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Systemic disease, medications can cause or influence dry eye

Diabetes, genetics, allergies and Sjögrens’ syndrome are all associated with dry eye.

by Milton M. Hom, OD, FAAO

This course is jointly sponsored by PCON, The State University of New York State College of Optometry and Vindico Medical Education. It is COPE-approved for 2 continuing education credits.

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An organ can be defined as “A relatively independent part of the body that carries out one or more special functions.” We learned in optometry school that the eye is an organ. What relationship does an organ have to the rest of the body? “Relatively independent” is a good term to use.

What happens in the rest of the human body may or may not directly affect the eye. In many ways, the eye is protected from the rest of the body because it is a closed system, with proposed reflex loops or arcs within it. For instance, the loops affecting the tear film are the corneal-lacrimal gland, corneal-blinking and the blinking-meibomian gland.

Several systemic conditions have no clinical relevance to the human eye. On the other hand, other conditions have a direct influence on the eye and, more specifically, cause dry eyes. These systemic conditions show that the eye is simply not independent, but rather dependent in relationship to the human body.

Diabetes and the eye

Diabetes has a special meaning to every eye doctor. In 2002, about 18.2 million people, or 6.3% of the total U.S. population, were diagnosed with diabetes. It is within our DNA as optometrists to investigate every time a patient speaks of the disease.

From the first year as an optometry student, the importance of diabetes to the eye is instilled within us. Diabetes affects many parts of the eye; one could argue it has some effect on nearly all of the primary components of the eye.

Studies show an intimate relationship between dry eye and diabetes. The connection between diabetes and dry eye has been well established. In a study by Ozdemir and colleagues, 41 patients with type 2 diabetes and 20 healthy subjects underwent routine ophthalmic examination, tear film break-up time (TBUT) test, Schirmer’s test, fluorescein dye test, rose bengal staining test and a subjective questionnaire. TBUT and Schirmer’s test values were significantly lower in people with diabetes when compared with controls. People with diabetes had significantly more abnormal fluorescein and rose bengal staining than in the control group. Poor metabolic control, panretinal argon laser photocoagulation and proliferative diabetic retinopathy are high risk factors for dry eyes.

In another study, Goebbels performed fluorophotometry, Schirmer’s test, TBUT and impression cytology in 86 patients with diabetic retinopathy and 84 controls. People with diabetes showed decreased Schirmer’s test readings and significantly more frequent and pronounced signs of conjunctival metaplasia. In contrast to the other studies mentioned, unstimulated basal tear flow and TBUT were normal.

With respect to prevalence of diabetes and dry eye, Jain reviewed 400 patients with dry eye and found that 20% had diabetes. In another study by Li, 111 patients with type 2 diabetes and 100 control subjects were evaluated with TBUT, corneal fluorescein staining, Schirmer’s I test and tear film lipid layer observation with Tearscope (Keeler, Broomall, Pa.). When compared with the controls, patients with type 2 diabetes had higher dry eye scores, reduced TBUT but similar Schirmer’s I scores. The researchers found that more people with diabetes were diagnosed with dry eye (19.8% of people with diabetes vs. 8.0% of controls).

Seifart and colleagues compared 92 patients with diabetes with a group of controls. Nearly 53% of all patients with diabetes complained of dry eye symptoms vs. 9.3% of the controls. They found TBUT values lower than 10 seconds in 94.2% of the people with diabetes and in only about 6% of the controls.

For severity of diabetes and dryness, Yoon and colleagues looked at scoring of keratoepitheliopathy, corneal sensitivity test, TBUT, Schirmer’s test and conjunctival impression cytology in 94 diabetic eyes and 60 normal eyes. The degree of keratoepitheliopathy was severe, and the corneal sensitivity, TBUT and tear secretion were significantly lower in the patients with diabetes. Conjunctival impression cytology showed a higher grade of conjunctival squamous metaplasia and lower goblet cell density in the patients with diabetes. All parameters were related to the status of metabolic control, diabetic neuropathy and stage of diabetic retinopathy.

Nepp and colleagues graded 144 eyes according to the Early Treatment Diabetic Retinopathy Study and looked for dry eyes with the Schirmer’s test, break-up time, lipid layer thickness, fluorescein and rose bengal staining of the cornea and impression cytology. They also administered a questionnaire to participants. They found that the severity of keratoconjunctivitis sicca correlated with the severity of the diabetic retinopathy.

In a study by Dogru and colleagues, 88 diabetic eyes and 40 eyes healthy controls had corneal sensitivity measurements, Schirmer’s test, TBUT and conjunctival impression cytologic analysis. The mean corneal sensitivity was significantly lower in patients with diabetes when compared with controls. TBUT and Schirmer’s values were also significantly lower in patients with diabetes as well as in those with peripheral neuropathy and poor metabolic control. Impression cytologic analysis showed goblet cell loss and conjunctival squamous metaplasia, both of which again related to peripheral neuropathy, poor diabetic control and decreased corneal sensitivity. However, they found no relation to disease duration or status of diabetic retinopathy.

