Dry eye is a prevalent ocular disorder worldwide and recognized as one of the most frequent reasons for seeking eye care. Whether locally or systemically initiated, inflammation plays a key role in the pathogenesis of dry eye. Approximately half of the patients with clinically significant dry eye have an underlying systemic inflammatory or autoimmune disease. One serious disease that causes significant dry eye is Sjögren's syndrome (SS). SS is an autoimmune disorder characterized by immune-mediated destruction of the salivary and lacrimal glands, with subsequent development of sicca symptoms. It is one of the most common autoimmune diseases in adults, affecting 1% to 4% of the general population. Approximately 10% of patients with clinically significant dry eye have underlying SS. Currently, the diagnosis of SS among dry eye patients is delayed by about a decade, largely due to lack of awareness and also diversity of patient symptoms and signs, adding to the complexity of diagnosis. Importantly, patients with SS are at risk for many ocular and systemic complications including central nervous system and visceral organ involvement as well as lymphoma. In fact, SS is the autoimmune disease most frequently associated with lymphoma. Therefore, identifying the subset of dry eye patients with SS is relevant.

Diagnosis of SS remains challenging mainly due to the lack of definitive diagnostic tests. The presence of aqueous-deficient dry eye is an integral part of diagnostic criteria for SS. Arguably, the hallmark of SS-related dry eye is conjunctival vital dye staining related to loss or alteration of the ocular surface mucins. A healthy conjunctiva is essential for ocular surface health as conjunctival goblet cells are responsible for secretion of the large gel-forming mucin MUC5AC which plays an important role in maintenance of the tear film on the ocular surface. Reduction of MUC5AC levels in tears of patients with SS has been demonstrated in a single previous study. The investigators also found lower levels of tear MUC5AC, and higher levels of IL-6 an IL-8 in patients with SS-dry eye in comparison to non-SS dry eye and controls. In addition, the investigators found the conjunctival lissamine green staining has a role in differentiating SS versus non-SS dry eye, independently of the dry eye severity.

In addition, increased levels of cytokines such as interleukin (IL)-13, IL-21, and interferon-gamma (IFN-γ) in tears and conjunctiva have previously been shown to correlate with goblet cell loss in SS as well as non-SS-dry eye patients. In murine studies, IFN-γ and tumor necrosis factor alpha (TNF-α) were reported to inhibit MUC5AC secretion in goblet cells stimulated with a cholinergic agonist. Such inhibition correlated with the expression of inflammatory cytokines in the conjunctiva of a mouse model of SS and significantly reduced tear MUC5AC levels. Nevertheless, targeting tear and ocular surface mucins and the relationships to various cytokines in dry eye as a diagnostic or therapeutic area has yet to be extensively studied.

Furthermore, it is well known that patients with SS-related dry eye have much more significant visual complaints than ocular discomfort symptoms arguably due to high corneal punctate erosion scores and diminished corneal subbasal nerve plexus when compared with non-SS dry eye patients. Although the exact mechanism of this is not known, cytokine levels in the tear film might possibly be a contributing factor. Indeed, the worsening of the corneal staining after prolonged gazing, could possibly be attributable to lack of tear film mucin as the investigators demonstrated the correlation between the conjunctival lissamine green staining (a surrogate for goblet cell density which secrete the mucin).

Lastly, although the advent of targeted biological treatments and other factors has led to renewed interest in Sjögren's among rheumatologists and immunologists, its ocular manifestations and burden remain underappreciated. As an example, the most widely used Sjögren's disease activity tool, the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), does not include the extraglandular ocular manifestations of Sjögren's, such as corneal melt/perforation, uveitis, scleritis, retinal vasculitis, and optic neuritis. In addition, the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) only includes one item that addresses the severity of dryness, but this refers to overall dryness and not specifically ocular dryness. Most importantly, these tools do not include any visual symptoms related to dry eye, such as blurred vision and visual or ocular fatigue. The investigators' most recent study points to a significant toll that the ocular manifestations of Sjögren's can have on patients emotionally, physically, and financially, in fact much more pronounced than other manifestation.