**2.1 Classification**

The DED classification is based on its pathophysiology, acuodeficiency dry eye (ADDE), and evaporative dry eye (EDE). The limit in these categories is extremely diffuse [6]. The Sjogren's syndrome–related ADDE is a secondary phenomenon to immune-mediated exocrinopathy affecting the lacrimal and salivary glands [6]. Findings include decreased tear flow, staining of the ocular surface of injured tissue with vital dyes, and increased tear osmolarity. Meibomian gland dysfunction is also common in SS patients, with a resulting increase in tear evaporation, exacerbating decreased tear production [7, 8].

ADDE not associated with Sjogren's syndrome may be due to primary or secondary deficiency of the lacrimal gland, obstruction of the ducts of the lacrimal gland, and reflex hyposecretion [6]. EDE is due to an excessive loss of water from the exposed ocular surface, in the presence of a normal secretory function, the causes can be extrinsic due to harmful exposure of the ocular surface or intrinsic affecting internal structures or dynamics of the eyelid, may be due to causes related to the eyelid (e.g., Meibomian gland dysfunction [MGD] or decreased blinking) [6].

## **2.2 Pathophysiology**

Tear hyperosmolarity stimulates a cascade of events in ocular surface epithelial cells involving the signaling pathways of MAP and NFkB kinases and the generation of inflammatory cytokines (interleukin 1 [IL-1α; IL-1β]; tumor necrosis factor α [TNFα]) and proteases, such as MMP-9. This stimulates and readies inflammatory cells on the ocular surface, which become a reservoir for inflammatory mediators. These mediators, in an environment of tear hyperosmolarity, cause a decrease in the expression of mucin in the glycocalyx, the apoptotic death of the superficial epithelial cells, and the loss of goblet cells. However, hyperosmolarity also causes corneal epithelial cell death through nonapoptotic processes. Goblet cell loss is a feature of all types of DED, which is reflected in the reduction of tear levels of MUC5AC. The alteration of mucin expression in the glycocalyx is probably one of the reasons why ocular surface staining occurs in DED and, since it affects the ocular surface wetting, leads to an early

*Current Diagnostic Tests for Dry Eye Disease in Sjögren's Syndrome DOI: http://dx.doi.org/10.5772/intechopen.103671*

breakdown of the film tear. This amplifies or triggers hyperosmolarity on the ocular surface, with which the vicious circle is closed and the mechanism that perpetuates the disease is established [6]. In ADDE, tear hyperosmolarity occurs when tear secretion is reduced due to lack of production, under normal conditions of evaporation from the eye. In EDE, tear hyperosmolarity is caused by excessive evaporation of the tear film with a normally functioning tear gland [6].

## **2.3 Eye manifestations**

Patients with dry eye present with eye irritation, foreign body sensation, burning, tearing, photophobia, stinging, or sharp intermittent pain. They may also complain of blurred vision that improves with blinking or the instillation of artificial tears; and they may have all, some, or none of these symptoms. A well-conducted medical history contributes greatly to a correct diagnosis and guides a more focused slit lamp examination; therefore, a thorough slit lamp examination should be performed prior to performing any other tests, which may alter or mask relevant examination data, resulting in a misdiagnosis. Signs of dry eye identified on slit lamp examination include superficial corneal erosions, inadequate tear lake volume, early tear film breakdown time, conjunctival hyperemia, conjunctival surface irregularities, and meibomian gland dysfunction [7].

## **2.4 Diagnosis of DED**

The evaluation of the tear function is carried out by means of different tests that translate into the presence or absence of DED; however, there is no gold standard for the diagnosis of dry eye disease; therefore, they must frequently be associated with each other for a reliable diagnosis; The most used in the basic ophthalmology office are mentioned in order to compare them with the new technologies for the diagnosis of dry eye and the sequence of how they should be applied; according to diagnosis report methodology subcommittee of the international dry eye workshop (2007) [8]. This is summarized in **Table 1**.

## **2.5 Current methods of diagnosis**

Symptoms and signs found during history and slit lamp examination may suggest dry eye due to water deficiency, evaporation, or both. Additional tests should be performed because the ophthalmologist may be the one who detects SS in a patient with no previous medical history or who debuts with ocular symptoms. Therefore,


**Table 1.** *Test sequence basic.*

**Figure 1.** *Sequence of evaluations and tests in dry eye.*

the choice of complementary diagnostic methods plays a very important role in the diagnosis, in the same way the sequence to carry out the tests and its correctly applied methodology will be a key point for a successful diagnosis, preventing the tests from overlapping and reporting false negatives or positives [9]. The suggested sequence of evaluations and tests is shown in **Figure 1**.

## *2.5.1 Symptom questionnaire*

The ocular surface disease index (OSDI) was developed to provide a rapid assessment of the symptoms of eye irritation caused by dry eye disease and its impact on vision-related functioning. It is a 12-item questionnaire to evaluate ocular symptoms, functional limitations, and environmental factors related to the environment. Each item has five categories with three subscales with their own type of question; emphasis is placed on symptoms such as photophobia, grit, eye pain, blurred vision, in a period of 2–4 weeks before the visit. The OSDI is a self-administered questionnaire, it contains 12 items to evaluate the symptoms of the ocular surface; that implies little burden and little time for the patient. The OSDI has an overall score and three subscale scores: (A) ocular symptoms [three items], (B) vision-related function [six items], and (C) environmental triggers [three items]. Each OSDI item is scored on a Likert-type scale ranging from 0 to 4 points, where 0 indicates none of the time and 4 all of the time.