Lissamine green staining
Lissamine green staining: This is the type of staining seen in the conjunctiva of a dry eye patient.

Image: HOM MM

What is interesting is none of the studies on the diabetic-dry eye connection involved lissamine green staining. Lissamine green staining is preferred over rose bengal because it is a more comfortable (less stinging) stain. The staining profile of lissamine green and rose bengal is similar.

Lastly, a study by Hom and colleagues took a different perspective and examined a family history of diabetes and frequency of dry eye. They gave 392 patients a simple questionnaire about diabetic history and asked them to categorize their level of discomfort due to ocular dryness. People with diabetes were more likely to have more severe levels of dryness than nondiabetics. Patients with a family history of diabetes also showed a greater tendency to have dry eye.

The dryness we see in people with diabetes is very different than the dryness we see with others. Two different tear protein profiles are involved. In a study by Grus and colleagues, 255 controls and 260 patients with diabetes mellitus showed differences in tear protein patterns.

Genetics play a role

When considering a link between a family history of diabetes and dry eyes, one may conclude that genetics can be a factor in dry eye.

A study of identical twins raised separately showed that both twins had dry eyes, according to Bolstad and colleagues. There has been a genetic connection shown with Sjögren’s syndrome, according to research from Bolstad and Jonsson and Sawalha. Genetics probably plays a large role in whether a patient suffers from dryness.

Medications as culprits

One of the most common links between dry eye and systemic disease is not a condition itself; medications are a significant cause of dryness. Note one simple rule of thumb: If the drug causes dry mouth, it will cause dry eyes.

Medications that cause dry eye include diuretics, drugs commonly used to treat high blood pressure, antihistamines and decongestants, sleeping pills, birth control pills, tricyclic antidepressants, isotretinoin-type drugs for acne treatment, gastric medications (such as for irritable bowel syndrome) and opiate-based pain relievers such as morphine. One of the most commonly prescribed classes of drugs is the nonsedating antihistamines. Allergies are common, and this class of drugs is the number-one treatment.

The nonsedating antihistamines are primarily geared for rhinitis treatment. One of the principal reasons for using an antihistamine is to dry the nasal passages to stop the rhinitis. A side effect is drying of the other mucus membranes, in our case, the eyes.

Looking into the side effects listed for nonsedating antihistamines, dry eyes or altered lacrimation have an incidence of less than 5%, according to results from Hom. Unfortunately, this does not parallel the experience many eye care practitioners have with nonsedating antihistamines.

A study by Welch looked at the tear film after 4 days of Claritin (loratadine, Schering) use. Fluorophotometry measured tear flow and volume. The tear flow and volume were decreased. Corneal staining increased one grade in 76% of the patients. Conjunctival staining showed a mean increase of one grade in 74%.

Why is there such a large discrepancy between altered lacrimation and our clinical experience? Most of the side effects are based on clinical studies submitted to the Food and Drug Administration for the package insert. Eye care practitioners probably did not perform the clinical studies for oral nonsedating antihistamines. The principal investigators were most likely allergists or primary care physicians — as well they should be. However, their ability to recognize dry eye would not be as fine-tuned as an eye doctor’s.

Conjunctivitis and allergies

Most patients with seasonal or perennial allergies also have allergic conjunctivitis. The two often go hand in hand. Why does allergy commonly affect the eyes? Let us say the triggering allergen is pollen. Pollen is often airborne because it is small.

Three areas or points of attack usually trigger the allergic response: the eyes, the nose and the lungs. Pollen faces a more difficult pathway to reach the lungs. The nose is more exposed, but it has cilia to act as a protective filter. The eyes are the most exposed of the three attack points. More often than not, the eyes are the first to encounter airborne pollen. Because of the high exposure, allergic conjunctivitis is quite common with allergies.

When the pollen is intrusive enough to reach the lungs, asthma is commonly associated with allergies. If the pollen reaches the nose, the usual response is rhinitis. When it reaches the eyes, we most commonly see itchiness.

As an aside, prescribing a topical anti-allergy medication in addition to a nonsedating antihistamine works well. Using a nonsedating antihistamine or an asthma inhaler is a strong clinical indicator that allergic conjunctivitis will also be present.

Allergy medication and dry eye

This discussion leads us into another consideration. We prescribe topical anti-allergy medications for allergies, but do these medications also work for dryness? We know there is significant crossover in signs and symptoms between allergy and dry eyes. Many times, the differential diagnosis is not clear.

I believe there is crossover in treatment. Prior to prescriptive medications indicated for dry eyes, my number-one pharmaceutical choice for dryness was topical anti-allergy medications.

We know that one of the principal causes and consequences of dry eye is inflammation. An increase of inflammatory factors (cytokines) in the tear film indicates an inflammatory response. The more cytokines present, the greater the inflammatory response.

