Special Report: TFOS DEWS II

By Stephen Daily

The long-awaited Tear Film & Ocular Surface Society (TFOS) Dry Eye Workshop II (DEWS II) report was published on July 21, 2017, updating the definition of dry eye disease (DED) and potentially impacting the way the disease is diagnosed and examined.

The workshop involved 150 clinical and basic research experts from 23 countries, who utilized an evidence-based approach and a process of open communication, dialogue, and transparency to achieve a global consensus concerning multiple aspects of dry eye disease. The TFOS DEWS II report is the sequel to the original TFOS DEWS publication of 2007.

“The original DEWS stimulated a huge amount of new research throughout the world—both basic and clinical,” David A. Sullivan, PhD, senior scientist at the Schepens Eye Research Institute/Massachusetts Eye and Ear and associate professor at Harvard Medical School in Boston, said in an interview with Advanced Ocular Care. “Over the past 10 years, there’s been a dramatic increase in our understanding of dry eye disease. And to effectively update our understanding of the classification, diagnosis, epidemiology, pathophysiology, and management therapy of the disease, we launched TFOS II workshop.”

According to the findings of the workshop, which were published in the Ocular Surface Journal,1 dry eye is redefined as “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.”

Inclusion of the phrase “loss of homeostasis” is novel, and this definition clarified, based on recent peer-reviewed evidence, that tear film hyperosmolarity and ocular surface inflammation have causal etiologic roles, along with the addition of neurosensory abnormalities (contributing to the common mismatch between signs and symptoms), according to the report.

The report also updates the classification and diagnosis of dry eye, critically evaluates the epidemiology, etiology, mechanism, and impact of this disorder, addresses its management and therapy, and proposes recommendations for the design of clinical trials to assess new pharmaceutical interventions for dry eye treatment.

“[The DEWS II report] has redefined dry eye disease; it has reclassified dry eye disease,” Dr. Sullivan said. “It has made recommendations concerning diagnostics as well as an algorithm to associate that with management and therapy.”

Below are the categories of DED and the TFOS DEWS II analysis/findings as stated in the report.

Sex, Gender, and Hormones

That DED occurs more frequently in women than men suggests there are sex-related differences underlying its etiology. There is a difference between sex and gender. Sex refers to the classification of living things according to their reproductive organs and functions assigned by chromosomal complement (ie, male and female). Gender refers to a person’s self-representation as a man or woman, and how social institutions respond to that person based upon the individual’s gender presentation. While sex, gender, and hormones play a major role in the regulation of the ocular surface and adnexal tissues and in the difference in DED prevalence between men and women, further research is needed to clarify the precise nature, extent, and mechanisms of these sex, gender, and endocrine effects on the eye in health and disease. A deeper understanding of these issues may result in improved, more tailored, and appropriate options for the treatment of DED.

Epidemiology

The epidemiology of DED continues to be a challenge due to the lack of a standardized worldwide definition. This has resulted in epidemiologic studies using different diagnostic criteria based on symptoms and signs and self-reported diagnoses. Although new information on the prevalence of DED has been published since the initial TFOS DEWS report, there is only one population-based study on the prevalence of DED south of the equator, with much of the attention being focused on Asia and Europe. The prevalence of DED, with and without symptoms, ranges from 5% to 50%. Prevalence of DED based on signs is even more variable, reaching up to 75% in some populations. The challenge is that the criteria for positive signs have varied between studies, which may reflect secondary outcomes or be attributed to aging changes.

To date, very few studies have been conducted in younger populations, and this information may be very valuable as the data published so far suggests a lower prevalence of DED in younger subjects. What is it about these individuals that is different? Is it tear film composition, tear thickness, lid differences in tightness or shape, or corneal or conjunctival sensitivity? Asian ethnicity appears to be a risk factor, but the reason for this is, as yet, unclear. Higher rates of DED in women compared to men only become significant with increasing age. The most severe economic impact of DED likely results from indirect costs related to decreased work productivity. Future needs include a detailed evaluation of the prevalence of DED of varying severity, prevalence in youth, incidence studies in various populations, and the impact of the use of current technologies such as mobile devices. The effects of climate, environmental, and socioeconomic factors warrant further study. Finally, the natural history of DED in treated and untreated individuals remains an important area for future research.

Tear Film

DED implies major changes to the tear film structure and function. Historically, the tear film has been viewed as a 3-layer “sandwich” composed of distinct lipid, aqueous, and mucin layers. Evidence continues to support the more contemporary two-phase model of the tear film, with a lipid layer overlying a mucoaqueous phase. While it may be that the whole tear film (lipids, mucins, proteins, and salts) prevents tear film evaporation and collapse, additional studies are needed to confirm or deny this concept. The lipid layer contains polar and nonpolar lipids. The mucoaqueous layer contains at least four major mucins and over 1500 different proteins and peptides and overlies the carbohydrate-rich glycocalyx of the apical epithelium. While tear proteins are reported to change in DED, no definitive set of proteins or changes in protein levels have been validated to aid in diagnosis. There is a need to further characterize the biochemistry of the tear film to identify new markers that can be used to diagnose and, perhaps, predict and treat DED. There is also a need for ways to measure tear film osmolarity and markers of inflammation dynamically over the whole ocular surface.

Pain and Sensation

Nociceptive pain occurs in response to actual or threatened damage to tissues, while neuropathic pain occurs due to a lesion within the somatosensory nervous system. Sensory nerves comprise polymodal nociceptor neurons, pure mechano-nociceptor neurons, and cold thermoreceptor neurons. Polymodal nociceptors respond to chemical, mechanical, and thermal stimuli and are sensitized by inflammatory mediators. Mechano-receptors respond to mechanical forces. Cold thermoreceptors continuously discharge nerve impulses at the normal ocular surface temperature, responding to warming or cooling and to osmolarity increases, likely contributing to reflex control of basal tear production and blinking. To date, studies suggest potential merit in exploring treatment strategies involving cold receptors to manage DED symptoms.

