New Directions in Dry Eye: TFOS DEWS II Report

Lauri R. Graham

Disclosures

September 06, 2017

The Tear Film & Ocular Surface Society International Dry Eye Workshop II (TFOS DEWS II) is an extensive, multipart report that updates our understanding of dry eye disease. Medscape spoke with J. Daniel Nelson, MD, the chair of TFOS DEWS II and staff physician in the department of ophthalmology at HealthPartners Medical Group in Bloomington, Minnesota, about the importance of this report and its clinical implications.

J. Daniel Nelson, MD

Medscape: Ten years have passed between the publication of TFOS DEWS I and TFOS DEWS II. In that time, what do you see as one (or more) of the key changes in dry eye?

Dr Nelson: One of the changes is that the number of publications related to dry eye has substantially increased; it doubled between the first National Eye Institute/Industry Workshop on Clinical Trials in Dry Eye report (in 1995) and TFOS DEWS I (in 2007) and now it has doubled again. Clinical, pharmaceutical, and industry interest in dry eye has increased as well, along with basic science. Part of this increased interest stems from more ocular surgeries being performed (eg, LASIK, cataract surgery) where preparation of the ocular surface is important to ensure an optimal refractive outcome. When I first started practicing 35 years ago, there just was not that much interest because of the lack of good diagnostic tools and treatments. But then in a relatively short time, within the past decade or so, we have seen advances in our diagnostic tools and have had new medications come to the market.

Medscape: This is a very extensive report, developed over the course of 2 years. Could you briefly discuss the approach taken to its development, and also its objectives?

Dr Nelson: A steering committee, consisting of 25 dry eye experts from around the world, determined the specific aims and mission, along with the strategy, tactics, structure, methods of communication, timeline, milestones, and conflict-of-interest policy. The steering committee created 12 subcommittees, from which 10 became the clinical areas of the final reports; the other two were an industrial liaison committee and a public liaison committee. The steering committee also developed the objectives, which were to update the definition, classification, and diagnosis of dry eye disease; to critically assess the etiology, mechanism, distribution, and impact of dry eye disease; and to address the management and therapy of dry eye disease.

Medscape: In your opinion, what was the biggest challenge in developing this report?

Dr Nelson: Timeliness, and also ensuring that it was evidence based. We were focusing on a critical assessment of the literature, not parochial feelings or beliefs; there had to be evidence and support. And while the report is lengthy, it is the state of the art, based upon our best current knowledge.

Medscape: What are you most proud of in regard to this report?

Dr Nelson: I am proud that we came up with an updated definition of dry eye disease. It took a lot of work to get to a definition, and I am pleased with it, and also with the classification scheme. We did not make the definition so narrow that there was no room to further refine it in the future. I also think it will help clinicians, as well as industry, pharmaceutical, and research, in pointing them in new directions.

Defining Dry Eye

Medscape: Speaking of the definition of dry eye, there has been controversy surrounding it in the past. Why was updating the definition important, and what is novel about it?

Dr Nelson: The new definition is: "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 etiologic roles." The terminology was critical.

It was important to retain the word "disease," from a patient care perspective as well as for regulatory agencies and industry. If it is not a disease, then why are we interested?

The novel word in the definition is "homeostasis." We debated this term but believed that it was general enough that it would allow future research into the question of "What disturbs the homeostasis (the normal state) of the tear film in dry eye disease?"

Symptoms are still a critical part of the definition and the term is meant to be inclusive of not just pain and discomfort, but visual disturbances as well. We have added tear film instability, hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities as playing key etiologic roles. In the definition from TFOS DEWS I, the words "hyperosmolarity" and "inflammation" were controversial because, at that time, it was not known if they were underlying etiologic factors or simply markers of the disease. Now we know that they are. We also know that there are many different triggers that can result in ocular surface inflammation, tear film instability, hyperosmolarity, and neurosensory abnormalities, which may direct future research and clinical development of tests and treatments.

In regard to neurosensory abnormalities, this is one of the hottest topics in the past few years and was important to include in the definition and classification. This stems from the fact that signs and symptoms in dry eye do not always correlate. If a patient has symptoms but no signs, they have either neurosensory abnormalities (or neuropathic pain) or preclinical dry eye. On the flip side, a patient may have signs but no symptoms and thus could be at risk for dry eye. Now, if a patient has symptoms and signs, a questionnaire helps differentiate between dry eye disease and other ocular surface diseases. Once it is known to be dry eye disease, then key clinical tests (ie, tear breakup time, tear osmolarity, ocular surface staining) can be performed to further classify the type of dry eye.

I do not think one should separate the definition from the classification; the definition and classification need to be viewed together to fully understand what dry eye disease is.

So the key takeaway in the definition is the loss of tear film homeostasis. I do not think one should separate the definition from the classification; the definition and classification need to be viewed together to fully understand what dry eye disease is.

Focusing on Specific Clinical Areas

Medscape: TFOS DEWS II includes 10 subcommittee reports that focus on specific clinical areas. One is the Definition and Classification Report, which we have discussed, but would you briefly highlight what is covered in the other reports and what you think are the key takeaway points?

Dr Nelson: The other reports are Sex, Gender & Hormones; Epidemiology; Tear Film, Pain & Sensation; Pathophysiology; Iatrogenic Dry Eye; Diagnostic Methodology; Management & Therapy; and Clinical Trials.

The Sex, Gender & Hormones report stresses that there is a difference between sex and gender, and it highlights that hormones are involved in dry eye disease, and that androgens are important in the regulation of the ocular surface.

As borne out in the Epidemiology report, while dry eye disease is more common in women, this correlation increases with age. This report also showed that there has been a lack of consistency in how individuals with dry eye disease are classified. We found eight useful epidemiologic studies, but none were from south of the equator—mostly Asia, Europe, and the United States. It seems, from an epidemiologic study, that we find a higher prevalence of the disease in Asia. It is also important to keep in mind that there are no incidence studies.

