Multifaceted dry eye disease defined in long-awaited TFOS DEWS II report

Aptly published in the Dry Eye Awareness Month of July was the long-awaited Tear Film and Ocular Surface Society Dry Eye Workshop II report. Ten years have passed since the TFOS DEWS I report was published, and this new iteration discloses the results of years of intensive work by 150 experts from 23 countries, working in 12 subcommittees, who considered the wide-ranging, multiple aspects of dry eye disease.

“Our objective was to achieve a global consensus concerning multiple aspects of dry eye disease,” David A. Sullivan, PhD, the workshop organizer, said. “More specifically, the TFOS DEWS II sought to update the definition, classification and diagnosis of dry eye disease, critically evaluate the epidemiology, pathophysiology, mechanism and impact of this disorder, address its management and therapy, and develop recommendations for the design of clinical trials to assess pharmaceutical interventions for dry eye disease treatment.”

Throughout the world, countless individuals experience tear film dysfunctions, which are collectively diagnosed as dry eye disease (DED). In fact, DED is one of the most frequent causes of patient visits to eye care practitioners. Often underdiagnosed and underestimated, DED can be a disabling condition that greatly affects quality of life through chronic pain and decreased vision, while possibly limiting work, social life and daily routines. In several studies, the impact of moderate to severe dry eye on patients’ lives was estimated by utility assessment to be comparable to conditions such as severe angina and hospital dialysis.

DED also represents a substantial economic burden related to the direct cost of medications and medical fees and the indirect cost of impaired productivity.

“The burden of dry eye for the USA health care system alone is estimated to be more than $3.8 billion, and because of diminished productivity, $55.4 billion for the USA society overall,” Sullivan said.

Source: Sullivan AG

A revised definition

The first TFOS DEWS definition of dry eye, released in the 2007 report, stated:

‘‘Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.’’

For the first time, DED was acknowledged as a disease, and its multifactorial etiology was highlighted. However, the etiological mechanism was not specified and “increased osmolarity and inflammation were described as casual and not causal markers of the disease,” the authors of the TFOS DEWS II report noted.

“Surveying the workshop’s members showed support for the original TFOS DEWS definition to be revised. Of the responders, 77% voted in favor of changing the definition, and many expressed the desire to simplify it into a single sentence, as it was noted that the two-sentence definition was often incompletely quoted. However, it was also agreed that key etiological elements should be included to enable differentiation of dry eye disease from other ocular surface diseases,” Jennifer P. Craig, MCOptom, PhD, said.

The workshop was an evidence-based process, so in recognizing the published literature of the last 10 years, it was considered important to acknowledge the role of neurosensory abnormalities.

“Over these 10 years, there has been increasing evidence of how neurosensory dysfunction can be a component of dry eye symptoms. Neuropathic pain occurs due to overt damage within the somatosensory nervous system, distinguishing it from DED,” Craig said.

The new definition now states:

“Dry eye is a multifactorial disease of the ocular surface characterized 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 etiological roles.”

Signs and symptoms

The Definition and Classification Subcommittee was further tasked with resolving confusion over the interpretation of the first DEWS classification scheme, primarily related to the distinction between the evaporative and aqueous-deficient categories.

“There are myriad etiological triggers that are capable of setting off the vicious cycle of dry eye disease. Once into the vicious cycle, further changes occur, often making the distinction between the aqueous-deficient and evaporative components extremely blurred,” Craig said.

The DED classification includes both signs and symptoms because, as Craig said, a diagnosis of dry eye on the basis of just one or the other would result in such low specificity that it could apply to almost anyone, especially given the overlap in symptoms between DED and other ocular surface diseases.

“This would not benefit patients for whom treatment could be more poorly directed, nor would it benefit future research or therapeutic drug or device design. Therefore, to reduce the risk of false positives, it was deemed important to include both signs and symptoms in making a diagnosis of dry eye,” she said.

The report, however, does acknowledge exceptions to the rule in instances in which patients present with signs but no symptoms or symptoms without signs.

“Signs may be identified incidentally at a routine eye exam, prior to ophthalmic surgery or when corneal sensitivity is reduced. On the other hand, patients may present with symptoms that we are unable to confirm objectively, for example in very early preclinical disease or where there might be a neuropathic element to the condition,” Craig said.

