Our understanding of dry eye disease (DED) has grown tremendously in recent years. As the prevalence of associated systemic conditions grows, optometrists must be aware of the connections between systemic conditions and DED.1,2 Autoimmune diseases such as Sjögren’s syndrome (SS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are often linked to DED, for example.3,4 Diabetes mellitus (DM) also is an important systemic cause of dry eye.5 Consequently, both DM and SS are key systemic conditions clinicians should explore when examining DED patients. These clinical clues can help optometrists intervene sooner to provide the best management options.

A sore, cracked tongue is suggestive of Sjögren’s syndrome.
A sore, cracked tongue is suggestive of Sjögren’s syndrome. Click photo to enlarge.


Research suggests more than 50% of patients with DM have dry eye, and significant associations exist between DED and the duration of diabetes and diabetic retinopathy.6-9 Meibomian gland dysfunction (MGD) is also associated with DM, and one study shows a significant increase in the frequency of MGD in diabetes patients compared with those unaffected.10,11 

Clinical clues. Polyuria and polydipsia are known symptoms of DM, and patients often report typical dry eye symptoms such as burning, foreign body and gritty sensations and sore eyes.6-8 However, practitioners should be mindful that patients with longstanding diabetes may report fewer symptoms as a result of diabetic corneal neuropathy.5 A closer examination is warranted in patients presumed to suffer from DED who present with insignificant symptoms or none at all. 

Intraductal meibomian gland probing, a manual procedure to open the meibomian orifices, can be considered in ocular rosacea patients with MGD.
Intraductal meibomian gland probing, a manual procedure to open the meibomian orifices, can be considered in ocular rosacea patients with MGD. Click photo to enlarge. 

While many DED diagnostic tests may be useful, common tests such as the Schirmer’s type 1 test without anesthesia, tear film break-up time (TBUT) and ocular surface vital dye staining may underestimate the presence of DED in patients with Type 2 diabetes.12 Tear osmolarity (Tearlab) may be particularly useful to detect DED in patients with Type 2 diabetes.12 A study comparing tear osmolarity with common DED diagnostic tests in patients with Type 2 diabetes found osmolarity had a greater diagnostic accuracy than Schirmer’s type 1 test, TBUT, rose bengal and fluorescein staining.12 

Corneal staining also may be useful in predicting the presence of DED associated with certain systemic diseases. Patients with diabetes are prone to corneal erosions, and  one study found corneal sodium fluorescein staining of the inferior corneal zone was predictive of DED in diabetic patients.13,14 

Marked neovascularization of the iris in this patient was caused by uncontrolled proliferative diabetic retinopathy. Photo: Aaron Bronner, OD
Marked neovascularization of the iris in this patient was caused by uncontrolled proliferative diabetic retinopathy. Click photo to enlarge. Photo: Aaron Bronner, OD

Customized care. While the current treatment recommendations for diabetic and non-diabetic DED are essentially the same, recent research can guide us in customized treatment plans. 

Dietary supplementation with omega-3 fatty acids (FAs), for example, may prevent or even reverse insulin resistance while also improving tear film function and DED symptoms in Type 2 diabetes patients.15-17 The Dry Eye Assessment and Management (DREAM) study—the first large-scale, multicenter, double-masked randomized controlled trial investigating omega-3 FA use for DED—may soon provide a clearer understanding of the efficacy and safety of omega-3 FAs in treating DED. The estimated completion date of the DREAM study is October 2017.18 

As chronic hyperglycemia is a risk factor for diabetes-associated DED, patient education on glycemic control is still fundamental, as is education on the chronic nature of their dry eye.5,19 These patients can be asymptomatic, and encouraging both annual ocular surface and fundus evaluations is imperative. Assessment of the retina and the ocular surface should become an integral part of our routine exams when diabetes is suspected. 

Referral to an internist, including requests for blood glucose and HbA1c testing, is vital to our management of these patients as well.

Sjögren’s Syndrome

When you suspect a DED patient may have an autoimmune disease, RA, SLE or even sclerodermas are among the conditions on the list. But when a DED patient cites a sore, cracked  tongue, one of the most prevalent systemic diseases associated with DED, Sjögren’s syndrome, should move to the top of the list.20 

While SS can occur alone in its primary form, about half of SS is found in the presence of another autoimmune connective tissue disease such as RA, and is known as secondary SS.21,22 Immune-mediated damage to the exocrine glands, in particular the lacrimal and the salivary glands, results in the hallmark symptoms of dry eye and dry mouth.22 These and a host of other systemic symptoms can be subtle, episodic and nonspecific, resulting in diagnostic delays.21 Dry eye is often an early symptom, and a timely diagnosis can mitigate serious systemic complications such as lymphoma.  

Sodium fluorescein corneal staining of a Sjögren’s syndrome patient prior to scleral contact lens wear.
Reduced sodium fluorescein corneal staining of the same patient three weeks post-scleral lens wear.
At top, sodium fluorescein corneal staining of a Sjögren’s syndrome patient prior to scleral contact lens wear. At bottom, reduced sodium fluorescein corneal staining of the same patient three weeks post-scleral lens wear. Click photos to enlarge.

