What's New in Ocular and Oral Aspects of Sjögren's Syndrome and Do New Treatments Work?

Nurhan Sutcliffe; Alberto Recchioni; Shireen Hilmi; Saaeha Rauz; Anwar R. Tappuni


Rheumatology. 2021;60(3):1034-1041. 

In This Article

New Investigations for Diagnosis in SS: Eye Involvement

Following the latest Dry Eye Workshop II report (2017), the core mechanism of dry eye disease (DED) development has been suggested to be tear film hyperosmolarity[9] (Figure 1). The increased 'saltiness' of the tear film is responsible for starting a cascade of inflammatory processes (mostly an increase in IL-1 and TNF-α) whose primary targets are epithelial cells, conjunctival goblet cells (columnar epithelial cells) and the epithelial glycocalyx (pericellular matrix) of the cornea. In this respect, both aqueous deficient dry eye (ADDE) and evaporative dry eye (EDE) have hyperosmolarity of the tear film in their aetiology—ADDE because of reduced lacrimal secretion and EDE because of a hyperevaporative state. Therefore, intrinsically both types of DED can be seen as evaporative forms.

Figure 1.

The vicious circle of dry eye disease
(Adapted by permission from Springer Nature, The Definition and Classification of Dry Eye Disease by Anthony J. Bron © 2015.)

Despite some conflicting results due to the lack of clear distinguishing features in DED, tear osmolarity was suggested to be one of the best markers in DED diagnosis across normal, mild/moderate and severe groups.[10] However, the authors also suggested considering a set of different clinical measures to overcome any issues experienced with diagnosis differentiation when using tear osmolarity. Additionally, other studies have suggested that its measurement variability may limit its diagnostic power[11,12] and Szczesna-Iskander[12] suggested that the TearLab Osmolarity System (TearLab, Escondido, CA, USA) requires at least three consecutive measurements to obtain clinically reliable values. In an article by

Ng et al.,[13] in RA cohorts with or without secondary SS, the researchers remarked that tear film osmolarity was found to be increased in patients with RA with or without secondary SS. However, the authors also suggested that testing osmolarity itself could not replace the Schirmer test and ocular staining scores that are also included in the diagnostic criteria provided by the ACR–EULAR in 2016.[14]

Newer promising devices, similar to the lab-on-a-chip concept already observed in the TearLab Osmolarity System, are currently under development. One of these is the TearLab Discovery, which is the next generation in terms of a comprehensive in vitro diagnostic testing platform. The device is capable of measuring tear proteins by collecting only 1 nl of tear film, which should allow testing in eyes with extremely reduced tear volume as in severe SS. Additionally, it can measure MMP-9 levels, which have been demonstrated to be involved in the injury process of the corneal epithelium, due to its effect on losing epithelial barrier function and surface regularity.[15] In a study by Kuo et al.,[15] an increased tear MMP-9:lactoferrin concentration ratio was significantly correlated with the level of ocular inflammation in the SS group with DED compared with non-SS patients. The authors suggested that the balance in the level of MMP-9 against lactoferrin could help to track DED exacerbation and indicated that MMP-9 and lipocalin-1 can be considered as laboratory biomarkers for SS patients with DED. In contrast to the TearLab Discovery, which should be released on the market in the near future, InflammaDry (Quidel, San Diego, CA, USA) has been tested in DED cohorts, with high positive and negative agreement for determining the condition.[16] The device, after collecting up to six swabs in the lower tarsal conjunctiva, can determine the amount of MMP-9 (>40 or <40 ng/ml) in the tear film in <10 min without the need for laborious analytical procedures.[17]

The complex multilayer structure of the tear film is composed of a lipid layer in contact with the external environment (outer) and an aqueous layer (intermediate) that is mixed with the mucinous compound (inner) in contact with the corneal epithelial cells forming the muco-aqueous gel layer. The most important functions are performed by the lipid layer, such as reducing tear film evaporation, lowering tear film surface tension and lubricating the eyelids.[18] The lipids consist of low-polarity (wax and cholesterol esters) and high-polarity (phospholipids) types that are produced by the tarsal glands [frequently referred as Meibomian glands (MGs)] in the upper and inferior tarsal conjunctiva of the eyelids.[19] MG dysfunction (MGD) occurs after obstruction of the glandular orifice and represents the key factor in EDE, which is the most common type of DED.[20] In a study of individuals >40 years of age, the prevalence rate of MGD ranged from 38 to 68%,[21,22] and Far East Asian populations are more affected compared with those in Europe.[23] If the obstruction of these orifices is not resolved, the secretory system can undergo atrophic changes, which are defined as MG loss or atrophy, leaving the eyelid margin thickened and indurated.

The gold standard technique for assessing MG architecture is meibography using new generation non-contact infrared meibography, allowing the clinician to detect and objectively quantify abnormalities in the MG, such as loss, dropout, shortening, dilation and tortuosity[24] (Figure 2).

Figure 2.

Non-contact infrared meibography scans acquired from the upper eyelids of two different patients. (A) A healthy patient with a mild dropout of the glands (yellow area). (B) An MGD patient with evaporative dry eye and a severe dropout of the glands (yellow area). Note the gland shape marked in red (courtesy of AR).

MG atrophy can be quantified by several grading scales: the most accepted are the Meiboscore described by Arita et al.[25] and the Meiboscale from Pult and Riede-Pult.[26] Both scales require manual quantification of the area of loss (counting or exporting the images for further analysis), which can lead to bias from the evaluator.[27] To overcome this limitation, newer devices are currently on the market to automatically classify the dropout area using custom in-built software for MG recognition (Figure 3).

Figure 3.

Automatic quantification of the MG scan and the percentage of MG atrophy/dropout (courtesy of AR)