Introduction to Dry eyes and Sjogren's syndrome

[Mike Bartolatz]

The Ocular Surface in Rheumatoid Arthritis

Michael E. Stern, PhD · Robert Fox, MD, PhD

Introduction



SLIDE 1 In the United States, approximately 4 million people have Sjögren's syndrome, which is a systemic autoimmune disease that involves signature symptoms of dry eye (keratoconjunctivitis sicca [KCS]) and dry mouth.1 It has been determined that 20% of cases of Sjögren's syndrome are secondary to rheumatoid arthritis. Other autoimmune diseases including systemic lupus erythematosus are also known to induce dry eye.

Dry eyes are an extremely common problem in the general population and are a particular problem in patients with arthritis. When patients describe symptoms of grittiness and discomfort, they are actually describing the increased sense of friction as the upper eyelid moves over the conjunctiva and cornea. This friction becomes more severe as a result of an inadequate tear film. The irritated ocular surface has an appearance similar to a chronic wound. Therefore, a paradox exists in that patients complain about dry eyes while ophthalmologists talk about glands and rheumatologists measure blood tests. This is because an understanding of the symptoms and an approach to treatment depends on recognition that the dry eye syndrome is a result of functional/structural deficiency of a functional circuit (Slide 1). 2

It is important for a rheumatologist who is managing the care of this type of patient to understand what dry eye is and how it must be managed.



The Lacrimal Functional Unit

Normal Tear Secretion
KCS is not a disease of lack of tears but rather a disease of alterations in tear composition in all of the three major layers: the aqueous, the mucins, and the lipids. 3,4 In the normal individual, the tears secreted to the ocular surface function to eliminate bacteria and viruses, as well as to be supportive (trophic) to the ocular surface epithelium. These are referred to as "ocular surface supportive tears."

In the normal individual, tear secretion is engendered through subconscious stimulation of the ocular surface, giving rise to afferent nerve impulses through several branches of the trigeminal nerve (V). The ocular surface is heavily enervated by sensory nerves that travel directly to the central nervous system (afferent). In fact, the ocular surface is the most densely innervated organ in the body. These sensory nerves eventually end up in a specific region of the mid-brain called the lacrimatory nucleus. This section of the brain also receives neural input from higher cortical centers. Therefore, patients may experience ocular dryness as part of the aging process, which often is related to medication use (e.g., anticholinergic agents such as antidepressants, anti-muscle spasm medications, antihypertensives) and atypical depression syndromes such as fibromyalgia. After the net signal is integrated in the lacrimatory nucleus, a net signal is then sent back to the glands and the blood vessels must supply the water that ultimately will be pumped into the tear film.

These impulses travel to the central nervous system where they are integrated with cortical and other types of input. This results in secretomotor efferent action potentials through the facial nerve (VII) to the main and accessory lacrimal glands. This reflex including the ocular surface, lacrimal glands, and interconnecting innervation is referred to as the "lacrimal functional unit." This activity is maintained in a noninflammatory environment through the presence of systemic androgens. These steroid-like hormones suppress the initiation of inflammation even in the face of chronic stimulation of the lacrimal functional unit.5,6

The Etiology and Pathophysiology of Dry Eye

When the level of circulating androgens are suppressed below a presumed threshold as they are in aging (at the time of menopause) or due to a pathological event, this protective umbrella is compromised.7 Although this does not mean that an individual has KCS at this point, the environment for it to occur is now in place. When the lacrimal functional unit is chronically activated, such as in the case of ocular surface infection (viral or bacterial), persistent wind, low humidity, or allergy, a neurogenic inflammation can be initiated within the tear secreting cells of the lacrimal glands. This is disease initiation. A population of immunovigilant T cells, which migrates through the lacrimal glands in the normal situation, becomes activated and starts to secrete proinflammatory cytokines. These immune cells normally undergo programmed cell death (apoptosis) in the normal or noninflamed state. In an environment of inflammation, apoptosis is aborted and the activated T cells accumulate within the lacrimal gland.8 The large amount of synthesis and secretion of proinflammatory cytokines results in the ocular surface being bathed by pro-inflammatory tears.



SLIDE 2 The result of this process is an inflammation of the other end of the lacrimal functional unit - the ocular surface, particularly the conjunctiva (Slide 2). The homing and accumulation of T cells within the conjunctiva result in a chronic inflammation in the ocular surface that is believed to be the basis of patient symptoms.

As a result of the inadequate tear film, the ocular surface undergoes repeated trauma from the eyelid traversing the ocular surface, and an inflammation that involves the epithelial cells perpetuates the inflammatory process and symptoms of pain that return to the central nervous system. The specific mechanisms by which the arthritic process interferes with the lacrimal glands are complex but involve the partial destruction of the secretory glandular cells, the release of inflammatory mediators (cytokines, chemokines and growth factors), as well as the release of inflammatory enzymes that degrade the underlying architecture of the cell matrix (that is responsible for adequate glandular function).

Therapeutic Approach to KCS
Whether the disease etiology stems from systemic autoimmunity, such as in the case of Sjögren's syndrome or rheumatoid arthritis, or is a local immune event, such as in primary non-Sjögren's KCS, a common pathophysiology is seen.9 This commonality is manifest in the lymphocyte driven inflammation within the ocular surface.

Treatment of KCS requires a team approach. The ophthalmologist should examine the tear film to determine the extent of the wound reaction and the rheumatologist must measure blood tests that reflect the release of inflammatory lymphocyte hormones to adjust the therapy. The patient contributes to this team approach by carefully avoiding any environmental stresses to the tear film such as dry, windy areas or smoky rooms.

Treatment of KCS involves a two-pronged strategy. First, one must eliminate environmental irritants and decrease eyelid-induced shear forces on the ocular surface. This is accomplished with the use of artificial tears. Sufficient use of artificial tears with increased residence time on the ocular surface will allow epithelial healing. Many patients report at least partial diminishing of symptoms with this treatment. In patients with mild KCS, this will result in some resolution of underlying inflammation. The second approach to therapy requires that the underlying immune-cell based inflammation be controlled. This can be accomplished with the use of topical steroids; however, this must be done with care due to the well-known side effect profile of this class of compound which includes increased intraocular pressure, cataracts, and delayed wound healing. Topical cyclosporine A has been used with success in that this compound has three mechanisms of action related to this disease. First, it prevents T cells from activating and inducing inflammation. Secondly, it acts as an anti-inflammatory, and, thirdly, it prevents apoptosis in lacrimal gland tear-secreting cells.

The magnitude of the problem of dry eyes is reflected by a visit to any grocery store where the shelf space devoted to artificial tears is extensive. It is estimated that 3% of the adult population has arthritis and 20% of rheumatoid arthritis patients have dry eye. Due to problems arthritics have with their hands, the ease of application of artificial tears with any frequency is critical. New therapies would be beneficial to patients to improve their ability to work in an air-conditioned, low humidity environment. The use of artificial tears is essential to prevent complications such as corneal abrasions. Rheumatologists have become the primary care providers for many arthritis patients in order to deal with chronic ocular problems. It becomes necessary for the ophthalmologist and rheumatologist to work together to provide educational materials to help their patients identify symptoms and optimize treatment.



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