Challenges of DED epidemiology

The complex relationship between signs and symptoms and the variety of definitions, classification systems and diagnostic pathways have made the research and interpretation of epidemiological data particularly challenging.

“In the Epidemiology Subcommittee, we looked at a variety of definitions because of this problem and decided to work out prevalence for each of these definitions. If you look at the report, based on the definition, there is a huge range of prevalence rates. The other issue is that studies included very diverse age groups in different locations in the world,” Susan Vitale, PhD, MHS, said.

Based on a symptom definition or self-reported diagnosis of DED, in the U.S. roughly 4 million to 5 million people older than 50 years have DED. In Asia and the Middle East, the numbers appear to be higher.

“On the whole, we are safe to say that many millions of people in the world have DED, and our conclusion regarding prevalence is that it ranges between 5% and 50%. A huge range indeed,” Vitale said.

The same committee reviewed evidence for different risk factors. The consistent risk factors that were confirmed were older age, female sex, Asian ethnicity, meibomian gland dysfunction (MGD), Sjögren’s syndrome, connective tissue disease, androgen deficiency, estrogen replacement therapy, hematopoietic stem cell transplantation, use of specific medications and contact lens wear. Several environmental factors were suggested to affect DED, such as wind, low humidity, pollution and high altitude. The impact of air pollution needs further study to integrate location-based health data and corresponding environmental data conditions, Vitale said.

“Several studies have described the impact of using visual displays, working in low-humidity rooms and the so-called sick building syndrome on DED,” she said.

Neuropathic pain

Research over the past 10 years has deepened the understanding of the complex changes that occur in the ocular surface sensory pathways when the conjunctiva and cornea are affected by DED. This has led to the need to clarify the reasons that lie behind the apparently inexplicable lack of correlation between severe and persistent symptoms of discomfort and pain and the lack of objective signs that may be found in a significant number of cases. These patients typically remain symptomatic despite adherence to therapy and drift into a condition of chronic pain.

The report makes a clear distinction between nociceptive pain “that arises from actual or threatened damage to tissues and is due to the activation of nociceptors” and neuropathic pain “caused by a lesion or disease of the somatosensory nervous system.”

The nociceptors are sensory receptors that encode and signal to the brain a mechanical, thermal or chemical insult to the tissue.

“Under normal conditions, they warn the brain that the eye is dry. The neurosensory cortex reads the information, sends the alarm through the symptoms and activates compensatory strategies such as increased tear secretion,” Carlos Belmonte, MD, PhD, said.

When sensory receptors are damaged, the whole system becomes chronically dysregulated.

“The nerve fibers begin to fire on their own rhythm, sending signals also in presence of a normal tear film, and this perpetuates the sensation of pain. The result is that you can put tears back in the eye, but the damaged nerves keep sending abnormal signals. This is what we call neuropathic pain,” Belmonte said.

He suggested that one way of differentiating neuropathic pain from DED is by instillation of a drop of local anesthetic in the eye. If the pain disappears, it means that the origin is peripheral, at the level of the ocular surface.

“But if the cause is neuropathic, not only in the periphery but in the upper level of the nervous system, even if you silence the signals, still the pain persists. It is a very clear criterion to determine if the pain is due to the abnormal functioning of the nerves, if it is central neuropathic pain as we call it,” he said.

When to refer

Neuropathic pain is disabling and difficult to treat. Chronic pain and severe functional impairment often lead to depression.

“These patients cannot open their eyes properly, cannot do outdoor activities, and cannot read or watch TV. They are severely limited in practically everything and find no relief. No wonder they commonly experience depression,” Belmonte said.

At this point, the problem is no longer one for the ophthalmologist but instead one for the neurologist and pain specialist.

“The ophthalmologists don’t have a specific training to treat pain. When nerves chronically respond abnormally, the treatment consists of reducing their excitability with medications such as antiepileptic drugs and antidepressants, or with other forms of treatment. This requires specialized skills because many of these drugs have side effects, and you need to find a balance between the reduction of the sensation and the physical and psychological health of the person,” Belmonte said.