Clinical clues. To identify SS-associated DED (SS-DED), ask about classic dry eye and dry mouth, as well as prolonged persistent fatigue and joint pain—common SS symptoms.23 Because some classic SS symptoms may not be obvious (a patient may not realize they have dry mouth), clinicians should also explore other nonobvious symptoms such as difficulty talking and swallowing and dental or gum problems.23

As in diabetes-related DED, SS patients may have objective signs of DED without subjective symptoms. A recent study indicates as many as 40% of SS patients with clear objective evidence of DED reported no symptoms.24,25 

Important clinical tests in this patient population include ocular vital dye staining and Schirmer’s type 1 testing. The most recently proposed 2016 classification criteria for SS by the American College of Rheumatology/European League Against Rheumatism includes an Ocular Staining Score equal to or greater than five and Schirmer’s type 1 test less than 5mm in five minutes.26 

Although SS falls under the umbrella of aqueous-deficient DED, SS patients may have a combination of aqueous-deficient and evaporative DED.4,27 Additionally, ocular surface changes in SS patients may be attributed in part to MGD.28 In a recent study comparing MGD in patients with SS, non-SS dry eye and non-dry eye controls, SS patients had more severe MGD with poorer mean meiboscore and meibomain gland expressibility than non-SS dry eye patients.29 

Evaluating DED in patients with SS should include assessment of tear film stability and meibomian gland function. SS-DED may be differentiated from dry eye that is associated with other systemic conditions through various in-office means, such as ocular staining patterns. In one study, researchers showed temporal conjunctival rose bengal staining is a sensitive test for SS and perhaps can be used to differentiate SS-DED from other forms of dry eye.30  Additionally, patchy, central corneal fluorescein staining may also be a good indicator of SS.31

In some states, optometrists can use the Sjö test (Bausch + Lomb), a simple in-office blood test, to diagnose this condition early. Otherwise, patients can be sent to a local laboratory for testing. Referral to a rheumatologist is still advised even when blood tests are negative but symptoms and signs of SS are present. If you or the rheumatologist suspect a false negative test, salivary biopsy may be necessary to confirm the diagnosis.32 

Don’t Miss These Often Overlooked Associations

While Type 2 diabetes and Sjögren’s syndrome have a high prevalence in our DED patient population, a variety of other systemic diseases warrant consideration. 

Graves’ disease. Dry eye is a frequent cause of ocular discomfort in Graves’ disease, a common autoimmune condition.1,2  While the association between Graves’ disease and dry eye is well established, the pathophysiology is not completely understood. The latest evidence points to mechanical impairment of the eyelids, as well as immune-mediated lacrimal gland dysfunction and meibomian gland dysfunction. In a study examining morphologic changes in the meibomian glands of patients with Graves’ orbitopathy compared with controls, a higher prevalence of MGD and more severe dry eye symptoms existed in the Graves’ orbitopathy group than in the control group.3 

Multiple sclerosis (MS). This demyelinating disease can lead to severe dry eye. In MS, poor corneal sensory impulse conduction can result in insufficient tear production, and lagophthalmos-associated DED can occur due to poor motor control.4 These patients may have limited ability to instill drops and perform lid hygiene properly; thus, punctal plugs, humidifiers and in-office blepharitis therapies may be crucial. 

Rosacea. Many patients with cutaneous rosacea cope with ocular symptoms.5 Patients with cutaneous rosacea can develop blepharitis, MGD and associated DED; sometimes, these precede the cutaneous signs. Conventional blepharitis and MGD therapies such as eyelid hygiene and warm compresses, respectively, are mainstay therapies for mild cases. More advanced cases may necessitate topical or oral azithromycin and newer therapies such as intense pulse light and intraductal meibomian gland probing. Rosacea patients should also avoid any triggers such as stress, spicy food, alcohol and excessive sun exposure.6

Pediatric dry eye. Today, we are seeing more DED in children, likely due to the growing use of electronic devices.7 Nonetheless, dry eye in otherwise healthy children is not common and should prompt investigation into a systemic cause such as juvenile RA, juvenile-onset SLE, diabetes, vitamin A deficiency and Riley-Day syndrome.8,9 

Systemic medications. While necessary to treat many conditions, pharmaceuticals such as diuretics, antihypertensives, beta-blockers, antidepressants, antipsychotics, antihistamines, decongestants, gastrointestinal medications, oral contraceptives and analgesics may all cause or exacerbate dry eye. 

