Holistic Management of Chronic Dry Eye and Inflammation

While the signs and symptoms of DED for any given patient may only be brought to the attention of the ECP periodically, the chronic nature of the condition must be appreciated to provide optimal management. Indeed, most patients with DED have a chronic condition.³ As Lyndon Ferguson and Andrew Bowden write, from a management standpoint, it is most practical to consider all cases of DED to be of a chronic and progressive nature with episodic rather than continuous signs and symptoms.³

A common broad approach can be applied to managing most chronic DED cases. This approach aims to address the fundamental elements of DED, outlined in the DEWS II definition,4 by restoring tear film stability, reducing tear film osmolarity, and breaking the vicious cycle of ocular surface inflammation.

Put simply, the two primary aims of managing chronic DED are to:

1. Improve stability of the tear film, and
2. Reduce ocular surface inflammation.

As eye care practitioners it is easy to focus on the tear film, however the significance of reducing inflammation cannot be overstated. Of course, improving tear film stability and reducing osmolarity will create a virtuous cycle and help reduce ocular surface inflammation. ECPs can also offer patients anti-inflammatory treatments that directly target ocular surface inflammation.

Patients usually provide the first indication of the presence of DED by describing symptoms. Some may express concern about clinical signs, such as redness, but most patients presenting with DED describe the way their eyes feel, using descriptive terms like ‘irritated’, ‘gritty’ or ‘sore’. Furthermore, patients with DED will judge the success (or otherwise) of a management regimen based primarily on an improvement in symptoms. Patient symptoms in DED are primarily driven by ocular surface inflammation. Therefore, if we aim to make our patients feel better, it is useful for ECPs to understand the mechanisms responsible for ocular surface inflammation in DED and the management options available to reduce it.

WHY IS THE EYE DRY?

As is eloquently stated in the DEWS II report, dry eye refers to a ‘loss of homeostasis of the tear film’.4 Much has been written about the myriad of diagnostic techniques that can be used for assessing and categorising DED based on quantifiable properties of the tear film.5 For practical purposes, DED is often categorised as either aqueous deficient dry eye (ADDE) where insufficient tear volume exists, or evaporative dry eye (EDE), where tear volume is normal yet tear film stability between blinks is poor. Many patients with chronic DED may have tear film properties that are characteristic of both aqueous deficient and evaporative DED. The TFOS DEWS II report describes this as the ‘aqueous/evaporative spectrum’. Understanding where a chronic DED patient falls along this spectrum will aid in directing the management plan.

Diagnostic methodology is common for all DED, including chronic DED. While a myriad of clinical procedures may be applied in practice, diagnosis can be simplified into three steps:

1. Assessment of patient history and symptoms,
2. Assessment of tear film quality, and
3. Assessment of tear volume.

A list and description of the clinical procedures used to make these assessments is described in the DEWS II diagnostic methodology report.⁵

Taking a thorough history is essential to identify modifiable risk factors, to appreciate the timeline of the disease and the frequency of flares, to determine any current or previous exacerbating factors (‘triggers’), and to appreciate the impact on the patient’s quality of life. Asking the patient to complete a standardised questionnaire; e.g., an ocular surface disease index (OSDI) or dry eye questionnaire (DEQ-5), is a valuable way to establish a baseline and monitor symptoms.

A full list of risk factors relating to DED is beyond the scope of this article. However, when considering chronic DED, any associated chronic comorbidities should receive attention. Common conditions associated with an increased risk of DED include diabetes, thyroid disfunction, autoimmune disease, sleep disorders, and depression. Additionally, prescription medications may increase the risk of a patient developing DED. Many of these, such as beta-blockers, antihistamines, tricyclic antidepressants, and hormone replacement therapy, have a high prevalence in the population. Patients with dry eye disease and systemic comorbidities have been shown to display significantly greater signs of ocular surface inflammation than those without systemic ailments.⁶ The DEWS II report provides a full list of comorbidities known to be associated with DED, along with medications associated with DED and the strength of evidence supporting these associations.⁷ Of course, in many cases comorbidities and medications are not modifiable but should nonetheless be considered when devising a management strategy.

