Dry Eye Disease

EYSUVIS ® (Kala Pharmaceuticals, Inc.) was approved by the FDA in 2020 for the short-term (up to 2 weeks) treatment of Dry Eye Disease. EYSUVIS contains a sterile, topical anti-inflammatory corticosteroid loteprednol etabonate 2.5 mg (0.25%) and the preservative benzalkonium chloride 0.01%. It is administered as 1-2 drops in each eye four times daily. {www.accessdata.fda.gov/drugsatfda_docs/label/2020/210933s000lbl.pdf}

EYSUVIS demonstrated a larger reduction in ocular discomfort severity and conjunctival hyperaemia compared to vehicle. {www.accessdata.fda.gov/drugsatfda_docs/label/2020/210933s000lbl.pdf}

There was no significant difference in dry eye incidence or progression between loteprednol etabonate 0.5% and cyclosporine A 0.05% at 1 year. {Boynton GE, Raoof D, Niziol LM, Hussain M, Mian SI. Prospective Randomized Trial Comparing Efficacy of Topical Loteprednol Etabonate 0.5% Versus Cyclosporine-A 0.05% for Treatment of Dry Eye Syndrome Following Hematopoietic Stem Cell Transplantation. Cornea. 2015 Jul;34(7):725-32.}

Both loteprednol and artificial tears showed significantly improved Ocular surface disease index scores at 2, 4, and 8 weeks, with significantly more improvement in loteprednol group. Pretreatment with the latter also significantly reduced topical cyclosporine stinging. {Sheppard JD, Donnenfeld ED, Holland EJ, Slonim CB, Solomon R, Solomon KD, McDonald MB, Perry HD, Lane SS, Pflugfelder SC, Samudre SS. Effect of loteprednol etabonate 0.5% on initiation of dry eye treatment with topical cyclosporine 0.05%. Eye Contact Lens. 2014 Sep;40(5):289-96.}

In a subset of patients with at least moderate clinical inflammation, there was a significant difference (conjunctival staining) between both groups at 2 weeks, although this was non-significant at 4 weeks. {Pflugfelder SC, Maskin SL, Anderson B, Chodosh J, Holland EJ, De Paiva CS, Bartels SP, Micuda T, Proskin HM, Vogel R. A randomized, double-masked, placebo-controlled, multicenter comparison of loteprednol etabonate ophthalmic suspension, 0.5%, and placebo for treatment of keratoconjunctivitis sicca in patients with delayed tear clearance. Am J Ophthalmol. 2004 Sep;138(3):444-57.}

CEQUA ® (Sun Pharmaceuticals Industries, Inc.) was approved by the FDA in 2019 for the treatment of Dry Eye Disease. CEQUA contains Cyclosporine 0.9mg/mL (0.09%), a calcineurin inhibitor and is administered in each eye twice daily. {www.accessdata.fda.gov/drugsatfda_docs/label/2018/210913s000lbl.pdf}

CEQUA-treated patients demonstrated significant improvements in corneal and conjunctival staining. {Goldberg DF, Malhotra RP, Schechter BA, Justice A, Weiss SL, Sheppard JD. A Phase 3, Randomized, Double-Masked Study of OTX-101 Ophthalmic Solution 0.09% in the Treatment of Dry Eye Disease. Ophthalmology. 2019 Sep;126(9):1230-1237.}

CEQUA demonstrated a statistically significant higher percentage of eyes with increases of ≥ 10 mm from baseline in Schirmer wetting than in vehicle-treated patients (17% vs 9%).{www.accessdata.fda.gov/drugsatfda_docs/label/2018/210913s000lbl.pdf}

XIIDRA ® (Shire US, Inc.) was approved by the FDA in 2016 for the treatment of Dry Eye Disease. XIIDRA contains Lifitegrast 50mg/mL (5%) , a Lymphocyte function-associated antigen-1 (LFA-1) antagonist and is administered in each eye twice daily. {www.accessdata.fda.gov/drugsatfda_docs/label/2016/208073s000lbl.pdf}

Lifitegrast significantly improved symptoms of eye dryness on eye dryness score, but did not improve ocular discomfort score compared to placebo. {Holland EJ, Luchs J, Karpecki PM, Nichols KK, Jackson MA, Sall K, Tauber J, Roy M, Raychaudhuri A, Shojaei A. Lifitegrast for the Treatment of Dry Eye Disease: Results of a Phase III, Randomized, Double-Masked, Placebo-Controlled Trial (OPUS-3). Ophthalmology. 2017 Jan;124(1):53-60.}

XIIDRA demonstrated a larger reduction in eye dryness score and inferior fluorescein corneal staining score compared to vehicle. {www.accessdata.fda.gov/drugsatfda_docs/label/2016/208073s000lbl.pdf}

Lifitegrast ophthalmic solution 5.0% significantly reduced symptom of eye dryness. Lifitegrast ophthalmic solution 5.0% did not significantly reduce corneal staining or conjunctival staining compared to placebo. {Tauber J, Karpecki P, Latkany R, Luchs J, Martel J, Sall K, Raychaudhuri A, Smith V, Semba CP. Lifitegrast Ophthalmic Solution 5.0% versus Placebo for Treatment of Dry Eye Disease: Results of the Randomized Phase III OPUS-2 Study. Ophthalmology. 2015 Dec;122(12):2423-31.}

Lifitegrast ophthalmic solution 5.0% significantly reduced corneal fluorescein and conjunctival lissamine staining compared to placebo.

