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Supplements Management and Pharmacoeconomics of Dry Eye Disease: The Role of Cyclosporine
Prevalence, Burden, and Pharmacoeconomics of Dry Eye Disease
Stephen C. Pflugfelder, MD
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Richard G. Fiscella, BS Pharm, MPH; Jeffrey T. Lee, PharmD, FCCP; John G. Walt, MBA; and Todd D. Killian, MBA, MS
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Management of Dry Eye
Michael A. Lemp, MD
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Management of Dry Eye

Michael A. Lemp, MD
• In a single-blind trial,32 DED patients were randomly assigned to 30 days of treatment with either a topical corticosteroid, fluorometholone; a topical nonsteroidal antiinflammatory drug (NSAID), flurbiprofen; or artificial tears alone. (All patients received artificial tears, but these were used QID in the artificial tears–only group, and as many as 8 times daily in the corticosteroid and NSAID groups.) The corticosteroid group had significantly improved symptom scores on days 15 and 30, compared with the other groups. Corneal staining and goblet cell numbers were also improved with topical corticosteroid treatment compared with the other 2 treatments.50
• In a double-blind, placebo-controlled trial, 64 DED patients were randomized to either a topical corticosteroid (loteprednol etabonate 0.5%) or vehicle, QID for 4 weeks. Both groups experienced a significant treatment effect compared with baseline, but the primary subjective and objective outcomes (worst symptom score and fluorescein staining score, respectively) did not differ between the groups. A post-hoc subset analysis suggested that patients with at least moderate clinical inflammation are more likely to show significant benefits with loteprednol.51

• In a double-blind trial,41 DED patients each received prednisolone 0.1% in one randomly selected eye, versus hyaluronic acid 0.1% in the other eye, TID for 28 days. Compared with baseline, both treatments improved symptom scores and TBUT, but not Schirmer scores. Prednisolone was significantly better than hyaluronic acid in improving symptom scores at day 28; however, there was no between- group difference in TBUT. Prednisolone, but not hyaluronic acid, improved impression cytology scores and decreased the tear concentration of neurotrophic growth factor (NGF). (Elevated NGF levels are associated with inflammation.52)

In another trial, 15 patients with Sjögren syndrome received unpreserved methylprednisolone 1%, TID for 2 weeks, followed by punctal occlusion. This group was compared with 15 Sjögren syndrome patients who were treated directly with punctal occlusion alone. The group initially treated with the corticosteroid had significantly improved symptoms and corneal staining at 1 week and at 2 months, compared with the group receiving only punctal occlusion.53

Although topical corticosteroids are effective, they are generally recommended only for short-term use because prolonged use may result in AEs including ocular infection, glaucoma, and cataracts. However, corticosteroids may differ in their propensity to cause these complications. For example, some evidence suggests that loteprednol, which is rapidly metabolized to inactive metabolites, may have a better safety profile than other corticosteroids. 51 In a summation of randomized studies, treatment with loteprednol etabonate (0.5% concentration) for >28 days resulted in a 2% incidence of elevated intraocular pressure, compared with a 7% incidence with prednisolone acetate (1% concentration) and 0.5% incidence with placebo.54

Oral tetracyclines have been used off-label to treat DED, primarily DED associated with ocular rosacea. Although oral doxycycline has an FDAapproved indication for inflammatory lesions (papules and pustules) of rosacea, it is not FDA approved for ocular rosacea.55

It has been suggested that reduction of bacterial flora may decrease the breakdown of meibomian lipid. However, tetracyclines are used in DED primarily for their anti-inflammatory rather than antibacterial actions. Mechanisms may include decreased matrix metalloproteinase activity, and decreased production of proinflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor-alpha.2 Several small, randomized clinical trials, mostly in ocular rosacea, provide limited evidence of efficacy.

• Oral oxytetracycline, topical fusidic acid, and the 2 agents combined (neither agent available in the United States) were compared in a double-blind, partial crossover study involving 43 patients with long-term blepharitis (of whom 18 had rosacea). All patients received double placebo during run-in and washout periods. Among the patients with blepharitis and rosacea, 75% had symptomatic improvement with fusidic acid, 50% with oxytetracycline, but only 35% with the combination. Among the patients with nonrosacea blepharitis, none responded to fusidic acid alone, but 25% improved with oxytetracycline and 30% with the combination. No statistical analysis was reported for comparison among the active treatments.56
• In a double-blind trial involving 35 patients with ocular rosacea, oral oxytetracycline significantly improved nonspecific clinical signs compared with placebo.57
• Twenty-eight patients with ocular rosacea were randomized to either oral tetracycline (250 mg QID for 4 weeks, then 250 mg BID for 5 months) or meibomian gland expression. Compared with baseline, tetracycline significantly improved TBUT but not Schirmer scores. Meibomian gland expression produced no significant improvement in either measurement compared with baseline.

No between-group statistical analysis was reported.58 No randomized trials of doxycycline or minocycline for ocular rosacea or DED have been published.

