Aqueous Deficiency Dry Eye Syndrome

Pathophysiology

Any lacrimal acinar destruction or dysfunction can lead to tear hyperosmolarity and ultimately symptoms and signs of dry eye disease. Dryness results because of a diminished aqueous tear pool despite normal rates of tear evaporation. When the tear film is hyperosmolar, the ocular surface epithelial cells also become hyperosmolar. A cascade of inflammatory events then leads to the formation of inflammatory cytokines, including interleukin 1-α, interleukin-1-β, tumor necrosis factor α, and matrix metalloproteinases (MMPs), including MMP-9. These inflammatory markers are present in the tear film regardless of whether ocular inflammation is coming from the lacrimal gland or from the conjunctiva itself.

Classically, it has been taught that the tear film has three distinct layers: mucous, aqueous, and lipid. This concept has been revised per the Tear Film and Ocular Surface Society Dry Eye Workshop (TFOS DEWS II). The Tear Film Subcommittee now recommends a two-phase model of the tear film. This model is composed of a lipid layer overlying a muco-aqueous phase. The lipid component interacts with the underlying mucin and aqueous components to diminish loss via evaporation and contribute to a more stable tear film between blinks. The largest component of tears is the aqueous component, which comes from the primary and accessory lacrimal glands. The lacrimal glands produce about 0.2 mL of tears in 24 hours. The aqueous component serves as a physical barrier and source of nutrients for the underlying cornea and conjunctiva.

Lacrimal aqueous secretions are derived from the serous secreting acini and mucous secreting acini. Serous cells secrete salts, including sodium, potassium, chloride, and calcium, and proteins (an estimated 200–300 different type of polypeptides in humans). The specific protein content of lacrimal secretions varies depending on the stimulatory input the gland receives. The electrolyte salts create an osmotic force that pulls water from the lacrimal gland to form the majority of the tear volume. Mucous secreting acini secrete soluble mucins such as Muc7. Immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies are secreted by plasma and epithelial cells within the lacrimal gland. At this time, it is uncertain whether there is reduced or increased evaporation in aqueous deficiency dry eye disease.

Aqueous tear production is largely due to a reflex by subconscious stimulation of the ocular surface and nasal mucosa. This stimulation causes a sensory afferent signal from the conjunctiva and cornea that via the trigeminal nerve travels to the central nervous system in the superior salivary nucleus in the pons. Efferent parasympathetic fibers in the facial nerve then pass in the nervus intermedius to the pterygopalatine ganglion. Postganglionic parasympathetic fibers then arise and terminate in the main and accessory lacrimal glands, conjunctival goblet cells, and meibomian glands to stimulate tear production and secretion in response to efferent signals.

Aqueous tear deficiency dry eye has two major subclasses: Sjögren syndrome dry eye (SSDE) and non-Sjögren syndrome dry eye (NSSDE).

Sjögren Syndrome Dry Eye

Sjögren syndrome is an autoimmune exocrinopathy characterized by lymphocytic infiltration of secretory glands. In the Western world, Sjögren syndrome is the most common cause of inflammatory infiltration of the lacrimal gland. When the eyes are involved, activated T-cells infiltrate the lacrimal gland, leading to acinar and ductal cell death and hyposecretion of tears. The same process can occur in the salivary gland leading to diminished saliva secretion. Once the inflammatory cascade is activated, autoantigens are expressed at the surface of epithelial cells, including autoantigens fodrin, Ro, and La. Tissue specific CD4 and CD8 cells are retained. A reversible neurosecretory block leads to hyposecretion. Locally released inflammatory cytokines and circulating antibodies, including anti-M3 antibody, are directed against muscarinic receptors within the lacrimal gland.

