Patient Care
`
`You have a broad range of therapies to alleviate the symptoms of
`keratoconjunctivitis sicca and other forms of dry eye. Researchers and
`drug manufacturers hope to expand your therapeutic arsenal.
`
`Rob Murphy
`Managing Editor
`
`Up to 10 million Americans suffer the daily misery of chronic dry eye syndrome.
`Unrelenting ocular irritation and photophobia are a way of life. Dry eye syndrome,
`whether stemming from aqueous deficiency or accelerated tear evaporation, is the most
`common treatable eye condition you encounter in the clinic. In the face of such a
`stubborn and implacable malady, savvy clinicians use every conceivable countermeasure
`to bring some relief to their patients. Current treatments are essentially palliative. New
`therapies target the root causes of the disease. (See table 1.)
`
`Causes and Defects
`
`The first step in managing dry eye is to determine what’s causing it. Inflammation of the
`lacrimal gland and denervation of the cornea can curb tear production. Meibomian gland
`dysfunction and incomplete lid closure are frequently to blame for rapid tear evaporation.
`Obtain a probing history for systemic health factors (Sjögren’s syndrome, other collagen
`vascular diseases, allergies), medications (antihistamines, oral NSAIDs, oral beta
`blockers), environmental factors (dust, smoke, pets) and anything else that may trigger or
`worsen symptoms.
`
` “I see a lot of patients in this area who are taking a variety of over-the-counter
`medications for allergies or sinus problems, and those typically are antihistamines and
`decongestants,” says James L. Fanelli, O.D., a private practitioner in Wilmington, N.C.
`“These people will get a pharmacologically induced dry eye because of all the
`medications.” The dryness stems from the parasympatholytic effects of these agents. If
`patients can discontinue their medications, they may find relief from their ocular
`symptoms.
`
`Encourage patients to avoid environments that may exacerbate their discomfort, say a
`smoky barroom or a dusty attic. Maybe they can change their environment. “One thing1
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`that helps for people with really severe dry eye is to have them use a humidifier in their
`bedroom at night and moisten the air,” Atlanta clinician Paul C. Ajamian, O.D., says.
`
`Be sure to do a careful check of the lids. Meibomian gland stenosis and blepharitis are
`common triggers of dry eye. “Look at the lid margins for signs of chronic staph lid
`disease,” Dr. Ajamian advises. “A lot of dry eye patients have chronic staph, and yet we
`just focus on the dry eye portion and ignore the lid-hygiene portion.”
`
`Many patients who have had LASIK experience dry eye symptoms following the
`procedure. Dry eye researcher Jeffrey P. Gilbard, M.D., attributes this to corneal
`denervation. “When you cut the flap, you cut the corneal nerves,” he says. “And just as
`irritated eyes tear more, eyes that are numb tear less.” A recent study in Australia found
`that 100% of LASIK patients receiving TheraTears—the artificial tears developed by Dr.
`Gilbard—were symptom-free at one month post-op compared to just 20% of the
`untreated control group. New York surgeon Eric D. Donnenfeld, M.D., is now
`investigating the efficacy of cyclosporine (Restasis, Allergan Pharmaceuticals) in treating
`post-LASIK dry eye.
`
`What’s Happening Now
`
`Dry eye therapy is a sequence of palliative measures tailored to the severity of the
`presentation. Clinicians typically begin with non-preserved low-viscosity artificial tears
`prescribed every two hours or so. Among the more popular choices are GenTeal (CIBA
`Vision), Hypotears PF (CIBA Vision), Moisture Eyes (Bausch & Lomb
`Pharmaceuticals), Refresh Plus (Allergan), Refresh Tears (Allergan), Tears Naturale Free
`(Alcon) and TheraTears (Advanced Vision Research). Patients may especially like the
`convenience of GenTeal and Refresh Tears, which come bottled in a multi-dose
`formulation with a relatively non-toxic preservative that’s neutralized upon instillation.
`Look for a multi-dose formulation of TheraTears come spring.
`
`“TheraTears seems to be winning more and more support,” Dr. Fanelli says. Rabbit
`studies showed that its electrolyte solution—sodium, potassium, bicarbonate, chloride,
`magnesium and phosphate—lowers elevated tear osmolarity and improves the eye’s
`electrolyte balance. Even so, while Dr. Fanelli favors GenTeal and Refresh Plus, he says
`it usually comes down to trial-and-error. “There’s no magic involved,” he says. “It’s a
`matter of finding the drop that gives you the longest-lasting and most-comfortable
`relief.” Seattle clinician Kathy Yang Williams, O.D., favors preservative- and
`lanolin-free Hypotears PF for those with associated atopic eye disease to reduce the
`potential for a hypersensitivity reaction.