What is one of the primary benefits of topical anti-allergy medications? They reduce cytokines in the tear film. Because dry eye has some connection to inflammation, anti-allergy medications have a treatment role because of their anti-inflammatory effects. Combined with the fact that these topicals have extremely high safety profiles, they are a useful option.

Steroids offer a much more potent anti-inflammatory effect. They work extremely well for allergic conjunctivitis and are superior to the anti-allergy topicals. If the itch is too great for an anti-allergy topical, steroids are in order. Steroids have tremendous cytokine lowering effects. They clean up the tear film rapidly. Research has shown that steroids are efficacious with dry eye.

However, steroids themselves pose a problem with significant side effects. Cataracts and glaucoma come to mind for ketone steroids. The more modern class of steroids, the ester steroids, are much safer – so safe that many practitioners are prescribing ester steroids on a maintenance basis.

The drawback for the ester steroids is the dosing. Although more efficacious than topical anti-allergy medications, they need to be dosed three or four times a day. Many patients prefer the twice or once daily dosing of anti-allergy topical medications.

Cyclosporine also has cytokine-reducing properties. Again, the same anti-inflammatory effects are in play as anti-allergy topicals and ester steroids. The difference is that cyclosporine is indicated specifically for dry eye. The other medications are indirectly indicated or not indicated at all.

Sjögren’s syndrome

Sjögren’s syndrome has been well connected to dry eye. The definition of Sjögren’s syndrome has changed over the years. In the past, Sjögren’s was known as a triad of conditions: dry mouth, dry eyes and associated autoimmune disorders. These autoimmune disorders include conditions such as rheumatoid arthritis and systemic lupus. Rheumatological diagnosis centers around the parotid gland. A biopsy of saliva glands around the face or under the surface of the inner lip helps establish a diagnosis.

Sjögren’s syndrome affects between 1 and 4 million people in the United States, or about 0.4% of the population. Most people are older than 40 years at the time of diagnosis. Women are nine times more likely to have it than men. A small percentage of people with Sjögren’s syndrome develop lymphoma.

See the accompanying chart for the 2007 Report of the Dry Eye Workshop’s classification system for symptoms and signs of primary and secondary Sjögren’s syndrome.

2007 Report of the Dry Eye Workshop

Associated dry mouth

Just as Sjögren’s syndrome causes dry eye, it also causes dry mouth. The multitude of remedies for dry mouth vary from simple to prescriptive.

If the salivary glands still produce some saliva, they can be stimulated to make more with chewing gum or hard candy. It must be sugar-free, because dry mouth makes one extremely prone to progressive dental decay.

Sips of water or another sugar-free, non-carbonated drink throughout the day can help keep the mouth wet, especially when one is eating or talking. Sipping liquids every few minutes may reduce or remove the mucus coating inside the mouth that increases the feeling of dryness.

An oil- or petroleum-based lip balm or lipstick can soothe dry, cracked lips. Patients can use a saliva substitute if there is little saliva or none at all. These products mimic some of the properties of saliva, which means they make the mouth feel wet. Gel-based saliva substitutes tend to give the longest relief, but as with all saliva products, their effectiveness is limited by the fact that you eventually swallow them.

At least two prescription drugs stimulate the salivary glands to produce saliva: pilocarpine (Salagen, MGI Pharma) and cevimeline HCI (Evoxac, Daiichi Sankyo Inc.). The effects last for a few hours, and a patient can take the drug three or four times a day.

People with dry mouth can easily get a mouth infection from Candida. About one-third of people with Sjögren’s syndrome experience candidiasis infection. Most often, it causes red patches and a burning sensation. This occurs particularly on the tongue and corners of the lips, according to the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Web site.

A higher frequency of meibomian gland dysfunction occurs in Sjögren’s patients, according to the 2007 Report of the Dry Eye Workshop. If lid disease is present, lid hygiene and massage is an important first-line treatment.

Oral minocycline or doxycycline can be added. Minocycline 50 mg should be taken twice a day for 2 weeks, then 50 mg a day per month. Minocycline is recommended because it has the fewest side effects and induces minimal photosensitization. Taper the minocycline for long-term management.

Treatment may need to continue for months depending on the response. Usually a positive effect is seen within 8 weeks. Be aware that minocycline can cause stained teeth, vaginitis in women and photosensitivity.

Doxycycline should be dosed as 50 mg twice a day for 1 to 2 months. Once symptoms improve, reduce the dose to once daily for an additional month. Women of child-bearing age in whom pregnancy is possible, women who are nursing and children should avoid this drug. Doxycycline can cause increased photosensitivity and sensitivity to dairy products/antacids.

Consider Periostat (20 mg doxycycline, Collagenex) twice a day for 1 to 2 months, then once a day for an additional month if the patient experiences gastric problems. When no lid disease is present, Sjögren’s syndrome can be treated with artificial tears, cyclosporine and topical steroids.

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