A history of contact lens wear and/or ophthalmic surgery will also increase the risk of chronic DED. DED is four times more likely in contact lens wearers than those who don’t use contact lenses.^1,8 Many ECPs will be familiar with the associated risk of DED following corneal refractive surgery,⁷ but may be surprised to learn that the prevalence of DED also increases significantly following cataract surgery,⁹ vitreoretinal surgery,¹⁰ and blepharoplasty.¹¹

Once a patient’s position on the aqueous deficient/evaporative spectrum has been established, modifiable risk factors have been addressed, and non-modifiable risk factors have been identified, the ECP is in a position to address the cause of the patient’s symptoms – inflammation.

To gain a better understanding of inflammation, it is worth taking time to consider the immune processes driving this inflammation at the ocular surface.

IMMUNITY AND THE OCULAR SURFACE

The action of the human immune systems can be divided into two categories – innate immunity and adaptive immunity. Under normal physiological conditions, insult to the ocular surface results in an innate immune response that leads only to limited tissue damage and a relatively prompt return to homeostasis. However, in the case of chronic DED, hyperosmolarity and stressed epithelial cells initiate an innate immune response that can lead to a self-sustaining, ‘vicious cycle’ of inflammation of the ocular surface.¹²

In DED, the innate immune response is initially triggered by tear film hyperosmolarity, tear film instability, and epithelial desiccation.¹³ Corneal epithelial cells respond directly to hyperosmotic stress by producing matrix metalloproteinases (MMPs) and other inflammatory mediators such as chemokines, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1, IL-6, and IL-8.^12,13 This results in the activation of sensory nerves, leading to patient discomfort.¹⁴

Key cells in the innate immune response at the ocular surface are the antigen presenting cells (APCs) such as monocytes, macrophages, and conventional dendritic cells. The presence of proinflammatory mediators, released by corneal epithelium in response to hyperosmotic stress, leads to the activation and maturation of these APCs.

Put simply, the adaptive immune response leads to the generation and recruitment of effector T cells.¹⁵ Once activated by the innate immune response, mature APCs (mAPCs) adhere to lymphatic endothelium, a process which is mediated by the interaction of lymphocyte function antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1). mAPCs then enter the afferent lymphatics via transendothelial migration, and through chemotaxis migrate to the lymph node. (Chemotaxis is the directed migration of cells in response to concentration gradients of extracellular signals. In ocular lymphatics, this process is facilitated by chemokine receptor 7 (CCR7). Within the lymph node, mAPCs are presented to naive T cells (T₀), stimulating T₀ cell differentiation into effector T-cell subsets (Th ₁, Th ₂, Th ₁₇, T_reg).¹⁶ Effector T cells then migrate to the ocular surface via efferent blood vessels and transendothelial migration, which is again mediated by LFA-1:ICAM-1. T_h 1 and T_h 17 are the primary lymphocyte cells involved in ocular surface damage and inflammation in chronic DED.17 These activated T cells migrate to the ocular surface epithelium, leading to epithelial damage and tear film dysfunction,¹⁸ and the process begins again. Hence, the ‘vicious cycle of inflammation’ in chronic DED.

In addition to causing further epithelial damage, activated T_h 1 and T_h 17 cells secrete the proinflammatory cytokines, interferon gamma (IFN-g) and interleukin-17 (IL-17), that amplify the inflammatory response. IFN-g promotes conjunctival goblet cell loss and epithelial cell apoptosis.¹⁹ IL-17 upregulates the production of MMPs by corneal epithelial cells.²⁰