We have previously been taught that the tear film consists of three layers. The Tear Film report emphasizes that the tear film is a two-phase model with a lipid phase overlying a muco-aqueous gel phase. Also, the report states that the entire tear film and its components are responsible for limiting evaporation, not just the lipid layer. So when we talk about evaporative dry eye, it is not just lipids from the Meibomian glands that inhibit evaporation; it is all components of the entire tear film.

An interesting takeaway from the Pain & Sensation report is that dry eye induces nerve damage, and that actually dominates over inflammation in causing symptoms. While inflammation is important in causing symptoms and damage from dry eye disease, just the dryness itself can cause damage. This nerve damage causes an abnormality, primarily in the cold receptors, and opens the possibility of further research into the role of cold receptors in dry eye disease. This report also states that pain is a critical component of dry eye, but not all eye pain is due to dry eye. This gets at the idea of neuropathic pain in patients.

The Pathophysiology report emphasizes the "vicious circle" of dry eye disease, in that there are many different ways in which to enter this circle and end up with loss of tear film homeostasis. Often, the beginning point or the endpoint is tear film hyperosmolarity. The report states that the core mechanism of dry eye is evaporative-induced tear film hyperosmolarity that triggers a cascade of events leading to inflammation and ocular surface damage, and that leads to further evaporation and even higher osmolarity. The report still emphasizes evaporative and aqueous-deficient dry eye. We debated whether there were better ways to further classify dry eye disease, but those terms are commonly used and seem to have stuck, albeit they may not be entirely the best terms.

The Iatrogenic Dry Eye report emphasizes that patients and clinicians alike are the source of many issues related to dry eye. Surgical procedures, toxic medications, systemic medication side effects, and contact lenses can be culprits because they all can disturb tear film homeostasis.

I alluded to this before, but the Diagnostic Methodology report emphasizes a screening questionnaire to separate other ocular surface diseases from dry eye disease. One of the key diagnostic tests is tear breakup time, and the report recommends noninvasive tear breakup time as being preferred. Tear film osmolarity and ocular surface staining are used to further refine the diagnosis.

While the Management and Therapy report stresses a step-wise approach, it also stresses an individualization of that approach. For example, you may go right to step three or you may start at step one, or you may use all the steps at once; it depends on the patient being treated. New products and interventions have come out, and even though research is still ongoing, they have been included in this step-wise approach as to where they best fit.

The Clinical Trials report emphasized the importance of not only understanding this disease process but also structuring clinical trial design in a way that will lead to regulatory approval of products and devices. I think this will be the bible for how industry, or individuals, approach future clinical trial design.

Medscape: Which of these subcommittee reports are new since the publication of TFOS DEWS I?

Dr Nelson: The new reports are Sex, Gender & Hormones; Tear Film; Pain & Sensation; and Iatrogenic Dry Eye. We added them, as there was more interest and research available this time around. Also, in TFOS DEWS I, much of the pathophysiology was included as part of the definition report; with TFOS DEWS II, we separated it out. In TFOS DEWS II, we used the Pathophysiology Report as the basis for developing the definition and classification of dry eye disease.

Diagnosis and Management: Primary Takeaways

Medscape: In your opinion, what are the primary takeaways from the Diagnostic Methodology and Management & Therapy reports that eye care providers should most be aware of?

Dr Nelson: The primary takeaways are understanding how to diagnose patients with dry eye disease, and then based on that diagnosis, how to treat them. These two reports are tied together in the sense that by having a diagnosis, you know where to start treatment; the step-wise approach is key. You also cannot just say that everybody with symptoms and signs has dry eye. You have to start with a questionnaire to separate dry eye disease from other ocular surface diseases, perform the recommended testing, and then proceed with the treatment.

Medscape: Was there anything in these two reports that particularly resonated with you in terms of diagnosing or treating dry eye?

Dr Nelson: For me, it's that the real key to treatment is understanding the patient whom you are treating: Do they have dry eye disease or some other ocular surface disease, or am I dealing with neuropathic pain? Particularly for patients with neuropathic pain, they are desperate and uncomfortable and are willing to try anything. They are also patients who are susceptible to the placebo effect, which is a real effect, and while they may believe that a treatment might help them, it may not be the best treatment for them. I think a key future direction is determining how we can better treat patients with neuropathic pain. Many of these patients have a systemic pain syndrome, and a more systemic approach—with help from other medical specialists—is needed.

Medscape: What will be the overall clinical implications of this report? How will it benefit eye care providers in their evaluation and treatment of patients with dry eye?

Dr Nelson: While I think the report will be well received, some people will certainly disagree with elements of it, likely more from personal opinion and experience. However, I firmly believe that the report represents the current state of dry eye disease as we know it. I also believe that the report will help clinicians, industry, regulatory agencies, and researchers in their understanding of dry eye disease and will lead to the development of new diagnostic tests and treatments that will benefit patients and the clinicians who treat them. In the end, it is our patients with dry eye disease who we need to help.

What I am suggesting to my colleagues is that they read these three reports: Definition and Classification, Diagnostic Methodology, and Management and Therapy. They are going to give you the meat for your clinical practice.

What I am suggesting to my colleagues is that they read these three reports: Definition and Classification, Diagnostic Methodology, and Management and Therapy first. They are going to give you the meat for your clinical practice. Then go back and read the other reports to fill in background knowledge. For example, the Iatrogenic Dry Eye report highlights issues that can contribute to dry eye problems of which clinicians may be unaware. Some of the reports are more technical, but for those interested in dry eye, they will find them interesting. I know I did.

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