The total OSDI score was then calculated based on the following formula; OSDI = [(Sum of the scores of all answered questions) × 100]/[(Total number of answered questions) × 4].

Overall and subscale OSDI scores range from 0 to 100. Based on their OSDI scores, patients can be classified as normal (0–12 points) or mild (13–22 points), moderate (23–32 points) or severe ocular surface disease (33–100 points) [10]. The reliability indices of the OSDI recently reported indicate that it is adequate, the Pearson correlation was higher than 0.8, and the ICC range was from 0.827 to 0.982; In addition, it was evaluated that it has a parallel reliability between the written and web versions [11].

## *2.5.2 Tear osmolarity*

Tear osmolarity in normal subject ranges from 308 to 312 mOsm/l [12]. In individuals with DED associated with SS, osmolarity is significantly higher than in subjects with DED not associated with SS and even more than in healthy controls [13]. Also some studies have shown positive correlations between tear osmolarity and

## *Current Diagnostic Tests for Dry Eye Disease in Sjögren's Syndrome DOI: http://dx.doi.org/10.5772/intechopen.103671*

disease activity in patients with SS [14]. Dry eye can be due to both increased evaporation, deficiency in its production, and alteration of the composition, in all cases the pathophysiological sequence culminates with an increase in the osmolarity of the tear film (hyperosmolarity) [15].

The evaporation of a smaller volume for the same surface increases osmolarity during the first 24 h from the beginning of the volumetric decrease [16]. Hyperosmolarity causes epithelial damage directly as it causes cell desquamation, complete disappearance of the superficial epithelial cell layers, decrease in cytoplasmic density, and accumulation of rows of mucus product of osmotically altered goblet cells. This phenomenon is generally evident between 15 and 30 days after the osmolar change of the tear film [17]. The epithelium of the cornea and conjunctiva must be completely moistened for complete wettability; the ocular surface conditions warrant that the surface tension of the aqueous layer at the interface with the epithelium is lower than the surface tension of the epithelium that is exposed to the medium [18]. In the mucous layer, mucopolysaccharides are directly responsible for maintaining surface tension stability. Under hyperosmolar conditions, there is accumulation of mucus and destruction of mucin-secreting cells, which causes an increase in surface tension with the consequent decrease in the wettability of the corneoconjunctival epithelium. The principle of osmosis is characterized by the flow of a solvent through a semipermeable membrane, which is generated when there is a difference in concentrations on one side of the membrane; this movement tends to equalize the solute concentrations on both sides, and there the flow stops. The corneoconjunctival epithelium and the mucous layer are a semipermeable barrier on the ocular surface, by increasing osmolarity in the aqueous layer; the aqueous gradient through the water protein channels present in the stroma and toward the aqueous humor; they change in the opposite direction. This directional fluid change produced by hyperosmolarity can cause dehydration of Sulfated Glycosaminoglycan (GAGS) that occupies the spaces between the collagen fibers of the stroma [19, 20]. When these glycoprotein structures are dehydrated, the correct water balance of the stroma will be affected, which will affect the normal maintenance of corneal transparency [21].

The osmolarity of the tear film in dry eye triggers inflammation, immunological processes, and the presence of autoantigens that enhance the inflammatory process. As an example of this, inflammatory markers such as NF-Kβ that migrates from the nucleus to the cytoplasm in the inflammatory process are directly related to the phenomenon of hyperosmolarity of the tear film. Nuclear translocation of NF-Kβ has been shown to be directly proportional to increased tear film osmolarity [22].

Hyperosmolarity is so important in the pathophysiology of dry eye disease that increased osmolarity of the tear film has been suggested to induce functional and structural damage to the corneal nerves and neurotoxicity [23].

The TFOS Dry Eye Workshop II (DEWS II) subcommittee report concluded: "Tear hyperosmolarity is considered to be the trigger for a cascade of signaling events within surface epithelial cells, leading to the release of inflammatory mediators and proteases. These mediators and tear hyperosmolarity cause the loss of goblet cells, epithelial cells and damage to the epithelial glycocalyx. The inflammatory mediators of activated T cells, recruited on the ocular surface, reinforce the damage; resulting in punctiform epitheliopathy characteristic of DED and tear film instability leading to early tear film rupture. This rupture increases the hyperosmolarity of the tear and completes the vicious circle events that cause damage to the ocular surface" [24]. While sophisticated equipment is required to measure tear film osmolarity, we can assess the sodium concentration that we obtain from tears by wetting a Whatman 41 paper strip in the usual

way for the Schirmer test, then colorimetrically measuring the sodium concentration in that. More specifically, the Tear Lab osmolarity system is designed to measure tear osmolarity and facilitate diagnosis in patients with suspected dry eye syndrome. Tear Lab measures osmolarity in 10 s and integrates seamlessly into clinical workflow. The evaluation of tear osmolarity has been shown to be a superior marker to determine the severity of DED, with respect to TBUT, Schirmer I, corneal and conjunctival staining, Meibomian classification and OSDI, whose specificities are (60%, 79%, 85%, 67%, 76%, and 79%) respectively. The test card in conjunction with the Tear Lab Osmolarity System offers a quick and easy method to determine tear osmolarity using nanoliter (nl) volumes of tear fluid obtained directly from the edge of the eyelid. To perform a test, a new test card must be inserted into the collecting pen; then contact the tip of the pen with the tear meniscus, located on the lower eyelid. Once the collection is complete, the pen is placed in the reader's docking station, which will display a quantitative osmolarity test result on the liquid crystal display (LCD) (**Figure 2**). The Tear Lab osmolarity system simplifies the tear collection process by eliminating the need to move tear fluid samples and reducing the risk of evaporation [25].
