is still not enough, I add systemic anti-inflammatory therapy and, in severe cases, surgery,” Benitez del Castillo said.
Two new approaches come from Japan. One is diquafosol, which promotes the secretion of tears as well as mucin from the conjunctival epithelium.
“Unlike artificial tears, it stimulates secretion by the patients’ own cells,” Shimazaki said.
The other drug is rebamipide, which has been used for almost 30 years in the treatment of gastric ulcer.
“The mechanism is protection of mucous membranes, and the conjunctiva is one of the mucous membranes. It also increases the secretion of mucin, the number of goblet cells in the conjunctiva and, in some way that is not yet fully understood, it suppresses inflammation,” he said.
Dry eye and refractive procedures
Cataract and corneal refractive surgeons are nowadays fully aware of the critical role of the ocular surface for the success of refractive procedures and of the way dry eye can affect IOL power calculations and visual outcomes.
“If there is dry eye, topography maps show missing keratometry data due to the irregular tear film. Keratometry values and axes will therefore not be reliable, and patients may end up with 1 D to 2 D of unexpected refractive surprise. With toric and multifocal IOLs, outcomes that miss the refractive target are very disappointing to the doctor and patient and may require a second surgical procedure, IOL exchange, piggybacking or a surface procedure,” Aylin Kiliç MD, OSN Europe Edition Board Member, said.
Patients who present with dry eye before lens surgery are asked to return after an intensive course of treatment and no contact lens wear for 2 to 3 weeks. If epithelial profile maps and topography maps still show irregularity, dry eye treatment is continued for a few more weeks. Only after surface regularity is confirmed, Kiliç makes a plan for surgery.
Postoperative dry eye is another critical point for clear vision. Even if there is no dry eye preoperatively, postsurgical dry eye after premium IOL insertion is possible as a consequence of pre-existing subclinical dryness, ocular surface irritation caused by topical anesthesia, preservatives in the eye drops used during surgery or disruption of corneal innervations from surgical incisions.
“A suboptimal tear film may lead to an increase in total and higher-order aberrations and reduction in retinal image quality. Patients sometimes do not complain of classical dry eye symptoms and the only problem they report may be vision,” Kiliç said.
LASIK is an even more classic cause of postoperative dry eye, due to the severing of corneal nerves. According to Kiliç, the most important step for prevention is detailed preoperative screening. Postoperatively, dry eye treatment should be administered as a precaution, even if patient tear production ordinarily is normal.
“Patients with mild dry eye symptoms should be treated with artificial tears. I routinely recommend prescription eye drops to prevent dryness and corticosteroids to reduce inflammation. For moderate symptoms, punctal plugs and topical cyclosporine can be used,” she said. “Taking omega-3 supplements, drinking plenty of water and eating food rich in ‘good fats,’ such as salmon, may help to maintain a healthy ocular surface and prevent dry eye.” – by Michela Cimberle
- References:
- Barabino S, et al. Exp Eye Res. 2010;doi:10.1016/j.exer.2010.07.008.
- Barabino S, et al. Ocul Surf. 2016;doi:10.1016/j.jtos.2016.04.005.
- Baudouin C, et al. Br J Ophthalmol. 2014;doi:10.1136/bjophthalmol-2013-304619.
- Baudouin C, et al. Br J Ophthalmol. 2016;doi:10.1136/bjophthalmol-2015-307415.
- Belmonte C, et al. Curr Ophthalmol Rep. 2015;doi:10.1007/s40135-015-0073-9.
- Brignole-Baudouin F, et al. Acta Ophthalmol. 2011;doi:10.1111/j.1755-3768.2011.02196.x.
- Bron AJ, et al. Ocul Surf. 2014;doi:10.1016/j.jtos.2014.02.002.
- Chao W, et al. Ocul Surf. 2016;doi:10.1016/j.jtos.2015.11.003.
- The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;doi:10.1016/S1542-0124(12)70081-2.
- Dogru M, et al. Expert Opin Investig Drugs. 2013;doi:10.1517/13543784.2013.838557.
- Parra A, et al. Pain. 2014;doi:10.1016/j.pain.2014.04.025.
- Research in dry eye: report of the Research Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;doi:10.1016/S1542-0124(12)70086-1.
- Sullivan DA, et al. Ocul Surf. 2012;doi:10.1016/j.jtos.2012.02.001.
- Tsubota K, et al. Ocul Surf. 2016;doi:10.1016/j.jtos.2016.09.003.
- For more information:
- Stefano Barabino, MD, PhD, is associate professor of ophthalmology at Genoa University, Italy. He can be reached at Università degli Studi di Genova, Cinica Oculistica, Viale Benedetto XV 5, 16135 Genova, Italy; email: stebarabi@gmail.com.
- José Manuel Benitez del Castillo, MD, PhD, is director of the ocular surface department at San Carlos Hospital and professor of ophthalmology at Complutense University of Madrid. He can be reached at email: benitezcastillo@gmail.com.
- Aylin Kiliç, MD, PhD, is senior consultant and director of the Refractive Surgery Department at Istanbul Eye Hospital, Istanbul, Turkey. She can be reached at email: aylinkilicdr@gmail.com.
- Jun Shimazaki, MD, PhD, is professor of ophthalmology at Tokyo Dental College, Ichikawa General Hospital Chiba. He can be reached at email: jun@eyebank.or.jp.
Disclosures: Barabino reports he is a consultant to TRB Chemedica, SIFI and Farmigea. Benitez del Castillo reports he is a consultant to Alcon, Allergan, Bausch + Lomb and Théa. Kiliç reports no relevant financial disclosures. Shimazaki reports he is a consultant to Otsuka Pharmaceutical and Santen Pharmaceutical.
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