Sex, gender and hormones

This report explores the major roles played by sex, gender and hormones in the regulation of ocular surface and adnexal tissues, and in the difference in DED prevalence between women and men. The authors make a distinction between the words “sex” and “gender” on purpose because these words have distinct meanings. “Sex” refers to the classification of living things, generally as male or female, according to their reproductive organs and chromosomal complement. “Gender” refers to a person’s self-representation as a man or woman, or how social institutions react to that person based on the individual’s gender presentation, Sullivan explained.

As written in the report, “sex matters.” Sex-related differences, which appear to be due to the action of hormones as well as genetic factors, exist in almost every cell in the human body and directly or indirectly influence numerous physiological and pathological functions. Gender, in turn, is associated with many health disparities.

“Overall, both sex and gender affect dry eye disease risk, presentation of the disease, immune responses, pain, care-seeking behaviors, service utilization and many other facets of eye health,” Sullivan said.

New approach to diagnosis

The TFOS DEWS II diagnostic methodology report suggested a simple algorithm for diagnosing DED based on the assessment of symptoms and objective findings.

“With respect to symptoms, we recommended either the five-item dry eye questionnaire or the Ocular Surface Disease Index questionnaire. If the symptom questionnaire is positive for DED, three tests should be performed, namely osmolarity, ocular surface staining and tear breakup time,” OSN Cornea/External Disease Board Member Preeya K. Gupta, MD, said.

Noninvasive breakup time techniques have become popular in both clinical practice and research, but they may not be available to all.

“If anyone has documented symptoms based on the questionnaire and one of those tests is abnormal, the diagnosis of DED is confirmed. From there, further testing is recommended to delineate the different subgroups of dry eye,” Gupta said.

In recent times, DED has been recognized to be mixed-mechanism in many cases and requires assessment of both the aqueous deficiency and evaporative dry eye components.

“To assess aqueous deficiency, meniscometry is recommended as a noninvasive method to indirectly assess tear volume. Diagnostic tests for evaporative DED, which is a large percentage of cases, are basically focused on the meibomian glands and may include manual expression, meibography and interferometry. Once the subtype of DED has been identified, the diagnostic information can be used to choose therapy options,” Gupta said.

This new algorithm, relatively simple and broadly accessible to clinicians, is based on a large body of evidence, steadily grown over the past 10 years.

“The report as a whole has three times the references of the first report, which shows how much the interest in dry eye has grown because it affects so many people,” she said.

The new evidence has brought substantial changes with regard to diagnosis. These include a new attention to forms of mixed-mechanism disease, based on evidence that the distinction between aqueous deficiency and evaporation is blurred.

“This has an important impact on clinical practice. If it is no longer apples and oranges but something in between, our approach changes entirely,” Gupta said.

A second aspect is the greater emphasis on MGD, which has been recognized to be the most common cause of evaporative DED. Finally, the role of neurosensory abnormalities and neuropathic pain has been fully acknowledged in the new report. In the algorithm, patients who report symptoms and therefore have positive results on the questionnaire, but no abnormalities in the osmolarity, tear breakup time or ocular surface staining tests, are not diagnosed as DED but as possibly having neuropathic pain or other ocular surface abnormality, and directed to a different treatment pathway.

Treatment options

A lot has changed in the treatment scenario since the first TFOS DEWS report. A better understanding of the pathogenesis and mechanisms involved in DED has led to new, more specific treatment options.

One of them, currently undergoing a multicenter trial in Europe, is SYL1001 (Sylentis), which specifically addresses pain. The active component is a small interference RNA inhibitor of the transient receptor potential vanilloid 1, a mediator of pain sensation in the eye.

“This eye drop formulation may be a breakthrough for patients who have symptoms and not signs. It acts on neuropathic pain by blocking the receptors and, importantly, does so without reducing tear production,” José Manuel Benitez del Castillo, MD, PhD, said.

Tear stimulation approaches are evolving rapidly and raising great interest.

“It’s a new old news. We had pilocarpine, and in Japan and Korea there is diquafosol ophthalmic solution (Diquas, Santen), which we hope to have in Europe and the USA soon. Lacritin (TearSolutions) is another promising drug, soon entering the phase of human trials. There is also a device, an intranasal tear stimulator called [TrueTear], that is showing interesting results,” Benitez del Castillo said. TrueTear (Allergan), formerly known as the Oculeve intranasal tear stimulator, was cleared by the FDA in April.

Artificial tears are still the standard treatment, but they are completely different from natural tears, he said.