Topical cyclosporine was approved by the FDA in December 2002. According to product information, cyclosporine ophthalmic emulsion 0.05% (Restasis) is indicated “to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca. Increased tear production was not seen in patients currently taking topical anti-inflammatory drugs or using punctal plugs.”59

Topical cyclosporine is currently the only pharmacologic treatment that is FDA approved specifically for DED. As previously noted, topical corticosteroids are approved for corticosteroidresponsive inflammatory conditions of the ocular surface (which presumably include DED); oral doxycycline is approved for inflammatory skin lesions of rosacea (but not for ocular rosacea); and pilocarpine and cevimeline are approved for dry mouth (but not dry eye) symptoms associated with Sjögren syndrome.

Evidence suggests that cyclosporine is diseasemodifying rather than merely palliative. In studies of DED patients, cyclosporine reduced conjunctival IL-6 levels,60 decreased activated lymphocytes in the conjunctiva,61 reduced conjunctival inflammatory and apoptotic markers,62,63 and increased conjunctival goblet cell numbers.64

Pivotal clinical trials. The efficacy and safety of cyclosporine ophthalmic emulsion (0.1% and 0.05%) in moderate to severe DED were demonstrated in two 6-month, multicenter, randomized, double-blind, vehicle-controlled phase 3 trials. Although both cyclosporine and vehicle significantly decreased symptoms and objective signs compared with baseline, cyclosporine was significantly more effective than vehicle in improving several efficacy outcomes. Two objective outcomes— corneal fluorescein staining and the Schirmer test with anesthesia—were significantly more improved with cyclosporine (both 0.05% and 0.1%) than with vehicle. Three subjective outcomes— blurred vision, need for artificial tears, and physician’s evaluation of global response—were significantly improved with cyclosporine 0.05% (but not 0.1%) compared with vehicle. There were no between-group differences in conjunctival staining, Schirmer test without anesthesia, or symptoms other than blurred vision.65

Most AEs reported during the phase 3 trials were mild to moderate and transient. The most common treatment-related AEs were ocular burning and stinging, occurring in 16.1% and 4.5%, respectively, of the cyclosporine 0.1% group; 14.7% and 3.4% of the cyclosporine 0.05% group; and 6.5% and 1.4% of the vehicle group. Burning and/or stinging led to discontinuation in 3.1% of the cyclosporine 0.1% group, 1.7% of the cyclosporine 0.05% group, and 1.7% of the vehicle group. The investigators noted that only 2 patients (both in the vehicle group) developed ocular infection during treatment.65

A multicenter, nonrandomized, open-label, phase 3 extension trial was conducted to further evaluate safety. Four hundred twelve patients who had previously been treated with cyclosporine (0.1% or 0.05%) for 6 to 12 months subsequently received cyclosporine 0.1% for an additional 1 to 3 years. The most common AEs were burning (10.9%), stinging (3.9%), and conjunctival hyperemia (3.4%). Most AEs were mild to moderate; no serious AEs occurred. Efficacy evaluation (for the first year only of the extension studies) showed that previous improvements in objective and subjective outcomes were maintained. More than 95% of responding patients said they would continue cyclosporine, and nearly 98% said they would recommend it to others.66

Systemic exposure. In the phase 3 trials, cyclosporine blood levels were measured in 128 patients. Even after 9 to 12 months of treatment, trough levels were below the quantification limit of 0.1 ng/mL in 100% of samples collected from patients receiving 0.05% cyclosporine, and in all but 5.5% of samples collected from patients receiving 0.1% cyclosporine. Among the 5.5%, none had levels >0.3 ng/mL.67

Serial postdose samples were also collected from 26 patients after 9 to 12 months of treatment. Only 1.4% of samples—all from patients receiving 0.1% cyclosporine—were above the quantification limit, and those were barely detectable.67

These blood levels are orders of magnitude lower than those occurring during oral immunosuppressive therapy with cyclosporine.67 Furthermore, in the extension studies, nonocular AEs occurred in only 1% of patients (2 cases of moderate headache, 1 moderate allergic reaction, and 1 mild case of alopecia).66 Thus, it can be concluded that the risk of systemic toxicity is minimal.

Topical NSAIDs have been used off-label in DED. Two small randomized trials provide limited evidence of efficacy.

• In a 28-day open-label trial, topical diclofenac 0.1% QID was compared with saline 5% QID in 32 patients with secondary Sjögren syndrome and filamentary keratitis. Both treatments resulted in disappearance of filaments by day 28; however, the diclofenac group improved significantly more rapidly. Symptomatic improvement was also significantly faster with diclofenac.68

• In a 6-week open-label trial in 52 DED patients, topical ketorolac 0.4% significantly reduced symptoms and corneal staining when used adjunctively during induction of topical cyclosporine therapy, compared with cyclosporine alone.69

Despite some evidence of efficacy, serious safety concerns have been raised regarding the use of topical NSAIDs in DED. NSAIDs (especially diclofenac) reduce corneal sensitivity, potentially contributing to corneal damage in DED by interfering with reflex tearing and blinking. Cases of corneal melting have been reported, especially in postoperative settings.70,71 Because topical NSAIDs can promote corneal melting in patients with a compromised ocular surface, their use in DED is controversial. Some experts feel that they have no role in the treatment of DED.

 
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