The main lacrimal gland is regulated by autonomic sympathetic and parasympathetic innervations, which, in turn, are regulated by reflex influences from sensory neurons supplying the ocular surface. Little is known about the neuronal control of the accessory lacrimal glands. Similarly, only a single study to date has shown a role for sensory or autonomic nerves or their neurotransmitters in meibomian gland regulation. Although activation of sensory neurons in the rat cornea results in goblet cell secretion, the efferent nerve type(s) involved in this reflex remain to be established. Inflammation causes sensitization of polymodal and mechano-receptors and depresses cold thermoreceptor activity. However, the most prominent nerve disturbance is with the cold thermoreceptors, suggesting that dryness-induced nerve damage dominates over inflammation—again, emphasizing a need to focus on possible treatment strategies involving cold thermoreceptors.

Pathophysiology

Meibomian gland dysfunction (MGD) and Sjögren and non-Sjögren lacrimal disease remain leading causes of DED, and many hybrid forms of DED exist. The vicious circle is an accepted central mechanism that explains how ocular surface damage is initiated and perpetuated in DED. There is strong evidence that tear hyperosmolarity can damage epithelial cells directly or can initiate inflammatory events that result in damage to epithelial cells, surface microvilli, barrier function, the glycocalyx, and goblet cells. Epithelial cell damage, lipid layer and blinking abnormalities, defective glycocalyx, loss of gel mucin, and reduction in tear volume may, individually or in combination, result in loss of lubrication between the globe and eyelids, resulting in increased friction and symptoms. The role of increased friction in DED and its subsequent sequelae deserves further investigation.

Inflammation of the ocular surface can cause inhibition of lacrimal secretion and loss of epithelial barrier function at the ocular surface. Tear film breakup, leading to localized hyperosmolarity, can result in ocular surface damage either directly or through the cascade of inflammation that it initiates. Improved understanding of the role of subclinical inflammation in the early stages of DED also warrants further study.

Iatrogenic Dry Eye

Topical and systemic medications, contact lenses, ophthalmic surgeries, and nonsurgical procedures can cause DED. Preservatives such as benzalkonium chloride in ophthalmic formulations can exacerbate DED through toxic and proinflammatory effects. Systemic medications can result in decreased tear production, altered sensory input, and reflex tear secretion. Contact lenses and their associated care solutions can induce DED. Refractive and corneal surgeries can cause or aggravate DED due to the transection of corneal nerves or through the use of postoperative topical medications. Cosmetic and functional eyelid surgeries, botulinum toxin injections, and even cataract surgery along with its post procedure topical medications, can lead to DED. Future recommendations for research include conducting further epidemiologic studies to better define risk factors, creating less toxic medications and preservatives, devising less invasive ophthalmic procedures, and developing strategies for the detection of early DED prior to surgical interventions.

Diagnostic Methodology

The sensitivity and specificity of tests for the diagnosis of DED are each highly dependent on the inclusion criteria for DED, the severity of the disease group and the population studied. The research evidence suggests that the best clinical approach involves triaging questions and risk factor analysis as part of a traditional patient history, leading to a detailed anterior eye examination and differential diagnosis based on the answers. If DED is suspected, a positive result to a screening questionnaire such as the 5-item Dry Eye Questionnaire (DEQ-5) or the Ocular Surface Disease Index (OSDI) should trigger further evaluation, with tear break-up time (noninvasive methods preferred), tear film osmolarity determination, and ocular surface staining (including the cornea, conjunctiva, and lid margin) with fluorescein and lissamine green. Identification of a disruption in tear film homeostasis with these tests allows a diagnosis of dry eye to be made. This standardized approach will facilitate improved epidemiological DED research and therapeutic regulatory approvals in the future. Other tests such as meibography, lipid layer interferometry, evaporation, and tear volume measurements can help clarify where the individual with DED falls on the evaporative and aqueous deficient DED subtype classification spectrum and promote the selection of appropriate therapeutic interventions. New approaches and better-validated instrumentation and techniques are needed to assess DED more critically and to link underlying causes in an individual to the most suitable therapies to manage the disease

Management and Therapy

Restoration of tear film homeostasis is the ultimate goal in the management of DED, and this involves breaking the vicious circle of the disease. Determining whether the major cause(s) of an individual’s DED pertains predominantly to aqueous tear deficiency or to evaporative causes, or both, and it is critical in helping select the most appropriate management strategy. Our failure to resolve patient symptoms and signs may relate more to a lack of success in determining and targeting the underlying nature or cause of a patient’s DED than a failure of the treatment itself. Management of DED is often complex. The challenge remains to develop management and treatment strategies that are not overly complicated for our patients. Although staged management and treatment recommendations are presented, the heterogeneity of the DED patient population mandates that practitioners manage and treat patients based on individual profiles, characteristics and responses. Additional topical therapies that are effective and inexpensive are needed.

Clinical Trials

Clinical trial conduct should be consistent with good clinical practice, including the use of good manufacturing practice quality clinical trial materials. Design, treatments, and sample size need to align with the investigational treatment, the objectives of the study, and the phase of development. For pivotal studies, there should be a priority selection of the outcome measure, and an appropriate sample size.

1. Nelson J, Craig J, Akpek E, et al. TFOS DEWS II introduction. Ocul Surf. 2017;15(3):269-275.

Stephen Daily
• executive editor, news, Advanced Ocular Care and Eyewiretoday.com
sdaily@bmctoday.com