“[Several] new approaches [appear to] stimulate patients’ ability to produce natural tears, which is what we really want,” he said.

Patients with dry eye due to MGD also have new approaches available. LipiFlow (TearScience) helps to remove blockage and restore oil flow to the tears. BlephEx (BlephEx LLC) performs microblepharoexfoliation to clean the lid margin. Intense pulsed light has shown efficacy in scientific study.

“Lipid layer-related dry eye is the most frequent. Evaporative, or at least partially evaporative, dry eye is 85% of the cases and is often related to MGD,” Benitez del Castillo said.

Among anti-inflammatory drugs, Xiidra (lifitegrast ophthalmic solution 5%, Shire) is now used in the U.S. but is not yet available in Europe. Combination with cyclosporine complements the anti-inflammatory action with the immunomodulatory component.

New biologics are under investigation. Lubricin is a lubricating protein that was first discovered in synovial fluid. Used topically on the eye, it seeks to prevent shear stress at the cornea-lid interface.

“It is a very promising drug. By reducing friction between lid and globe, it prevents the onset of inflammation,” Benitez del Castillo said.

These approaches can be combined in various ways according to the type and severity of DED.

“In moderate to severe dry eye, we can work on several paths. We increase tear production using pilocarpine or one of the new drugs, or using the [TrueTear] instrument. A punctum plug does not increase tear production but it increases tear volume by decreasing tear evacuation. Then we reduce inflammation using lifitegrast and/or cyclosporine. There are different approaches to treat the same problem,” he said.

The report acknowledged that there is increasing evidence that nutrition plays a role in DED. In modern times, the dietary habits of the Western world are greatly imbalanced in relation to the intake of anti-inflammatory omega-3 and pro-inflammatory omega-6 essential fatty acids (EFA).

“Fifty years ago we were eating more omega-3, and the relation between omega-3 and omega-6 was 1 to 1. But now we are eating less fish and more meat, so the relation between omega-3 and omega-6 is 1 to 40,” Benitez del Castillo said. “Dietary modifications, including EFA supplementation, can positively impact DED.” – by Michela Cimberle

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• For more information:
• Carlos Belmonte, MD, PhD, is emeritus professor of human physiology at University Miguel Hernández and senior researcher at Institute of Neurosciences in Alicante. He can be reached at Universidad Miguel Hernández, Avda. Ramón y Cajal, s/n 03550 San Juan de Alicante, Alicante, Spain; email: carlos.belmonte@umh.es.
• José Manuel Benitez del Castillo, MD, PhD, is head of ophthalmology at San Carlos Hospital and professor of ophthalmology at Complutense University of Madrid. He can be reached at email: benitezcastillo@gmail.com.
• Jennifer P. Craig, MCOptom, PhD, is associate professor in the department of ophthalmology at University of Auckland. She can be reached at University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; email: jp.craig@auckland.ac.nz.
• Preeya K. Gupta, MD, is associate professor of ophthalmology at Duke University Eye Center. She can be reached at Duke University, Department of Ophthalmology, Box 3802, Durham, NC 27710; email: preeya.gupta@duke.edu.
• David A. Sullivan, PhD, is associate professor in the department of ophthalmology at Harvard Medical School and a senior scientist at Schepens Eye Research Institute. He can be reached at email: david_sullivan@meei.harvard.edu.
• Susan Vitale, PhD, MHS, is a research epidemiologist at the National Eye Institute. She can be reached at National Institutes of Health, 10 Center Drive, Room 10D45, Mail Stop 1863 Bethesda, MD 20892-1863; email: sev@nei.nih.gov.

Disclosures: Belmonte reports he is a shareholder of Avizorex pharma. Benitez del Castillo reports he is a consultant to Novartis, Allergan, Théa, Bausch + Lomb and Dompé. Craig reports she consults or has received research funding from Oculeve, Allergan, Manuka Health NZ, E-Swin, CooperVision, Alcon, Optima Pharmaceuticals, OPSM NZ, Akorn, Medmont and Carl Zeiss Meditec. Gupta reports she is a consultant to Alcon, Johnson & Johnson Vision, Bio-Tissue, TearLab, TearScience, NovaBay and Allergan. Sullivan reports he is a founder of Singularis/Lubris and a consultant to M.G. Therapeutics. Vitale reports no relevant financial disclosures.

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