New thinking in dry eye disease

Pubblicato il

lunedì, 15 Dicembre 2014

Argomento

Dry Eye

Read the interview of Prof. Michael A. Lemp.

Introduction
The field of Dry Eye Disease (DED) research has been very active over the last few decades and the pace has quickened particularly in the last few years. In 2007 the international summation of the state of the field was the Dry Eye Workshop Report (DEWS)¹. While this universally accepted document presented an accurate picture of a consensus as to how the disease was viewed by experts in 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 initiation and progression of the disease process, identifying its essential components, judging severity, designing clinical trials to assess new treatments and confounding variables such as the lack of correlation between objective signs of disease and symptoms.
Over the past five years there has been a considerable literature developed in these areas of research. The two most investigated topics in DED have been inflammation and tear osmolarity. Newer findings have shed much light on the pathophysiology of DED, the relationship between clinical signs and symptoms, newer disease markers, and the development of disease. These findings, which will be summarized here, have led to new fundamental concepts in understanding DED.

Contemporary problems in Dry Eye Disease
This very common condition which affects up to 20% of the population in Europe, North America, and Asia, leads to significant burdens on patients and the societies in which they live^2,3. Principal challenges to a better understanding of this disease include:
– There is a poor correlation between objective signs of disease and patient reported symptoms.
– There are frequently disagreements between objective signs of disease particularly in the early stage of disease.
– Conventional endpoints in clinical trials for new therapeutic agents have proven inadequate resulting in almost no new therapeutic agents approved for clinical use despite hundreds of studies.
– There is poor repeatability in most clinical tests for diagnosis.
– Sensitivity and specificity data is contradictory and confusing in many papers.
– While inflammation has been shown to play an important role in the development of DED, many patients exhibit no clinical evidence of inflammation.

Newer concepts in Dry Eye Disease
Addressing these issues has become easier relying on newer data which have given rise to newer concepts which shed considerable light on the character of the disease, its development and severity and may lead the way to more effective management of the disease.

Tear Film Dynamics
The Lacrimal Functional Unit (LFU) is in a dynamic equilibrium in normal subjects with a finely integrated system involving the lids, ocular surface, lacrimal and meibomian glands and the naso-lacrimal ducts which are linked via a neural network⁴. One of the most important shifts in understanding DED is the recognition that tear instability is a fundamental feature of DED not seen in normals. Tear instability and tear hyperosmolarity are closely linked⁵. This knowledge opens the doors to new diagnostics and therapeutics.
The mechanisms which control the LFU have been thought to operate unilaterally. Recent findings in patients with unilateral herpetic keratitis with decreased sensation and an unstable tear film have been shown to have a decrease in Schirmer test in the contralateral unaffected eye⁶. This suggests a bilateral central nervous system input into tear dynamics. The bilaterality of DED is seen in the random distribution of objective test values over time in both eyes. Recent studies of tear osmolarity have demonstrated the bilateral effects of loss of tear film stability and emphasizes the necessity to test both eyes, noting the higher value which is more indicative of the disease severity and the inter-eye variability which is a measure of tear instability and disease severity⁷. Both values are key to assessing severity of DED.

Prevalence of DED
While many of those afflicted with DED are females in the menopausal and peri-menopausal age groups, increasingly it is being recognized that with further aging both sexes are almost equally affected by DED.

Role of Symptoms in DED
It has been thought that DED is a symptom-driven disease². Recent studies, however show that many patients with clear objective evidence of DED are asymptomatic⁸. Another population-based study showed that MGD is quite prevalent in an older population and there are more cases without symptoms that those with symptoms⁹. So diagnosing DED on the basis of symptoms alone is unwarranted.

Relationship among Signs and with Symptoms
Recent studies have documented that objective signs do not correlate well with each other, particularly in mild-moderate disease and nor do they correlate well with symptoms¹⁰. This is thought to be due to the independent nature of the information they provide about different manifestations of the disease at different timepoints in disease progression.
A composite severity scale using all commonly used diagnostic tests, equally weighted has been developed¹¹ and recently validated¹². Tear osmolarity is the only single test which has a linear relationship to disease severity over the entire spectrum of disease¹¹.

Inflammation
While a great deal of attention has been given to the role of inflammation in the pathogenesis of DED, its exact place in the causal chain of events is unclear.
Inflammation leads to a vicious cycle that reinforces itself with each repetition, leading to a vortex of increasing severity of clinical expression of disease¹³.
Systemic immune disorders, such as Sjögren syndrome and graft v. host disease stimulate potent inflammatory cells and cytokines that provoke more extensive inflammation that results in greater clinical expression of DED¹⁴.
Increased osmolarity of the tear film stimulates inflammation of the ocular surface through alteration of epithelial immune receptors and APCs, with subsequent recruitment of immunocompetent lymphocytes¹⁴.
Although many proinflammatory proteins are expressed in tears, there is no singular chemical entity or combination of them that has been shown to indicate disease severity over the entire range of disease. HLA-DR expression, a manifestation of auto-immune processes in conjunctival epithelial cells, has been shown to correlate with increased tear osmolarity in patients with systemic disease¹⁵.
Anti-inflammatory therapies (corticosteroids, cyclosporine, resolvins) can modulate the degree of inflammation in DED and ameliorate the damaging effects of the inflammation on the ocular surface.

Tear Osmolarity
Over 140 peer-reviewed articles on tear osmolarity have been published in the last six years. Using an office based electrical impedance device using only a 50nl sample from the marginal tear strip, this technology allows for rapid, accurate measurement. It is important to test both eyes, use the higher figure which is more indicative of disease severity and note the inter-eye difference which is a measure of tear instability present in patients with DED but not normal⁷.
This technology has been shown to be the best single metric for the diagnosis of DED including both subtypes of disease⁷. Examination of the external eye and other tests will distinguish between the subtypes.
Effective treatment results in lowering of the osmolarity and a decrease in inter-eye variability. Studies have shown that tear osmolarity responds to cyclosporine A over a 2 month period of treatment with symptom improvement lagging by 1-2 months¹⁰. This therapeutic effect was not seen in other objective tests including Schirmer, tear breakup time, corneal or conjunctival staining.
This is an exciting time for new advances in understanding DED which can be transferred into clinical practice with earlier more accurate diagnosis and management. It is hoped these advances will lead to a wider variety of new therapeutic options soon.

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

Michael A. Lemp, MD, is a clinical professor of ophthalmology at Georgetown University and George Washington University and is founding editor of The Ocular Surface. His major areas of research interest include dry eye, the ocular surface, corneal and cataract surgery, contact lenses, and laser and other forms of refractive correction of vision.

References
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2. The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5(2):93-107.
3. Pflugfelder SC. Prevalence, burden, and pharmacoeconomics of dry eye disease. Am J Manag Care. 2008 Apr;14(3 Suppl):S102-6.
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14. Pflugfelder SC, Corrales RM, de Paiva CS. T helper cytokines in dry eye disease. Exp Eye Res. 2013 Sep 4. pii: S0014-4835(13)00252-2.d10.1016/j.exer.2013.08.013.
15. Versura P, Profazio V, Schiavi C, Campos EC. Hyperosmolar stress upregulates HLA-DR expression in human conjunctival epithelium in dry eye patients and in vitro models. Invest Ophthalmol Vis Sci 2011;52(8):5488-96.