Is It Sjögren Syndrome or Something Else?

Dry eye disease (DED) invokes an image of red, burning, irritated eyes that become noticeable in individuals who actively use digital devices, live in low humidity environments, or take antihistamines for allergies. These scenarios, in addition to advanced age, may increase one’s risk of developing DED, a condition in which triggers can be exacerbated by external factors. This condition is referred to as non-Sjögren DED. Its effects can be mitigated through the use of lubricants, antiinflammatory medications, and the avoidance of causative agents.

DED can also occur when an individual’s own body attacks its moisture-producing glands. In this case, although the symptoms are similar, the cause is internal and is recognized as the autoimmune condition known as Sjögren syndrome (SS). This systemic inflammatory disease primarily affects the lacrimal and salivary glands and may exist as a primary disorder. There are also secondary forms of SS, associated with other autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, or systemic sclerosis.¹ Therefore, it is important to differentiate non-SS from SS DED in order to assist in the diagnosis of these seemingly similar syndromes (Table).

WHAT IS DRY EYE?

The definition of DED has evolved greatly as we have developed a better understanding of the mechanism of tear production and the composition of the tear film. In the Tear Film & Ocular Surface Society Dry Eye Workshop II Report, DED was redefined as a “multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.”²

Factors contributing to DED come from three sources: the meibomian glands, the goblet cells on the conjunctival surface, and the lacrimal glands. Each one produces a distinct layer of the tear film that keeps the eye moist and functional for good vision and comfort.

The Meibomian Glands

The meibomian glands produce meibum, the top lipid layer of the tear film, composed of several types of fats needed to keep the layer in balance. One of the key components of the meibum is triglycerides. In patients with meibomian gland dysfunction (MGD), triglycerides are converted to diglycerides and monoglycerides by the enzyme lipase. This transforms the meibum from a thin, serous oil into a thicker, gelatinous lard. This conversion, also known as inspissation, leads to deterioration of the tear film, causing fluctuations and blurring of the patient’s vision. In non-SS DED, tear film breakup time (TBUT) decreases when the lipid layer becomes compromised through the aging process, compounded by a poor diet filled with saturated fat.

The oral consumption of gamma linoleic acid (GLA) and alpha linoleic acid, fatty acids found in foods such as salmon and nuts or in supplements such as HydroEye (ScienceBased Health), can help to prevent this deterioration of the tear film. One can replenish the diminishing tear film by combining the unique omega fatty acid GLA from black currant seed oil with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from ultrapure US Pharmacopeia–verified fish oil. This blend assists in blocking the formation of proinflammatory prostaglandins while stimulating production of antiinflammatory prostaglandins.³ GLA works through its metabolite, dihomo-gamma linoleic acid, to stimulate the tear-specific prostaglandin E1, which reduces inflammation and supports tear production.⁴ Consequently, this adjunctive therapy containing GLA can help reduce inflammation and maintain corneal smoothness while improving symptoms of DED.⁵

According to the Sjögren’s Foundation, 90% of patients with SS are women 40 years of age or older who report having disturbed sleep, depressed mood, and fatigue, all of which lead to the development of MGD.⁶ However, in patients with SS, the meibomian glands are not affected initially, but rather deteriorate at least 3 years after its onset.⁷ This delay may be attributed to damage over time to the lacrimal gland, causing a decrease in tear film volume, thereby deteriorating the meibomian glands. Evaporative DED in SS also may be related to immune-mediated androgen deficiency, cytokine-induced disruption of neural–meibomian gland epithelial cell interactions, and secondary aqueous tear deficiency.⁸ More research is needed to fully understand the etiology of MGD in patients with SS.

The Goblet Cells

The goblet cells assist in the production of the innermost layer of the tear film, the mucin layer, which provides the protective coating to the corneal epithelium.⁹ In non-SS DED, loss of goblet cells is an early cause of DED. Reduction of mucin contributes to tear film instability and loss of homeostasis due to increased levels of inflammatory cytokines.¹⁰ When this damage occurs, the mucin layer may be sparse and lead to filaments on the corneal surface.

In patients with SS, by contrast, the body attacks its own exocrine glands. When white blood cells infiltrate the tear glands, this leads to a decrease in tear production. The tear fluid shows reduced levels of the goblet cell–specific mucin protein MUC5AC. Deficiency of this protein in tears is one of the mechanisms responsible for tear film instability in SS.¹¹ Staining of the conjunctival surface with lissamine green may aid in diagnosis.

Moreover, inadequacy of the mucin layer may increase symptoms of pain and burning associated with DED, requiring stronger mitigating factors than the use of lubricating artificial tears alone. A viable treatment option may incorporate cyclosporine ophthalmic emulsion 0.05% (Restasis, Allergan) or cyclosporine ophthalmic solution 0.09% (Cequa, Sun Ophthalmics) drops, as this immunosuppressive agent increases goblet cell density and production of the immunoregulatory factor TGF-Β2 in the bulbar conjunctiva.¹² Patients’ symptoms should begin to subside with continued twice daily use of these drops.

The Lacrimal Glands

The lacrimal glands produce the aqueous layer, the bulk of the tear film sandwiched between the lipid and mucin layers. Severity of symptoms increases as aqueous production decreases, while infiltrative cytokines rise with age or other external factors. Use of computers and systemic medications amid a dry, windy environment can intensify non-SS DED.

Yet, in SS, DED is a comorbidity of the autoimmune disease, in which circulating autoantibodies are produced by B-lymphocytic cells. Antibodies can play a role in the initiation of the immune attack against the lacrimal gland. The most commonly detected antibodies are SS-A/Ro and SS-B/La, which are hallmarks for diagnosis.¹³ In addition, an upward surge of cytokines can further inflame the lacrimal glands, impairing their function.

No single test to confirm a diagnosis of SS exists. Optometrists should work in tandem with rheumatologists, and even dentists, to conduct tests and inquire about a patient’s signs to aid in identification. Eye care practitioners can test for the inflammatory tear marker matrix metallopeptidase-9 (InflammaDry, Quidel) and stain with lissamine green to detect devitalized tissue (Figure). Rheumatologists can perform a blood workup aimed at autoantibody testing for SS-A/Ro and SS-B/La. The assays available at present will not confirm 100% autoantibody sensitivity; however, the positivity rate is reasonably significant at 70% for the SS-A/Ro antibody and 40% for SS-B/La. Plus, a dentist can evaluate salivary flow and gland biopsy to analyze lymphocyte infiltration to corroborate the findings.

DON’T BE FOOLED

Ultimately, early diagnosis and appropriate treatment are crucial in improving the quality of life of individuals with SS. Symptoms develop gradually and can mimic other conditions, including menopause, lupus, rheumatoid arthritis, and chronic fatigue syndrome. SS is often underdiagnosed or misdiagnosed and requires a multidisciplinary approach in order to be properly identified.⁶ It can take up to 3 years before recognizable onset of symptoms, including dry eyes, dry mouth, and dry hands, which, together with the aid of matrix metallopeptidase-9 inflammatory testing and lissamine green staining, can assist the optometrist in differentiation of this cryptic condition.