Alcohol. The link between DED and alcohol is controversial. One study found that alcohol consumption may be a significant risk factor for dry eye.10 Others suggest alcohol serves a protective role in the development of DED and that drinking and DED may be unrelated.11,12 Based on a meta-analysis of 10 studies, researchers surmise that alcohol-induced peripheral neuropathy may falsely reduce the prevalence of DED.10

1. Gürdal C, Saraç O, Genç I, et al. Ocular surface and dry eye in Graves’ disease. Curr Eye Res. 2011;36(1):8–13.
2. Brent GA. Graves’ disease. N Engl J Med. 2008;358:2544-54.
3. Kim YS, Kwak AY, Lee SY, et al. Meibomian gland dysfunction in Graves’ orbitopathy. Can J Ophthalmol. 2015;50(4):278-82.
4. Prasad S, Galetta SL. Eye movement abnormalities in multiple sclerosis. Neurol Clin. 2010;28(3):641-55.
5. Ghanem VC, Mehra N, Wong S, Mannis MJ. The prevalence of ocular signs in acne rosacea: comparing patients from ophthalmology and dermatology clinics. Cornea. 2003;22(3):230-3.
6. Abokwidir M, Feldman SR. Rosacea management. Skin Appendage Disord. 2016;2(1-2):26-34.
7. Moon JH, Kim KW, Moon NJ. Smartphone use is a risk factor for pediatric dry eye disease according to region and age: a case control study. BMC Ophthalmol. 2016 Oct 28;16(1):188.
8. Gunay M, Celik G, Yildiz E, et al. Ocular surface characteristics in diabetic children. Curr Eye Res. 2016 Dec; 41(12):1526-31.
9. Gawdat G, El-Fayoumi D, Marzouk H, Farag Y. Ocular manifestations in children with juvenile-onset systemic lupus erythematosus. Semin Ophthalmol. 2017 Mar 24:1-7.
10. You YS, Qu NB, Yu XN. Alcohol consumption and dry eye syndrome: a Meta-analysis. Int J Ophthalmol. 2016 Oct 18; 9(10):1487-92.
11. Chia EM, Mitchell P, Rochtchina E, at al. Prevalence and associations of dry eye syndrome in an older population: the Blue Mountains Eye Study. Clin Exp Ophthalmol. 2003;31(3):229-32.
12. Tan LL, Morgan P, Cai ZQ, Straughan RA. Prevalence of and risk factors for symptomatic dry eye disease in Singapore. Clin Exp Optom. 2015;98(1):45-53.  

Customized care. Once the diagnosis is confirmed with a rheumatologist, ODs play a key role in providing customized DED management with new clinical practice guidelines for SS in the United States.33 The recommended DED treatment strategies include both conventional and unconventional therapies such as artificial tears, topical corticosteroids, punctal plugs, autologous serum eye drops (ASEDs) and therapeutic contact lenses.33 

Since investigators believe SS-DED is driven by an inflammatory mechanism, anti-inflammatory or immune-modulatory agents are well-suited to treat DED in these patients.34 Research shows Restasis (cyclosporine 0.05%, Allergan) is an effective treatment and may also help SS patients with evaporative DED by treating MGD.35-37 

Compounded topical cyclosporine at higher concentrations—including cyclosporine 0.5% to 2% suspension in gum cellulose and cyclosporine 0.2% ointment—may help patients unsuccessful with Restasis.38 Sun Pharma recently announced successful Phase 3 clinical trial results for Seciera (cyclosporine A 0.09% ophthalmic solution).39  

Tacrolimus is an another option for SS-DED. In one study, topical 0.03% tacrolimus eye drops improved tear film stability and ocular surface status in SS-related DED.40 

Xiidra (lifitegrast ophthalmic solution, Shire) has been successful in randomized, double-masked, multicenter, placebo-controlled studies in improving DED symptoms and signs—promising results for SS patients.41 

Omega-3 FA supplementation is also a good anti-inflammatory management option. However, high intake of omega-3 FAs can cause excessive bleeding in some patients, and patients should take then under a physician’s care.25 

Although SS patients are treated with Plaquenil (hydroxychloroquine, Sanofi-Aventis) systemically, it is known to cause retinopathy and its benefit for SS-DED is controversial.42,43,44 While research shows Plaquenil improves dry eye in primary Sjögren’s subjects, other studies show no clinical benefit.42,43 Clinicians should follow the 2016 updated visual screening guidelines for long-term Plaquenil therapy.44 

The secretagogues oral pilocarpine and cevimeline are indicated for dry mouth in SS patients, but their benefit for SS-DED is controversial.31 While some research shows they improve DED symptoms and signs, others show they were ineffective in improving DED signs.25 

Recently, scleral gas permeable lenses have gained attention for their success in treating SS-DED. Although no studies specifically investigate the outcomes of scleral lenses in patients with SS, these patients have been included in several study groups and have benefited from scleral lenses.45-47 Anecdotally, practitioners find SS patients have improved symptoms and signs with scleral lenses and indicate a significant improved quality of life. 

SS-DED can be severe, and other therapies typically reserved for refractory DED such as sutureless amniotic membranes and autologous serum drops may be helpful for these patients. Sutureless amniotic membranes act as bandage and restore the epithelium and control inflammation.48 ASEDs also promote epithelialization and can be an effective DED treatment for SS patients.49-51 Punctal plugs combined with ASEDs may have an additive effect and perhaps should be considered in recalcitrant cases after using ASEDs alone.51 

Dry eye disease is associated with several systemic diseases with serious complications. Fortunately, optometrists are in a vital position to address these patients’ dry eye needs and manage their holistic health approach.

Dr. Mickles is associate professor at Nova Southeastern University College of Optometry and its Dry Eye Service coordinator. She is a fellow of the American Academy of Optometry. 

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