Lifitegrast ophthalmic solution 5.0% significantly improved symptoms of ocular discomfort and eye dryness compared to placebo.

There was no significant improvementof OSDI score. {Sheppard JD, Torkildsen GL, Lonsdale JD, D’Ambrosio FA Jr, McLaurin EB, Eiferman RA, Kennedy KS, Semba CP. Lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease: results of the OPUS-1 phase 3 study. Ophthalmology. 2014 Feb;121(2):475-83.}

RESTASIS ® (Allergan, Inc.) was approved by the FDA in 2002 for the treatment of Dry Eye Disease. RESTASIS contains Cyclosporine 0.5mg/mL (0.05%) , a Calcineurin inhibitor and is administered in each eye twice daily. {www.accessdata.fda.gov/drugsatfda_docs/label/2012/050790s020lbl.pdf}

Cochrane review: “Evidence on the effect of CsA on ocular discomfort and ocular surface and tear film parameters such as corneal fluorescein staining, Schirmer’s test, and TBUT is inconsistent and sometimes may not be different from vehicle or artificial tears for the time periods reported in the trials.” {de Paiva CS, Pflugfelder SC, Ng SM, Akpek EK. Topical cyclosporine A therapy for dry eye syndrome. Cochrane Database Syst Rev. 2019 Sep 13;9:CD010051.}

RESTASIS demonstrated statistically significant increases in Schirmer wetting of 10 mm versus vehicle at six months (15% vs 5%). {www.accessdata.fda.gov/drugsatfda_docs/label/2012/050790s020lbl.pdf}

Cyclosporin A 0.05% and 0.1%, gave significantly greater improvements then vehicle in corneal staining and categorized Schirmer values, and in the subjective measures of blurred vision, need for concomitant artificial tears, and the physician’s evaluation of global response to treatment. {Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology. 2000 Apr;107(4):631-9.}

Autologous serum eyedrops are thought to alleviate dry eye by supplying tear components including growth factors, vitamins and proteins that aid in the maintenance of the ocular surface. {Higuchi A. Autologous Serum and Serum Components. Invest Ophthalmol Vis Sci. 2018 Nov 1;59(14):DES121-DES129. doi: 10.1167/iovs.17-23760.}

Analysis of 10 studies on the use of autologous serum-based eye drops for severe dry eye disease and 4 studies for treatment of persistent epithelial defect.

• Conclusions
  • Severe dry eye:
    • 8 studies reported improved symptoms of severe Dry eye disease. All noted improvement in at least 1 clinical sign
  • Persistent epithelial defect:
    • 3 of 4 studies demonstrated an improvement rate of > 90% {Shtein RM, Shen JF, Kuo AN, Hammersmith KM, Li JY, Weikert MP. Autologous Serum-Based Eye Drops for Treatment of Ocular Surface Disease: A Report by the American Academy of Ophthalmology. Ophthalmology. 2020 Jan;127(1):128-133.}

Analysis of 5 Randomized controlled trials that compared autologous serum eye drops vs artificial tears or saline in individuals with dry eye of various aetiology (eg. Sjogren’s syndrome, non-Sjogren’s syndrome, Post-LASIK).

• Conclusions:
  • Certainty of evidence judged as low/very low.
  • There might be some benefit in symptoms with autologous serum eyedrops compared with artificial tears in the short‐term, but no evidence of an effect after two weeks of treatment was found.
  • Large, high-quality RCTs needed to assess benefit in Dry eye disease {Pan Q, Angelina A, Marrone M, Stark WJ, Akpek EK. Autologous serum eye drops for dry eye. Cochrane Database Syst Rev. 2017 Feb 28;2:CD009327.}

There was a significantly higher tear break up time and decrease in Ocular Surface Disease index score in autologous serum eyedrops group vs preservative-free artificial tears at 1 month. {Celebi AR, Ulusoy C, Mirza GE. The efficacy of autologous serum eye drops for severe dry eye syndrome: a randomized double-blind crossover study. Graefes Arch Clin Exp Ophthalmol. 2014 Apr;252(4):619-26.}

There was a significantly higher decrease in Ocular Surface Disease index score in autologous serum eyedrops group vs artificial tears in severe dry eye disease patients (n=12) at 2 weeks, but no significant change in objective parameters {Urzua CA, Vasquez DH, Huidobro A, Hernandez H, Alfaro J. Randomized double-blind clinical trial of autologous serum versus artificial tears in dry eye syndrome. Curr Eye Res. 2012 Aug;37(8):684-8. doi: 10.3109/02713683.2012.674609.}