`For more severe or refractory presentations, you may wish to graduate to moderate-
`viscosity artificial tears such as Bion Tears (Alcon) or OcuCoat PF (B&L
`Pharmaceuticals), or high-viscosity products such as AquaSite (CIBA Vision), Celluvisc
`(Allergan) or Murocel (B&L Pharmaceuticals). As an alternative, these patients may find
`relief with the newer gel formulations GenTeal Gel (CIBA Vision) or Tears Again
`(OcuSoft). Ointments may work well for the most severe cases that require nighttime
`therapy.
`
`Punctal plugs can be effective for moderate to severe dry eye when artificial tears alone
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`don’t bring relief. Some clinicians favor the CIBA Vision line of punctal plugs that come
`with a preloaded device that makes insertion easy. But don’t wait too long to plug. “I
`don’t think twice anymore about plugging,” Dr. Fanelli says. “I’m not going to put them
`through this regimen where they have to use tears every hour and ointments at night.” He
`likes to do a monocular trial by plugging the upper and lower puncta of one eye for a few
`days to see if it works.
`Especially severe and recalcitrant keratoconjunctivitis sicca may call for a short-term
`course of topical steroids. A 1999 study published in Ophthalmology by Peter Marsh,
`M.D., and Stephen Pflugfelder, M.D., found that a 2-week course of topical
`methylprednisolone relieved the irritation of dry eye, and in many patients that relief
`lasted weeks or months after they stopped therapy. Loteprednol etabonate 0.2% (Alrex,
`B&L Pharmaceuticals) or loteprednol etabonate 0.5% (Lotemax, B&L Pharmaceuticals)
`may be well-suited for this purpose because they’re less likely than other steroids to
`increase intraocular pressure. “With the advent of some of the newer steroids, certainly
`it’s nice to be able to prescribe medications like that without the risk of more serious
`complications,” Dr. Williams says. Topical methylprednisolone 1% used tid or qid for
`3-4 weeks can be a safe and effective regimen.
`
`Meanwhile, you may need to address associated lid disease. In cases of staph blepharitis,
`Dr. Ajamian prescribes lid scrubs and a broad-spectrum antibiotic ointment such as
`polysporin. For dry eye symptoms associated with meibomian gland disease, Miami
`clinician Terri Rose, O.D., favors a 6-8 week course of oral doxycycline. “Dosing varies
`by physician, but an average course might be 100mg bid for 6-8 weeks,” says Dr. Rose,
`who is on staff at the Bascom Palmer Eye Institute. “The use of an antibiotic in a
`non-infectious condition has to do with the effect of doxycycline on lipid production and
`its effectiveness as an anti-inflammatory agent.”
`
`What’s to Come
`
`The dry eye treatment that’s attracted the most attention in the last year is one that hasn’t
`even obtained FDA approval. Clinical investigators who have given their patients topical
`cyclosporine 0.05% (Restasis, Allergan Pharmaceuticals) say this immunomodulatory
`agent effectively reduces the signs and symptoms associated with keratoconjunctivitis
`sicca. Although Allergan was rebuffed in its bid last July to win FDA approval, the
`company has responded to the agency’s concerns and hopes to get the green light to
`market the product by summertime (see “What Ever Happened to Restasis?”).
`
`Cyclosporine targets the immune-based inflammation that shuts down tear production in
`the lacrimal gland. “T-lymphocytes infiltrate the lacrimal gland, and they cause
`inflammation,” explains Dr. Donnenfeld, a clinical investigator for cyclosporine. “The
`acinar cells—those are the ones that secrete the tears—fibrose and die. The tear
`production stops, and you end up with a dry eye. What cyclosporine does, it’s a specific
`T-cell modulator that inhibits T-lymphocytes reversibly, and in doing so stops the
`inflammatory cycle so that the inflammatory cells die a normal death and stop secreting
`the inflammatory mediators. The lacrimal gland tissue that’s still viable comes back so
`that the patient starts inducing their own tears.”
`Although the FDA-mandated phase 3 trials showed that cyclosporine was clinically
`effective with negligible side effects (transient burning), Dr. Donnenfeld and other3
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`clinicians say it doesn’t work for all patients. “One of the problems with cyclosporine is
`that we don’t know who is going to be a good candidate for its use and who is not, and
`that’s one of the things we’re still working out right now,” he says.
`
`Further back in the pipeline is another potentially fruitful dry eye therapy, this one based
`on the sex-hormones known as androgens. Animal models show that androgens play a
`key role in regulating the function of both the lacrimal and meibomian glands. David A.