The exact pathogenesis of Sjögren syndrome is not completely understood but is likely multifactorial and involving both T-cells and B-cells. While the exact triggers leading to their activation are not known, risk factors include genetics, androgen status, and exposure to environmental agents. Genetically, HLA-DQ1 and HLA-DQ2 are associated with increased risk of development of Sjögren syndrome. Low androgen status factors an inflammatory environment within target tissues. Environmental pollution and virus exposure, specifically infections with lacrimal gland tropism, are also believed to be risk factors for the development of Sjögren syndrome. Nutritional deficiency of ω-3 and other unsaturated fatty acids has also been reported in patients with Sjögren syndrome. Environmental factors leading to increased evaporative loss, including low humidity, high wind velocity, and increased ocular surface exposure, also can invoke inflammation on the ocular surface and lead to an exacerbation of ADDE related symptoms.

There are two forms of Sjögren syndrome: primary and secondary Sjögren syndrome. An internationally accepted classification system has been created due to European and American collaboration to further characterize each form of Sjögren syndrome. The American-European consensus group (AECG) classification includes both subjective symptoms and objective signs to characterize primary Sjögren syndrome. Primary Sjögren syndrome (pSS) refers to aqueous deficiency dry eye disease combined with dry mouth in the presence of autoantibodies. Evidence of reduced salivary secretion and a positive focus score on minor salivary gland biopsy are also classification criteria. There is no standard clinical presentation for primary Sjögren syndrome. The symptoms of primary Sjögren syndrome can be divided into three groups: sicca syndrome, general symptoms, and systemic manifestations. Sicca syndrome is a combination of xerophthalmia (dryness of mouth), xerostomia (dryness of oral cavity), and/or pharynx or larynx dryness. Vaginal dryness can also be present in female patients. These symptoms are part of the AECG classification criteria for primary Sjögren syndrome and occur in greater than 95% of patients. Patients with sicca syndrome experience a higher rate of depression and decreased quality of life compared with patients without sicca syndrome according to the SF-36 depression scale.

The most common general symptom of primary Sjögren syndrome is fatigue, which is present in 70%–80% of patients with pSS. Chronic pain, fibromyalgia, polyarthralgia, depression, and anxiety are also common general symptoms of pSS. About 71% of patients with primary Sjögren syndrome also have extraglandular manifestations. Of these, lymphoma has the highest risk of mortality, with mucosa-associated lymphoid tissue (MALT) lymphoma being the most common subtype, often presenting in the parotid glands. A large cohort study demonstrated a fivefold higher relative risk of lymphoma in pSS patients, with a lifetime risk of approximately 10% of developing lymphoma. Arthritis, involving most commonly the proximal interphalangeal and metacarpal-phalangeal joints, and interstitial lung disease are also commonly associated with patients with primary Sjögren syndrome. Renal failure also occurs in approximately 24% of patients with pSS; therefore glomerular filtration rate monitoring is essential in these patients.

The diagnosis of pSS is based on AECG classification criteria ( Table 32.1 ). Treatment of primary Sjögren syndrome requires a multidisciplinary team, including a clinical immunologist or rheumatologist, an ophthalmologist, and a dentist. Depending on the patient’s predominant symptoms, their treatment regimen can be tailored to include both local and systemic therapies. Treatment of xerophthalmia related to pSS will be discussed later in this chapter. Ocular surface staining via lissamine green and fluorescein are valuable clinical tests to assess ocular surface health. A low Schirmer and ocular surface staining highly correlate with positive Sjögren serology and a positive lacrimal gland biopsy. Caffery et al. demonstrated that rose Bengal staining of the temporal conjunctival is the most important sign in distinguishing pSS from non-SS dry eye disease.

Secondary Sjögren syndrome consists of the features of primary Sjögren syndrome with the features of over autoimmune connective diseases. Rheumatoid arthritis is the most common accompanying disease, with secondary Sjögren syndrome estimated to be present in 20% of patients with rheumatoid arthritis. Systemic lupus erythematosus, polyarteritis nodosa, granulomatosis with polyangiitis, systemic sclerosis, primary biliary sclerosis, and mixed connective tissue disease are other autoimmune processes commonly associated with secondary Sjögren syndrome.

Secondary Lacrimal Gland Deficiencies