MEIBOMIAN GLAND DYSFUNCTION AND INFLAMMATION

Under normal conditions, healthy meibomian glands express meibum with each blink, allowing a lipid layer to form across the tear film that maintains the integrity to the tear film between blinks and prevents desiccation of the ocular surface epithelium.²¹ In meibomian gland dysfunction (MGD), excessive meibum secretions contaminate the epithelial glycocalyx, leading to poor wettability, while inadequate secretions result in increased tear evaporation. While MGD is recognised as the primary cause of evaporative dry eye,²² the report by the International Workshop on Meibomian Gland Dysfunction noted that published estimates of patients with concomitant aqueous deficient DED and MGD varied from 50% to 75%.²³

When chronic DED results in a selfperpetuating cycle of inflammation, the presence of inflammatory cytokines induces the expression of cornified envelope precursors by the ocular surface epithelium. This results in the keratinisation of meibomian gland orifices and MGD.²⁴ As ECPs we must, therefore, appreciate that MGD can be both the cause and the result of chronic DED.²⁵ In chronic DED, while either ocular surface inflammation or MGD may be the trigger, the recruitment of the other results in the co-occurrence of the two processes, a scenario that Baudouin et al. described as ‘the double vicious cycle’. ²⁵

MANAGEMENT

The DEWS II management and therapy report provides a detailed summary of management options for DED.²⁶ The report recommends staged management, with interventions and strategies grouped into stages one through four. While the authors state that the staged management algorithm is not meant to represent a rigid stepwise approach, it does progress from low risk, commonly available therapies such as topical lubricants and eyelid hygiene, to more specialised and/or invasive treatments.

Topical immunosuppressive or immunomodulatory drugs are placed in stage two of the DEWS II management algorithm.²⁶ Commercial formulations of both ciclosporin and lifitegrast are available in Australia and can be prescribed by therapeutic endorsed optometrists. Both drugs suppress the ocular surface immune response. Ciclosporin is a calcinernin inhibitor, which acts within the cytoplasm of T cells, reducing the production of inflammatory cytokines and diminishing the inflammatory effect of the effector T cells.²⁷ Lifitegrast is an integrin antagonist that acts to inhibit the binding of LFA-1 and ICAM-1, thereby inhibiting the migration of APCs and T cells through the lymphatic pathway and diminishing inflammation.²⁸

Intense pulsed light (IPL) therapy is also found in stage two of the DEWS II management algorithm.²⁶ IPL has been shown to be effective at reducing the signs and symptoms of DED.^29,30 While the mechanisms of action of IPL are still the subject of debate, there is evidence that IPL therapy upregulates anti-inflammatory cytokines and down-regulates pro-inflammatory cytokines.³¹ IPL decreases the concentration of MMPs in skin fibroblasts,³² and it has been proposed that it may have the same action on corneal epithelial cells. Treatments that clear meibomian gland obstruction, such as lipiflow thermal pulsation, or manual gland warming and expression, will also have a positive effect on establishing normal physiological function and therefore, will assist in reducing inflammation in the short and long term.³³

Patient education also plays a critical role in the management of chronic DED. Patients need to be made aware of the chronic nature of the disease and of reasonable time frames for the improvement of signs, and in particular symptoms. Many patients present with ocular surface inflammation and MGD that has persisted for years or decades, making it unrealistic to expect resolution after a few days or weeks. Improvement of symptoms may take many months, and full resolution of symptoms may never be achieved. However, by understanding the vicious cycle of inflammation at the ocular surface, and taking steps to break or slow this cycle, we can offer our patients an improved quality of life.

Lyndon Ferguson MSc BApp.Sci (Optom) DipTp (IP) is an optometrist with a special interest in dry eye and ocular surface disease. He completed research on dry eye disease as part of his postgraduate studies. He practises at Envision Optical on the Gold Coast, Queensland.

Andrew Bowden B App.Sci (Optom) (Hons) GCOT CO CACL (ACO) is a graduate of Queensland University of Technology with a special interest in dry eye diagnosis and management. He practises at his own private two location group, Envision Optical on the Gold Coast. He has performed IPL for dry eyes since 2015 and was recently elected Vice President and Treasurer of the newly established Dry Eye Society.

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