Evaluation of Current and Emerging Treatments for Lid Margin Disease

In keeping with their different pathophysiologies, anterior and posterior blepharitis require different treatments. Treatment goals are similar, but diverge when considering the different pathophysiologies of anterior and posterior blepharitis. The current target profile for optimal treatment of anterior blepharitis includes broad-spectrum antimicrobial activity to eliminate bacteria. Additionally, an anti-inflammatory effect should be achieved and optimal penetration of the therapeutic agent into the site of the disease in the lid tissue is necessary. Convenient dosing for patients is essential to promote compliance. For patients with posterior lid margin or meibomian gland disease, reducing inflammation, assuring optimal penetration, and providing convenient dosing are also important treatment goals. In addition, anti-lipase activity should be achieved to inhibit the degradation of meibomian gland lipids into free fatty acids and soaps that can cause a pathognomonic foamy tear film.

Treatment strategies for anterior blepharitis include lid hygiene, anti-inflammatory agents, and antibiotics. —Marguerite B. McDonald, MD, FACS

Current Therapy Overview

The current treatment for anterior blepharitis typically consists of lid hygiene including the use of hot compresses and commercial lid scrubs, corticosteroids for persistent inflammation, and antibiotic ointments at the lid margin. Typical antibacterial agents used in the treatment of blepharitis include:

• Macrolides (erythromycin)
• Bacitracin
• Sulfonamides (sulfacetamide)
• Aminoglycosides (tobramycin, gentamicin)
• Fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin)

Paradoxically, long-term use of aminoglycosides can scar the meibomian gland orifices and lead to blepharitis. Accordingly, they should be used for only short-term treatment.

For posterior blepharitis, corticosteroid and antibiotic ointments are also frequently prescribed and may be supplemented with an oral tetracycline such as doxycycline. In addition, lid hyperthermia, nutritional supplements, and topical cyclosporine may be used.

Blepharitis Clinical Trials

Treatments for posterior blepharitis include antibiotics, corticosteroids, lid hyperthermia, nutritional supplements, and topical cyclosporine. —Marguerite B. McDonald, MD, FACS

Until recently, there was a paucity of studies that specifically addressed anterior or posterior blepharitis, resulting in clinical treatment decisions being made based on studies of other disease states. More studies are now being performed, particularly with regard to meibomian gland disease, and landmark trials are providing valuable data to guide treatment options. Although many of these trials are open label, outcome variables such as height of the collarettes in millimeters and number of meibomian gland inclusions are evaluated by masked observers. In addition, comparative trials using a different treatment in each eye of the same patient are being replaced by independent group comparisons, in response to evidence suggesting study subjects were making dosing errors.

Cyclosporine

In a randomized trial of cyclosporine in the treatment of meibomian gland disease, 12 patients treated with 0.05% topical cyclosporine for 3 months experienced significant reductions in lid margin vascular injection (P<.05), tarsal telangiectasia (P<.05), and corneal fluorescein staining (P<.05) compared with 14 control patients treated with artificial tears.¹ In addition, although meibomian gland dysfunction was unchanged in the control group, meibomian gland inclusions were reduced by >50% in the patients on cyclosporine (P<.001). Despite this demonstration of efficacy, cyclosporine is not regarded as a primary treatment for meibomian gland disease.²

Azithromycin

Posterior lid margin disease is often considered the ocular manifestation of rosacea, a common inflammatory skin disorder. In a recently reported randomized, open-label trial, the efficacies of azithromycin and doxycycline in the treatment of rosacea were compared.³ During the 3 months of the study, the azithromycin group started on 500 mg 3 times a week, tapering to 250 mg 3 times a week during the second month, followed by 250 mg twice a week for the remainder of the treatment interval. The doxycycline group was treated with 100 mg a day for the 3-month treatment interval. Statistically significant improvement was obtained with both drugs, and neither drug was more effective than the other. Accordingly, the scientific basis for investigating this therapy in meibomian gland dysfunction was established.

Azithromycin vs Erythromycin

In a prospective study of azithromycin in the treatment of chronic mixed (seborrheic and staphylococcal) anterior blepharitis, 67 patients (134 eyes) were treated with azithromycin ophthalmic solution 1%, and 8 patients (16 eyes) with erythromycin ophthalmic ointment.⁴ Efficacy endpoints included the height of collarettes, percent ulceration at the base of the lashes, lash matting, and lid margin erythema. Clinical resolution after 4 weeks was 98.5% for patients in the azithromycin group and 37.5% in the erythromycin group. At 8 weeks, the total clinical resolution remained at 98.5% of patients in the azithromycin group, and the longer treatment resulted in an increase to 50% total clinical resolution in the erythromycin group.

