A new approach to Dry Eye

Pubblicato il

Monday, 15 December 2014

Argomento

Dry Eye

Read the interview with Prof. Michael A. Lemp.

Introduction (Read the original article in English)
Dry eye research has been very active over the past decades and, in particular, its pace has accelerated in recent years. In 2007, the TFOS Dry Eye WorkShop report (DEWS)¹ represented the international synthesis of the state of the art in this area of research. Although this universally accepted document presented an accurate picture of the existing consensus on how this disease was viewed by experts from different scientific and medical disciplines, it was clear that there were large gaps in the knowledge base and significant challenges in the following areas: understanding the pathogenesis and progression of the disease, identifying its essential components, assessing the degree of severity, designing clinical trials to test new therapies, and some contradictory variables, such as the lack of correlation between objective signs and symptoms of the disease.
Over the past five years, a considerable number of scientific articles have been published on these areas of research. The two most investigated topics in dry eye have been inflammation and tear osmolarity. The most recent discoveries have shed much light on the pathophysiology of dry eye, the relationship between clinical signs and symptoms, new markers, and the development of pathology. These discoveries, which you will find summarised in this article, have led to new concepts fundamental to the understanding of dry eye.

Topical issues in dry eye
This widespread condition, which affects up to 20% of the population in Europe, North America and Asia, places significant burdens on patients and the society in which they live^2,3.
The main challenges for a better understanding of this pathology include:
- The existence of a poor correlation between objective signs of the disease and symptoms reported by the patient.
- Frequent discrepancies between objective signs of the disease, particularly in the early phase of the disease.
- Conventional endpoints in clinical trials for new therapeutic agents have proven, despite hundreds of studies, to be inadequate and have resulted in almost no new therapeutic agents approved for clinical use.
- The poor repeatability of most clinical diagnostic tests.
- Sensitivity and specificity data are contradictory and confusing in many published studies.
- Although inflammation has been shown to play an important role in the development of dry eye, many patients present no clinical evidence of inflammation.

New dry eye concepts
Addressing these issues has become easier with reference to the most recent data, which have given rise to new concepts focusing on the character of the disease, its development and severity, and which can lead to more effective disease management.

Tear film dynamics
The Lacrimal Functional Unit is in dynamic equilibrium in normal subjects through a finely integrated system that includes the eyelids, the ocular surface, the lacrimal and Meibomian glands and the naso-lacrimal ducts, which are connected through a neural network⁴. One of the most significant changes in the understanding of dry eye is the recognition that tear instability, absent in normal subjects, is a fundamental aspect of the condition. Lacrimal instability and hyperosmolarity are closely linked⁵. This awareness opens the door to new diagnostic and therapeutic developments.
Previously, it was thought that the mechanisms controlling the Lacrimal Functional Unit functioned unilaterally. Recent data have shown that in unilateral herpetic keratitis patients with reduced sensitivity and an unstable tear film, a reduction of the Schirmer test is also observed in the healthy contralateral eye⁶. This finding suggests a bilateral central nervous system input in tear dynamics. Dry eye bilaterality is denoted by the random distribution in both eyes of objective test results over time. Recent studies on tear osmolarity have demonstrated the bilateral effects of loss of tear film stability and have emphasised the need to test both eyes, noting the higher value, which is most representative of disease severity, and the variability between the two eyes, which provides a measure of tear instability and disease severity⁷. Both values play a key role in assessing the severity of dry eye.

Prevalence of dry eye
Although many dry-eye patients are menopausal or peri-menopausal women, there is growing evidence that with ageing both sexes are almost equally affected by dry eye.

Role of symptoms in dry eye
It was believed that in the case of dry eye, symptoms were always detectable². Recent studies, however, show that many patients with clear objective evidence of dry eye are asymptomatic⁸. Another population study showed that Meibomian Gland Dysfunction (MGD) is often prevalent in the older population and that more asymptomatic cases than symptomatic cases are present⁹. It is therefore not justified to diagnose dry eye on the basis of symptoms alone.

Relationship between signs and symptoms
Recent studies have shown that objective signs are not correlated with each other, particularly in the case of mild-to-moderate pathology, and that they do not necessarily correlate with symptoms¹⁰. This is thought to be due to the independent nature of the information these data provide on different disease manifestations at different stages of disease progression.
It was developed¹¹ and recently validated¹² a composite severity scale, using all commonly used diagnostic tests of equivalent weight. Tear osmolarity is the only test that has a linear relationship with disease severity across the entire disease spectrum¹¹.

Inflammation
While much attention has been given to the role of inflammation in the pathogenesis of dry eye, its exact place in the causal chain of events is unclear.
Inflammation leads to a vicious circle that is self-feeding each time it is repeated, leading to a vortex of increasing severity of the clinical expression of the disease¹³.
Systemic disorders of the immune system, such as Sjögren's syndrome and graft versus host disease, stimulate powerful inflammatory cells and cytokines that cause more extensive inflammation resulting in increased clinical expression of dry eye¹⁴.
Increased osmolarity of the tear film stimulates inflammation of the ocular surface through an alteration of immune epithelial receptors and APCs (Antigen-Presenting Cells), with subsequent recruitment of immunocompetent lymphocytes¹⁴.
Although many pro-inflammatory proteins are expressed in tears, there is no single chemical entity or combination of them that has been shown to be indicative of disease severity across the disease spectrum. Expression of HLA-DR, a manifestation of autoimmune processes in the cells of the conjunctival epithelium, has been shown to correlate with increased tear osmolarity in patients with systemic disease¹⁵.
Anti-inflammatory therapies (corticosteroids, cyclosporine, resolvine) can modulate the degree of inflammation in the dry eye and ameliorate the damaging effects of inflammation on the ocular surface.

Tear osmolarity
Over the past six years, more than 140 peer-reviewed articles on tear osmolarity have been published. With an ambulatory device for measuring electrical impedance using only a 50 nl sample taken from a tear strip at the margin, this technology allows for a quick and accurate measurement. It is important to test both eyes, use the higher value that is more representative of disease severity and note the difference between the eyes, which is a measure of tear instability present in dry eye patients but not in normal subjects⁷.
This technology has proven to be the best single measurement for dry eye diagnosis considering both subgroups of the disease⁷. The external examination of the eye and other tests will then serve to distinguish the sub-types.
Effective treatment results in a lowering of osmolarity and a reduction in variability between the two eyes.
Studies have shown that tear osmolarity responds to cyclosporine A after a 2-month treatment period with an improvement in symptoms that persists for 1-2 months¹⁰. This therapeutic effect was not observed with other objective tests, including Schirmer's test, Tear BreakUp Time, corneal or conjunctival staining.
This is an exciting time for advances in the understanding of dry eye that can be transferred to clinical practice, with earlier and more accurate diagnosis and management of the condition.
Our hope is that these advances will soon lead to a wider range of new treatment options.

Michael A. Lemp
E-mail: malemp@lempdc.com

Michael A. Lemp is Professor of Ophthalmology at Georgetown University and George Washington University and is one of the founders of the journal The Ocular Surface.
His main areas of research include dry eye, ocular surface, corneal and cataract surgery, contact lenses, laser correction and other techniques of refractive defects.

Bibliography
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