`Sullivan, Ph.D., of the Schepens Eye Research Institute in Boston recently found that
`women who lack functioning androgen receptors had a significant increase in dry eye
`signs and symptoms. Another study revealed that patients with Sjögren’s syndrome were
`androgen-deficient. Both studies support Dr. Sullivan’s hypothesis that androgen-
`replacement therapy may benefit patients with lacrimal and meibomian gland
`dysfunction.
`Allergan holds the license to any potential therapy based on Dr. Sullivan’s research. The
`company put on hold a multicenter phase 2 study originally planned for last summer.
`Still, Dr. Sullivan remains optimistic. “We think it looks promising,” he says. “Every
`study we’ve been able to throw at it, with every control we can, so far they’ve been
`consistent with the hypothesis.”
`
`Finally, keep an eye on what’s happening down at Bascom Palmer. Searching for a target
`at which to aim a potential therapy, Dr. Pflugfelder has been looking for molecules that
`are elevated in dry eye but normal in healthy individuals. He thinks he’s found a
`collagenase enzyme that fits the bill. “There’s one specifically called MMP9 that’s very
`high in dry eye patients in their tear fluid and almost nondetectable in normals,” he says.
`“For the first time, I have a marker that goes up in dry eye and not in normal eyes. I think
`it’s definitely something to look into, inhibiting that.” Interestingly, we already have a
`medication that acts as a potent inhibitor of MMP9—the tetracyclines. Dr. Pflugfelder
`hopes to develop other therapies based on what he’s learning.
`
`Dry eye will remain fertile ground for research as long as patients continue to suffer.
`Chronic keratoconjunctivitis sicca is a miserable way to go through life. Just ask your
`patients. They’ll appreciate anything you can do to ameliorate their lot.
`
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`
`The people at Allergan Pharmaceuticals thought they had a good thing going when they
`approached the FDA last July for approval to market cyclosporine 0.05% (Restasis) as a
`treatment for dry eye. The two arms of the phase 3 clinical studies had gone well,
`demonstrating that the
`T-lymphocyte inhibitor effectively reduces the signs and symptoms of
`keratoconjunctivitis sicca with minimal adverse events.
`
`But then something funny happened. The ophthalmic advisory panel for the FDA was
`less than impressed with Allergan’s clinical data. The panelists issued a so-called
`“approvable letter” listing several points they wanted the company to address before they
`would recommend approval. “We have been reviewing the data and looking to see if in
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`fact we could present the data from those studies in a way that would better present our
`case,” Allergan spokesman Ira Haskell says.
`
`“Unfortunately, the two arms of the phase 3 trial did not completely replicate themselves
`in terms of the signs and symptoms that reached statistical significance,” investigator
`Steven E. Wilson, M.D., wrote in a paper presented last September at a Research to
`Prevent Blindness seminar. One problem was that cyclosporine’s vehicle, a castor oil
`emulsion, may have worked a little too well in the trials.
`
`“I don’t know that the panel was that impressed that there was that much difference
`between the drug and the vehicle,” says investigator Stephen Pflugfelder, M.D., who
`testified before the FDA panel on behalf of Allergan. “The vehicle itself is better than
`any artificial tear. You know, if they had compared the drug to artificial tears, they would
`have won hands down, I’m sure.”
`
`Allergan expects to hear back from the FDA by June, Mr. Haskell says. In the meantime,
`someone should consider packaging castor oil as a treatment for dry eye. Apparently, it’s
`the next best thing to cyclosporine.—R.M.
`top
`
`Low-Viscosity Artificial Tears
`
`GenTeal (CIBA Vision)
`Hypotears PF (CIBA Vision)
`Moisture Eyes (Bausch & Lomb
`Pharmaceuticals)
`Refresh Plus (Allergan)
`Refresh Tears (Allergan)
`Tears Naturale Free (Alcon)
`TheraTears (Advanced Vision Research)
`Moderate-Viscosity
`Artificial Tears
`
`Bion Tears (Alcon)
`OcuCoat PF (B&L Pharmaceuticals)
`
`High-Viscosity
`Artificial Tears
`
`AquaSite (CIBA Vision)
`Celluvisc (Allergan)
`Murocel (B&L Pharmaceuticals)
`Gel Formulations
`
`GenTeal Gel (CIBA Vision)
`Tears Again (OcuSoft)
`Lubricating Ointments
`
`Hypotears (CIBA Vision)
`Moisture Eyes (B&L
`Pharmaceuticals)
`Refresh PM (Allergan)
`Duratears Naturale (Alcon)
`
`Return to February Highlights
`© Review of Optometry OnLine
`February 15, 2000
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