In this randomized controlled trial of autologous serum eyedrops vs artificial tears after LASIK (54 eyes of 27patients), findings were:

• Significantly great tear break up time in autologous serum eyedrops group at 6 months.
• Lower rose bengal staining score in autologous serum group at 1 and 3 months.
• No difference in subjective dryness score or Schirmer test/fluorescein score between both groups. {Noda-Tsuruya T, Asano-Kato N, Toda I, Tsubota K. Autologous serum eye drops for dry eye after LASIK. J Refract Surg. 2006 Jan-Feb;22(1):61-6.}

There were significant improvement in mean tear break up time, fluorescein and rose bengal staining scores, and subjective symptoms scores in autologous serum eyedrops group vs preservative-free artificial tears in severe Dry eye patients (37 eyes of 20 patients). {Kojima T, Ishida R, Dogru M, Goto E, Matsumoto Y, Kaido M, Tsubota K. The effect of autologous serum eyedrops in the treatment of severe dry eye disease: a prospective randomized case-control study. Am J Ophthalmol. 2005 Feb;139(2):242-6.}

OC-01 (varenicline solution) nasal spray was well tolerated and showed a clinically meaningful effect on signs and symptoms of dry eye disease. {Wirta D, Vollmer P, Paauw J, Chiu KH, Henry E, Striffler K, Nau J; ONSET-2 Study Group. Efficacy and Safety of OC-01 (Varenicline Solution) Nasal Spray on Signs and Symptoms of Dry Eye Disease: The ONSET-2 Phase 3 Randomized Trial. Ophthalmology. 2022 Apr;129(4):379-387.}

Clinical trial of thermal pulsation vs warm compresses in patients with meibomian gland loss (50 patients). Findings:

• Tear break-up time was modestly improved in the thermal pulsation group at 1 month, with no significant difference at 3 months.
• There was also no significant difference in irritation symptom, tear break up time, Schirmer test, and gland secretion variables between patients with different grades of gland loss or function at follow-ups. {Zhao Y, Veerappan A, Yeo S, Rooney DM, Acharya RU, Tan JH, Tong L. Clinical Trial of Thermal Pulsation (LipiFlow) in Meibomian Gland Dysfunction With Preteatment Meibography. Eye Contact Lens. 2016 Nov;42(6):339-346.}

Randomized controlled trial of MeiboPatch ® vs LipiFlow ® in patients with meibomian gland dysfunction (30 patients). Findings:

• 3 x and 2 x more functional meibomian glands at 3 months in the LipiFlow group and MeiboPatch group respectively
• Lipiflow had more rapid improvement in first month of treatment {Baumann A, Cochener B. [Meibomian gland dysfunction: a comparative study of modern treatments]. J Fr Ophtalmol. 2014 Apr;37(4):303-12.}

Randomized controlled trial of LipiFlow ® thermal pulsation system vs combined twice-daily lid warming and massage for 3 months in patients with meibomian gland dysfunction (31 patients). Findings:

• Significant reduction in OSDI score in LipiFlow group at 1- and 3-months vs lid-margin hygiene group.
• Significant improvement in expressible meibomian glands compared to the baseline parameters, but no significant difference between the two groups {Finis D, Hayajneh J, König C, Borrelli M, Schrader S, Geerling G. Evaluation of an automated thermodynamic treatment (LipiFlow®) system for meibomian gland dysfunction: a prospective, randomized, observer-masked trial. Ocul Surf. 2014 Apr;12(2):146-54.}

Prospective study of LipiFlow ® thermal pulsation system in patients with meibomian gland dysfunction (21 patients). Findings:

• Significant improvement in Meibomian gland scores, tear break up time and symptom scores (OSDI and SPEED questionnaires) at 1 month, which was maintained at 9 months follow up. {Greiner JV. A single LipiFlow® Thermal Pulsation System treatment improves meibomian gland function and reduces dry eye symptoms for 9 months. Curr Eye Res. 2012 Apr;37(4):272-8.}

Randomized controlled trial of LipiFlow ® thermal pulsation system vs iHeat warm compresses in meibomian gland dysfunction (139 patients). Crossover between groups after 2 weeks. Findings:

• Significant improvement in meibomian gland secretion and tear break up time at 2- and 4- weeks in LipiFlow group vs no significant change in control group.
• Significantly greater reduction in dry eye symptoms in LipiFlow group vs control, including in crossover group.
• There was no significant difference between groups in the incidence of non-serious, device-related adverse events. {Lane SS, DuBiner HB, Epstein RJ, Ernest PH, Greiner JV, Hardten DR, Holland EJ, Lemp MA, McDonald JE 2nd, Silbert DI, Blackie CA, Stevens CA, Bedi R. A new system, the LipiFlow, for the treatment of meibomian gland dysfunction. Cornea. 2012 Apr;31(4):396-404.}