Should We Reconsider the Classification of Patients with Dry Eye Disease?

Keywords:

• Classification
• definition
• dry eye
• inflammation
• symptoms

Dry eye symptoms affect between 7% and 34% of the global population, with lower rates reported in the US (7%) and higher rates in Taiwan and Japan (34%).¹ A population-based cohort study has shown that dry eye disease is most common in women and the elderly.² The same study showed the association of dry eye symptoms with past and current smoking and various conditions including a history of arthritis, thyroid disease, gout, diabetes, and hypercholesterolemia.²

The definition of dry eye disease has evolved over time. The definition adopted in 1995 by the National Eye Institute/Industry Dry Eye Workshop stated that “dry eye is a disorder of the tear film due to tear deficiency or excessive evaporation, which causes damage to the interpalpebral ocular surface and is associated with symptoms of ocular discomfort.”³ The Tear Film and Ocular Surface Society Dry Eye Workshop (TFOS DEWS) updated the definition in 2007, proposing that

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 and is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.⁴

We now know that dry eye disease is a progressive disease that affects the entire ocular surface unit.⁵ Both reduced aqueous tear flow caused by impaired lacrimal fluid delivery and increased tear film evaporation caused by an environmental stressor or Meibomian gland dysfunction contribute to hyperosmolarity and nerve terminal overstimulation, triggering a cascade of events involving other parts of the ocular surface unit.^5–7 Progressive dry eye disease affects multiple components of the ocular surface unit including epithelial cells, goblet cells, the lid margin, tear film, and the spreading and composition of lipids. Eventually, early dry eye disease becomes an irreversible chronic inflammatory condition exacerbated by reduced aqueous tear flow, increased tear film evaporation, and repeated nerve stimulation.⁸ If the disease remains untreated, these processes result in a self-perpetuating vicious circle of inflammation leading to treatment-refractory disease and permanent damage to the ocular surface.^9,10

In patients with early dry eye disease, an ideal treatment should help them to exit this vicious circle of inflammation or prevent them from entering it in the first place.^6,9 Therapeutically, normal homeostasis at the ocular surface can be restored by correcting tear film instability, inflammation, and epithelial damage; once a patient has exited the vicious circle, symptoms typically resolve or become more sporadic, and superficial epithelial disease heals.⁶ Indeed, the ability of a patient to exit the vicious circle of inflammation may be perceived as either a sign of therapeutic success or the adaptation of the ocular surface unit to the stimulus at the origin of the disease.

However, the heterogeneity of dry eye disease presentations and, specifically, differences in the disease course remain challenging from a clinical perspective. For example, while patients with dry eye disease associated with Sjogren’s syndrome or photorefractive surgery present with similar symptoms, dry eye disease associated with Sjogren’s syndrome is unlikely to improve significantly over time. By contrast, patients with dry eye disease associated with photorefractive surgery tend to have better symptom outcomes over time. Patients presenting with early stage dry eye also have a clinical picture that differs from both Sjogren’s syndrome and advanced stage dry eye.

Crucially, the current TFOS DEWS guidelines published in 2017 do not capture this patient heterogeneity, even though all of these patients with dry eye disease could, hypothetically, be enrolled in a trial as patients with identical diseases.¹¹ The 2017 definition proposed by TFOS DEWS suggests that

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.¹¹

The symptomatology reported in this definition is binary and does not account for differences in the duration of symptoms. Furthermore, the dry eye severity grading system proposed in 2007 – and confirmed in 2017 – reports a correlation between symptom severity and signs of ocular disease, but this is not completely accurate from a clinical point of view. We propose that the symptomatology of dry eye disease should be considered as an independent factor.

Specifically, we suggest a new way of considering patients with dry eye disease, by incorporating different clinical forms and integrating disease progression and temporal patterns of symptoms (Table 1). With this new approach, we would probably also be able to express the ability of patients to exit the vicious circle of inflammation and account for the wide range of pathogenic processes and immune responses across a heterogeneous population of patients – for example, the difference between patients with sporadic or intermittent symptoms or patients with symptoms only in special conditions (e.g., air-conditioning, prolonged exposure to PC screen) who are able to exit the vicious circle and patients with persistent or permanent symptoms who may have lost the ability to compensate for damage to the ocular surface and will exit the vicious circle either rarely or never. The proposed evaluation does not aim to be a classification of the severity of dry eye. We agree that such a classification would benefit from the inclusion of clinical signs, but we are now aware that corneal sensitivity plays an important role and determines the lack of correlation between symptoms and signs in dry eye patients.¹² Therefore, the use of the Cochet–Bonnet esthesiometer or the development of another diagnostic tool to evaluate corneal sensitivity in clinical practice would certainly help to better classify patients with dry eye disease.

TABLE 1. Proposal for evaluating dry eye disease based on the frequency of symptoms

Frequency of dry eye symptoms	Symptomatology
Sporadic	Occasional dry eye feeling in specific situations (not every time)
Intermittent	Dry eye feeling all/most of the time in specific situations
Persistent	Dry eye symptoms almost daily that do not last all day long
Permanent (chronic)	Dry eye symptoms daily that last almost all day long

The differences in symptoms are captured in our proposal, and in our opinion, these changes could be related to the differential involvement of the immune system in dry eye. We hypothesize that the immune system is involved in early stage dry eye when symptoms are sporadic or intermittent. Inflammation has the purpose to adapt the ocular surface to stressful conditions and to restore the homeostatic state. If the stressful conditions persist, such as in the advanced stage, the innate and adaptive immune responses lead to development disease of the homeostasis and/or autoinflammatory disease associated with the persistent and permanent symptomatology of dry eye.¹³ Resolving the early stage of inflammation – or so-called para-inflammation – is, therefore, crucial in preventing disease progression and the involvement of adaptive immunity which leads to advanced stage dry eye. Currently, we have a lot of data regarding inflammation in advanced stage dry eye,¹⁴ but we probably need to further investigate the mechanisms involved in the early stage dry eye.

We hope that our proposal will trigger a broader debate on reconsidering the importance of the frequency of symptoms in classifying dry eye disease and possibly the role of inflammation in the staging of the disease. Indeed, it may provide clinicians with clearer guidance on stepping up (or stepping down) therapy and help them to tailor treatment.¹⁵ Furthermore, it may even have a broader benefit to clinical medicine, by helping to inform the design of future clinical trials and – possibly – to try to redefine dry eye disease.

Declaration of interest

The authors report no conflicts of interest.

Acknowledgments

The medical writing support was provided by Thierry Deltheil, PhD of Synergy Vision Ltd (London, UK), funded by Santen.

Additional information

Funding

This work was supported by Santen SA [financial support for medical writing].