Azithromycin for Moderate to Severe Disease

A 4-week, open-label, single group pilot study enrolled 26 patients with moderate to severe blepharitis (anterior or posterior) at 2 centers.⁵ Azithromycin solution 1% was administered twice a day for 2 days, then once a day on days 3 to 28. Lid scrubs and hot compresses were not allowed during the study and for 2 weeks after treatment was completed. Patients with other serious ocular pathology were excluded. Clinical signs including plugging of the meibomian glands, eyelid margin hyperemia, ocular discharge, and palpebral conjunctival hyperemia were evaluated. Using a 4-point scale with higher scores relating to more severe disease, significant improvement was achieved at the end of the 4-week treatment in both investigator-rated signs (Table 1) and subject-reported symptoms (Table 2). Of particular importance was the maintenance of significant improvement in both signs and symptoms through the 4-week post-treatment follow-up visit (Table 1 and Table 2).

Treatment was well-tolerated, and no safety issues developed during the study. Eleven ocular adverse events were classified as related or possibly related to treatment and included 4 cases of mild eye pain, 3 complaints of blurred vision, 3 eyes that were mildly irritated, and 1 eye with discharge.

Short-term Azithromycin with Mechanical Therapy vs Mechanical Therapy Alone

Another recent azithromycin trial was a single-center, open-label, blinded observer, randomized pilot study evaluating the safety and efficacy of 2 weeks of azithromycin in combination with mechanical therapy compared with mechanical therapy alone in patients with posterior blepharitis.⁶ Patients in the azithromycin group administered 1 drop of azithromycin 1% twice daily on days 1 and 2, and once daily on days 3 through 14. Both groups applied warm compresses to each eye for 5- to 10-minute intervals twice daily throughout the study period. Efficacy endpoints included lid debris, eyelid margin hyperemia, swelling of the eyelid margin, the degree of meibomian gland plugging, and the quality of meibomian gland secretions when the lid was pressed (clear liquid or opaque and paste-like), measured on a scale of 0 (normal) to 4 (very severe). In addition, safety measurements (including intraocular pressure, biomicroscopy, external eye exam, best-corrected visual acuity, ophthalmoscopy, and adverse event monitoring) and patient-rated global efficacy assessments (0 = deterioration through 4 = excellent) were obtained.

At baseline, the mean score for eyelid margin hyperemia in the azithromycin group was 3.2 (severe), which decreased to 1.1 (mild) during the 2 weeks of treatment. This represented a 67% improvement from baseline compared with 10% using warm compresses alone. In addition, the degree of meibomian gland plugging in the azithromycin group decreased from 3.0 (severe) to 0.9 (mild) during the 2 weeks of treatment (Figure 1). This 71% improvement compares with 7% using warm compresses alone. Finally, the quality score for meibomian gland secretions decreased from 2.5 (moderate) to 0.8 (mild) in the azithromycin group, representing a 67% improvement, compared with 11% in the warm compresses only group. The 2-week values were significantly different between groups for each of the 3 endpoints (P<.001).

In the per protocol analysis, 75% of patients in the azithromycin solution group rated treatment efficacy as excellent (complete relief of ocular signs and symptoms) or good (distinct relief of ocular signs and symptoms) compared with 18% in the warm compresses alone group (P=0.024). The majority of patients (73%) who received only warm compresses rated their treatment as fair (some relief from ocular signs and symptoms).

No safety issues were detected during the study. Two reported adverse events were considered possibly related to the study drug, including 1 case of blurred vision and 1 case of ocular burning. No significant changes in ophthalmoscopy, biomicroscopy/external eye exam, best-corrected visual acuity, or intraocular pressure measurements occurred during the study.

In summary, clinicians’ understanding of the pathophysiology of blepharitis is changing as more research is performed in this area. Data from recent studies showed that azithromycin solution provides more relief with a shorter course of therapy compared with erythromycin ointment. Azithromycin treatment with or without lid hyperthermia and hygiene also resulted in a statistically significant improvement in blepharitis and was shown to be superior to using hot compresses alone.

References

1. Perry HD, Doshi S, Donnenfeld ED, Biser SA, Bloom AH. Double Masked Randomized Controlled Study Evaluating Topical 0.05% Cyclosporine A in the Treatment of Meibomian Gland Dysfunction (Posterior Blepharitis). Investigative Ophthalmology and Visual Science. 2003;44:E-Abstract 1395.
2. American Academy of Ophthalmology. Summary Benchmarks for Preferred Practice Pattern Guidelines. Blepharitis. November 2008. Available at: www.aao.org. Accessed November 8, 2008
3. Akhyani M, Ehsani AH, Ghiasi M, Jafari AK. Comparison of efficacy of azithromycin vs. doxycycline in the treatment of rosacea: a randomized open clinical trial. International Journal of Dermatology. 2008;47:284-288.
4. John T, Shah A. Poster presented at: The XXVI Congress of the European Society of Cataract and Refractive Surgeons; September 14-17, 2008; Berlin, Germany.
5. Ophthalmic Research Associates based in Andover, Massachusetts.
6. Luchs J. Efficacy of topical azithromycin ophthalmic solution 1% in the treatment of posterior blepharitis. Advances in Therapy. 2008;25:858-870.